NZ750013B2 - Carbamoyloxymethyl triazole cyclohexyl acids as lpa antagonists - Google Patents

Carbamoyloxymethyl triazole cyclohexyl acids as lpa antagonists

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Publication number
NZ750013B2
NZ750013B2 NZ750013A NZ75001317A NZ750013B2 NZ 750013 B2 NZ750013 B2 NZ 750013B2 NZ 750013 A NZ750013 A NZ 750013A NZ 75001317 A NZ75001317 A NZ 75001317A NZ 750013 B2 NZ750013 B2 NZ 750013B2
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New Zealand
Prior art keywords
methyl
independently selected
alkyl
oxy
compound
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Application number
NZ750013A
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NZ750013A (en
Inventor
Peter Tai Wah Cheng
James R Corte
Suresh Dhanusu
Tianan Fang
Sutjano Jusuf
Robert F Kaltenbach Iii
Lawrence J Kennedy
Jun Li
Ramesh Babu Reddigunta
Kumaravel Selvakumar
Original Assignee
Bristol Myers Squibb Company
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Application filed by Bristol Myers Squibb Company filed Critical Bristol Myers Squibb Company
Priority claimed from PCT/US2017/038216 external-priority patent/WO2017223016A1/en
Publication of NZ750013A publication Critical patent/NZ750013A/en
Publication of NZ750013B2 publication Critical patent/NZ750013B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/08—Saturated compounds containing ether groups, groups, groups, or groups
    • C07C62/10—Saturated compounds containing ether groups, groups, groups, or groups with a six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

The present invention provides compounds of Formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, wherein R6 is optionally substituted cycloalkyl, and wherein the remaining substituents are as defined herein. These compounds are selective lysophosphatidic acid (LPA) receptor inhibitors, and thereby useful for treating e.g. fibrosis of organs, liver diseases, cell proliferative diseases, inflammatory diseases, gastrointestinal tract diseases, renal diseases, urinary tract-associated diseases, pancreas disease, abnormal angiogenesis-associated diseases, scleroderma, brain-associated diseases, neuropathic pain, peripheral neuropathy and ocular diseases. cid (LPA) receptor inhibitors, and thereby useful for treating e.g. fibrosis of organs, liver diseases, cell proliferative diseases, inflammatory diseases, gastrointestinal tract diseases, renal diseases, urinary tract-associated diseases, pancreas disease, abnormal angiogenesis-associated diseases, scleroderma, brain-associated diseases, neuropathic pain, peripheral neuropathy and ocular diseases.

Description

The present ion provides nds of Formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, wherein R6 is optionally substituted cycloalkyl, and wherein the remaining substituents are as defined . These compounds are selective lysophosphatidic acid (LPA) receptor inhibitors, and thereby useful for ng e.g. fibrosis of organs, liver diseases, cell proliferative diseases, inflammatory diseases, gastrointestinal tract diseases, renal diseases, urinary tract-associated es, pancreas disease, abnormal angiogenesis-associated diseases, scleroderma, brain-associated diseases, neuropathic pain, peripheral neuropathy and ocular diseases.
NZ 750013 CARBAMOYLOXYMETHYL TRIAZOLE CYCLOHEXYL ACIDS AS LPA ANTAGONISTS FIELD OF THE INVENTION The t invention s to novel substituted triazole compounds, compositions containing them, and methods of using them. Described herein is, for example, the ent or prophylaxis of disorders ated with one or more of the lysophosphatidic acid (LPA) ors.
OUND OF THE INVENTION Lysophospholipids are membrane-derived bioactive lipid mediators, of which one of the most medically important is lysophosphatidic acid (LPA). LPA is not a single molecular entity but a collection of endogenous structural variants with fatty acids of varied lengths and s of saturation (Fujiwara et al., J Biol. Chem., 2005, 280, 35038- 35050). The structural backbone of the LPAs is derived from glycerol-based olipids such as phosphatidylcholine (PC) or phosphatidic acid (PA).
The LPAs are bioactive lipids (signaling lipids) that regulate various cellular signaling pathways by binding to the same class of 7-transmembrane domain G protein- coupled (GPCR) ors (Chun, J., Hla, T., Spiegel, S., Moolenaar, W., Editors, Lysophospholipid Receptors: Signaling and Biochemistry, 2013, Wiley; ISBN: 978 4704 & Zhao, Y. et al, Biochim. Biophys. Acta (BBA)-Mol. Cell Biol. Of Lipids, 2013, 1831, 86–92). The currently known LPA receptors are designated as LPA1, LPA2, LPA3, LPA4, LPA5 and LPA6 (Choi, J. W., Annu. Rev. Pharmacol. Toxicol., 2010, 50, 157-186).
The LPAs have long been known as precursors of phospholipid biosynthesis in both eukaryotic and prokaryotic cells, but the LPAs have emerged only recently as signaling molecules that are rapidly produced and released by activated cells, notably platelets, to influence target cells by acting on specific urface receptors (see, e.g., Moolenaar et al., BioEssays, 2004, 26, 870-881, and van Leewen et al., m. Soc.
Trans., 2003, 31, 1209-1212). Besides being synthesized and processed to more complex phospholipids in the endoplasmic reticulum, LPAs can be generated through the hydrolysis of pre-existing phospholipids following cell activation; for example, the sn-2 position is commonly missing a fatty acid residue due to deacylation, leaving only the sn- 1 hydroxyl esterified to a fatty acid. Moreover, a key enzyme in the production of LPA, autotaxin LD/NPP2), may be the product of an oncogene, as many tumor types up- regulate autotaxin (Brindley, D., J. Cell Biochem. 2004, 92, 900-12). The concentrations of LPAs in human plasma & serum as well as human oalveolar lavage fluid (BALF) have been reported, including inations made using sensitive and specific LC/MS & LC/MS/MS procedures (Baker et al. Anal. Biochem., 2001, 292, 287-295; Onorato et al., J. Lipid Res., 2014, 55, 1784-1796).
LPA influences a wide range of biological responses, ranging from induction of cell proliferation, stimulation of cell migration and e retraction, gap junction closure, and even slime mold chemotaxis (Goetzl, et al., Scientific World J., 2002, 2, 324- 338; Chun, J., Hla, T., Spiegel, S., Moolenaar, W., Editors, ospholipid Receptors: Signaling and Biochemistry, 2013, Wiley; ISBN: 978 4704). The body of knowledge about the biology of LPA continues to grow as more and more ar systems are tested for LPA responsiveness. For instance, it is now known that, in addition to stimulating cell growth and proliferation, LPAs promote cellular tension and cellsurface fibronectin binding, which are ant events in wound repair and ration naar et al., BioEssays, 2004, 26, 1). Recently, anti-apoptotic activity has also been ascribed to LPA, and it has recently been reported that PPAR is a receptor/target for LPA (Simon et al., J. Biol. Chem., 2005, 280, 14656-14662).
Fibrosis is the result of an uncontrolled tissue healing process leading to excessive accumulation and insufficient resorption of extracellular matrix (ECM) which ultimately results in gan failure (Rockey, D. C., et al., New Engl. J. Med., 2015, 372, 1138- 1149). ly it was ed that the LPA1 receptor was over-expressed in idiopathic pulmonary fibrosis (IPF) patients. LPA1 receptor knockout mice were also protected from bleomycin-induced lung fibrosis (Tager et al., Nature Med., 2008, 14, 45-54).
Thus, nizing the LPA1 receptor may be useful for the treatment of fibrosis such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis, arterial fibrosis and systemic sclerosis, and thus the diseases that result from fibrosis (pulmonary fibrosis-Idiopathic Pulmonary Fibrosis [IPF], hepatic fibrosis-Non-alcoholic Steatohepatitis [NASH], renal fibrosis-diabetic nephropathy, systemic sclerosis-scleroderma, etc.) It is an object of the present invention to provide an nist of one or more LPA receptors and/or a compound of formula (I) and/or a compound of formula (X) and/or a pharmaceutical composition and/or a method of treating fibrosis and/or method of treatment as sed herein and/or use of a compound of formula (I) or (X) in the manufacture of a medicament for treating fibrosis and/or use of a compound of formula (I) or (X) in the cture of a medicament for treating conditions disclosed herein and/or to at least provide the public with a useful choice.
SUMMARY OF THE INVENTION In a first claimed aspect, the t invention provides a compound according to Formula (I): or stereoisomers, tautomers, a pharmaceutically acceptable salts, or solvates thereof, wherein R2 is ndently selected from H and C1-4 alkyl substituted with 1-5 R9; R13 is independently selected from H, D, and C1-4 alkyl substituted with 1-3 R9; R3 and R4 are independently selected from H, C1-7 alkyl substituted with 1-3 R9, 7)r-C3-8 cycloalkyl substituted with 1-3 R8, -(CR7R7)r-aryl substituted with 1-3 R8, C2-7alkenyl substituted with 1-3 R9, -(CR7R7)r6 membered heterocyclic ring substituted with 1-3 R8, -(CR7R7)r6 membered heteroaryl ring substituted with 1-3 R8, or R3 and R4 combine with the N to which they are attached to form a 4-9 membered cyclic ring substituted with 1-3 R8; X1, X2, X3, and X4 are independently selected from CR5 and N; provided no more than two of X1, X2, X3, or X4 are N; R5 is independently selected from H, F, Cl, OR7, CN, , C1-4 alkyl substituted with 1-5 R9, C1-4 alkoxy substituted with 1-5 R9, and C1-4 alkyl substituted with 1-5 R9; R6 is C3-8 cycloalkyl which is substituted with R10 and (–CH2)0-1R11; R7 is independently selected from H, C1-4 alkyl, and C3-6 cycloalkyl; or R7 and R7, together with the carbon atom to which they both attach, form a C3-6 cycloalkyl ring; R8 is independently selected from H, D, C1-6 alkyl substituted with 1-5 R9, C2-6 l, C2-6 alkynyl, phenyl, -(CH2)r-C3-6 cycloalkyl, F, Cl, Br, CN, COOH, and C1-4 alkoxy; R9 is ndently selected from H, D, F, Cl, NH2, OH, OC1-5alkyl, C1-5alkyl, C1-5 heteroalkyl C3-6 cycloalkyl, and phenyl, wherein when R9 is Cl, NH2 or OH it is not substituted on C1 of the the alkyl to which it is attached; R10 is independently selected from H, D, C1-4 alkyl, F, Cl, Br, OR7, NHC(=O)OR7, and NHC(=O)OR7; R11 is ndently selected from H, CN, R12, tetrazolyl, , and R12 is independently selected from OH, OC1-4 alkyl, NH2, NHCH2CH2SO3H, and NHSO2C1-4alkyl; r is independently selected from zero, 1, 2, 3, and 4, and n is slected from 1, 2, 3, or 4.
In a second claimed aspect, the present invention provides a compound of Formula (X): or an enantiomer, a diastereomer, or a isomer thereof, wherein R20 is ndently C1-6 alkyl or H; R21 is independently C1-6 alkyl or H; X5 and X6 are independently CH or N; and X7 is Br.
In a third claimed aspect, the present invention provides a ceutical composition comprising one or more compounds according to the first or second claimed aspects and a pharmaceutically acceptable carrier or t.
In a fourth d , the present invention provides a compound according to the first or second claimed aspects for use in therapy.
In a fifth claimed aspect, the t invention provides a method of treating fibrosis in a mammal comprising administering a eutically effective amount of a compound according to the first or second claimed aspects or a pharmaceutically acceptable salt thereof to the mammal in need thereof, wherein the mammal is not a human.
In a sixth claimed aspect, the present invention provides a method of treating lung fibrosis (idiopathic pulmonary fibrosis), asthma, chronic obstructive pulmonary disease , renal fibrosis, acute kidney injury, chronic kidney disease, liver is (non- alcoholic steatohepatitis), skin fibrosis, fibrosis of the gut, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, bowel cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, cancer pain, tumor metastasis, transplant organ rejection, scleroderma, ocular fibrosis, age related macular degeneration (AMD), diabetic retinopathy, collagen ar e, atherosclerosis, Raynaud’s phenomenon, or neuropathic pain in a mammal comprising administering a therapeutically effective amount of a compound according to the first or second claimed aspects or a pharmaceutically acceptable salt thereof to the mammal in need thereof, wherein the mammal is not a human.
In a seventh claimed aspect, the present invention provides use of a compound according to the first or second claimed aspects or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating fibrosis in a .
In an eighth claimed aspect, the t ion provides use of a compound according to the first or second claimed aspects or a pharmaceutically able salt f in the manufacture of a medicament for treating lung fibrosis (idiopathic pulmonary fibrosis), asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute kidney injury, c kidney disease, liver fibrosis (non-alcoholic steatohepatitis), skin fibrosis, fibrosis of the gut, breast cancer, pancreatic cancer, ovarian , prostate cancer, glioblastoma, bone cancer, colon cancer, bowel cancer, head and neck cancer, ma, multiple myeloma, chronic lymphocytic leukemia, cancer pain, tumor asis, transplant organ ion, scleroderma, ocular fibrosis, age related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atherosclerosis, Raynaud’s phenomenon, or neuropathic pain in a mammal.
The present disclosure provides novel substituted triazole compounds ing stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, which are useful as antagonists against one or more of the lysophosphatidic acid (LPA) receptors, especially the LPA1 receptor.
The present disclosure also provides processes and intermediates for making the compounds of the present invention.
The present disclosure also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, ers, pharmaceutically able salts, es or gs thereof.
The compounds of the invention may be used in the treatment and/or prophylaxis of conditions in which LPA plays a role.
The compounds of the present invention may be used in therapy.
The compounds of the present invention may be used for the manufacture of a medicament for the treatment and/or prophylaxis of a ion in which tion of the physiological activity of LPA is useful, such as es in which an LPA receptor participates, is involved in the etiology or pathology of the disease, or is otherwise associated with at least one symptom of the disease.
In another aspect, the present disclosure is directed to a method of treating is of organs (liver, kidney, lung, heart and the like as well as skin), liver diseases (acute tis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic hepatitis (NASH), liver hypofunction, c blood flow disorder, and the like), cell erative disease [cancer (solid tumor, solid tumor asis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL) and the like) and invasive metastasis of cancer cell, and the like], inflammatory disease (psoriasis, pathy, pneumonia and the like), gastrointestinal tract disease able bowel syndrome (IBS), inflammatory bowel disease (IBD), abnormal pancreatic secretion, and the like), renal disease, urinary tractassociated disease (benign prostatic hyperplasia or symptoms associated with neuropathic bladder disease, spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis, symptoms derived from diabetes, lower urinary tract disease (obstruction of lower urinary tract, and the like), inflammatory disease of lower urinary tract, dysuria, frequent urination, and the like), pancreas e, abnormal angiogenesis-associated disease (arterial obstruction and the like), scleroderma, brain-associated disease (cerebral infarction, cerebral hemorrhage, and the like), neuropathic pain, peripheral neuropathy, and the like, ocular disease (age-related macular degeneration (AMD), diabetic pathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma filtration surgery ng, and the like).
In another aspect, the present disclosure is directed to a method of treating diseases, disorders, or conditions in which activation of at least one LPA receptor by LPA contributes to the symptomology or progression of the disease, disorder or condition.
These diseases, disorders, or conditions may arise from one or more of a genetic, iatrogenic, immunological, infectious, lic, oncological, toxic, al, and/or traumatic etiology.
In another aspect, the present disclosure is directed to a method of treating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial is and systemic sclerosis comprising administering to a patient in need of such treatment a compound of the present invention as described above.
In one aspect, the present disclosure provides methods, compounds, pharmaceutical compositions, and medicaments described herein that comprise antagonists of LPA receptors, especially antagonists of LPA1.
The nds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two other agent(s).
These and other features of the invention will be set forth in expanded form as the disclosure continues.
In the description in this specification reference may be made to t matter that is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person d in the art and may assist in g into practice the invention as defined in the claims of this application.
DETAILED DESCRIPTION OF THE INVENTION I. COMPOUNDS OF THE INVENTION In one aspect, the t disclosure provides, inter alia, nds of Formula or stereoisomers, ers, pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein R2 is independently selected from H and C1-4 alkyl substituted with 1-5 R9; R13 is independently selected from H, D, and C1-4 alkyl substituted with 1-3 R9; R3 and R4 are ndently selected from H, C1-7 alkyl substituted with 1-3 R9, - (CR7R7)r-C3-8 cycloalkyl substituted with 1-3 R8, -(CR7R7)r-aryl substituted with 1-3 R8, C2-7alkenyl substituted with 1-3 R9, -(CR7R7)r6 membered heterocyclic ring substituted with 1-3 R8, -(CR7R7)r6 membered heteroaryl ring substituted with 1-3 R8, or R3 and R4 combine with the N to which they are attached to form a 4-9 membered heterocyclic ring tuted with 1-3 R8; X1, X2, X3, and X4 are ndently selected from CR5 and N; provided no more than two of X1, X2, X3, or X4 are N; R5 is independently selected from H, F, Cl, OR7, CN, N(R7)2, C1-4 alkyl substituted with 1-5 R9, C1-4 alkoxy substituted with 1-5 R9, and C1-4 heteroalkyl substituted with 1-5 R9; R6 is C3-8 lkyl which is substituted with R10 and (–CH2)0-1R11; R7 is independently selected from H, C1-4 alkyl, and C3-6 cycloalkyl; or R7 and R7, together with the carbon atom to which they both attach, form a C3-6 cycloalkyl ring; R8 is ndently selected from H, D, C1-6 alkyl substituted with 1-5 R9, C2-6 alkenyl, C2-6 alkynyl, phenyl, -(CH2)r-C3-6 cycloalkyl, F, Cl, Br, CN, COOH, and C1-4 ; R9 is independently selected from H, D, F, Cl, NH2, OH, OC1-5alkyl, C1-5alkyl, C1-5 heteroalkyl C3-6 cycloalkyl, and phenyl, wherein when R9 is Cl, NH2 or OH it is not substituted on C1 of the the alkyl to which it is attached; R10 is ndently selected from H, D, C1-4 alkyl, F, Cl, Br, OR7, NHC(=O)OR7, and NHC(=O)OR7; R11 is independently selected from H, CN, –C(=O)R12, olyl, , and R12 is independently selected from OH, OC1-4 alkyl, NH2, NHCH2CH2SO3H, and NHSO2C1-4alkyl; r is independently selected from zero, 1, 2, 3, and 4, and n is slected from 1, 2, 3, or 4.
In another embodiment, the present disclosure includes compounds of Formula (I), wherein R3 and R4 are independently selected from H, C1-7 alkyl substituted with 1-3 R9, - (CR7R7)r-C3-8 cycloalkyl tuted with 1-3 R8, -(CR7R7)r-aryl tuted with 1-3 R8, C2-7alkenyl substituted with 1-3 R9, -(CR7R7)r6 membered heterocyclic ring substituted with 1-3 R8, -(CR7R7)r6 membered heteroaryl ring substituted with 1-3 R8, and R3 and R4 combine with the N to which they are attached to form the following: , , , , , , , , , , , or , each of which may be substituted with 1-3 R8, and n equals 1 or 2.
In another embodiment, the present disclosure includes compounds of Formula (I) wherein, R3 and R4 are ndently selected from H, C1-7 alkyl substituted with 1-3 R9, 7)r-C3-8 cycloalkyl substituted with 1-3 R8, -(CR7R7)r-aryl substituted with 1-3 R8, C2-7alkenyl substituted with 1-3 R9, , , , , , , , , , each of which can be substituted with 1-3 R8, and R3 and R4 combine with the N to which they are attached to form a 4-9 membered heterocyclic ring substituted with 1-3 R8; and n equals 1 or 2.
In another embodiment, the present disclosure includes compounds of Formula (II): or stereoisomers, ers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R2 is independently selected from H and C1-4 alkyl substituted with 1-5 R9; R13 is independently selected from H, D, and C1-4 alkyl substituted with 1-3 R9; R3 and R4 are independently selected from H, C1-7 alkyl substituted with 1-3 R9, -(CR7R7)r-C3-6 cycloalkyl substituted with 1-3 R8, and 7)r-aryl substituted with 1-3 R8; X1, X2, X3, and X4 are independently selected from CR5 and N; provided no more than two of X1, X2, X3, or X4 are N; R5 is independently selected from H, F, Cl, OR7, CN, N(R7)2, C1-4 alkyl tuted with 1-5 R9, C1-4 alkoxy substituted with 1-5 R9, and C1-4 heteroalkyl substituted with 1-5 R9; R6 is ; R7 is independently selected from H, C1-4 alkyl, and C3-6 cycloalkyl; or R7 and R7, together with the carbon atom to which they both , form a C3-6 lkyl ring; R8 is independently selected from H, C1-6 alkyl substituted with 1-5 R9, C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3-6 cycloalkyl, F, Cl, Br, CN, =O, and CO2H; R9 is ndently ed from H, F, Cl, NH2, OH, lkyl, C1-5alkyl, C1-5 heteroalkyl C3-6 cycloalkyl, and phenyl, wherein when R9 is Cl, NH2 or OH it is not substituted on C1 of the the alkyl to which it is attached; R10 is independently selected from H, D, C1-4 alkyl, F, Cl, Br, OR7, NHC(=O)OR7, and NHC(=O)R7; R11 is independently selected from CN, –C(=O)R12, tetrazolyl, , and R12 is independently selected from OH, OC1-4 alkyl, NH2, NHCH2CH2SO3H, and NHSO2C1-4alkyl; and r is independently selected from zero, 1, 2, 3, and 4.
In another aspect, the present disclosure provides compounds of Formula (III): (III) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R2 is independently selected from CH3 and CD3; R13 is independently selected from H and C1-4 alkyl; R3 is ndently selected from H and C1-4 alkyl; R4 is independently selected from C1-6 alkyl substituted with 1-3 R9, -(CR7R7)r-C3-6 cycloalkyl substituted with 1-3 R8, and -(CR7R7)r-aryl substituted with 1-3 R8; R5 is independently selected from H, F, Cl, CN and C1-4 alkyl; provided one of R5 is H; R6 is ; R7 is independently selected from H, C1-4 alkyl, and C3-6 cycloalkyl; or R7 and R7, together with the carbon atom to which they both , form a C3-6 cycloalkyl ring; R8 is independently selected from H, C1-6 alkyl substituted with 1-5 R9, C3-6 cycloalkyl, F, Cl, Br, CN, =O, and COOH; R9 is independently selected from H, F, Cl, NH2, OH, OC1-5alkyl, kyl, C3-6 cycloalkyl, and phenyl, wherein when R9 is Cl, NH2 or OH it is not substituted on C1 of the the alkyl to which it is attached; R10 is independently selected from H, D, C1-4 alkyl, and F; R11 is independently selected from CN, –C(=O)R12, and tetrazolyl; R12 is independently ed from OH, OC1-4 alkyl, NH2, and 1-4alkyl; and r is independently selected from zero, 1, 2, 3, and 4.
In another aspect, the present disclosure provides compounds of Formula (IV): or stereoisomers, tautomers, pharmaceutically able salts, solvates, or prodrugs thereof, wherein R2 is independently selected from CH3 and CD3; R13 is independently selected from H and C1-4 alkyl; R3 is independently selected from H and C1-4 alkyl; R4 is independently selected from C1-6 alkyl, , , , , and ; R5 is independently selected from H, F, Cl, and C1-4 alkyl; provided one of R5 is H; R7 is independently selected from H, C1-4 alkyl, and C3-6 cycloalkyl; R8 is ndently selected from H, C1-6 alkyl substituted with 1-5 R9, C3-6 cycloalkyl, F, Cl, Br, CN, =O, and COOH; R9 is independently selected from H, F, Cl, NH2, OH, OC1-5alkyl, C1-5alkyl, C3-6 cycloalkyl, and , wherein when R9 is Cl, NH2 or OH it is not substituted on C1 of the the alkyl to which it is attached; R10 is independently ed from H, D, C1-4 alkyl, and F; R11 is independently selected from CN, –C(=O)R12, and ; and R12 is independently ed from OH, NH2 and NHSO2C1-4alkyl.
In another aspect, the present disclosure provides compounds of Formula (III) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or gs thereof, wherein R4 is independently selected from , , , , , , , , , , , , , , , , , , , , , , , and ; and R8 is independently selected from H, F, Cl, Br, CN, and C1-4 alkyl; and other les are as defined in Formula (IV).
In another aspect, the present disclosure provides compounds of Formula (V): (V) or stereoisomers, tautomers, ceutically acceptable salts, solvates, or prodrugs thereof, wherein R2 is independently selected from CH3 and CD3; R13 is independently selected from H and CH3; R3 is independently selected from H and CH3; R4 is independently selected from , , , , , , , , , , , , , , , , , , , , , , , and ; and R5 is independently selected from H, F, and C1-4 alkyl; R8 is ndently ed from H, F, Cl, Br, CN, and C1-4 alkyl; R10 is independently selected from H, D, and F; and R11 is independently selected from–C(=O)OH, and –C(=O)NHSO2Me.
In another aspect, the present disclosure provides compounds of Formula (VI): or stereoisomers, tautomers, pharmaceutically able salts, solvates, or prodrugs thereof, wherein R2 is independently ed from CH3 and CD3; R13 is independently selected from H and CH3; R3 is independently selected from H and CH3; R4 is independently selected from , , , , , , , , , , , , , and ; R5 is independently selected from H and CH3; and R8 is independently selected from H, F, Cl, Br, CN, and C1-4 alkyl.
In another aspect, the t disclosure provides compounds of Formula (VII): (VII) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R2 is independently selected from CH3 and CD3; R13 is independently selected from H and C1-4 alkyl; R3 is independently selected from H and C1-4 alkyl; R4 is independently selected from C1-6 alkyl substituted with 1-3 R9, (CR7R7)r-C3-6 cycloalkyl substituted with 1-3 R8, and -(CR7R7)r-aryl substituted with 1-3 R8; R5 is independently ed from H, F, Cl, CN, and C1-4 alkyl; R6 is ; R7 is independently selected from H, C1-4 alkyl, and C3-6 cycloalkyl; or R7 and R7, together with the carbon atom to which they both attach, form a C3-6 cycloalkyl ring; R8 is independently selected from H, C1-6 alkyl tuted with 1-5 R9, C3-6 cycloalkyl, F, Cl, Br, CN, =O, and COOH; R9 is independently selected from H, F, Cl, NH2, OH, OC1-5alkyl, C1-5alkyl, C3-6 cycloalkyl, and , wherein when R9 is Cl, NH2 or OH it is not substituted on C1 of the the alkyl to which it is attached; R10 is independently selected from H, C1-4 alkyl, and F; R11 is independently selected from CN, –C(=O)R12, olyl, , and R12 is independently selected from OH, OC1-4 alkyl, NH2, NHCH2CH2SO3H, and NHSO2C1-4alkyl; and r is independently selected from zero, 1, 2, 3, and 4.
In another aspect, the t disclosure provides compounds of Formula (VI) or stereoisomers, ers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R1 is independently selected from CH3 and CD3; R2 is independently selected from H and CH3; R3 is independently selected from H and CH3; R4 is independently ed from C1-6 alkyl, , , , , and ; R5 is independently selected from H, F, Cl, and C1-4 alkyl; R6 is R7 is independently selected from H, C1-4 alkyl, and C1-6 cycloalkyl; and R8 is independently selected from H, F, Cl, Br, CN, and C1-4 alkyl.
In another aspect, the present disclosure provides compounds of Formula (VIII): (VIII) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, n R2 is independently selected from CH3 and CD3; R13 is ndently selected from H and CH3; R3 is independently selected from H and CH3; R4 is independently selected from , , , , , , , , , , , , , , , , , , , , , , , and ; R5 is independently selected from H, F, and CH3; and R8 is independently selected from H, F, Cl, Br, CN, and C1-4 alkyl.
In another aspect, the present sure provides compounds of Formula (IX): or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs f, wherein R2 is independently selected from CH3 and CD3; R13 is independently selected from H and C1-4 alkyl; R3 is independently selected from H and C1-4 alkyl; R4 is independently selected from C1-6 alkyl substituted with 1-3 R9, (CR7R7)r-C3-6 cycloalkyl substituted with 1-3 R8, and -(CR7R7)r-aryl substituted with 1-3 R8; R5 is independently selected from H, F, Cl, CN, and C1-4 alkyl; R6 is independently selected from R7 is independently selected from H, C1-4 alkyl, and C3-6 cycloalkyl; or R7 and R7, together with the carbon atom to which they both attach, form a C3-6 cycloalkyl ring; R8 is independently selected from H, C1-6 alkyl substituted with 1-5 R9, C3-6 cycloalkyl, F, Cl, Br, CN, =O, and COOH; R9 is independently selected from H, F, Cl, NH2, OH, OC1-5alkyl, C1-5alkyl, C3-6 cycloalkyl, and phenyl, wherein when R9 is Cl, NH2 or OH it is not substituted on C1 of the the alkyl to which it is ed; R10 is independently selected from H, and F, R11 is independently ed from CN, –C(=O)R12, tetrazolyl, , and ; R12 is independently selected from OH, OC1-4 alkyl, NH2, NHCH2CH2SO3H, and NHSO2C1-4alkyl; and r is independently ed from zero, 1, 2, 3, and 4.
In yet another embodiment, the present disclosure includes a compound of Formula (I) or (II) selected from the group of: , , , , , , , , , , , , , , and , or an enantiomer, a diastereomer, a stereoisomer, or a pharmaceutically acceptable salt thereof.
In yet another embodiment, the present sure includes a compound of Formula (I) or (II) selected from the group of: , , , , , , , , and , or an enantiomer, a diastereomer, a stereoisomer, or a pharmaceutically acceptable salt thereof.
In yet another embodiment, the present disclosure includes compound of Formula (I) or (II) wherein said compound has the formula: , an enantiomer, a diastereomer, a stereoisomer, or a pharmaceutically acceptable salt thereof.
In yet another embodiment, the present disclosure includes compound of Formula (I) or (II) wherein said compound has the formula: , an enantiomer, a diastereomer, a stereoisomer, or a pharmaceutically acceptable salt thereof.
In yet r ment, the present disclosure includes compound of Formula (I) or (II) wherein said compound has the formula: , an enantiomer, a diastereomer, a stereoisomer, or a pharmaceutically acceptable salt thereof.
In yet another embodiment, the present disclosure includes compound of Formula (I) or (II) wherein said compound has the formula: , an enantiomer, a diastereomer, a stereoisomer, or a pharmaceutically acceptable salt f.
In yet r embodiment, the t disclosure includes compound of Formula (I) or (II) wherein said compound has the formula: , an enantiomer, a diastereomer, a stereoisomer, or a ceutically acceptable salt thereof.
In yet another embodiment, the present disclosure includes compound of Formula (I) or (II) wherein said compound has the formula: , an enantiomer, a diastereomer, a stereoisomer, or a pharmaceutically able salt thereof.
In yet r embodiment, the present sure includes compound of Formula (I) or (II) wherein said compound has the formula: , an enantiomer, a diastereomer, a stereoisomer, or a pharmaceutically acceptable salt thereof.
In yet another embodiment, the present disclosure includes compound of Formula (I) or (II) wherein said compound has the a: , or an enantiomer, a diastereomer, a stereoisomer, or a pharmaceutically acceptable salt thereof.
In yet another embodiment, the present disclosure includes compound of Formula (I) or (II) wherein said compound has the formula: , an enantiomer, a diastereomer, a stereoisomer, or a pharmaceutically able salt thereof.
In yet another embodiment, the present disclosure includes compound of Formula (I) or (II) wherein said compound has the formula: , an enantiomer, a diastereomer, a stereoisomer, or a pharmaceutically acceptable salt f.
For any and all of the embodiments, substituents are selected from among from a subset of the listed atives. For example, in some embodiments, R12 is -OH, -OC1-4 alkyl, or -NHSO2C1-4 alkyl. In some embodiments, R12 is –OH or -OC1-4 alkyl. In some embodiments, R12 is -OH. In some embodiments, R12 is -OC1-4 alkyl. In some embodiments, R12 is -OCH3 or -OCH2CH3. In some embodiments, R 12 is C1- 4alkyl.
In some embodiments, R3 is C1-4 alkyl; R5 is H or C1-4 alkyl. In some embodiments, R12 is -OH, -OCH3, -OCH2CH3, -NHSO2CH3 or -NHSO2CH2CH3; R3 is – CH3, CD3 or –CH2CH3. In some embodiments, R12 is -OH, -OCH3, H3, - NHSO2CH3 or -NHSO2CH2CH3; R3 is –CH3, CD3, or –CH2CH3; R5 is H or C1-4 alkyl.
In some embodiments, R4 is wherein is 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4- ethylphenyl, 2-deuteromethylphenyl, 3-deuteromethylphenyl, 4-deuteromethylphenyl, 2- uoromethylphenyl, fluoromethylphenyl, 4-monofluoromethylphenyl, 2- romethylphenyl, 3-difluoromethylphenyl, 4-difluoromethylphenyl, 2- cyclopropylphenyl, 3-cyclopropylphenyl, 4-cyclopropylphenyl, 2-cyclobutylphenyl, 3- cyclobutylphenyl, 4-cyclobutylphenyl, 2-cyclopentylphenyl, 3-cyclopentylphenyl, 4- cyclopentylphenyl, 2-cyclohexylphenyl, 3-cyclohexylphenyl or 4-cyclohexylphenyl.
In some embodiments, R4 is –(CHR7)r-C3-6 cycloalkyl and r is 0, 1, or 2, and R7 is H or . In some embodiments, r is 0, R4 is cyclopropyl, utyl, cyclopentyl, or cyclohexyl and R7 is H or methyl. In some embodiments, r is 1, R4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, R7 is H or methyl.
In some embodiments, R3 is C1-4 alkyl, R4 is –(CHR7)r-C3-6 cycloalkyl, and r is 0, 1, or 2, and R7 is H or methyl. In some embodiments, R3 is –CH3, CD3, or –CH2CH3, R4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, r is 0 or 1, and R7 is H or .
In some embodiments, R3 is –CH3, R4 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, r is 1, R7 is H or .
In some embodiments, R3 is C1-4 alkyl, R4 is C1-4 alkyl, and R7 is H or methyl. In some embodiments, R3 is –CH3, CD3, or –CH2CH3, R4 is –CH3, CD3, –CH2CH3, – CH2CH2CH3, –CH(CH3)2, –CH2CH2CH2CH3, –CH2CH(CH3)2, or –CH(CH3)3, and R7 is H or methyl. In some embodiments, R3 is –CH3, R4 is –CH2CH3, –CH2CH2CH3, – CH(CH3)2, –CH2CH2CH2CH3, –CH2CH(CH3)2, or –CH(CH3)3, R7 is H or methyl.
In some embodiments, R1 is H or C1-2 alkyl, R2 is H or C1-2 alkyl, R3 is C1-2 alkyl, R4 is )r-C3-6 cycloalkyl and r is 1, R5 is H or C1-2 alkyl, R6 is entyl or cyclohexyl, R7 is H or C1-2 alkyl, R8 is H, R9 is H, R10 is H, and R11 is –C(=O)OH.
In some embodiments, R1 is H or methyl, R2 is H or methyl, R3 is methyl, R4 is – yclopropyl, –CHR7-cyclobutyl, cyclopentyl, or –CHR7-cyclohexyl, R5 is H or methyl, R6 is cyclohexyl, R7 is H or methyl, R8 is H, R9 is H, R10 is H, and R11 is – C(=O)OH.
In some embodiments, the pharmaceutically acceptable salt of the compound of Formulas (I) - (IX) is a sodium salt.
Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
In another aspect, the present disclosure provides a compound selected from any subset list of compounds exemplified in the present application.
In r embodiment, the present disclosure includes compounds of Formula (X) or an enantiomer, a diastereomer, or a stereoisomer thereof, wherein R20 is independently selected from C1-6 alkyl or H; R21 is independently selected from C1-6 alkyl or H; X5 and X6 are independently ed from CH or N; and X7 is selected from Cl, Br, or F.
In another ment, the present disclosure includes compounds of Formula (XI): (XI), or an omer, a diastereomer, or a stereoisomer thereof.
In another aspect, the present disclosure provides a compound selected from the list below: (1S,3S)((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (1) (1S,3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (2) (1S,3S)((6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl) -1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (3) trans(4-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)phenoxy)cyclohexanecarboxylic acid (4) (1S,3S)(4-(5-(((Cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (5) (1R,3R)(4-(5-(((Cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (6) hyl(4-(((1S,3S)((methylsulfonyl)carbamoyl)cyclohexyl)oxy)phenyl)- 1H-1,2,3-triazolyl)methyl cyclopentyl(methyl)carbamate (7) No names for (8) and (9) (1S,3S)(4-(1-Methyl(((methyl(2-methylpentanyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (10) 3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)fluorocyclohexanecarboxylic acid (11) (1S,3S)(4-(5-(1-(((cyclobutylmethyl)(methyl)carbamoyl)oxy)ethyl)methyl- 1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (12) (5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)fluorocyclohexanecarboxylic acid (13) (4-(5-(((1S,3S)carbamoylcyclohexyl)oxy)methylpyridinyl)methyl-1H- 1,2,3-triazolyl)methyl (cyclobutylmethyl)(methyl)carbamate (14) (4-(5-(((1S,3S)cyanocyclohexyl)oxy)methylpyridinyl)methyl-1H- 1,2,3-triazolyl)methyl (cyclobutylmethyl)(methyl)carbamate (15) (4-(5-(((1S,3S)(1H-tetrazolyl)cyclohexyl)oxy)methylpyridinyl) -1H-1,2,3-triazolyl)methyl (cyclobutylmethyl)(methyl)carbamate (16) (1-methyl(6-methyl(((1S,3S) ((methylsulfonyl)carbamoyl)cyclohexyl)oxy)pyridinyl)-1H-1,2,3-triazolyl)methyl (cyclobutylmethyl)(methyl)carbamate (17) 3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (18), (1S,3S)((2-methyl(1-methyl(((methyl((R) phenylethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane- 1-carboxylic acid (19), (1S,3S)((6-(5-((((1-cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (20), (1S,3S)((6-(1-methyl(((methyl((R)phenylethyl)carbamoyl)oxy)methyl)- ,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (21), (1S,3S)((6-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (22), (1S,3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (23), (1S,3S)((6-(1-methyl(((methyl(pentanyl)carbamoyl)oxy)methyl)-1H- 1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (24), (1S,3S)((6-(5-(((((R)cyclopropylethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (25), (1S,3S)(4-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)fluorophenoxy)cyclohexanecarboxylic acid (26), (1S,3S)(4-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)fluorophenoxy)cyclohexanecarboxylic acid (27), (1S,3S)(2-fluoro(1-methyl(((methyl(pentanyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (28), (1S,3S)((6-(5-(((((R)cyclopropylethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (29), (1S,3S)((6-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (30), (1S,3S)((2-methyl(1-methyl(((methyl(pentan bamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane carboxylic acid (31), (1S,3S)((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (32), (1S,3S)((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (33), (1S,3S)((6-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (34), (1S,3S)((6-(5-((((4-chlorobenzyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (35), (1S,3S)(4-(5-(((((R)cyclopropylethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylphenoxy)cyclohexanecarboxylic acid (36), (1S,3S)(4-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylphenoxy)cyclohexanecarboxylic acid (37), (1S,3S)(4-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylphenoxy)cyclohexanecarboxylic acid (38), (1S,3S)(2-methyl(1-methyl(((methyl(pentan bamoyl)oxy)methyl)-1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (39), (1S,3S)(4-(5-(((butyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylphenoxy)cyclohexanecarboxylic acid (40), (1S,3S)(4-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylphenoxy)cyclohexanecarboxylic acid (41), (1S,3S)((6-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (42), (1S,3S)((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (43), )(4-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)fluorophenoxy)cyclohexanecarboxylic acid (44), (1S,3S)(4-(5-((((1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)methyl- ,3-triazolyl)fluorophenoxy)cyclohexanecarboxylic acid (45), (1S,3S)(4-(5-(((butyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)fluorophenoxy)cyclohexanecarboxylic acid (46), (1S,3S)(2-fluoro(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (47), (1S,3S)(4-(5-((((1-cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (isomer 1) (48), (1S,3S)(4-(5-((((1-cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)methyl- ,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (isomer 2) (49), (1S,3S)((6-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (50), (1S,3S)(4-(5-(((((R)cyclopropylethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (51), (1S,3S)(4-(5-(((((S)cyclopropylethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (52), (1S,3S)(4-(5-(((isobutyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)phenoxy)cyclohexanecarboxylic acid (53), (1S,3S)(4-(5-((((1-cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (54), (1S,3S)(4-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (55), (1S,3S)(4-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylphenoxy)cyclohexanecarboxylic acid (56), (1S,3S)(4-(1-methyl(((methyl(pentanyl)carbamoyl)oxy)methyl)-1H- triazolyl)phenoxy)cyclohexanecarboxylic acid (57), (1S,3S)(4-(1-methyl(((methyl(pentyl)carbamoyl)oxy)methyl)-1H-1,2,3- triazolyl)phenoxy)cyclohexanecarboxylic acid (58), (1S,3S)(4-(1-methyl(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3- triazolyl)phenoxy)cyclohexanecarboxylic acid (59), (1S,3S)(4-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)phenoxy)cyclohexanecarboxylic acid (60), (1S,3S)(4-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (61), (1R,3R)(4-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)phenoxy)cyclohexanecarboxylic acid (62), (1R,3R)(4-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylphenoxy)cyclohexanecarboxylic acid (63), (1S,3S)(4-(5-(((butyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)phenoxy)cyclohexanecarboxylic acid (64), (1S,3S)(4-(5-((((1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (65), (1S,3S)(4-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (66), (1S,3S)(4-(5-((((1-cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (67), (1S,3S)(4-(5-(((sec-butyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)phenoxy)cyclohexanecarboxylic acid (68), (3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylicd acid (69), (1S,3S)(4-(5-(((((R)cyclopropylethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)fluorophenoxy)cyclohexanecarboxylic acid (70), (1S,3S)(4-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)phenoxy)cyclohexanecarboxylic acid (71), hyl(4-(((1R,3R)((methylsulfonyl)carbamoyl)cyclohexyl)oxy)phenyl)- 1H-1,2,3-triazolyl)methyl cyclopentyl(methyl)carbamate (72), (1S,3S)(4-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)phenoxy)cyclohexanecarboxylic acid (73), (1S,3S)(4-(5-((((Dicyclopropylmethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (74), )(4-(1-methyl(((methyl(1-propylcyclopropyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (75), (1S,3S)(4-(1-methyl(((methyl(pentanyl)carbamoyl)oxy)methyl)-1H- 1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (76), (1S,3S)((6-(1-methyl(((methyl(pentanyl)carbamoyl)oxy)methyl)-1H- 1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (77), (1S,3S)((6-(1-methyl(((methyl(2-methylpentan yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane carboxylic acid (78), (1S,3S)((6-(1-methyl(((methyl(1- methylcyclopropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridin yl)oxy)cyclohexanecarboxylic acid (79), (1S,3S)((6-(5-((((Dicyclopropylmethyl)(methyl)carbamoyl)oxy)methyl) -1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (80), (1S,3S)((6-(1-methyl(((methyl(1- propylcyclopropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridin yl)oxy)cyclohexanecarboxylic acid (81, 82), (1S,3S)((2-Methyl(1-methyl(((methyl(pentan yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (83), (1S,3S)((2-methyl(1-methyl(((methyl(2-methylpentan yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (84), (1S,3S)((2-methyl(1-methyl(((methyl(1- cyclopropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridin yl)oxy)cyclohexanecarboxylic acid (85), (1S,3S)((6-(5-((((Dicyclopropylmethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (86), (1S,3S)((2-methyl(1-methyl(((methyl(1- propylcyclopropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridin yl)oxy)cyclohexanecarboxylic acid (87), (rac)-trans((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)fluorocyclohexanecarboxylic acid (88), trans((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)pyridinyl)oxy)fluorocyclohexanecarboxylic acid (89), 3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)pyridinyl)oxy)fluorocyclohexanecarboxylic acid (90), trans((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (91), cis((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (92), cis((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclopentanecarboxylic acid (93), (1S,3S)(4-(5-(1-((cyclopentyl(methyl)carbamoyl)oxy)ethyl)methyl-1H- 1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (94), (Cis)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (Enantiomer A, 95), (Cis)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (Enantiomer B, 96), (1R,3R)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (97), (1S,3S)((6-(5-((((2-fluorobenzyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (98), (1S,3S)((6-(5-((((1-cyclobutylpropyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (99), )((2-methyl(1-methyl(((methyl(1- phenylcyclopropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridin yl)oxy)cyclohexanecarboxylic acid (100), )((2-methyl(1-methyl(((methyl(3,3,3- trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridin yl)oxy)cyclohexanecarboxylic acid (101), (1S,3S)((6-(5-(((bicyclo[1.1.1]pentanyl(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (102), (1S,3S)((2-methyl(1-methyl(((methyl(phenethyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (103), (1S,3S)((2-methyl(1-methyl(((methyl(propyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (104), (1S,3S)((6-(5-(((bicyclo[1.1.1]pentanylcarbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (105), (1S,3S)((6-(5-((((1,3-dimethylcyclobutyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (Enantiomer A, 106) (1S,3S)((6-(5-((((1,3-dimethylcyclobutyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (Enantiomer B, 107), (1S,3S)((6-(5-((((cyclobutylmethyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (108), (1S,3S)((6-(5-((((cyclopentylmethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (109), (1S,3S)((6-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl) (methyl-d3)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (110), )((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)(methyl-d3)- 1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (111), (1S,3S)((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)(methyl-d3)-1H-1,2,3- triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (112), (1S,3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)(methyld3 )-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (113), (1S,3S)- 3-((6-(5-((((cyclobutylmethyl)(methyl-d3)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (114), (3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylicd acid (115), (1S,3S)((6-(5-(((isobutyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (116), (1S,3S)((2-methyl(1-methyl(((methyl((tetrahydro-2H-pyran yl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane ylic acid (117), (1S,3S)((2-methyl(1-methyl(((methyl(pyridin ylmethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane carboxylic acid (118), )((6-(5-(((ethyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (119), (1S,3S)((2-methyl(1-methyl(((methyl(pyridin ylmethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane carboxylic acid (120), (1S,3S)((2-methyl(1-methyl(((methyl(pyrimidin ylmethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane ylic acid (121), (1S,3S)((2-methyl(1-methyl(((methyl(pyridin ylmethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane carboxylic acid (122), (1S,3S)((2-methyl(1-methyl(((methyl(pyrazinylmethyl) carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy) cyclohexane carboxylic acid (123), (1S,3S)((2-methyl(1-methyl(((methyl((1-methyl-1H-pyrazol yl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane carboxylic acid (124), (1S,3S)((2-methyl(1-methyl(((methyl(morpholin yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane carboxylic acid (125), (1S,3S)((2-methyl(1-methyl(((methyl((tetrahydrofuran yl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane carboxylic acid (126), (1S,3S)((6-(5-(((butyl(ethyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (127), (1S,3S)((6-(5-(((ethyl(propyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (128), (1S,3S)((6-(5-((((1-isopropylcyclopropyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (129), (1S,3S)((6-(5-((((1-isobutylcyclopropyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (130), (1S,3S)((6-(5-((((1-ethylcyclopropyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (131), (1S,3S)((2-methyl(1-methyl(((methyl(1- propylcyclobutyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridin yl)oxy)cyclohexanecarboxylic acid (132), )((6-(5-((((1-ethylcyclobutyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (133), (1S,3S)((6-(5-(((2-azaspiro[3.3]heptanecarbonyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (134), (1S,3S)((6-(5-(((6-azaspiro[3.4]octanecarbonyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (135), (1S,3S)((6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (136), (1S,3S)((6-(5-(((3,3-dimethylpiperidinecarbonyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (137), (1S,3S)((6-(5-(((isopropyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (138), (1S,3S)((6-(5-((((3,3-difluorocyclobutyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (139), (1S,3S)((6-(5-(((3,3-dimethylpyrrolidinecarbonyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (140), (1R,3S)((6-(5-((((3,3-difluoro- cyclobutyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy) cyclohexanecarboxylic acid; cis isomer from epimerization in final ester hydrolysis (141), (1S,3S)((6-(5-(((cyclopropyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (142), )((6-(5-(((3,3-difluoro- pyrrolidinecarbonyl)oxy)methyl)methyl- ,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (143), (1S,3S)((6-(5-(((5-azaspiro[2.4]heptanecarbonyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (144), (1S,3S)((6-(5-(((((3,3-difluoro- cyclobutyl)methyl)(methyl)carbamoyl )oxy)methyl)methyl-1H-1,2,3-triazolyl)methylpyridin yl)oxy)cyclohexanecarboxylic acid (145), (1R,3S)((2-methyl(1-methyl(((methyl(spiro[2.3]hexan yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane carboxylic acid (cis isomer from epimerization in final ester ysis) (146), (1S,3S)((2-methyl(1-methyl(((3-methylpyrrolidine carbonyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (mixture of diastereomers) (147), (1S,3S)((6-(5-(((azabicyclo[2.2.1]heptanecarbonyl)oxy)methyl) -1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (mixture of diastereomers) (148), (1S,3S)((2-methyl(1-methyl(((octahydrocyclopenta[b]pyrrole carbonyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (mixture of diastereomers) (149), (1S,3S)((6-(5-(((3-(cyclopropylmethyl)pyrrolidinecarbonyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (mixture of diastereomers) (150), (1S,3S)((6-(5-(((3-isobutylpyrrolidinecarbonyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid re of diastereomers) (151), (1S,3S)((6-(5-(((2-ethylpyrrolidinecarbonyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (mixture of diastereomers) (152), (1S,3S)((6-(5-(((2-isobutylpyrrolidinecarbonyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (mixture of diastereomers) (153), (1S,3S)((2-methyl(1-methyl(((2-(trifluoromethyl)pyrrolidine carbonyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (mixture of diastereomers) (154), )((6-(5-(((3,3-dimethylazetidinecarbonyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (155), (1S,3S)((2-methyl(1-methyl(((3-methylazetidine carbonyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (156), (1S,3S)((2-methyl(1-methyl(((2-methylazetidine carbonyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridineyl)oxy)cyclohexanecarboxylic acid (mixture of diastereomers) (157), (1R,3S)((2-methyl(1-methyl(((methyl(spiro[3.3]heptan yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane carboxylic acid (158), (1S,3S)((6-(5-(((2-azaspiro[3.4]octanecarbonyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (159), (1R,3S)((6-(5-((((3,3-dimethylcyclobutyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (cis isomer from ization in final ester hydrolysis step) (160), (1S,3S)((2-methyl(1-methyl(((3-methylpiperidine carbonyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (mixture of diastereomers) (161), (1S,3S)((6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (162), (1S,3S)((6-(5-(((3-isopropylpyrrolidinecarbonyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (mixture of diastereomers) (163), (1S,3S)((6-(5-(((3-cyclopropylpyrrolidinecarbonyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (mixture of diastereomers) (164), (1S,3S)((6-(5-(((3-ethylpyrrolidinecarbonyl) thyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (mixture of reomers) (165), (1S,3S)((2-methyl(1-methyl(((3-propylpyrrolidine carbonyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy) cyclohexanecarboxylic acid (mixture of diastereomers) (166), (1S,3S)((6-(5-(((azabicyclo ]heptanecarbonyl)oxy) methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy) exanecarboxylic acid (167), (1S,3S)((6-(5-((((3,3-dimethyl- cyclobutyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy) cyclohexanecarboxylic acid (168), (1S,3S)((2-methyl(1-methyl(((3-phenylpyrrolidinecarbonyl) oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (mixture of diastereomers) (169), (1S,3S)((6-(5-(((tert-butyl (methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (170), (1S,3S)((6-(5-(((6-azaspiro [2.5]octanecarbonyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (171), (1R,3S)((2-methyl(1-methyl(((methyl(3-methylbuten yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy) exane carboxylic acid (cis isomer from ization during final hydrolysis step) (172), (1S,3S)((6-(1-methyl(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3- triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (173), (1S,3S)((6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (174), (1S,3S)((6-(5-(((6-azaspiro[3.4]octanecarbonyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)pyridinyl)oxy) cyclohexanecarboxylic acid (175), (1S,3S)((6-(5-(((2-azaspiro[3.3]heptanecarbonyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)pyridinyl)oxy) cyclohexanecarboxylic acid (176), (1S,3S)((2-methyl(1-methyl(((methyl(3-methylbuten yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy) cyclohexane carboxylic acid (177), (1S,3S)((6-(5-((((1-fluoromethylpropanyl)(methyl) carbamoyl)oxy)methyl)methyl-1H-1,2,3-triazolyl)methyl- pyridin )cyclohexanecarboxylic acid (178), (1S,3S)((2-methyl(1-methyl(((methyl(spiro[2.3]hexan yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy) cyclohexane carboxylic acid (179), (1S,3S)((6-(1-methyl(((methyl(spiro[3.3]heptan yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy) cyclohexane carboxylic acid (180), (1S,3S)((6-(5-((((3,3-dimethylcyclobutyl)(methyl)carbamoyl)oxy)methyl) -1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (181), (1S,3S)((6-(5-((((3-fluorocyclobutyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (mixture of diastereomers) (182), (1S,3S)((6-(1-methyl(((methyl(spiro[2.3]hexan yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane carboxylic acid (183), (1S,3S)((6-(5-(((((2,2- dimethylcyclopropyl)methyl)(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3-triazol- 4-yl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (mixture of diastereomers) (184), )((6-(5-(((((2,2- dimethylcyclopropyl)methyl)(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3-triazol- 4-yl)pyridinyl)oxy)cyclohexanecarboxylic acid (mixture of diastereomers) (185), )((6-(5-(((((2,2- rocyclopropyl)methyl)(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3-triazol- 4-yl)pyridinyl)oxy)cyclohexanecarboxylic acid (mixture of diastereomers) (186), (1S,3S)((6-(5-((((3-fluoromethylbutyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (187), (1S,3S)((6-(5-((((3-fluoromethylbutyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (188), (1S,3S)((6-(5-(((((1-fluorocyclobutyl)methyl)(methyl)carbamoyl)oxy)methyl)- 1-methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (189), (1S,3S)((6-(5-((((3-fluoropropyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (190), (1S,3S)((6-(5-((((4-fluorobutyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (191), (1S,3S)((6-(5-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (192), (1R,3R)((2-methyl(1-methyl(((methyl(propyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (193), (1S,3S)((6-(5-((((cyclopropylmethyl)(methyl) carbamoyl)oxy)methyl)methyl-1H-1,2,3-triazolyl)ethylpyridin yl)oxy)cyclohexanecarboxylic acid (194), (1S,3S)((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)ethylpyridinyl)oxy)cyclohexanecarboxylic acid (195), (1S,3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- ,3-triazolyl)ethylpyridinyl)oxy)cyclohexanecarboxylic acid (196), (1S,3S)((2-ethyl(5-(((isobutyl(methyl)carbamoyl) oxy)methyl)methyl- 1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (197), (1S,3S)((6-(5-(((benzylcarbamoyl)oxy)methyl)methyl-1H-1,2,3-triazol yl)ethylpyridinyl)oxy)cyclohexanecarboxylic acid (198), )((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)ethylpyridinyl)oxy)cyclohexanecarboxylic acid (199), (1S,3S)((2-ethyl(1-methyl(((methyl(propyl)carbamoyl)oxy)methyl)-1H- 1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (200), (1S,3S)((6-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)ethylpyridinyl)oxy)cyclohexanecarboxylic acid (201), (1S,3S)((2-ethyl(5-(((ethyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (202), (1S,3S)((6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)methyl-1H- triazolyl)ethylpyridinyl)oxy)cyclohexanecarboxylic acid (203), (1S,3S)((6-(5-(((3,3-dimethylazetidinecarbonyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)ethylpyridinyl)oxy)cyclohexanecarboxylic acid (204), (1S,3S)((6-(5-(((bicyclo[1.1.1]pentanylcarbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)ethylpyridinyl)oxy) cyclohexanecarboxylic acid (205), (1S,3S)((6-(5-(((bicyclo[1.1.1]pentanyl(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)ethylpyridinyl)oxy)cyclohexanecarboxylic acid (206), (1S,3S)((2-ethyl(1-methyl(((methyl(1-propylcyclopropyl) carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy) cyclohexane carboxylic acid (207), (1S,3S)((2-ethyl(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (208), (1S,3S)((6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)ethylpyridinyl)oxy)cyclohexanecarboxylic acid (209), (1S,3S)((6-(5-(((2-azaspiro[3.3]heptanecarbonyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)ethylpyridinyl)oxy)cyclohexanecarboxylic acid (210), (1S,3S)((6-(5-(((5-azaspiro[2.4]heptanecarbonyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)ethylpyridinyl)oxy)cyclohexanecarboxylic acid (211), (1S,3S)((5-(5-(((butyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)pyrazinyl)oxy)cyclohexanecarboxylic acid (212), (1S,3S)((5-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)pyrazinyl)oxy) cyclohexanecarboxylic acid (213), )((5-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)pyrazinyl)oxy) cyclohexanecarboxylic acid (214), (1S,3S)((5-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)pyrazinyl)oxy)cyclohexanecarboxylic acid (215), (1S,3S)((3-methyl(1-methyl(((methyl(propyl)carbamoyl)oxy)methyl)- ,3-triazolyl)pyrazinyl)oxy)cyclohexanecarboxylic acid (216), (1S,3S)((5-(5-(((butyl (methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazol yl)methylpyrazinyl)oxy) cyclohexanecarboxylic acid (219), (1S,3S)((5-(5-((((cyclopropyl-methyl)(methyl)carbamoyl) oxy)methyl) methyl-1H-1,2,3-triazolyl)methyl- pyrazinyl)oxy)cyclohexanecarboxylic acid (220), (1S,3S)((5-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylpyrazinyl)oxy)cyclohexanecarboxylic acid (221), (1S,3S)((5-(5-(((isopentyl (methyl)carbamoyl)oxy)methyl)methyl-1H- triazolyl)methylpyrazinyl)oxy) cyclohexanecarboxylic acid (222), (1S,3S)((3-methyl(1-methyl(((methyl(pentyl)carbamoyl) thyl)- 1H-1,2,3-triazolyl)pyrazinyl)oxy)cyclohexanecarboxylic acid (223), (1S,3S)((5-(5-(((isobutyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylpyrazinyl)oxy) cyclohexanecarboxylic acid (224), (1S,3S)((5-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyrazinyl) oxy)cyclohexanecarboxylic acid (225), (1S,3S)((5-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyrazinyl)oxy)cyclohexanecarboxylic acid (226), (1S,3S)((5-(5-((((cyclopentylmethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyrazinyl)oxy)cyclohexanecarboxylic acid (227), (1S,3S)((5-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylpyrazinyl)oxy) cyclohexanecarboxylic acid (228), (1S,3S)((5-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyrazinyl) oxy)cyclohexanecarboxylic acid (229), (1S,3S)((5-(5-((((3-fluoropropyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylpyrazinyl) oxy)cyclohexanecarboxylic acid (230), (1S,3S)((3-methyl(1-methyl(((methyl(neopentyl)carbamoyl) oxy)methyl)-1H-1,2,3-triazolyl)pyrazinyl)oxy)cyclohexanecarboxylic acid (231), (1S,3S)((5-(5-((((2-fluoromethylpropyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyrazinyl) oxy)cyclohexanecarboxylic acid (232), (1S,3S)((5-(5-(((((1-fluorocyclobutyl )methyl)(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3-triazolyl) pyrazinyl)oxy)cyclohexanecarboxylic acid (233), )((5-(5-(((((1- fluorocyclopentyl)methyl)(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3-triazol yl)methylpyrazinyl)oxy)cyclohexanecarboxylic acid (234), (1S,3S)((3-methyl(1-methyl(((methyl(((1R,2R) methylcyclopropyl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyrazin yl)oxy)cyclohexanecarboxylic acid (235), (1S,3S)((3-methyl(1-methyl(((methyl(((1S,2S)methyl cyclopropyl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyrazin yl)oxy)cyclohexanecarboxylic acid (236), )((5-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)(trifluoromethyl)pyridinyl)oxy)cyclohexane carboxylic acid (237), (1S,3S)((5-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)(trifluoromethyl)pyridinyl)oxy)cyclohexanecarboxylic acid (238), (1S,3S)((5-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)(trifluoromethyl)pyridinyl)oxy)cyclohexanecarboxylic acid (239), (1S,3S)((5-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)(trifluoromethyl)pyridinyl)oxy)cyclohexanecarboxylic acid (240), (1S,3S)((6-(5-(2-(((Cyclobutylmethyl)(methyl)carbamoyl)oxy)ethyl)methyl- 1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (241), (1S,3S)((2-Methyl(1-methyl(2-((methyl(propyl)carbamoyl)oxy)-ethyl)- 1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid, TFA salt (242), (1S,3S)((6-(5-(2-((Cyclopentyl-(methyl)carbamoyl)oxy)ethyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (243), (1S,3S)((6-(5-(2-((Benzyl(methyl)-carbamoyl)oxy)ethyl)methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (244), (1S,3S)((6-(5-(2-((Isobutyl-(methyl)carbamoyl)oxy)ethyl)methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (245), (1S,3S)((2-Methyl(1-methyl(2-((pyrrolidinecarbonyl)oxy)-ethyl)-1H- 1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid, TFA salt (246), (1S,3S)((6-(5-(2-((Cyclobutyl(methyl)carbamoyl)oxy)ethyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclo-hexanecarboxylic acid, TFA salt (247), )((6-(5-(2-(((Cyclobutyl-methyl)carbamoyl)oxy)ethyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid, TFA salt (248), (1S,3S)((6-(5-(3-((Benzyl(methyl)carbamoyl)oxy)propyl)methyl-1H-1,2,3- lyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (249), (1S,3S)((2-methyl(1-methyl(((methyl(2- propoxyethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridin yl)oxy)cyclohexanecarboxylic acid (250), (1S,3S)((6-(1-methyl(((methyl(((1R,2R) methylcyclopropyl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridin yl)oxy)cyclohexanecarboxylic acid (251), (1S,3S)((6-(1-methyl(((methyl(((1S,2S) methylcyclopropyl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridin yl)oxy)cyclohexanecarboxylic acid (252), (1S,3S)((6-(5-((((2-fluoromethylpropyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy) cyclohexanecarboxylic acid (253), )((5-(5-((((2-fluorobutyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyrazinyl)oxy)cyclohexanecarboxylic acid; mixture of diastereomers (254), (1S,3S)((6-(5-((((2-fluorobutyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid; mixture of diastereomers (255), (1S,3S)((6-(5-((((4-fluoropentyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (256), (1R,3S)((2-methyl(1-methyl(((methyl(((1R,2R) cyclopropyl)methyl) carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridin yl)oxy)cyclohexanecarboxylic acid (257), (1R,3S)((2-methyl(1-methyl(((methyl(((1S,2S) methylcyclopropyl)methyl) carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridin yl)oxy)cyclohexanecarboxylic acid (258), (1S,3S)((6-(5-((((2,2-difluoropropyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (259), (1S,3S)((6-(5-((((3-fluorobutyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (260), )((6-(5-((((2-fluoropropyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid (261), (1S,3S)((2-methyl(1-methyl(((methyl((2-methyl cyclopropyl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl) pyridin yl)oxy)cyclohexanecarboxylic acid; mixture of diastereomers (262), (1S,3S)((2-methyl(1-methyl (((methyl((1-methylcyclopropyl l)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl) pyridin )cyclohexanecarboxylic acid (263), (1S,3S)((2-methyl(1-methyl(((methyl(neopentyl) carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy) cyclohexane carboxylic acid (264), (1S,3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)(hydroxymethyl)pyridinyl)oxy)cyclohexanecarboxylic acid (265), (1S,3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)(fluoromethyl)pyridinyl)oxy)cyclohexanecarboxylic acid (266), (1S,3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)(difluoromethyl)pyridinyl)oxy)cyclohexanecarboxylic acid (267), (1S,3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)(methoxymethyl)pyridinyl)oxy)cyclohexanecarboxylic acid (268), (1S,3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)(trifluoromethyl)pyridinyl)oxy)cyclohexanecarboxylic acid (269), (1S,3S)((2-cyano(1-methyl(((methyl(propyl)carbamoyl)oxy)methyl)-1H- 1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (270), (1S,3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)(2-hydroxypropanyl)pyridinyl)oxy)cyclohexane carboxylic acid (271), (1S,3S)((2-Methoxy(1-methyl(((methyl(propyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (272), (1S,3S)((6-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)(trifluoromethyl)pyridinyl)oxy)cyclohexane carboxylic acid (273), (1S,3S)((6-(1-methyl(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3- triazolyl)(trifluoromethyl)pyridinyl) oxy)cyclohexanecarboxylic acid (274), (1S,3S)((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)(trifluoromethyl)pyridinyl)oxy)cyclohexanecarboxylic acid (275), (1S,3S)((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)(trifluoro methyl)pyridinyl)oxy) cyclohexanecarboxylic acid (276), )((2-(difluoromethyl)(1-methyl (((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridin )cyclohexanecarboxylic acid (277), (1S,3S)((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)(difluoromethyl)pyridinyl)oxy)cyclohexanecarboxylic acid (278), (1S,3S)((6-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)(difluoromethyl)pyridinyl)oxy) cyclohexane carboxylic acid (279), (1S,3S)((6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)(difluoromethyl) pyridinyl)oxy)cyclohexanecarboxylic acid (280), (1S,3S)((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)(difluoromethyl) pyridinyl)oxy)cyclohexanecarboxylic acid (281), (1S,3S)((6-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)(difluoromethyl)pyridinyl)oxy)cyclohexanecarboxylic acid (282), (1S,3S)((2-(methoxymethyl)(1-methyl(((methyl(propyl) carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (283), (1S,3S)((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)(methoxymethyl)pyridinyl)oxy)cyclohexane carboxylic acid (284), (1S,3S)((6-(5-((((cyclopropyl methyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)(methoxymethyl)pyridinyl)oxy)cyclohexane carboxylic acid (285), (1S,3S)((6-(5-(((cyclobutyl l)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)(methoxymethyl) pyridinyl) oxy)cyclohexanecarboxylic acid (286), (1S,3S)((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)(methoxymethyl) pyridinyl)oxy)cyclohexanecarboxylic acid (287), (1S,3S)((2-methyl(1-methyl((((methyl-d3)(propyl) carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy) cyclohexane carboxylic acid (288), (1S,3S)((2-cyano(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)- yl-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (289), (1S,3S)((6-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)cyanopyridinyl)oxy)cyclohexanecarboxylic acid (290), (1S,3S)((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)cyanopyridinyl)oxy)cyclohexanecarboxylic acid (291), (1S,3S)((2-cyano(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)- 1-methyl-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (292), (1S,3S)((2-cyano(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)methyl- ,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid (293), (1S,3S)((2-cyano(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)pyridinyl)oxy) cyclohexanecarboxylic acid (294).
In another embodiment, the compounds of the present invention have LPA1 IC50 values  10 µM.
In another embodiment, the compounds of the present invention have LPA1 IC50 values  1 µM.
In another embodiment, the compounds of the present invention have LPA1 IC50 values  0.1 µM.
In another embodiment, the compounds of the t invention have LPA1 IC50 values  0.05 µM.
In another embodiment, the compounds of the t invention have LPA1 IC50 values  0.01 µM.
II. OTHER MENTS OF THE INVENTION In some embodiments, the compound of Formulas (I) – (IX), or a pharmaceutically able salt thereof, is an antagonist of at least one LPA receptor. In some embodiments, the compound of Formulas (I)- (IX), or a pharmaceutically acceptable salt thereof, is an antagonist of LPA1. In some embodiments, the compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, is an antagonist of LPA2. In some embodiments, the compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt f, is an antagonist of LPA3.
In some embodiments, presented herein are compounds ed from active metabolites, tautomers, ceutically acceptable salts, es or prodrugs of a compound of Formulas (I) - (IX).
In another ment, the present disclosure provides a composition comprising at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a e thereof.
In another embodiment, the present ion provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
In r embodiment, the present disclosure provides a process for making a compound of the present invention.
In another embodiment, the present disclosure provides an intermediate for making a compound of the present invention.
In another embodiment, the present invention provides a pharmaceutical composition further comprising additional therapeutic agent(s).
In another embodiment, the present disclosure provides a method for the ent and/or prophylaxis of a condition ated with LPA receptor mediated fibrosis, sing administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof. As used herein, the term "patient" encompasses all mammalian species.
As used , "treating" or ment" cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting the disease-state, i.e., arresting it development; and/or (b) relieving the disease-state, i.e., causing regression of the disease state.
As used herein, "prophylaxis" is the protective treatment of a disease state to reduce and/or minimize the risk and/or reduction in the risk of ence of a disease state by administering to a patient a eutically effective amount of at least one of the compounds of the present invention or a or a isomer, a tautomer, a ceutically acceptable salt, or a solvate thereof. Patients may be selected for prophylaxis therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. For prophylaxis treatment, ions of the al disease state may or may not be presented yet. "Prophylaxis" treatment can be d into (a) primary prophylaxis and (b) secondary prophylaxis. Primary prophylaxis is defined as treatment to reduce or minimize the risk of a disease state in a patient that has not yet presented with a clinical disease state, whereas secondary prophylaxis is defined as minimizing or reducing the risk of a recurrence or second occurrence of the same or similar clinical disease state.
The present ion may be embodied in other specific forms t departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted . It is understood that any and all embodiments of the present invention may be taken in ction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is its own independent embodiment. Furthermore, any t of an ment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.
III. CHEMISTRY hout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof where such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cisand trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
The present compounds can be ed in optically active or racemic forms. Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present sure. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by tography or fractional crystallization. ing on the process conditions the end products of the present invention are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may be converted into another form. A free base or acid may be converted into a salt; a salt may be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers. Compounds of the t invention, free form and salts f, may exist in multiple eric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the ion.
The term "stereoisomer" refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable. The term "diastereomer" refers to stereoisomers that are not mirror images. The term "racemate" or "racemic mixture" refers to a ition composed of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity.
The symbols "R" and "S" ent the configuration of substituents around a chiral carbon atom(s). The isomeric descriptors "R" and "S" are used as described herein for indicating atom configuration(s) relative to a core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and d Chemistry, 68:2193-2222 (1996)).
The term "chiral" refers to the structural characteristic of a molecule that makes it impossible to superimpose it on its mirror image. The term "homochiral" refers to a state of enantiomeric purity. The term al activity" refers to the degree to which a homochiral molecule or nonracemic e of chiral molecules rotates a plane of polarized light.
As used herein, the term "alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1 to C10 alkyl" or "C1˗10 alkyl" (or alkylene), is intended to e C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl . Additionally, for example, "C1 to C6 alkyl" or "C1-C6 alkyl" denotes alkyl having 1 to 6 carbon atoms.
Alkyl group can be unsubstituted or substituted with at least one hydrogen being replaced by another chemical group. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tbutyl ), and pentyl (e.g., yl, isopentyl, neopentyl).
"Alkenyl" or "alkenylene" is intended to include hydrocarbon chains of either straight or branched configuration having the specified number of carbon atoms and one or more, preferably one to two, carbon-carbon double bonds that may occur in any stable point along the chain. For example, "C2 to C6 alkenyl" or "C2˗6 alkenyl" (or alkenylene), is intended to include C2, C3, C4, C5, and C6 alkenyl . Examples of alkenyl include, but are not limited to, ethenyl, enyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl propenyl, and 4-methylpentenyl.
"Alkynyl" or "alkynylene" is intended to e hydrocarbon chains of either straight or branched configuration having one or more, preferably one to three, carboncarbon triple bonds that may occur in any stable point along the chain. For example, "C2 to C6 alkynyl" or "C2˗6 alkynyl" (or alkynylene), is intended to include C2, C3, C4, C5, and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. "C1 to C6 alkoxy" or "C1˗6 alkoxy" (or alkyloxy), is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Example alkoxy groups e, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio" or lkoxy" ents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example, methyl-S- and ethyl-S-.
"Halo" or "halogen" includes fluoro (F), chloro (Cl), bromo (Br), and iodo (I).
"Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" that is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more fluorine atoms.
"Haloalkoxy" or "haloalkyloxy" ents a kyl group as defined above with the indicated number of carbon atoms ed through an oxygen bridge. For example, "C1 to C6 haloalkoxy" or "C1˗6 haloalkoxy", is intended to e C1, C2, C3, C4, C5, and C6 haloalkoxy . Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a kyl group as d above with the indicated number of carbon atoms attached through a sulphur bridge; for example, trifluoromethyl- S-, and pentafluoroethyl-S-.
The term "cycloalkyl" refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems. "C3 to C8 cycloalkyl" or "C3˗8 cycloalkyl" is intended to include C3, C4, C5, C6, C7, and C8 cycloalkyl groups, including monocyclic, bicyclic, and polycyclic rings. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched lkyl groups such as ylcyclopropyl and 2-methylcyclopropyl and spiro and bridged cycloalkyl groups are included in the definition of "cycloalkyl".
As used , "carbocycle", "carbocyclyl" or "carbocyclic residue" is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaturated or ic. Examples of such carbocycles include, but are not limited to, cyclopropyl, utyl, cyclobutenyl, cyclopentyl, cyclopentenyl, exyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, ctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, , naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, d rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). red carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, entyl, cyclohexyl, , and indanyl. When the term "carbocyclyl" is used, it is intended to include "aryl". A bridged ring occurs when one or more carbon atoms link two nonadjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
As used herein, the term lic carbocyclyl" or "bicyclic carbocyclic group" is ed to mean a stable 9- or 10-membered carbocyclic ring system that contains two fused rings and consists of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to a second ring; and the second ring is a 5- or 6-membered carbon ring which is saturated, partially unsaturated, or unsaturated. The bicyclic carbocyclic group may be attached to its pendant group at any carbon atom which results in a stable structure. The bicyclic carbocyclic group described herein may be substituted on any carbon if the resulting compound is . Examples of a bicyclic carbocyclic group are, but not d to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.
"Aryl" groups refer to monocyclic or polycyclic ic hydrocarbons, including, for example, phenyl, naphthyl, and phenanthranyl. Aryl moieties are well known and described, for example, in Lewis, R.J., ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York (1997). "C6 or C10 aryl" or "C6˗10 aryl" refers to phenyl and naphthyl. Unless ise specified, "aryl", "C6 or C10 aryl" or "C6˗10 aryl" or "aromatic residue" may be unsubstituted or substituted with 1 to 5 groups, preferably 1 to 3 groups, OH, OCH3, Cl, F, Br, I, CN, NO2, NH2, N(CH3)H, N(CH3)2, CF3, OCF3, C(=O)CH3, SCH3, S(=O)CH3, S(=O)2CH3, CH3, CH2CH3, CO2H, and CO2CH3.
The term "benzyl", as used herein, refers to a methyl group on which one of the hydrogen atoms is replaced by a phenyl group, wherein said phenyl group may optionally be substituted with 1 to 5 , preferably 1 to 3 groups, OH, OCH3, Cl, F, Br, I, CN, NO2, NH2, N(CH3)H, N(CH3)2, CF3, OCF3, C(=O)CH3, SCH3, S(=O)CH3, S(=O)2CH3, CH3, CH2CH3, CO2H, and CO2CH3.
As used herein, the term "heterocycle", "heterocyclyl", or "heterocyclic ring" is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic heterocyclic ring that is saturated, partially unsaturated, or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S; and including any clic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be ed (i.e., N→O and S(O)p, wherein p is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR n R is H or another tuent within the definition of the substitution of the heterocyclic ring). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a en atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be nized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
When the term "heterocyclyl" is used, it is intended to include heteroaryl.
Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always ts a monocyclic ring into a tricyclic ring.
When a ring is d, the substituents recited for the ring may also be present on the bridge.
Examples of heterocycles include, but are not limited to, acridinyl, azetidinyl, azocinyl, idazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, trazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2- dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, olidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, nyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, olyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, idinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, lyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, inyl, phenothiazinyl, athiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, linyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2- pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, thiadiazolyl, 1,2,5- azolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, nyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
Examples of 5- to 10-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl, olinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.
Examples of 5- to ered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, yl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. Also ed are fused ring and spiro compounds ning, for e, the above heterocycles.
As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclic group" is intended to mean a stable 9- or 10-membered heterocyclic ring system which contains two fused rings and consists of carbon atoms and 1, 2, 3, or 4 heteroatoms ndently selected from the group consisting of N, O and S. Of the two fused rings, one ring is a 5- or 6-membered clic aromatic ring comprising a 5-membered heteroaryl ring, a 6- membered aryl ring or a benzo ring, each fused to a second ring. The second ring is a 5- or ered monocyclic ring which is saturated, partially unsaturated, or unsaturated, and comprises a 5-membered heterocycle, a 6-membered heterocycle or a carbocycle (provided the first ring is not benzo when the second ring is a carbocycle).
The bicyclic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The bicyclic heterocyclic group described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
Examples of a bicyclic heterocyclic group are, but not d to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8- tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 4-tetrahydro- quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.
As used herein, the term tic heterocyclic group," "heteroaryl," or “heteroaryl ring” refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or bered bicyclic groups, and 11- to 14-membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings, said heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. Heteroaryl groups can be substituted or tituted. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another tuent within the definition of the substitution of the cyclic ring). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)p) and the nitrogen atoms may optionally be quaternized.
Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring.
The aryl ring system may contain zero, one, two or three tuents. Heteroaryl groups e, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, iazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane.
The term "counterion" is used to represent a negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
When a dotted ring is used within a ring structure, this indicates that the ring structure may be saturated, partially saturated or unsaturated.
As referred to herein, the term "substituted" means that at least one hydrogen atom is replaced with a non-hydrogen group, ed that normal valencies are maintained and that the substitution results in a stable compound. When a tuent is keto (i.e., =O), then 2 hydrogens on the atom are replaced. Keto substituents are not t on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a yl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).
In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present ion, these may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) to afford other compounds of this ion. Thus, shown and claimed nitrogen atoms are ered to cover both the shown nitrogen and its N-oxide (N→O) derivative.
When any variable occurs more than one time in any constituent or formula for a nd, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be tuted with 0-3 R groups, then said group may optionally be tuted with up to three R groups, and at each occurrence R is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a tuent is shown to cross a bond connecting two atoms in a ring, then such tuent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom in which such tuent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. ations of substituents and/or variables are sible only if such combinations result in stable compounds.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals t excessive toxicity, irritation, allergic response, and/or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of ceutically acceptable salts e, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or c acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
The ceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional al 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 e of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or itrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th n, Mack Publishing Company, Easton, PA (1990), the disclosure of which is hereby incorporated by reference.
In addition, nds of as (I)- (IX) may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., a compound of formula I) is a prodrug within the scope and spirit of the present disclosure. Various forms of prodrugs are well known in the art. For es of such prodrug derivatives, see: a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder, K. et al., eds., Methods in logy, 112:309-396, Academic Press (1985); b) Bundgaard, H., Chapter 5, "Design and Application of Prodrugs", A Textbook of Drug Design and Development, pp. 113-191, Krosgaard-Larsen, P. et al., eds., Harwood Academic Publishers (1991); c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992); d) ard, H. et al., J. Pharm. Sci., 77:285 (1988); and e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).
Compounds containing a carboxy group can form physiologically hydrolyzable esters that serve as prodrugs by being hydrolyzed in the body to yield formulas (I)- (IX) compounds per se. Such prodrugs are preferably administered orally since ysis in many instances occurs principally under the influence of the digestive enzymes.
Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of nds of formulas (I)- (IX)include C1˗6alkyl, C1˗6alkylbenzyl, 4- methoxybenzyl, indanyl, phthalyl, methoxymethyl, C1˗6 alkanoyloxy-C1˗6alkyl (e.g., acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), C1˗6alkoxycarbonyloxy- C1˗6alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, oxymethyl, phenylglycyloxymethyl, (5-methyloxo-1,3-dioxolenyl)-methyl), and other well-known physiologically hydrolyzable esters used, for example, in the penicillin and osporin arts. Such esters may be prepared by tional techniques known in the art.
Preparation of prodrugs is well known in the art and described in, for example, King, F.D., ed., Medicinal Chemistry: Principles and Practice, The Royal y of Chemistry, Cambridge, UK (1994); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal try, Academic Press, San Diego, CA (1999).
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. ium has one proton and one neutron in its nucleus and that has twice the mass of ordinary hydrogen. Deuterium can be represented by symbols such as "2H" or "D". The term "deuterated" herein, by itself or used to modify a compound or group, refers to replacement of one or more hydrogen atom(s), which is attached to carbon(s), with a deuterium atom. Isotopes of carbon include 13C and 14C. ically-labeled compounds of the invention can generally be prepared by conventional ques known to those skilled in the art or by processes analogous to those described , using an appropriate isotopically-labeled reagent in place of the non-labeled t otherwise employed. Such compounds have a y of potential uses, e.g., as standards and reagents in determining the ability of a potential pharmaceutical compound to bind to target proteins or receptors, or for imaging compounds of this invention bound to biological receptors in vivo or in vitro.
"Stable compound" and "stable ure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. It is red that compounds of the present ion do not contain a N-halo, S(O)2H, or S(O)H group.
The term "solvate" means a physical association of a compound of this disclosure with one or more solvent molecules, whether c or inorganic. This physical association es hydrogen bonding. In certain ces the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered ement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. "Solvate" encompasses both on-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.
The term “comprising” as used in this specification and claims means “consisting at least in part of”. When interpreting statements in this ication, and claims which include the term “comprising”, it is to be understood that other features that are additional to the es prefaced by this term in each statement or claim may also be present.
Related terms such as “comprise” and ised” are to be reted in similar manner.
IV. BIOLOGY Lysophospholipids are membrane-derived bioactive lipid mediators.
Lysophospholipids e, but are not limited to, lysophosphatidic acid l hydroxy-sn-glycerophosphate; LPA), sphingosine phate (S1P), lysophosphatidylcholine (LPC), and sphingosylphosphorylcholine (SPC).
Lysophospholipids affect fundamental ar functions that include cellular proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis.
These functions influence many ical processes that include neurogenesis, angiogenesis, wound healing, immunity, and carcinogenesis.
LPA acts through sets of ic G protein-coupled receptors (GPCRs) in an autocrine and paracrine fashion. LPA binding to its cognate GPCRs (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) activates intracellular signaling pathways to produce a variety of biological responses.
Lysophospholipids, such as LPA, are quantitatively minor lipid species ed to their major phospholipid counterparts (e.g., phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin). LPA has a role as a biological effector molecule, and has a diverse range of physiological actions such as, but not limited to, effects on blood pressure, platelet activation, and smooth muscle contraction, and a variety of cellular effects, which include cell growth, cell rounding, neurite retraction, and actin stress fiber formation and cell migration. The effects of LPA are predominantly or mediated.
Activation of the LPA receptors (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) with LPA mediates a range of downstream ing es. These include, but are not limited to, mitogen-activated protein kinase (MAPK) activation, adenylyl cyclase (AC) inhibition/activation, phospholipase C (PLC) activation/Ca2+ mobilization, arachidonic acid release, Akt/PKB activation, and the activation of small GTPases, Rho, ROCK, Rac, and Ras. Other pathways that are affected by LPA receptor activation include, but are not limited to, cyclic adenosine monophosphate (cAMP), cell division cycle 42/GTP-binding protein (Cdc42) , proto-oncogene serine/threonine-protein kinase Raf (c-RAF), protooncogene tyrosine-protein kinase Src (c-src), extracellular -regulated kinase (ERK), focal adhesion kinase (FAK), guanine nucleotide exchange factor (GEF), glycogen synthase kinase 3b (GSK3b), c-jun amino-terminal kinase (JNK), MEK, myosin light chain II (MLC II), nuclear factor kB (NF-kB), N-methyl-D-aspartate (NMDA) receptor activation, phosphatidylinositol 3-kinase (PI3K), protein kinase A (PKA), protein kinase C (PKC), ras-related C3 botulinum toxin ate 1 (RAC1). The actual pathway and realized end point are dependent on a range of variables that include receptor usage, cell type, expression level of a receptor or signaling protein, and LPA concentration. Nearly all mammalian cells, s and organs co-express several LPA-receptor subtypes, which indicates that LPA receptors signal in a cooperative manner. LPA1, LPA2, and LPA3 share high amino acid sequence similarity.
LPA is produced from activated platelets, ted adipocytes, neuronal cells, and other cell types. Serum LPA is produced by multiple enzymatic pathways that involve ylglycerol kinase, phospholipase A1, secretory phospholipase A2, and lysophospholipase D (lysoPLD), including autotaxin. Several enzymes are involved in LPA degradation: lysophospholipase, lipid phosphate phosphatase, and LPA acyl transferase such as endophilin. LPA concentrations in human serum are estimated to be 1–5 μM. Serum LPA is bound to n, low-density lipoproteins, or other proteins, which possibly protect LPA from rapid degradation. LPA molecular species with different acyl chain lengths and saturation are naturally occurring, ing itoyl (16:0), 1-palmitoleoyl (16:1), 1-stearoyl , 1-oleoyl (18:1), 1-linoleoyl (18:2), and 1- donyl (20:4) LPA. Quantitatively minor alkyl LPA has biological ties similar to acyl LPA, and different LPA species activate LPA receptor subtypes with varied cies.
LPA RECEPTORS LPA1 (previously called VZG-1/EDG-2/mrec1.3) couples with three types of G ns, Gi/o, Gq, and G12/13. Through activation of these G proteins, LPA induces a range of cellular responses through LPA1 including but not limited to: cell proliferation, serumresponse element (SRE) activation, mitogen-activated n kinase (MAPK) activation, adenylyl cyclase (AC) inhibition, phospholipase C (PLC) activation, Ca2+ mobilization, Akt activation, and Rho activation.
Wide expression of LPA1 is observed in adult mice, with clear presence in testis, brain, heart, lung, small intestine, stomach, spleen, thymus, and skeletal muscle.
Similarly, human tissues also express LPA1; it is present in brain, heart, lung, placenta, colon, small ine, prostate, testis, ovary, as, spleen, kidney, al muscle, and thymus.
LPA2 ) also couples with three types of G proteins, Gi/o, Gq, and G12/13, to mediate LPA-induced cellular ing. Expression of LPA2 is observed in the testis, kidney, lung, thymus, spleen, and stomach of adult mice and in the human testis, pancreas, prostate, thymus, spleen, and peripheral blood leukocytes. Expression of LPA2 is upregulated in various cancer cell lines, and several human LPA2 transcriptional variants with mutations in the 3'-untranslated region have been observed. ed deletion of LPA2 in mice has not shown any obvious phenotypic abnormalities, but has demonstrated a significant loss of normal LPA signaling (e.g., PLC activation, Ca2+ mobilization, and stress fiber formation) in primary cultures of mouse embryonic fibroblasts (MEFs). Creation of lpa1(-/-) lpa2 (-/-) double-null mice has ed that many LPA-induced responses, which include cell proliferation, AC tion, PLC tion, Ca2+ mobilization, JNK and Akt activation, and stress fiber formation, are absent or severely reduced in double-null MEFs. All these responses, except for AC inhibition (AC inhibition is nearly hed in LPA1 (-/-) MEFs), are only partially affected in either LPA1 (-/-) or LPA2 (-/-) MEFs. LPA2 contributes to normal LPA- mediated signaling responses in at least some cell types (Choi et al, Biochemica et Biophysica Acta 2008, 1781, p531-539).
LPA3 (EDG-7) is distinct from LPA1 and LPA2 in its ability to couple with Gi/o and Gq but not G12/13 and is much less responsive to LPA species with saturated acyl chains. LPA3 can mediate pleiotropic LPA-induced signaling that includes PLC tion, Ca2+ mobilization, AC inhibition/activation, and MAPK activation.
Overexpression of LPA3 in lastoma cells leads to neurite elongation, whereas that of LPA1 or LPA2 results in neurite retraction and cell rounding when ated with LPA. Expression of LPA3 is observed in adult mouse testis, kidney, lung, small ine, heart, thymus, and brain. In humans, it is found in the heart, pancreas, prostate, testis, lung, ovary, and brain (frontal cortex, hippocampus, and amygdala).
LPA4 (p2y9/GPR23) is of divergent sequence compared to LPA1, LPA2, and LPA3 with closer similarity to the platelet-activating factor (PAF) receptor. LPA4 mediates LPA induced Ca2+ mobilization and cAMP accumulation, and functional coupling to the G protein Gs for AC activation, as well as coupling to other G proteins. The LPA4 gene is expressed in the ovary, pancreas, thymus, kidney and skeletal muscle.
LPA5 (GPR92) is a member of the purinocluster of GPCRs and is urally most closely d to LPA4. LPA5 is expressed in human heart, placenta, , brain, lung and gut. LPA5 also shows very high expression in the CD8+ lymphocyte tment of the gastrointestinal tract.
LPA6 (p2y5) is a member of the purinocluster of GPCRs and is structurally most closely related to LPA4. LPA6 is an LPA receptor d to the G12/13-Rho signaling pathways and is expressed in the inner root sheaths of human hair les.
Illustrative Biological Activity Wound Healing Normal wound healing occurs by a highly coordinated sequence of events in which cellular, e factors and matrix components act in concert to repair the injury.
The healing response can be described as taking place in four broad, overlapping phases—hemostasis, inflammation, proliferation, and remodeling. Many growth factors and cytokines are released into a wound site to initiate and perpetuate wound g processes.
When wounded, damaged blood vessels te platelets. The activated platelets play pivotal roles in subsequent repair processes by releasing bioactive mediators to induce cell proliferation, cell migration, blood coagulation, and angiogenesis. LPA is one such mediator that is released from activated platelets; this s platelet aggregation along with mitogenic/migration effects on the surrounding cells, such as endothelial cells, smooth muscle cells, fibroblasts, and keratinocytes.
Topical application of LPA to cutaneous wounds in mice promotes repair processes (wound closure and increased neoepithelial thickness) by increasing cell proliferation/ migration without affecting secondary inflammation.
Activation of dermal fibroblasts by growth factors and cytokines leads to their subsequent ion from the edges of the wound into the provisional matrix formed by the fibrin clot whereupon the fibroblasts proliferate and start to restore the dermis by ing and organizing the characteristic dermal ellular matrix (ECM). The sing number of fibroblasts within the wound and continuous precipitation of ECM enhances matrix rigidity by ng small tractional forces to the newly formed granulation tissue. The increase in mechanical stress, in conjunction with transforming growth factor β (TGFβ), induces α-smooth muscle actin (α-SMA) expression and the uent transformation of lasts into myofibroblasts. Myofibroblasts facilitate granulation tissue remodeling via myofibroblast contraction and through the production of ECM components.
LPA regulates many important functions of fibroblasts in wound healing, including proliferation, migration, differentiation and contraction. Fibroblast proliferation is required in wound healing in order to fill an open wound. In st, fibrosis is characterized by intense proliferation and accumulation of myofibroblasts that actively synthesize ECM and proinflammatory cytokines. LPA can either increase or suppress the eration of cell types important in wound healing, such as epithelial and endothelial cells (EC),macrophages, keratinocytes, and fibroblasts. A role for LPA1 in LPA-induced proliferation was provided by the observation that LPA-stimulated eration of fibroblasts isolated from LPA1 receptor null mice was attenuated (Mills et al, Nat Rev.
Cancer 2003; 3: 582-591). LPA induces cytoskeletal changes that are integral to fibroblast adhesion, ion, differentiation and contraction.
Fibrosis Tissue injury initiates a complex series of host wound-healing responses; if successful, these responses e normal tissue structure and function. If not, these responses can lead to tissue fibrosis and loss of function.
For the majority of organs and tissues the development of fibrosis involves a multitude of events and factors. les involved in the development of is include proteins or peptides (profibrotic cytokines, chemokines, metalloproteinases etc.) and phospholipids. Phospholipids ed in the development of fibrosis include platelet activating factor (PAF), phosphatidyl choline, sphingosine-1 phosphate (S1P) and lysophosphatidic acid (LPA).
A number of muscular dystrophies are characterized by a progressive weakness and wasting of musculature, and by extensive fibrosis. It has been shown that LPA treatment of cultured myoblasts induced significant sion of connective tissue growth factor (CTGF). CTGF subsequently induces collagen, fibronectin and integrin sion and induces dedifferentiation of these myoblasts. Treatment of a variety of cell types with LPA induces reproducible and high level induction of CTGF (J.P. Pradere, et al., LPA1 receptor activation promotes renal interstitial fibrosis, J. Am. Soc. Nephrol. 18 (2007) 118; N. Wiedmaier, et al., Int J Med Microbiol; 298(3-4):231-43, 2008).
CTGF is a profibrotic cytokine, signaling down-stream and in parallel with TGFβ.
CTGF expression by gingival epithelial cells, which are involved in the development of gingival fibromatosis, was found to be bated by LPA treatment (A.
Kantarci, et al., J. Pathol. 210 (2006) .
LPA is associated with the progression of liver fibrosis. In vitro, LPA induces stellate cell and hepatocyte proliferation. These ted cells are the main cell type responsible for the accumulation of ECM in the liver. Furthermore, LPA plasma levels rise during CCl4-induced liver fibrosis in rodents, or in hepatitis C virus-induced liver fibrosis in humans (N. be, et al., Plasma lysophosphatidic acid level and serum autotaxin activity are increased in liver injury in rats in relation to its severity, Life Sci. 81 (2007) 1009–1015; N.Watanabe, et al., J. Clin. Gastroenterol. 41 (2007) 3).
An se of phospholipid concentrations in the bronchoalveolar lavage fluid in rabbits and rodents ed with bleomycin has been reported (K. Kuroda, et al., Phospholipid concentration in lung lavage fluid as biomarker for pulmonary fibrosis, Inhal. Toxicol. 18 (2006) 389–393; K. Yasuda, et al., Lung 172 (1994) ).
LPA is associated with heart disease and mycocardial remodeling. Serum LPA levels are increased after myocardial infarction in patients and LPA stimulates rat cardiac fibroblast proliferation and collagen production (Chen et al. FEBS Lett. 2006 Aug 21;580(19):4737-45).
Pulmonary Fibrosis In the lung, aberrant wound healing responses to injury contribute to the pathogenesis of fibrotic lung diseases. Fibrotic lung diseases, such as idiopathic pulmonary fibrosis (IPF), are associated with high morbidity and mortality.
LPA is an important mediator of fibroblast recruitment in pulmonary fibrosis.
LPA and LPA1 play key enic roles in pulmonary fibrosis. Fibroblast chemoattractant activity plays an important role in the lungs in patients with pulmonary fibrosis. Profibrotic effects of LPA1-receptor stimulation is explained by LPA1-receptormediated vascular leakage and increased fibroblast tment, both profibrotic .
The LPA-LPA1 pathway has a role in mediating last ion and vascular e in IPF. The end result is the nt healing process that characterizes this fibrotic condition.
The LPA1 receptor is the LPA or most highly expressed on fibroblasts obtained from patients with IPF. Furthermore, BAL obtained from IPF patients induced chemotaxis of human foetal lung lasts that was blocked by the dual LPA1- LPA3 receptor antagonist Ki16425. In an experimental bleomycin-induced lung injury mouse model, it was shown that LPA levels were high in bronchoalveolar lavage samples compared with unexposed controls. LPA1 knockout mice are protected from fibrosis after bleomycin challenge with reduced fibroblast accumulation and vascular leakage. In human subjects with IPF, high LPA levels were observed in bronchoalveolar lavage samples compared with healthy controls. Increased fibroblast chemotactic activity in these samples was ted by the Ki16425 indicating that fibroblast migration is mediated by the A receptor(s) y (Tager et al. Nature Medicine, 2008, 14, 45-54).
The LPA-LPA1 y is crucial in last recruitment and vascular leakage in pulmonary fibrosis.
Activation of latent TGF- by the v6 integrin plays a critical role in the development of lung injury and fibrosis (Munger et al. Cell, vol. 96, 319-328, 1999). LPA induces v6-mediated TGF- activation on human lung epithelial cells (Xu et al. Am. J.
Pathology, 2009, 174, 1264-1279). The LPA-induced v6-mediated TGF- activation is mediated by the LPA2 receptor. Expression of the LPA2 receptor is increased in epithelial cells and mesenchymal cells in areas of lung fibrosis from IPF patients compared to normal human lung tissue. The LPA-LPA2 pathway contributes to the activation of the TGF- y in pulmonary fibrosis. In some embodiments, compounds that inhibit LPA2 show efficacy in the treatment of lung fibrosis. In some embodiments, compounds that inhibit both LPA1 and LPA2 show improved efficacy in the treatment of lung fibrosis compared to compounds which inhibit only LPA1 or LPA2.
Renal is LPA and LPA1 are involved in the etiology of kidney fibrosis. LPA has effects on both proliferation and contraction of glomerular ial cells and thus has been implicated in proliferative glomerulonephritis (C.N. Inoue, et al., Clin. Sci. (Colch.) 1999, 96, 6). In an animal model of renal fibrosis [unilateral ureteral obstruction (UUO)], it was found that renal LPA receptors are expressed under basal conditions with an expression order of LPA2>LPA3=LPA1>>LPA4. This model mimics in an accelerated manner the development of renal is including renal inflammation, last tion and lation of extracellular matrix in the tubulointerstitium. UUO significantly induced LPA1-receptor expression. This was paralleled by renal LPA production (3.3 fold increase) in conditioned media from kidney explants. Contra-lateral kidneys exhibited no significant changes in LPA release and LPA-receptors expression.
This shows that a prerequisite for an action of LPA in fibrosis is met: production of a ligand (LPA) and induction of one of its receptors (the LPA1 receptor) (J.P. Pradere et al., Biochimica et sica Acta, 2008, 1781, 582-587).
In mice where the LPA1 receptor was knocked out (LPA1 (−/−), the development of renal fibrosis was significantly attenuated. UUO mice treated with the LPA or antagonist Ki16425 closely resembled the profile of LPA1 (−/−) mice.
LPA can ipate in intraperitonial accumulation of monocyte/macrophages and LPA can induce expression of the profibrotic cytokine CTGF in primary cultures of human fibroblasts (J.S. Koh,et al., J. Clin. Invest., 1998, 102, 716–727).
LPA treatment of a mouse epithelial renal cell line, MCT, induced a rapid increase in the expression of the profibrotic cytokine CTGF. CTGF plays a crucial role in UUO- induced tubulointerstitial fibrosis (TIF), and is involved in the profibrotic activity of TGFβ. This induction was almost completely suppressed by co-treatment with the LPA- receptor antagonist Ki16425. In one aspect, the profibrotic activity of LPA in kidney results from a direct action of LPA on kidney cells involving induction of CTGF.
Hepatic fibrosis LPA is implicated in liver disease and fibrosis. Plasma LPA levels and serum autotaxin (enzyme responsible for LPA production) are ed in hepatitis patients and animal models of liver injury in correlation with increased is. LPA also regulates liver cell function. LPA1 and LPA2 receptors are expressed by mouse hepatic stellate cells and LPA ates migration of hepatic myofibroblasts.
Ocular Fibrosis LPA is in involved in wound healing in the eye. LPA1 and LPA3 receptors are detectable in the normal rabbit corneal epithelial cells, keratocytes and endothelial cells and LPA1 and LPA3 expression are increased in corneal epithelial cells following injury.
LPA and its homologues are present in the aqueous humor and the lacrimal gland fluid of the rabbit eye and these levels are increased in a rabbit corneal injury model.
LPA induces actin stress fiber ion in rabbit corneal endothelial and lial cells and promotes contraction corneal fibroblasts. LPA also stimulates proliferation of human retinal pigmented epithelial cells Cardiac fibrosis LPA is implicated in myocardial tion and cardiac is. Serum LPA levels are increased in patients ing mycocardial infarction (MI) and LPA ates proliferation and collagen tion (fibrosis) by rat cardiac fibroblasts. Both LPA1 and LPA3 receptors are highly expressed in human heart tissue.
Treatment of Fibrosis In one , a nd of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, is used to treat or prevent fibrosis in a mammal. In one aspect, a compound of Formulas (I- (IX)), or a pharmaceutically acceptable salt thereof, is used to treat fibrosis of an organ or tissue in a mammal. In one aspect is a method for preventing a fibrosis condition in a mammal, the method comprising administering to the mammal at risk of developing one or more fibrosis conditions a eutically effective amount of a compound of Formulas (I- (IX)), or a pharmaceutically acceptable salt thereof. In one aspect, the mammal has been exposed to one or more nmental conditions that are known to increase the risk of fibrosis of an organ or tissue. In one , the mammal has been exposed to one or more environmental conditions that are known to increase the risk of lung, liver or kidney fibrosis. In one aspect, the mammal has a genetic predisposition of developing fibrosis of an organ or tissue. In one aspect, a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, is administered to a mammal to t or minimize scarring following injury. In one aspect, injury es surgery.
The terms “fibrosis” or “fibrosing disorder,” as used herein, refers to ions that are associated with the abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast tment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, , lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.
Exemplary diseases, disorders, or conditions that involve fibrosis include, but are not limited to: Lung diseases associated with fibrosis, e.g., idiopathic pulmonary fibrosis, pulmonary fibrosis secondary to systemic inflammatory disease such as toid arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis, radiation induced fibrosis, chronic obstructive pulmonary e , scleroderma, c asthma, silicosis, asbestos induced pulmonary or pleural fibrosis, acute lung injury and acute respiratory ss (including bacterial pneumonia induced, trauma induced, viral pneumonia induced, ventilator induced, non-pulmonary sepsis induced, and aspiration induced); Chronic pathies associated with injury/fibrosis (kidney fibrosis), e.g., glomerulonephritis secondary to systemic inflammatory diseases such as lupus and scleroderma, diabetes, ular nephritis, focal segmental ular sclerosis, IgA nephropathy, hypertension, allograft and Alport; Gut fibrosis, e.g., scleroderma, and radiation induced gut fibrosis; Liver fibrosis, e.g., cirrhosis, alcohol induced liver fibrosis, oholic hepatitis (NASH), biliary duct injury, primary biliary cirrhosis, infection or viral induced liver fibrosis (e.g., chronic HCV infection), and autoimmune hepatitis; Head and neck is, e.g., radiation induced; Corneal scarring, e.g., LASIK (laser-assisted in situ keratomileusis), corneal transplant, and trabeculectomy; Hypertrophic scarring and keloids, e.g., burn induced or al; and other fibrotic diseases, e.g., sarcoidosis, scleroderma, spinal cord injury/fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease, and Peyronie's disease.
In one aspect, a mammal suffering from one of the following non-limiting exemplary diseases, disorders, or conditions will benefit from therapy with a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof: atherosclerosis, thrombosis, heart e, itis, formation of scar tissue, restenosis, phlebitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, pulmonary inflammation, bowel adhesions, bladder is and cystitis, fibrosis of the nasal passages, tis, inflammation mediated by neutrophils, and fibrosis ed by fibroblasts.
In one aspect, a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, is administered to a mammal with fibrosis of an organ or tissue or with a predisposition of developing fibrosis of an organ or tissue with one or more other agents that are used to treat fibrosis. In one aspect, the one or more agents include corticosteroids. In one aspect, the one or more agents include suppressants. In one aspect, the one or more agents include B-cell antagonists. In one aspect, the one or more agents include uteroglobin.
In one aspect, a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, is used to treat a dermatological ers in a mammal. The term “dermatological er,” as used herein refers to a skin disorder. Such dermatological disorders include, but are not d to, proliferative or inflammatory disorders of the skin such as, atopic dermatitis, s disorders, collagenoses, psoriasis, scleroderma, psoriatic s, dermatitis, t dermatitis, eczema, urticaria, rosacea, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki Disease, rosacea, Sjogren-Larsso Syndrome, urticaria. In one aspect, a nd of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, is used to treat systemic sclerosis.
Pain Since LPA is released following tissue injury, LPA1 plays an important role in the initiation of neuropathic pain. LPA1, unlike LPA2 or LPA3, is expressed in both dorsal root ganglion (DRG) and dorsal root neurons. Using the antisense oligodeoxynucleotide (AS-ODN) for LPA1 and LPA1-null mice, it was found that LPA-induced mechanical nia and hyperalgesia is mediated in an LPA1-dependent manner. LPA1 and downstream CK activation play a role in the initiation of athic pain signaling. Pretreatment with Clostridium botulinum C3 exoenzyme (BoTXC3, Rho inhibitor) or Y-27632 (ROCK tor) completely abolished the allodynia and hyperalgesia in nerve-injured mice. LPA also induced demyelination of the dorsal root, which was prevented by BoTXC3. The dorsal root demyelination by injury was not observed in LPA1-null mice or AS-ODN injected wild-type mice. LPA signaling appears to induce important neuropathic pain markers such as n kinase Cγ (PKCγ) and a voltage-gated m channel α2δ1 t (Caα2δ1) in an LPA1 and Rho-dependent manner (M. Inoue, et al., Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling, Nat. Med. 10 (2004) 712–718).
In one aspect, a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, is used in the treatment of pain in a mammal. In one aspect, the pain is acute pain or chronic pain. In another aspect, the pain is athic pain.
In one aspect, a compound of as (I) - (IX), or a pharmaceutically acceptable salt thereof, is used in the treatment of fibromylagia. In one aspect, fibromyalgia stems from the formation of fibrous scar tissue in contractile (voluntary) muscles. is binds the tissue and inhibits blood flow, resulting in pain.
Cancer Lysophospholipid receptor signaling plays a role in the etiology of cancer.
Lysophosphatidic acid (LPA) and its G protein-coupled receptors (GPCRs) LPA1, LPA2, and/or LPA3 play a role in the development of several types of cancers. The initiation, progression and metastasis of cancer involve several concurrent and sequential processes ing cell proliferation and growth, survival and anti-apoptosis, migration of cells, penetration of foreign cells into defined cellular layers and/or organs, and promotion of angiogenesis. The control of each of these processes by LPA signaling in physiological and pathophysiological ions underscores the potential eutic usefulness of modulating LPA signaling pathways for the treatment of cancer, especially at the level of the LPA receptors or ATX/lysoPLD. Autotaxin (ATX) is a prometastatic enzyme initially isolated from the conditioned medium of human melanoma cells that ates a myriad of biological activities, ing angiogenesis and the promotion of cell growth, migration, al, and differentiation through the production of LPA (Mol Cancer Ther 2008;7(10):3352–62).
LPA signals through its own GPCRs leading to activation of multiple downstream effector pathways. Such downstream or pathways play a role in cancer. LPA and its GPCRs are linked to cancer h major oncogenic ing pathways.
LPA contributes to tumorigenesis by increasing motility and invasiveness of cells.
LPA has been implicated in the initiation or progression of ovarian cancer. LPA is present at icant concentrations (2–80 μM) in the ascitic fluid of n cancer patients.
Ovarian cancer cells constitutively produce increased amounts of LPA as compared to normal ovarian surface epithelial cells, the precursor of ovarian epithelial cancer.
Elevated LPA levels are also detected in plasma from patients with stage ovarian cancers compared with controls. LPA receptors (LPA2 and LPA3) are also overexpressed in ovarian cancer cells as compared to normal ovarian surface epithelial cells. LPA stimulates Cox-2 sion h transcriptional activation and post-transcriptional enhancement of Cox-2 mRNA in ovarian cancer cells. Prostaglandins produced by Cox-2 have been implicated in a number of human cancers and pharmacological tion of Cox-2 activity reduces colon cancer development and decreases the size and number of adenomas in patients with familial adenomatous polyposis. LPA has also been implicated in the initiation or progression of prostate cancer, breast cancer, melanoma, head and neck cancer, bowel cancer (colorectal cancer), thyroid cancer and other cancers (Gardell et al, Trends in Molecular Medicine, vol. 12, no. 2, p 65-75, 2006; Ishii et al, Annu. Rev. m, 73, 321-354, 2004; Mills et al., Nat. Rev. Cancer, 3, 582-591, 2003; Murph et al., Biochimica et sica Acta, 1781, 547-557, 2008).
The cellular responses to LPA are ed through the lysophosphatidic acid receptors. For example, LPA receptors mediate both migration of and invasion by pancreatic cancer cell lines: an antagonist of LPA1 and LPA3 (Ki16425) and LPA1- ic siRNA effectively blocked in vitro migration in response to LPA and peritoneal fluid (ascites) from pancreatic cancer patients; in addition, Ki16425 blocked the LPA- induced and ascites-induced invasion activity of a highly peritoneal metastatic pancreatic cancer cell line (Yamada et al, J. Biol. Chem., 279, 6595-6605, 2004).
Colorectal carcinoma cell lines show significant expression of LPA1 mRNA and respond to LPA by cell migration and production of angiogenic factors. Overexpression of LPA receptors has a role in the pathogenesis of thyroid cancer. LPA3 was ally cloned from prostate cancer cells, concordant with the ability of LPA to induce autocrine proliferation of prostate cancer cells.
LPA has stimulatory roles in cancer progression in many types of cancer. LPA is produced from and induces proliferation of te cancer cell lines. LPA induces human colon carcinoma DLD1 cell proliferation, migration, adhesion, and secretion of angiogenic factors through LPA1 ing. In other human colon carcinoma cells lines (HT29 and WiDR), LPA enhances cell proliferation and secretion of angiogenic factors.
In other colon cancer cell lines, LPA2 and LPA3 receptor activation results in proliferation of the cells. The genetic or cological manipulation of LPA metabolism, specific blockade of receptor signaling, and/or inhibition of downstream signal transduction pathways, represent ches for cancer therapies.
It has been reported that LPA and other phospholipids stimulate expression of interleukin-8 (IL-8) in ovarian cancer cell lines. In some ments, high concentrations of IL-8 in ovarian cancer correlate with poor initial response to chemotherapy and with poor prognosis, respectively. In animal models, expression of IL- 8 and other growth factors such as vascular endothelial growth factor (VEGF) is associated with increased genicity, ascites formation, enesis, and invasiveness of ovarian cancer cells. In some aspects, IL-8 is an important modulator of cancer progression, drug resistance, and prognosis in ovarian cancer. In some embodiments, a compound of Formulas (I) - (IX) inhibits or reduces IL-8 expression in ovarian cancer cell lines.
In one aspect, a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, is used in the treatment of cancer. In one aspect, a nd of Formulas (I) - (IX), or a ceutically acceptable salt f, is used in the treatment of ant and benign proliferative disease. In one aspect, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used to prevent or reduce proliferation of tumor cells, on and metastasis of carcinomas, pleural mesothelioma a, Cancer Sci., 2008, 99(8), 1603-1610) or peritoneal mesothelioma, cancer pain, bone metastases (Boucharaba et al, J. Clin. Invest., 2004, 114(12), 1714-1725; Boucharaba et al, Proc. Natl. acad. Sci., 2006, 103(25) 9643-9648). In one aspect is a method of treating cancer in a mammal, the method comprising administering to the mammal a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, and a second therapeutic agent, wherein the second therapeutic agent is an anti-cancer agent.
The term “cancer,” as used herein refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize d). The types of cancer e, but is not limited to, solid tumors (such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid), prostate, skin (melanoma or basal cell cancer) or hematological tumors (such as the leukemias) at any stage of the disease with or t metastases.
Additional miting es of cancers include, acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain , brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic cytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal , craniopharyngioma, cutaneous TCell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, moma, esophageal cancer, ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal l tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin ma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi sarcoma, kidney , Langerhans cell histiocytosis, laryngeal cancer, leukemia, Acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, liver , all cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenström macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, chronic myelogenous leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral , oropharyngeal cancer, osteosarcoma, malignant s histiocytoma of bone, ovarian cancer, ovarian epithelial , ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, ary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal , renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, kaposi, Sézary syndrome, skin cancer, small cell Lung , small intestine cancer, soft tissue a, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, T-cell lymphoma, testicular , throat cancer, thymoma and thymic carcinoma, thyroid , urethral cancer, uterine cancer, uterine a, vaginal cancer, vulvar , Waldenström macroglobulinemia, Wilms tumor.
The increased concentrations of LPA and vesicles in s from ovarian cancer ts and breast cancer effussions indicate that it could be an early diagnostic marker, a prognostic indicator or an indicator of response to therapy (Mills et al, Nat. Rev. Cancer., 3, 1, 2003; Sutphen et al., Cancer Epidemiol. kers Prev. 13, 1185-1191, 2004). LPA concentrations are consistently higher in ascites samples than in matched plasma samples. atory and Allergic Disorders In one aspect, LPA is a contributor to the pathogenesis of respiratory es. In one aspect the respiratory disease is asthma. Proinflammatory effects of LPA include degranulation of mast cells, contraction of smooth-muscle cells and release of cytokines from dendritic cells. Airway smooth muscle cells, epithelial cells and lung fibroblasts all show responses to LPA. LPA induces the secretion of IL-8 from human bronchial epithelial cells. IL-8 is found in increased trations in BAL fluids from patients with asthma, chronic obstructive lung disease, pulmonary sarcoidosis and acute respiratory distress syndrome and Il-8 has been shown to exacerbate airway inflammation and airway remodeling of asthmatics. LPA1, LPA2 and LPA3 receptors have all been shown to contribute to the LPA-induced IL-8 production. Studies cloning multiple GPCRs that are activated by LPA allowed the demonstration of the presence of mRNA for the LPA1, LPA2 and LPA3 in the lung (J.J.A. Contos, et al., Mol. Pharmacol. 58, 1188-1196, 2000).
The release of LPA from platelets activated at a site of injury and its ability to promote fibroblast proliferation and contraction are es of LPA as a mediator of wound repair. In the context of airway disease, asthma is an inflammatory disease where inappropriate airway ‘‘repair’’ processes lead to ural ‘‘remodeling’’ of the airway.
In asthma, the cells of the airway are t to ongoing injury due to a variety of insults, including allergens, pollutants, other inhaled environmental agents, bacteria and viruses, leading to the chronic inflammation that characterizes asthma.
In one aspect, in the asthmatic individual, the release of normal repair mediators, including LPA, is exaggerated or the actions of the repair mediators are inappropriately prolonged leading to inappropriate airway ling. Major structural features of the remodeled airway observed in asthma include a ned lamina laris (the basement membrane-like structure just beneath the airway epithelial cells), sed numbers and activation of myofibroblasts, thickening of the smooth muscle layer, increased numbers of mucus glands and mucus secretions, and alterations in the connective tissue and capillary bed throughout the airway wall. In one aspect, LPA contributes to these structural changes in the airway. In one aspect, LPA is involved in acute airway hyperresponsiveness in asthma. The lumen of the remodeled asthmatic airway is narrower due to the thickening of the airway wall, thus decreasing airflow. In one aspect, LPA butes to the long-term structural remodeling and the acute hyperresponsiveness of the asthmatic airway. In one aspect, LPA contributes to the esponsiveness that is a primary feature of acute exacerbations of asthma.
In addition to the cellular responses mediated by LPA, several of the LPA signaling pathway components leading to these responses are relevant to asthma. EGF receptor upregulation is induced by LPA and is also seen in asthmatic s (M. ma, et al., Am. J. Respir. Crit. Care Med. 157, 1907– 1912, 1998). Chronic inflammation is a contributor to asthma, and several of the transcription factors that are activated by LPA are known to be involved in inflammation (Ediger et al., Eur Respir J -769, 2003).
In one aspect, the fibroblast proliferation and contraction and ellular matrix secretion stimulated by LPA contributes to the fibroproliferative features of other airway diseases, such as the peribronchiolar fibrosis present in c bronchitis, ema, and interstitial lung disease. Emphysema is also associated with a mild fibrosis of the alveolar wall, a feature which is believed to ent an attempt to repair alveolar . In another aspect, LPA plays a role in the fibrotic interstitial lung diseases and obliterative bronchiolitis, where both en and myofibroblasts are increased. In another aspect, LPA is involved in several of the various syndromes that constitute c ctive pulmonary e.
Administration of LPA in vivo induces airway hyper-responsiveness, cratch ses, infiltration and activation of eosinophils and neutrophils, vascular remodeling, and ptive flexor ses. LPA also induces histamine release from mouse and rat mast cells. In an acute allergic reaction, histamine induces various responses, such as contraction of smooth muscle, plasma exudation, and mucus production. Plasma exudation is important in the airway, because the leakage and subsequent airway-wall edema contribute to the development of airway hyperresponsiveness. Plasma exudation progresses to ctival swelling in ocular ic disorder and nasal blockage in allergic rhinitis (Hashimoto et al., J Pharmacol Sci 100, 82 – 87, 2006). In one aspect, plasma exudation induced by LPA is ed by histamine release from mast cells via one or more LPA receptors. In one aspect, the LPA or(s) e LPA1 and/or LPA3. In one aspect, a compound of Formulas (I) - (IX), or a ceutically acceptable salt thereof, is used in the treatment of s allergic disorders in a mammal. In one aspect, a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, is used in the treatment of respiratory diseases, disorders or conditions in a mammal. In one aspect, a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, is used in the treatment of asthma in a mammal. In one aspect, a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, is used in the treatment of chronic asthma in a mammal.
The term “respiratory disease,” as used herein, refers to diseases affecting the organs that are involved in breathing, such as the nose, throat, larynx, eustachian tubes, trachea, bronchi, lungs, related muscles (e.g., diaphram and intercostals), and nerves.
Respiratory diseases include, but are not limited to, asthma, adult respiratory distress me and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic is, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis, and hypoxia.
The term “asthma” as used herein refers to any disorder of the lungs characterized by variations in pulmonary gas flow ated with airway constriction of whatever cause (intrinsic, extrinsic, or both; allergic or non-allergic). The term asthma may be used with one or more adjectives to indicate cause.
In one , presented herein is the use of a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, in the treatment or tion of chronic obstructive pulmonary e in a mammal comprising administering to the mammal at least once an effective amount of at least one compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof. In addition, chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis or emphysema, pulmonary hypertension, titial lung fibrosis and/or airway inflammation, and cystic fibrosis.
Nervous System The nervous system is a major locus for LPA1 expression; there it is spatially and temporally ted throughout brain development. Oligodendrocytes, the myelinating cells in the central nervous system (CNS), s LPA1 in mammals. In addition, Schwann cells, the myelinating cells of the eral nervous system, also express LPA1, which is involved in regulating n cell survival and morphology. These observations identify important functions for receptor-mediated LPA signaling in enesis, cell survival, and myelination.
Exposure of peripheral nervous system cell lines to LPA produces a rapid retraction of their processes resulting in cell ng, which was, in part, mediated by polymerization of the actin cytoskeleton. In one aspect, LPA causes neuronal degeneration under pathological conditions when the blood-brain barrier is damaged and serum components leak into the brain (Moolenaar, Curr. Opin. Cell Biol. 7:203-10, 1995). Immortalized CNS neuroblast cell lines from the cerebral cortex also y retraction responses to LPA exposure through Rho tion and actomyosin interactions. In one aspect, LPA is associated with post-ischemic neural damage (J.
Neurochem. 61, 340, 1993; J. Neurochem., 70:66, 1998).
In one aspect, provided is a compound of Formulas (I) - (IX), or a pharmaceutically able salt thereof, for use in the treatment or prevention of a nervous system disorder in a mammal. The term “nervous system disorder,” as used herein, refers to conditions that alter the structure or on of the brain, spinal cord or peripheral nervous system, including but not limited to Alzheimer’s Disease, cerebral edema, cerebral ia, stroke, multiple sclerosis, neuropathies, Parkinson’s Disease, those found after blunt or surgical trauma (including post-surgical cognitive ction and spinal cord or brain stem injury), as well as the neurological aspects of disorders such as degenerative disk disease and sciatica.
In one aspect, provided is a compound of Formulas (I) - (IX), or a pharmaceutically able salt thereof, for use in the treatment or prevention of a CNS disorder in a mammal. CNS disorders include, but are not limited to, multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, stroke, cerebral ischemia, retinal ischemia, post-surgical cognitive dysfunction, migraine, peripheral neuropathy/neuropathic pain, spinal cord , cerebral edema and head injury.
Cardiovascular Disorders Cardiovascular ypes observed after targeted on of lysophospholipid receptors reveal important roles for lysophospholipid signaling in the development and maturation of blood vessels, formation of atherosclerotic plaques and maintenance of heart rate (Ishii, I. et al. Annu. Rev. Biochem. 73, 321–354, 2004). Angiogenesis, the formation of new ary networks from pre-existing vasculature, is normally invoked in wound healing, tissue growth and myocardial angiogenesis after ischemic injury. e growth factors (e.g. vascular endothelial growth factor (VEGF)) and lysophospholipids control coordinated proliferation, migration, adhesion, differentiation and assembly of ar endothelial cells (VECs) and nding vascular smoothmuscle cells (VSMCs). In one aspect, dysregulation of the processes mediating angiogenesis leads to atherosclerosis, hypertension, tumor growth, rheumatoid arthritis and diabetic retinopathy (Osborne, N. and er, D.Y. Annu. Rev. l. 65, 23–43, 2003).
Downstream signaling ys evoked by lysophospholipid receptors include Rac-dependent lamellipodia formation (e.g. LPA1) and Rho-dependent -fiber formation (e.g. LPA1), which is important in cell migration and adhesion. Dysfunction of the vascular endothelium can shift the balance from vasodilatation to vasoconstriction and lead to hypertension and vascular remodeling, which are risk factors for atherosclerosis (Maguire, J.J. et al., Trends Pharmacol. Sci. 26, 448–454, 2005).
LPA contributes to both the early phase (barrier dysfunction and te on of the endothelium) and the late phase (platelet activation and intra-arterial thrombus formation) of atherosclerosis, in addition to its overall progression. In the early phase, LPA from numerous sources accumulates in lesions and activates its cognate GPCRs (LPA1 and LPA3) expressed on platelets , W. Biochim. Biophys. Acta 1582, 204–215, 2002; Rother, E. et al. Circulation 108, 7, 2003). This triggers et shape change and aggregation, g to intra-arterial thrombus formation and, ially, myocardial infarction and stroke. In support of its atherogenic activity, LPA can also be a mitogen and motogen to VSMCs and an activator of endothelial cells and macrophages. In one aspect, mammals with cardiovascular disease t from LPA receptor nists that prevent thrombus and neointima plaque formation.
In one aspect, a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, is used to treat or prevent cardiovascular disease in mammal.
The term “cardiovascular disease,” as used herein refers to diseases ing the heart or blood vessels or both, including but not limited to: arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; dial infarction; c or vascular aneurysm; vasculitis, stroke; peripheral ctive arteriopathy of a limb, an organ, or a tissue; reperfusion injury ing ischemia of the brain, heart or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, insufficiency limited to a single organ or tissue..
In one aspect, provided herein are s for preventing or treating vasoconstriction, atherosclerosis and its sequelae myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and stroke comprising administering at least once to the mammal an effective amount of at least one compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, or ceutical composition or medicament which includes a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof.
In one aspect, provided herein are methods for reducing cardiac reperfusion injury following myocardial ischemia and/or xic shock comprising administering at least once to the mammal an effective amount of at least one compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof.
In one aspect, provided herein are methods for reducing the constriction of blood vessels in a mammal comprising administering at least once to the mammal an effective amount of at least one compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof.
In one , provided herein are methods for lowering or preventing an increase in blood pressure of a mammal comprising administering at least once to the mammal an effective amount of at least one compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof.
Inflammation LPA has been shown to regulate immunological responses by modulating activities/functions of immune cells such as T-/B-lymphocytes and macrophages. In activated T cells, LPA activates IL-2 production/cell proliferation through LPA1 (Gardell et al, TRENDS in Molecular Medicine Vol.12 No.2 February 2006). Expression of LPA- induced inflammatory se genes is mediated by LPA1 and LPA3 (Biochem Biophys Res Commun. 363(4):1001-8, 2007). In on, LPA modulates the chemotaxis of inflammatory cells (Biochem Biophys Res Commun., 1993, 15;193(2), 497). The eration and cytokine-secreting activity in response to LPA of immune cells ( J.
Imuunol. 1999, 162, 2049), et aggregation activity in response to LPA, acceleration of migration activity in monocytes, activation of NF-κB in fibroblast, ement of fibronectin-binding to the cell surface, and the like are known. Thus, LPA is associated with various inflammatory/immune diseases.
In one aspect, a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt f, is used to treat or prevent inflammation in a mammal. In one aspect, nists of LPA1 and/or LPA3 find use in the treatment or prevention of matory/immune disorders in a mammal. In one aspect, the antagonist of LPA1 is a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof. es of inflammatory/immune disorders e psoriasis, rheumatoid arthritis, vasculitis, matory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle e, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, eczema, allogeneic or xenogeneic transplantation , bone , stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., oto's and mune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis.
Other Diseases, Disorders or Conditions In accordance with one aspect, are methods for treating, preventing, reversing, halting or slowing the progression of LPA-dependent or LPA-mediated diseases or conditions once it becomes clinically t, or treating the symptoms associated with or related to LPA-dependent or LPA-mediated diseases or ions, by administering to the mammal a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject already has a LPA-dependent or LPA- mediated disease or condition at the time of administration, or is at risk of developing a LPA-dependent or LPA-mediated disease or condition.
In certain s, the activity of LPA1 in a mammal is directly or indirectly modulated by the administration of (at least once) a therapeutically effective amount of at least one compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof.
Such modulation es, but is not limited to, reducing and/or inhibiting the activity of LPA1. In additional aspects, the activity of LPA in a mammal is directly or indirectly modulated, including reducing and/or inhibiting, by the administration of (at least once) a therapeutically effective amount of at least one compound of Formulas (I) - (IX), or a ceutically able salt f. Such modulation includes, but is not limited to, reducing and/or inhibiting the amount and/or activity of a LPA receptor. In one aspect, the LPA receptor is LPA1.
In one aspect, LPA has a contracting action on bladder smooth muscle cell isolated from bladder, and es growth of prostate-derived epithelial cell (J.
Urology, 1999, 162, 1779-1784; J. Urology, 2000, 163, 1027-1032). In another aspect, LPA contracts the urinary tract and te in vitro and increases intraurethral re in vivo (WO 02/062389).
In certain aspects, are methods for preventing or treating eosinophil and/or basophil and/or dendritic cell and/or neutrophil and/or monocyte and/or T-cell recruitment comprising administering at least once to the mammal an ive amount of at least one compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof.
In certain aspects, are methods for the treatment of cystitis, including, e.g.,interstitial cystitis, comprising administering at least once to the mammal a therapeutically effective amount of at least one compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof.
In accordance with one aspect, methods described herein include the diagnosis or determination of whether or not a patient is suffering from a LPA-dependent or LPA- mediated disease or condition by administering to the subject a therapeutically effective amount of a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, and determining whether or not the patient responds to the treatment.
In one aspect provided herein are nds of Formulas (I) - (IX), pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof, which are antagonists of LPA1, and are used to treat patients suffering from one or more LPA-dependent or LPA-mediated conditions or diseases, including, but not d to, lung fibrosis, kidney fibrosis, liver fibrosis, scarring, asthma, rhinitis, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, , pain, proliferative disorders and inflammatory conditions. In some embodiments, LPA-dependent ions or diseases e those wherein an absolute or relative excess of LPA is present and/or observed.
In any of the aforementioned aspects the LPA-dependent or LPA-mediated diseases or conditions include, but are not d to, organ fibrosis, asthma, ic disorders, c obstructive pulmonary disease, pulmonary ension, lung or pleural fibrosis, peritoneal is, arthritis, allergy, cancer, cardiovascular disease, ult respiratory distress syndrome, myocardial tion, aneurysm, stroke, and cancer.
In one aspect, a compound of as (I) - (IX), or a pharmaceutically acceptable salt f, is used to e the l ivity decrease caused by l operations such as laser-assisted in situ keratomileusis (LASIK) or cataract operation, corneal sensitivity se caused by corneal degeneration, and dry eye symptom caused thereby.
In one aspect, presented herein is the use of a compound of as (I)- (IX), or a pharmaceutically acceptable salt thereof, in the treatment or prevention of ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis in a mammal comprising administering at least once to the mammal an effective amount of at least one compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof.
In one aspect, presented herein is the use of a compound of as (I) - (IX), or a pharmaceutically acceptable salt thereof, in the treatment or prevention of Sjogren disease or inflammatory disease with dry eyes in a mammal comprising administering at least once to the mammal an effective amount of at least one compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof.
In one aspect, LPA and LPA receptors (e.g. LPA1) are involved in the pathogenesis of osteoarthritis (Kotani et al, Hum. Mol. , 2008, 17, 797). In one aspect, presented herein is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the treatment or prevention of osteoarthritis in a mammal comprising administering at least once to the mammal an effective amount of at least one compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof.
In one , LPA receptors (e.g. LPA1, LPA3) contribute to the enesis of rheumatoid arthritis (Zhao et al, Mol. Pharmacol., 2008, 73(2), 587-600). In one aspect, ted herein is the use of a compound of Formulas (I) - (IX), or a ceutically acceptable salt thereof, in the treatment or prevention of rheumatoid arthritis in a mammal comprising administering at least once to the mammal an effective amount of at least one nd of as (I) - (IX), or a pharmaceutically acceptable salt thereof.
In one aspect, LPA receptors (e.g. LPA1) contribute to adipogenesis. (Simon et al, J.Biol. Chem., 2005, vol. 280, no. 15, p.14656). In one aspect, presented herein is the use of a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, in the promotion of adipose tissue formation in a mammal comprising administering at least once to the mammal an effective amount of at least one compound of Formulas (I) - (IX), or a ceutically acceptable salt thereof. a. In Vitro Assays The effectiveness of compounds of the present invention as LPA1 tors can be determined in an LPA1 functional antagonist assay as follows: Chinese hamster ovary cells overexpressing human LPA1 were plated overnight (15,000 well) in poly-D-lysine coated 384-well microplates (Greiner bio-one, Cat#781946) in DMEM/F12 medium (Gibco, Cat#11039). Following overnight culture, cells were loaded with calcium indicator dye (AAT Bioquest Inc, Cat# 34601) for 30 minutes at 37 °C. The cells were then equilibrated to room temperature for 30 minutes before the assay. Test compounds solubilized in DMSO were transferred to 384 well ding surface plates (Corning, Cat# 3575) using the Labcyte Echo acoustic dispense and diluted with assay buffer [1X HBSS with calcium/magnesium (Gibco Cat# 14025- 092), 20 mM HEPES (Gibco Cat# 15630-080) and 0.1% fatty acid free BSA (Sigma Cat# A9205)] to a final concentration of 0.5% DMSO. Diluted compounds were added to the cells by FDSS6000 (Hamamatsu) at final concentrations ranging from 0.08 nM to 5 µM. and were then incubated for 20 min at room temperature at which time LPA (Avanti Polar Lipids Cat#857130C) was added at final concentrations of 10 nM to ate the cells.
The compound IC50 value was defined as the concentration of test compound which inhibited 50% of the calcium flux induced by LPA alone. IC50 values were determined by g data to a 4-parameter ic on (GraphPad Prism, San Diego CA). b. In Vivo Assays LPA Challenge with plasma histamine evaluation.
Compound is dosed orally p.o. 2 hours to CD-1 female mice prior to the LPA challenge. The mice are then dosed via tail vein (IV) with 0.15 mL of LPA in 0.1%BSA/ PBS (2 μg/µL). Exactly 2 minutes following the LPA nge, the mice are euthanized by decapitation and the trunk blood is collected. These samples are collectively centrifuged and individual 75 L samples are frozen at -20C until the time of the histamine assay.
The plasma ine analysis was run by standard EIA e Immunoassay) methods. Plasma samples were thawed and diluted 1:30 in 0.1% BSA in PBS. The EIA protocol for histamine is as outlined by the manufacturer was followed (Histamine EIA, Oxford Biomedical Research, EA#31).
The LPA used in the assay is formulated as follows: LPA (1-oleoylhydroxy-snglycerophosphate (sodium salt), 857130P, Avanti Polar ) is prepared in 0.1%BSA/PBS for total concentration of 2 μg/µL. 13 mg of LPA is weighed and 6.5 mL 0.1%BSA added, ed and sonicated for ~1 hour until a clear solution is achieved.
V. PHARMACEUTICAL COMPOSITIONS, FORMULATIONS AND COMBINATIONS In some embodiments, provided is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical ition also contains at least one pharmaceutically acceptable inactive ingredient.
In some embodiments, provided is a pharmaceutical composition comprising a therapeutically effective amount of a compound of as (I) - (IX), or a ceutically acceptable salt thereof, and at least one pharmaceutically acceptable inactive ingredient. In one , the pharmaceutical composition is formulated for intravenous ion, subcutaneous injection, oral administration, inhalation, nasal administration, topical administration, ophthalmic administration or otic stration.
In some embodiments, the pharmaceutical composition is a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop or an ear drop.
In some embodiments, the pharmaceutical composition further comprises one or more additional eutically active agents selected from: corticosteroids (e.g., dexamethasone or fluticasone), immunosuppresants (e.g., tacrolimus & pimecrolimus), analgesics, anti-cancer agent, anti-inflammatories, chemokine receptor antagonists, odilators, leukotriene receptor antagonists (e.g., montelukast or zafirlukast), leukotriene formation inhibitors, monoacylglycerol kinase inhibitors, phospholipase A1 inhibitors, phospholipase A2 inhibitors, and lysophospholipase D LD) inhibitors, autotaxin inhibitors, decongestants, stamines (e.g., loratidine), mucolytics, anticholinergics, antitussives, expectorants, anti-infectives (e.g., fusidic acid, particularly for treatment of atopic itis), anti-fungals (e.g., clotriazole, particularly for atopic dermatitis), anti-IgE antibody therapies (e.g., omalizumab), β-2 adrenergic agonists (e.g., albuterol or salmeterol), other PGD2 antagonists acting at other receptors such as DP antagonists, PDE4 tors (e.g., cilomilast), drugs that te cytokine production, e.g., TACE inhibitors, drugs that modulate activity of Th2 cytokines IL-4 & IL-5 (e.g., blocking monoclonal antibodies & soluble receptors), PPAR agonists (e.g., rosiglitazone and pioglitazone), 5-lipoxygenase inhibitors (e.g., zileuton).
In some embodiments, the pharmaceutical composition further comprises one or more additional anti-fibrotic agents selected from pirfenidone, nintedanib, thalidomide, carlumab, FG-3019, fresolimumab, interferon alpha, inized superoxide dismutase, umab, tanzisertib, tralokinumab, hu3G9, , IFN-gamma-1b, IW-001, PRM- 151, PXS-25, pentoxifylline/N-acetyl-cysteine, pentoxifylline/vitamin E, salbutamol sulfate, [Sar9,Met(O2)11]-Substance P, pentoxifylline, mercaptamine bitartrate, obeticholic acid, ol, GFT-505, pentaenoic acid ethyl ester, metformin, metreleptin, nab-CD3, oltipraz, IMME, MK-4074, PX-102, RO-5093151.
In some embodiments, ed is a method comprising administering a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, to a human with a LPA- dependent or LPA-mediated disease or condition. In some embodiments, the human is already being administered one or more additional therapeutically active agents other than a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering one or more additional therapeutically active agents other than a nd of as (I) - (IX), or a pharmaceutically acceptable salt thereof.
In some embodiments, the one or more additional therapeutically active agents other than a compound of as (I) - (IX), or a pharmaceutically acceptable salt thereof, are selected from: corticosteroids (e.g,. dexamethasone or asone), immunosuppresants (e.g., tacrolimus & pimecrolimus), sics, anti-cancer agent, anti-inflammatories, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists (e.g., montelukast or zafirlukast), leukotriene formation inhibitors, monoacylglycerol kinase inhibitors, phospholipase A1 inhibitors, phospholipase A2 inhibitors, and lysophospholipase D (lysoPLD) inhibitors, autotaxin inhibitors, estants, antihistamines (e.g., loratidine), mucolytics, olinergics, antitussives, expectorants, anti-infectives (e.g., fusidic acid, particularly for treatment of atopic dermatitis), anti-fungals (e.g., clotriazole, particularly for atopic dermatitis), anti-IgE antibody therapies (e.g., omalizumab), β-2 adrenergic agonists (e.g., albuterol or salmeterol), other PGD2 antagonists acting at other receptors such as DP antagonists, PDE4 inhibitors (e.g., cilomilast), drugs that modulate cytokine production, e.g. TACE inhibitors, drugs that modulate activity of Th2 cytokines IL-4 & IL-5 (e.g., blocking monoclonal antibodies & soluble receptors), PPAR agonists (e.g., rosiglitazone and pioglitazone), 5-lipoxygenase inhibitors (e.g., zileuton).
In some embodiments, the one or more additional therapeutically active agents other than a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, are other ibrotic agents selected from idone, nintedanib, thalidomide, carlumab, FG-3019, fresolimumab, interferon alpha, lecithinized superoxide dismutase, simtuzumab, tanzisertib, tralokinumab, hu3G9, AM-152, mma-1b, IW-001, PRM- 151, PXS-25, pentoxifylline/N-acetyl-cysteine, pentoxifylline/vitamin E, salbutamol sulfate, Met(O2)11]-Substance P, pentoxifylline, mercaptamine bitartrate, obeticholic acid, aramchol, GFT-505, eicosapentyl ethyl ester, metformin, metreleptin, muromonab-CD3, oltipraz, IMME, MK-4074, PX-102, RO-5093151.
In some embodiments, the one or more additional eutically active agents other than a compound of Formulas (I) - (IX), or a ceutically acceptable salt thereof, are selected from ACE inhibitors, ramipril, AII antagonists, irbesartan, antiarrythmics , dronedarone, PPAR activators, PPAR activators, tazone, rosiglitazone, prostanoids, endothelin receptor antagonists, elastase inhibitors, m antagonists, beta blockers, ics, aldosterone receptor antagonists, eplerenone, renin inhibitors, rho kinase inhibitors, soluble guanylate cyclase (sGC) activators, sGC sensitizers, PDE inhibitors, PDE5 tors, NO donors, digitalis drugs, P inhibitors, statins, bile acid reuptake inhibitors, PDGF antagonists, vasopressin antagonists, aquaretics, NHE1 inhibitors, Factor Xa antagonists, Factor XIIIa antagonists, agulants, anti-thrombotics, platelet inhibitors, profibroltics, thrombin-activatable fibrinolysis inhibitors (TAFI), PAI-1 inhibitors, ins, heparins, thromboxane antagonists, nin antagonists, COX inhibitors, aspirin, therapeutic antibodies, IIIa antagonists, ER antagonists, SERMs, tyrosine kinase inhibitors, RAF kinase inhibitors, p38 MAPK inhibitors, pirfenidone, multi-kinase inhibitors, nintedanib, sorafenib.
In some embodiments, the one or more additional therapeutically active agents other than a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, are selected from Gremlin-1 mAb, PA1-1 mAb, Promedior (PRM-151; recombinant human Pentraxin-2); FGF21, TGF antagonists, v6 & v panantagonists ; FAK inhibitors, TG2 inhibitors, LOXL2 inhibitors, NOX4 inhibitors, MGAT2 inhibitors, GPR120 agonists.
Pharmaceutical formulations described herein are administrable to a subject in a variety of ways by multiple stration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, uscular), intranasal, buccal, topical or ermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, es, pills, delayed release ations, extended release formulations, pulsatile e formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
In some embodiments, the compound of as (I) - (IX), or a ceutically acceptable salt thereof, is administered orally.
In some embodiments, the compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, is administered topically. In such embodiments, the compound of Formulas (I) - (IX), or a pharmaceutically able salt thereof, is formulated into a variety of topically administrable compositions, such as ons, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages, balms, creams or ointments. Such ceutical compounds can n solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. In one aspect, the compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt f, is stered topically to the skin.
In r aspect, the compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, is administered by inhalation. In one embodiment, the compound of as (I) - (IX), or a ceutically acceptable salt thereof, is administered by inhalation that directly targets the pulmonary system.
In another aspect, the compound of as (I) - (IX), or a pharmaceutically acceptable salt thereof, is ated for intranasal administration. Such ations include nasal sprays, nasal mists, and the like.
In another aspect, the compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, is formulated as eye drops.
In another aspect is the use of a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease, disorder or conditions in which the activity of at least one LPA receptor contributes to the pathology and/or ms of the disease or condition. In one embodiment of this aspect, the LPA is selected from LPA1, LPA2, LPA3, LPA4, LPA5 and LPA6. In one aspect, the LPA receptor is LPA1. In one aspect, the disease or condition is any of the diseases or conditions specified herein.
In any of the aforementioned aspects are further embodiments in which: (a) the effective amount of the compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, is systemically administered to the mammal; and/or (b) the effective amount of the nd is administered orally to the mammal; and/or (c) the ive amount of the compound is intravenously administered to the mammal; and/or (d) the effective amount of the compound is administered by tion; and/or (e) the effective amount of the compound is administered by nasal administration; or and/or (f) the effective amount of the compound is administered by injection to the mammal; and/or (g) the effective amount of the compound is administered topically to the mammal; and/or (h) the effective amount of the compound is administered by ophthalmic administration; and/or (i) the effective amount of the compound is administered rectally to the mammal; and/or (j) the effective amount is administered non-systemically or locally to the mammal.
In any of the aforementioned aspects are further embodiments comprising single administrations of the ive amount of the compound, including further embodiments in which (i) the compound is stered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) continually; or (iv) continuously.
In any of the aforementioned s are further embodiments sing multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug y, dosing of the compound is d. In one ment, the length of the drug holiday varies from 2 days to 1 year.
Also provided is a method of inhibiting the physiological activity of LPA in a mammal comprising administering a therapeutically effective amount of a compound of as (I) - (IX) or a pharmaceutically acceptable salt thereof to the mammal in need thereof.
In one aspect, provided is a medicament for treating a LPA-dependent or LPA- mediated disease or condition in a mammal comprising a therapeutically effective amount of a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof.
In some cases disclosed herein is the use of a compound of Formulas (I) - (IX), or a ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a pendent or LPA-mediated disease or condition.
In some cases disclosed herein is the use of a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, in the treatment or prevention of a LPA- dependent or LPA-mediated disease or ion.
In one aspect, is a method for treating or preventing a pendent or LPA- mediated disease or condition in a mammal comprising administering a therapeutically effective amount of a compound of Formulas (I) - (IX), or a ceutically able salt thereof.
In one aspect, LPA-dependent or LPA-mediated diseases or conditions include, but are not limited to, fibrosis of organs or tissues, scarring, liver diseases, dermatological conditions, cancer, cardiovascular disease, respiratory diseases or conditions, inflammatory disease, intestinal tract disease, renal disease, urinary tract-associated disease, inflammatory disease of lower urinary tract, dysuria, frequent urination, pancreas disease, arterial obstruction, cerebral infarction, cerebral hemorrhage, pain, peripheral neuropathy, and yalgia.
In one aspect, the pendent or LPA-mediated disease or ion is a respiratory disease or condition. In some embodiments, the respiratory disease or condition is asthma, chronic obstructive pulmonary disease (COPD), ary fibrosis, pulmonary arterial hypertension or acute respiratory distress syndrome.
In some ments, the LPA-dependent or diated disease or condition is selected from idiopathic pulmonary fibrosis; other e parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen ar disease, alveolar proteinosis, langerhans cell granulomatosis, ngioleiomyomatosis, inherited es (Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease); radiation induced is; chronic obstructive pulmonary disease (COPD); scleroderma; bleomycin induced pulmonary fibrosis; chronic asthma; silicosis; asbestos induced pulmonary fibrosis; acute respiratory ss syndrome (ARDS); kidney fibrosis; tubulointerstitium fibrosis; glomerular nephritis; focal segmental glomerular sclerosis; IgA nephropathy; hypertension; ; gut fibrosis; liver fibrosis; cirrhosis; alcohol induced liver fibrosis; toxic/drug induced liver fibrosis; romatosis; nonalcoholic steatohepatitis (NASH); biliary duct injury; primary biliary sis; infection induced liver fibrosis; viral induced liver fibrosis; and mune tis; corneal ng; hypertrophic scarring; Duputren disease, keloids, cutaneous fibrosis; ous scleroderma; spinal cord injury/fibrosis; myelofibrosis; vascular restenosis; atherosclerosis; arteriosclerosis; Wegener's granulomatosis; Peyronie's disease, chronic lymphocytic leukemia, tumor metastasis, transplant organ rejection, endometriosis, neonatal respiratory distress syndrome and neuropathic pain.
In one aspect, the LPA-dependent or LPA-mediated disease or condition is described herein.
In one aspect, provided is a method for the treatment or prevention of organ fibrosis in a mammal comprising administering a eutically effective amount of a compound of Formulas (I) - (IX) or a pharmaceutically acceptable salt thereof to a mammal in need thereof.
In one aspect, the organ fibrosis comprises lung fibrosis, renal fibrosis, or hepatic fibrosis.
In one aspect, ed is a method of improving lung function in a mammal comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to the mammal in need thereof. In one aspect, the mammal has been diagnosed as having lung fibrosis.
In one aspect, compounds disclosed herein are used to treat idiopathic pulmonary is (usual titial pneumonia) in a mammal.
In some embodiments, compounds sed herein are used to treat diffuse parenchymal interstitial lung diseases in mammal: iatrogenic drug induced, occupational/environmental (Farmer lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen ar disease (scleroderma and others), alveolar proteinosis, langerhans cell granulonmatosis, lymphangioleiomyomatosis, Hermansky- Pudlak Syndrome, Tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease.
In some embodiments, compounds disclosed herein are used to treat posttransplant fibrosis associated with chronic rejection in a mammal: Bronchiolitis obliterans for lung transplant.
In some embodiments, compounds sed herein are used to treat cutaneous fibrosis in a mammal: cutaneous scleroderma, Dupuytren disease, keloids.
In one aspect, compounds disclosed herein are used to treat c fibrosis with or without cirrhosis in a mammal: toxic/drug induced (hemochromatosis), alcoholic liver disease, viral hepatitis (hepatitis B virus, hepatitis C virus, HCV), nonalcoholic liver disease (NAFLD, NASH), lic and auto-immune disease.
In one aspect, compounds disclosed herein are used to treat renal fibrosis in a mammal: tubulointerstitium fibrosis, glomerular sclerosis.
In any of the aforementioned aspects ing the treatment of LPA dependent diseases or ions are further embodiments comprising administering at least one onal agent in on to the administration of a compound having the structure of as (I) - (IX), or a pharmaceutically acceptable salt thereof. In various embodiments, each agent is administered in any order, including simultaneously.
In any of the embodiments disclosed herein, the mammal is a human.
In some embodiments, compounds provided herein are administered to a human.
In some embodiments, compounds ed herein are orally administered.
In some embodiments, compounds provided herein are used as antagonists of at least one LPA receptor. In some embodiments, compounds provided herein are used for inhibiting the activity of at least one LPA receptor or for the treatment of a disease or condition that would benefit from tion of the activity of at least one LPA receptor.
In one aspect, the LPA receptor is LPA1.
In other embodiments, compounds provided herein are used for the formulation of a medicament for the inhibition of LPA1 activity.
Articles of manufacture, which include packaging material, a compound of Formulas (I) - (IX), or a pharmaceutically acceptable salt thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, tautomers, ceutically acceptable e, pharmaceutically active metabolite, ceutically acceptable prodrug, or ceutically acceptable solvate thereof, is used for inhibiting the activity of at least one LPA receptor, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from inhibition of the activity of at least one LPA receptor, are provided.
In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is lly for the purpose of providing a t for discussing the features of the ion. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.
VI. GENERAL SYNTHESIS ING SCHEMES The nds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, er with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as iated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the ormations being effected. It will be understood by those skilled in the art of organic sis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one ular process scheme over another in order to obtain a desired compound of the invention.
It will also be ized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the d practitioner is Greene et al., (Protective Groups in Organic Synthesis, Fourth Edition, Wiley-Interscience (2006)).
The nds of Formulas (I) - (IX) may be prepared by the exemplary processes described in the following schemes and working examples, as well as relevant published literature procedures that are used by one skilled in the art. Exemplary ts and procedures for these reactions appear herein after and in the working examples.
Protection and deprotection in the ses below may be carried out by procedures generally known in the art (see, for e, Wuts, P.G.M., Greene’s tive Groups in Organic Synthesis, 5th Edition, Wiley (2014)). General methods of organic synthesis and functional group transformations are found in: Trost, B.M. et al., Eds., Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, New York, NY (1991); Smith, M.B. et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. 7th Edition, Wiley, New York, NY (2013); Katritzky, A.R. et al., Eds., Comprehensive Organic Functional Group Transformations II, 2nd Edition, Elsevier Science Inc., Tarrytown, NY (2004); , R.C., Comprehensive Organic Transformations, 2nd Edition, Wiley-VCH, New York, NY (1999), and references therein.
Scheme 1 describes the synthesis of carbamoyloxymethyl triazole-aryloxy cyclohexyl acids 14. A dihalo (preferably dibromo) phenyl or azine (e.g. pyridine) derivative 1 is coupled with an appropriately protected (e.g. as a ydropyranyl ether) propargyl l 2 under Sonogashira conditions (e.g. Alper, P. et al, WO 2008097428) to give the corresponding bromo-aryl or bromo-heteroaryl protected propargyl l 3.
Thermal reaction of alkyne 3 with an alkyl azide 4 (with or without an appropriate catalyst; Qian, Y. et al, J. Med. Chem., 2012, 55 , 7920-7939 or Boren, B. C., et al., J.
Am. Chem. Soc., 2008, 130, 8923-8930) provides the corresponding regioisomeric protected hydroxylmethyl- triazoles, from which the desired le regioisomer 5 can be isolated. Reaction of the bromoaryl- or eteroaryl-triazoles 5 with pinacol diboronate in the presence of an appropriate palladium catalyst (Ishiyama, T. et al, J. Org.
Chem. 1995, 60, 7508-7510) provides the corresponding pinacol boronate 6, which is then oxidized with hydrogen peroxide to give the corresponding phenol or yheteroarene 7 (Fukumoto, S. et al, WO 2012137982). Reaction of phenol/hydroxyheteroarene 7 with a oxy cycloalkyl ester 8 under Mitsunobu reaction conditions (Kumara Swamy, K. C., Chem. Rev., 2009, 109, 2551-2651) furnishes the corresponding triazole cycloalkyl ether ester 9. Deprotection of the triazole 9 provides the triazole alcohol 10, which is then reacted with 4-nitrophenyl chloroformate in the presence of an appropriate base to give the corresponding triazole 4-nitrophenyl carbonate 11. The triazole 4-nitrophenyl carbonate 11 is then d with an amine 12 in the presence of an appropriate base to give the triazole carbamate 13, which then undergoes ester deprotection to give the desired carbamoyloxymethyltriazole-aryloxy cycloalkyl acids 14.
Scheme 1.
For the specific example of analogs 14, where R2 = CH3 e 1A), instead of using an alkyl azide for the cycloaddition to the protected hydroxyalkyl alkyne 3, trimethylsilyl azide is a viable replacement reagent (Qian, Y. et al, J. Med. Chem., 2012, 55 , 7920-7939) that can be used under either l or transition-metal catalyzed conditions (Boren, B.C. et. al., J. Am. Chem. Soc., 2008, 130, 8923-8930). Under these conditions, the desired triazole regioisomer 15 is ed as the major product of the 1,3- dipolar cycloaddition reaction, and the trimethylsilyl group is subsequently removed under standard desilylation conditions (e.g. Bu4NF, as in Qian, Y. et al, J. Med. Chem., 2012, 55, 7920-7939).
Scheme 1A.
Scheme 2 describes an alternative synthetic route to the carbamoyloxymethyl triazole -aryloxy cyclohexyl acids 14. A dihalo rably dibromo) phenyl or azine (e.g. pyridine) derivative 1 is d with propargyl l under Sonogashira conditions , P. et al, WO 2008097428) to give the corresponding bromo-aryl or bromo-heteroaryl propargyl alcohol 3. l reaction of alkyne 3 with an alkyl azide 4 (with or without an appropriate catalyst, Qian, Y. et al, J. Med. Chem., 2012, 55, 7920- 7939; Boren, B.C. et. al., J. Am. Chem. Soc., 2008, 130, 8923-8930) provides the corresponding regioisomeric hydroxymethyl -triazoles, from which the desired triazole somer 18 can be isolated. Triazole alcohol 18 is then reacted with 4-nitrophenyl chloroformate in the presence of an appropriate base to give the corresponding triazole 4- nitrophenyl carbonate 19, which is then reacted with an amine 12 in the presence of an appropriate base to give the aryl/heteroaryl-triazole carbamate 20. The bromoaryl /heteroaryl triazole 20 is then converted to the hydroxyaryl or hydroxy-heteroaryl triazole 21 via the corresponding boronate using the 2 step sequence [B(pin)2/Pd-catalysis followed by treatment with H2O2] described in Scheme 1. Hydroxyaryl/heteroaryl le 22 is then reacted with a 3-hydroxy cycloalkylester 8 under Mitsunobu reaction conditions (Kumara Swamy, K. C., Chem. Rev., 2009, 109, 2551-2651) to furnish the ponding triazole cycloalkyl ether ester 13 which is then deprotected to give the desired carbamoyloxy methyltriazole-aryloxy cyclohexyl acids 14.
Scheme 2. r ative synthesis of carbamoyloxymethyl triazole-aryloxy cyclohexyl acids 14 is described in Scheme 3. Reaction of an alkoxyphenyl or azine (e.g. pyridine) derivative 1 with trimethylsilyl ene under Sonogashira conditions (Alper, P. et al, WO 2008097428) gives the corresponding alkoxy-aryl or heteroaryl silyl acetylene 23, which is then lated under standard conditions (e.g. Bu4NF) to give the alkyne 24.
Thermal reaction of alkyne 24 with sodium azide gives the ponding triazole (Roehrig, U. et al, WO 2009127669), which is then alkylated with an alkyl iodide 25 under basic conditions to give a mixture of regioisomeric alkylated triazoles, from which the desired triazole regioisomer 26 can be isolated. Lithiation of triazole 26 (Hernandez, M. et al, US 20120115844) ed by reaction with a formylating agent, e.g. dimethyl formamide, provided the triazole aldehyde 27. Deprotection of the alkoxy group of arene/heteroarene 27 followed by reprotection of the phenol/hydroxy-heteroarene with a more labile protecting group (e.g. t-butyldimethylsilyl ether) gives the protected aryl/heteroaryl triazole aldehyde 28, which is then reduced by standard s (e.g.
NaBH4) to the corresponding triazole alcohol 29. Triazole alcohol 29 is reacted with 4- nitrophenyl chloroformate to give the corresponding triazole ophenyl carbonate 30.
This triazole carbonate 30 is then reacted with an amine 12 in the presence of an appropriate base to give the corresponding triazole carbamate, which subsequently undergoes deprotection to provide the hydroxy aryl/hetero-aryl le ate 21.
The hydroxy aryl/heteroaryl triazole carbamate 21 then is subjected to a Mitsunobu reaction with oxy cycloalkyl ester 8 to furnish the corresponding triazole cycloalkyl ether ester 13, followed by ester deprotection to give the desired carbamoyloxy methyltriazole-aryloxy cyclohexyl acids 14.
Scheme 3.
A different synthetic route for the preparation of le carbamate acids 14 is described in Scheme 4. The protected hydroxyaryl/heteroaryl triazole alcohol 29 is reacted with the intermediate nate generated from a carboxylic acid 31 under Curtius reaction conditions (Seiders, T. et al, WO 2011041694A2) to give the monoalkyl NH-carbamate 32. Base-mediated reaction of NH-carbamate 32 with an appropriate alkyl iodide 33 provides the ponding triazole N-disubstituted carbamate, which is then deprotected to provide the hydroxy aryl/heteroaryl triazole carbamate 21. Hydroxy aryl/heteroaryl triazole carbamate 21 then is subjected to a Mitsunobu reaction with 3- hydroxy cycloalkylester 8 to furnish the corresponding triazole cycloalkyl ether ester 13 followed by ester deprotection to give the d carbamoyloxy methyltriazole-aryloxy cyclohexyl acids 14. Alternatively, the triazole monoalkyl NH-carbamate 32 is deprotected to give the hydroxy aryl/heteroaryl triazole carbamate, which is then reacted with 3-hydroxy cycloalkylester 8 under Mitsunobu on conditions to provide the triazole-aryloxy exyl ester bamate 34. Intermediate NH-carbamate 34 is then alkylated with alkyl iodide 33 under basic ions; subsequent ester deprotection furnishes the desired carbamoyloxy methyltriazole-aryloxy cyclohexyl acids 14.
Scheme 4.
An alternative synthesis of carbamoyloxy methyltriazole-aryloxy cyclohexyl acids 14 from the protected hydroxyalkyltriazole cycloalkyl ether ester 9 is described in Scheme 5. ive deprotection of the alcohol of 9 ed by its reaction with the isocyanate generated from the Curtius rearrangement of an alkyl carboxylic acid 31 provides the triazole NH monoalkyl carbamate 34. The triazole NH-carbamate 34 is then alkylated with alkyl iodide 33 under basic ions, followed by ester deprotection to give the desired carbamoyloxy methyltriazole-aryloxy cyclohexyl acids 14.
Scheme 5.
Scheme 6 decribes the sis of carbamoyloxy methyltriazole-aryloxy -F cyclohexyl acids 42. Diels-Alder on of diene 35 and ethyl 2-fluoroacrylate 36 under thermal conditions (e.g. procedure of Kotikyan et al., Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (Engl.), 1971, 20, 292) gives the -F cyclohexyl ester 37. Hydrolysis of ester 37 under basic condition provides acid 38.
Iodolactonization (e.g. Nolsøe, J. M. J. et al., Eur. J. Org. Chem., 2014, 3051-3065) of the olefin with the ylic acid of 38 gives iodolactone 39. Deiodination under radical condition (e.g. AIBN/ (TMS)3SiH, ref. lialoglu , C. et al., Molecules, 2012, 17, 527- 555) affords lactone 40. ng of lactone 40 via acidic condition (e.g. AcCl in iPrOH) gives the -F cyclohexyl ester 41. The carbamoyloxy methyltriazole-aryloxy -F cyclohexyl acids 42 are synthesized from the -F cyclohexyl ester 41 following the general synthetic procedure described in Schemes 1 or 2.
Scheme 6.
Scheme 7 decribes the synthesis of carbamoyloxy methyltriazole-aryloxy cyclohexyl acids 44. Addition of an alkyl organometallic reagent (e.g R13Li or R13MgX) to aldehyde 28 gives triazole alcohol 43. The carbamoyloxy methyltriazole-aryloxy cyclohexyl acids 44 can then be synthesized from triazole alcohol 43 following the general synthetic procedure described in Scheme 3.
Scheme 7.
Scheme 8 bes the sis of carbamoyloxy methyltriazole-aryloxy cyclohexyl amides 45, tetrazoles 47 and acyl amide 48. Treatment of acid 14 with AcCl followed by ammonia gives primary amide 45. Dehydration of primary amide 45 with Burgess reagent (Talibi, P. et al., e-EROS Encyclopedia of Reagents for c Synthesis, published online 15 Sept. 2008, DOI: 10.1002/047084289X.rm095m.pub2) furnishes nitrile 46. Cycloaddition of azide to nitrile 46 affords the ole 47. In a similar manner to the preparation of amides 45, acyl sulfonamides 48 can be synthesized by the reaction of carboxylic acid 14 with methyl amide using standard coupling agents (e.g. EDC/DMAP).
Scheme 8 Scheme 9 describes the synthesis of carbamoyloxyethyl triazole-aryloxy cyclohexyl acids 53. The protected l intermediate 9 is deprotected to the corresponding alcohol, which is then oxidized to the corresponding aldehyde (e.g. Dess- Martin periodinane or Swern oxidation) which is then subjected to an olefination reaction (e.g. Witting or Peterson olefination reaction) which provides the terminal olefin 49.
Hydroboration of olefin 49 at the terminal carbon (e.g. with 9-BBN), ed by oxidative workup, provides the corresponding triazole ethyl alcohol 50. Triazole ethyl alcohol 50 is d with 4-nitrophenyl chloroformate in the presence of an riate base to give the corresponding triazole 4-nitrophenyl carbonate 51. The tri azole 4- nitrophenyl carbonate 51 is then reacted with an amine 12 in the ce of an appropriate base to give the triazole carbamate 52, which then undergoes ester deprotection to give the desired carbamoyloxyethyltriazole-aryloxy cycloalkyl acids 53.
Scheme 9.
Scheme 10 describes the sis of carbamoyloxypropyl triazole-aryloxy cyclohexyl acids 58. The protected alcohol intermediate 9 is deprotected to the corresponding alcohol, then is oxidized to the ponding aldehyde which is then subjected to olefination conditions (eg. Wittig reaction with a reagent with an appropriately protected alcohol such as 2-(benzyloxy) ethylidene) as shown) which provides olefin 54 as a mixture of cis/trans isomers. Hydrogenation of the olefin, followed by deprotection of the alcohol (e.g. using hydrogenolysis with H2), provides the ponding triazole alcohol 55. The triazole alcohol 55 is reacted with 4-nitrophenyl chloroformate in the presence of an appropriate base to give the corresponding triazole 4- nitrophenyl carbonate 56. The tri azole 4-nitrophenyl carbonate 56 is then reacted with an amine 12 in the ce of an appropriate base to give the triazole carbamate 57, which then undergoes ester deprotection to give the d oyloxypropyltriazole-aryloxy cycloalkyl acids 58.
Scheme 10.
Abbreviations as used , are defined as follows: "1 x" for once, "2 x" for twice, "3 x" for thrice, " °C" for degrees Celsius, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for ram or milligrams, "L" for liter or liters, "mL" for milliliter or milliliters, "μL" for microliter or microliters, "N" for normal, "M" for molar, "mmol" for millimole or millimoles, "min" for minute or minutes, "h" for hour or hours, "rt" for room temperature, "RT" for retention time, “RBF” for round bottom flask, "atm" for atmosphere, "psi" for pounds per square inch, "conc." for concentrate, “RCM” for losing metathesis, "sat" or "sat'd " for saturated, “SFC” for supercritical fluid chromatography "MW" for molecular weight, "mp" for melting point, "ee" for enantiomeric excess, "MS" or "Mass Spec" for mass spectrometry, "ESI" for electrospray ionization mass spectroscopy, "HR" for high resolution, "HRMS" for high resolution mass spectrometry, "LCMS" for liquid chromatography mass spectrometry, "HPLC" for high re liquid tography, "RP HPLC" for reverse phase HPLC, "TLC" or "tlc" for thin layer chromatography, "NMR" for nuclear magnetic nce spectroscopy, "nOe" for nuclear Overhauser effect spectroscopy, "1H" for proton, "δ" for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" for broad, "Hz" for hertz, and "", "", “”, "R", "S", "E", and "Z" are stereochemical designations familiar to one skilled in the art.
Me methyl Et ethyl Pr propyl i-Pr isopropyl Bu butyl i-Bu isobutyl t-Bu tert-butyl Ph phenyl Bn benzyl Boc or BOC tert-butyloxycarbonyl Boc2O di-tert-butyl dicarbonate AcOH or HOAc acetic acid AlCl3 aluminum trichloride AIBN Azobis-isobutyronitrile BBr3 boron tribromide BCl3 boron trichloride BEMP -butyliminodiethylamino-1,3-dimethylperhydro-1,3,2- diazaphosphorine BOP reagent benzotriazolyloxytris(dimethylamino)phosphonium uorophosphate Burgess reagent 1-methoxy-N-triethylammoniosulfonyl-methanimidate CBz carbobenzyloxy DCM or CH2Cl2 dichloromethane CH3CN or ACN acetonitrile CDCl3 deutero-chloroform CHCl3 chloroform mCPBA or m-CPBA meta-chloroperbenzoic acid Cs2CO3 cesium carbonate Cu(OAc)2 copper (II) acetate Cy2NMe N-cyclohexyl-N-methylcyclohexanamine DBU 1,8-diazabicyclo[5.4.0]undecene DCE 1,2 dichloroethane DEA diethylamine Dess-Martin 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol(1H)-one DIC or DIPCDI diisopropylcarbodiimide DIEA, DIPEA or diisopropylethylamine Hunig's base DMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethane DMF yl formamide DMSO dimethyl sulfoxide cDNA complementary DNA Dppp (R)-(+)-1,2-bis(diphenylphosphino)propane DuPhos (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene EDC N-(3-dimthylaminopropyl)-N΄-ethylcarbodiimide EDCI N-(3-dimthylaminopropyl)-N΄-ethylcarbodiimide hydrochloride EDTA ethylenediaminetetraacetic acid EtDuPhosRh(I) (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5- cyclooctadiene)rhodium(I) trifluoromethanesulfonate Et3N or TEA triethylamine EtOAc ethyl acetate Et2O diethyl ether EtOH ethanol GMF glass microfiber filter Grubbs II (1,3-bis(2,4,6-trimethylphenyl)imidazolidinylidene)dichloro (phenylmethylene)(triycyclohexylphosphine)ruthenium HCl hydrochloric acid HATU zabenzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate HEPES 4-(2-hydroxyethyl)piperaxineethanesulfonic acid Hex hexane HOBt or HOBT 1-hydroxybenzotriazole H2O2 hydrogen peroxide IBX 2-iodoxybenzoic acid H2SO4 sulfuric acid Jones reagent CrO3 in aqueous H2SO4, 2 M solution K2CO3 potassium carbonate K2HPO4 potassium phosphate dibasic (potassium hydrogen phosphate) KOAc potassium e K3PO4 potassium phosphate tribasic LAH lithium aluminum e LG leaving group LiOH lithium hydroxide MeOH methanol MgSO4 magnesium e MsOH or MSA methylsulfonic ethanesulfonic acid NaCl sodium chloride NaH sodium hydride NaHCO3 sodium bicarbonate Na2CO3 sodium carbonate NaOH sodium hydroxide Na2SO3 sodium sulfite Na2SO4 sodium sulfate NBS N-bromosuccinimide NCS N-chlorosuccinimide NH3 ammonia NH4Cl ammonium chloride NH4OH ammonium hydroxide O2- ammonium formate NMM N-methylmorpholine OTf triflate or trifluoromethanesulfonate Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd(OAc)2 palladium(II) acetate Pd/C palladium on carbon Pd(dppf)Cl2 [1,1΄-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) Ph3PCl2 triphenylphosphine dichloride PG protecting group POCl3 phosphorus oxychloride PPTS pyridinium p-toluenesulfonate i-PrOH or IPA isopropanol PS Polystyrene RT or rt room temperature SEM-Cl 2-(trimethysilyl)ethoxymethyl de SiO2 silica oxide SnCl2 tin(II) chloride TBAF tra-n-butylammonium fluoride TBAI n-butylammonium iodide TFA trifluoroacetic acid THF tetrahydrofuran THP tetrahydropyran TMSCHN2 Trimethylsilyldiazomethane TMSCH2N3 Trimethylsilylmethyl azide T3P propane phosphonic acid anhydride TRIS tris (hydroxymethyl) aminomethane pTsOH p-toluenesulfonic acid VII. ES The following Examples are offered as illustrative, as a partial scope and particular embodiments of the invention and are not meant to be limiting of the scope of the invention. iations and chemical symbols have their usual and customary meanings unless otherwise indicated. Unless otherwise indicated, the compounds described herein have been prepared, isolated and characterized using the schemes and other methods disclosed herein or may be ed using the same.
As appropriate, reactions were conducted under an atmosphere of dry nitrogen (or . For anhydrous reactions, DRISOLV® solvents from EM were employed. For other reactions, reagent grade or HPLC grade solvents were utilized. Unless otherwise stated, all commercially obtained reagents were used as received.
HPLC/MS and preparatory/analytical HPLC methods employed in characterization or purification of examples NMR (nuclear magnetic resonance) spectra were typically obtained on Bruker or JEOL 400 MHz and 500 MHz instruments in the indicated solvents. All chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as the internal standard. 1HNMR spectral data are typically reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, sep = septet, m = let, app = apparent), coupling nts (Hz), and ation.
In the examples where 1H NMR spectra were collected in d6-DMSO, a watersuppression sequence is often utilized. This ce ively suppresses the water signal and any proton peaks in the same region usually between 3.30-3.65 ppm which will affect the overall proton integration.
The term HPLC refers to a Shimadzu high performance liquid chromatography instrument with one of following methods: HPLC-1: Sunfire C18 column (4.6 × 150 mm) 3.5 m, nt from 10 to 100% B:A for 12 min, then 3 min hold at 100% B.
Mobile phase A: 0.05% TFA in CH3CN (95:5) Mobile phase B: 0.05% TFA in CH3CN:water (95:5) TFA Buffer pH = 2.5; Flow rate: 1 mL/ min; Wavelength: 254 nm, 220 nm.
HPLC-2: XBridge Phenyl (4.6 × 150 mm) 3.5 m, gradient from 10 to 100% B:A for 12 min, then 3 min hold at 100% B.
Mobile phase A: 0.05% TFA in water:CH3CN (95:5) Mobile phase B: 0.05% TFA in CH3CN:water (95:5) TFA Buffer pH = 2.5; Flow rate: 1 mL/ min; Wavelength: 254 nm, 220 nm.
HPLC-3: Chiralpak AD-H, 4.6 × 250 mm, 5 m.
Mobile Phase: 30% EtOH-heptane (1:1) / 70% CO2 Flow rate = 40 mL/min, 100 Bar, 35 °C; Wavelength: 220 nm HPLC-4: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-μm particles; Mobile Phase A: 5:95 CH3CN:water with 10 mM ; Mobile Phase B: 95:5 CH3CN:water with 10 mM NH4OAc; Temperature: 50 °C; Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
HPLC-5: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-μm les; Mobile Phase A: 5:95 CH3CN:water with 0.1% TFA; Mobile Phase B: 95:5 CH3CN:water with 0.1% TFA; ature: 50 °C; Gradient: 0-100% B over 3 min, then a 0.75-min hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
Intermediate 1 ()-cis-isopropyl rohydroxycyclohexanecarboxylate Intermediate 1A ()-ethyl 1-fluorocyclohexenecarboxylate A mixture of 20% ,3-diene in toluene (13.8 mL, 41.1 mmol) and ethyl 2- fluoroacrylate (3.07 mL, 27.4 mmol) was heated at 120 °C in a sealed tube for 7 days.
The reaction was cooled to rt and concentrated in vacuo. The residue was chromatographed (80 g SiO2) with EtOAc/Hexane (continuous gradient from 0% to 10% EtOAc over 20 min) to give ediate 1A (3.80 g, 22.1 mmol, 80 % yield) as a clear oil. 1H NMR (500 MHz, CDCl 3)  5.79 (ddd, J=9.9, 4.7, 2.2 Hz, 1H), 5.64 - 5.58 (m, 1H), 4.26 (q, J=7.2 Hz, 2H), 2.73 - 2.57 (m, 1H), 2.45 - 2.23 (m, 2H), 2.20 - 1.91 (m, 3H), 1.32 (t, J=7.2 Hz, 3H); 19F NMR (471 MHz, CDCl3)  -162.69 (s, 1F). ediate 1B ()fluorocyclohexene carboxylic acid A mixture of Intermediate 1A (3.80 g, 22.1 mmol) and aq. LiOH (55.2 mL of a 2.0 M solution, 110 mmol) in THF (50 mL) was stirred at rt for 18 h. The reaction was acidified to pH = 2 with conc. HCl (9.19 mL, 110 mmol), and then extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with water and concentrated in vacuo to give Intermediate 1B (3.0 g, 20.8 mmol, 94 % yield) as a light yellowish oil. 1H NMR (500 MHz, CDCl3)  5.81 (ddd, J=9.8, 4.6, 2.1 Hz, 1H), 5.66 - 5.58 (m, 1H), 2.76 - 2.59 (m, 1H), 2.49 - 2.37 (m, 1H), 2.35 - 2.23 (m, 1H), 2.22 - 1.92 (m, 3H); 19F NMR (471 MHz, CDCl3)  -163.02 (s, 1F).
Intermediate 1C ()fluoroiodooxabicyclo[3.2.1]octanone To a mixture of Intermediate 1B (3.0 g, 20.8 mmol) in water (20 mL) was added NaHCO3 (5.25 g, 62.4 mmol) portionwise and the mixture was d until it became homogeneous. An aq. I2 solution (prepared by dissolving I2 (5.81 g, 22.0 mmol) and KI (20.7 g, 125 mmol) in 20 mL water) was added and the reaction was stirred overnight at rt in the dark. Water (100 mL) was then added and the mixture was extracted with DCM (3 x 25 mL), washed with 10% aq. Na2S2O3 (20 mL x 2) and water, dried (MgSO4) and concentrated in vacuo. The residual crude oil was chromatographed (80 g SiO2) with EtOAc/Hexane (continuous gradient from 0% to 50% EtOAc over 20 min) to give Intermediate 1C (3.53 g, 13.1 mmol, 62.8 % yield) as a white solid. 1H NMR (500 MHz, CDCl3)  4.89 (dt, J=6.5, 3.5 Hz, 1H), 4.44 (q, J=4.6 Hz, 1H), 3.08 (dd, J=11.6, 1.9 Hz, 1H), 2.75 (tddd, J=11.3, 6.5, 3.3, 1.1 Hz, 1H), 2.50 - 2.38 (m, 1H), 2.34 - 2.17 (m, 2H), 2.11 - 1.99 (m, 1H); 13C NMR (126 MHz, CDCl 3)  172.2, 172.0, 93.6, 91.9, 78.4, 78.3, 39.2, 39.0, 29.7, 29.6, 28.4, 28.2, 20.2; 19F NMR (471 MHz, CDCl3)  -167.97 (s, 1F) Intermediate 1D ()fluorooxabicyclo[3.2.1]octanone To a solution of intermediate 1C (350 mg, 1.30 mmol) and AIBN (21 mg, 0.130 mmol) in e (5 mL) was added tris(trimethylsilyl)silane (0.60 mL, 1.94 mmol) nwise over 10 min at 60 °C. The reaction was stirred at 70 °C for 2 h, cooled to rt and then concentrated in vacuo. The residue was dissolved in EtOAc, washed with sat. aq.
NH4Cl, dried (MgSO4) and concentrated in vacuo. The crude oil was chromatographed (12 g SiO2) with EtOAc/Hexane (continuous nt from 0% to 30% EtOAc over 10 min) to give Intermediate 1D (124 mg, 0.860 mmol, 66.4 % yield) as a white solid. 19F NMR (471 MHz, CDCl3)  -167.01 (s, 1F); 1H NMR (500 MHz, CDCl 3)  4.98 - 4.81 (m, 1H), 2.75 (dtdd, , 6.8, 3.3, 1.7 Hz, 1H), 2.24 - 1.89 (m, 5H), 1.82 - 1.65 (m, 1H), 1.60 - 1.46 (m, 1H); 13C NMR (126 MHz, CDCl 3)  173.2, 173.0, 93.9, 92.3, 75.6, 75.5, 42.0, 41.9, 31.3, 31.1, 26.7, 17.7, 17.6 Intermediate 1 Acetyl chloride (0.061 mL, 0.860 mmol) was added portionwise to isopropanol (3 mL) at 0 °C and then stirred at rt for 30 min. Intermediate 1D (124 mg, 0.860 mmol) was added and the reaction was stirred overnight at rt, then was concentrated in vacuo. The residual crude oil was chromatographed (4 g SiO2) with EtOAc/Hexane (continuous gradient from 0% to 50% EtOAc over 10 min) to give Intermediate 1 (140 mg, 0.685 mmol, 80 % yield) as a clear oil. 1H NMR (500 MHz, CDCl 3)  5.08 (spt, J=6.3 Hz, 1H), 3.91 (tt, J=10.9, 4.4 Hz, 1H), 2.68 (br. s., 1H), 2.28 (dddt, J=13.5, 9.0, 4.6, 2.1 Hz, 1H), 2.06 - 1.98 (m, 1H), 1.96 - 1.87 (m, 1H), 1.82 - 1.62 (m, 4H), 1.37 - 1.22 (m, 7H); 19F NMR (471 MHz, CDCl3)  -162.93 (s, 1F); 13C NMR (126 MHz, CDCl 3)  170.9, 170.7, 95.7, 94.2, 69.3, 66.1, 40.7, 40.5, 33.9, 31.6, 31.4, 21.5, 19.1 Intermediate 2 isopropyl (3R)hydroxycyclohexanecarboxylated Intermediate 2A isopropyl )((tert-butyldimethylsilyl)oxy)cyclohexane ylate To a solution of (1S,3R)-isopropyl 3-hydroxycyclohexanecarboxylate (0.5 g, 2.68 mmol) and imidazole (0.238 g, 3.49 mmol) in DCM (4 mL) was added tertbutylchlorodimethylsilane (0.486 g, 3.22 mmol) in DCM (1 mL) dropwise over 5 min, stirred at rt overnight. The reaction was diluted with Et2O (20 mL). The mixture was washed with brine (10 mL); the white aqueous phase was separated and the organic phase was washed with water (10 mL), dried over Na2SO4 and trated in vacuo. The crude oil was chromatographed (80 g SiO2) using a gradient of EtOAc/Hexane (0% to 20% over min) to give (1S,3R)-isopropyl 3-((tertbutyldimethylsilyl )oxy)cyclohexanecarboxylate (0.60 g, 1.897 mmol, 70.7 % yield) as a clear oil. 1H NMR (500 MHz, CDCl3)  5.08 - 4.95 (m, 1H), 3.65 - 3.51 (m, 1H), 2.40 - 2.21 (m, 1H), 2.09 (d, J=12.7 Hz, 1H), 1.94 - 1.76 (m, 3H), 1.50 - 1.35 (m, 1H), 1.34 - 1.17 (m, 9H), 0.91 (s, 9H), 0.13 - 0.05 (m, 6H) Intermediate 2B isopropyl (1S,3R)((tert-butyldimethylsilyl)oxy)cyclohexane carboxylate A solution of LDA (1.664 ml, 3.33 mmol) was added under Ar to a solution of intermediate 2A (0.5 g, 1.66 mmol) in THF (6.66 mL) at -78° and the resultant mixture was stirred for 60 min. Then D2O (0.90 mL, 49.9 mmol) was added and the reaction was d to warm to rt. Saturated aq. NH4Cl (3 mL) was added and the solution was allowed to warm to rt. The reaction mixture was extracted with EtOAc (10 mL), and the ed organic extracts were washed with aq. HCl (10 mL of a 2 M solution), saturated aq. NaHCO3 and then brine. The organic layer was dried over MgSO4, filtered, then concentrated in vacuo to give an oil as the crude product (used in the next step without further purification) (1S,3R)-isopropyl 3-((tert- butyldimethylsilyl)oxy)cyclohexanecarboxylate (0.50 g, 1.66 mmol). LCMS, [M+H]+ = 302.1.
Intermediate 2 To a solution of intermediate 2B (0.53 g, 1.758 mmol) in THF (3 mL) was added Bu4NF (3.52 mL of a 1 M solution, 3.52 mmol) at rt and stirred overnight. The reaction was then quenched with 1.5 M aq. potassium phosphate (10 mL) and extracted with EtOAc (10 mL). The organic extract was concentrated in vacuo and chromatographed (24 g SiO2, continuous nt from 0 to 100% EtOAc/Hexanes over 30 min, then at 100% EtOAc for 10 min) to give ediate 2 (0.17 g, 0.908 mmol, 51.6 % yield). 1H NMR (500 MHz, CDCl3)  5.02 (dt, , 6.2 Hz, 1H), 4.11 (t, J=4.3 Hz, 1H), 1.84 (d, J=4.1 Hz, 3H), 1.77 - 1.68 (m, 1H), 1.65 - 1.49 (m, 5H), 1.24 (d, J=6.3 Hz, 6H).
Example 1 (1S,3S)((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid 1A 3-bromomethyl(3-((tetrahydro-2H-pyranyl)oxy)propynyl)pyridine To a solution of 2,5-dibromomethyl-pyridine (5 g, 21.11 mmol) and p ynyloxy) tetrahydro-2H-pyran (4.44 g, 31.7 mmol) in MeCN (42.2 mL) was added Et3N (8.83 mL, 63.3 mmol). The solution was degassed under N2, then dichlorobis (triphenylphosphine) palladium (II) chloride (0.74 g, 1.06 mmol) and CuI (0.20 g, 1.06 mmol) were added. The reaction was stirred at rt for 14 h, after which the reaction mixture was filtered through a Celite plug and the plug was washed with EtOAc (2 X 10 mL). The filtrate was concentrated in vacuo and the residue was chromatographed (SiO2; continuous gradient from 0% to 100% EtOAc in Hexanes for 20 min) to give the title compound as a white solid (6.0 g, 20.3 mmol, 96 % yield). 1H NMR (400 MHz, CDCl 3)  8.65 (d, J=2.0 Hz, 1H), 7.80 (dd, J=8.3, 2.3 Hz, 1H), 7.35 (dd, J=8.4, 0.4 Hz, 1H), 4.91 (t, J=3.3 Hz, 1H), 4.61 - 4.45 (m, 2H), 3.98 - 3.81 (m, 1H), 3.66 - 3.44 (m, 1H), 1.92 - 1.73 (m, 2H), 1.72 - 1.52 (m, 2H). LCMS, [M+H]+ = 298.0. 1B 3-bromomethyl(1-methyl(((tetrahydro-2H-pyranyl)oxy)methyl)-1H-1,2,3- triazolyl)pyridine A solution of 1A (6.0 g, 20.3 mmol) in toluene (20 mL) and TMSCH2N3 (7.85 g, 60.8 mmol) was heated at 90 °C under Ar for 15 h, then was cooled to rt. les were removed in vacuo and the e was dissolved in THF (20 mL). To the mixture was added TBAF (20.3 mL of a 1 M solution in THF, 20.3 mmol) at 0 C. After stirring for min, the reaction was complete as determined by analytical HPLC. Volatiles were removed in vacuo and the residue was chromatographed (SiO2, continuous gradient from 0% to 100% EtOAc in hexanes over 20 min) to give the title compound (2.1 g, 29 % yield) as a white solid. 1H NMR (400MHz, CHLOROFORM-d)  7.85 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.03 (br. s., 1H), 5.39 - 5.23 (m, 4H), 4.81 - 4.76 (m, 1H), 4.17 (s, 3H), 3.91 (ddd, J=11.3, 7.9, 3.3 Hz, 1H), 3.65 - 3.48 (m, 1H), 2.54 (s, 3H), 1.88 - 1.68 (m, 2H), 1.56 (br. s., 2H) Alternatively, 1B can be synthesized by the following procedure: To a stirred solution of 1A (4.0 g, 13.5 mmol) in DMF (45 mL) under N2 was added NaN3 (2.63 g, 40.5 mmol). The reaction mixture was stirred at 90 °C for 36 h, then was cooled to rt and filtered through Celite. To the filtrate was added K 2CO3 (3.73 g, 27.0 mmol) and the on mixture was d at rt for 10 min. CH3I (1.27 mL, 20.3 mmol) was added dropwise and the reaction mixture was stirred at rt for 16 h, then was diluted with water (150 mL) and extracted with EtOAc (2 x 100 mL). The ed c extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residual mixture of products (the 2 yl triazole regioisomers) were separated by flash chromatography (40 g Redisep® SiO2 column, eluting with 21 % EtOAc in hexanes). The desired regioisomer product, title nd 1B, was isolated as a white solid (1.0 g, 21%). LC-MS, [M+2]+ = 355.2. 1H NMR (400 MHz, CDCl 3)  ppm 8.64 (d, J=2.0 Hz, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.83 - 7.92 (m, 1H), 5.27 (s, 2H), 4.68 - 4.77 (m, 1H), 4.17 (s, 3H), 3.80 - 3.90 (m, 1H), 3.49 - 3.57 (m, 1H), 1.67 - 1.80 (m, 2H), 1.56 - 1.62 (m, 2H), 1.49 - 1.55 (m, 2H). 1C 2-methyl(1-methyl(((tetrahydro-2H-pyranyl)oxy)methyl)-1H-1,2,3-triazol yl)pyridinol To a degassed solution (sparged with Ar 3X) of 1B (213 mg, 0.60 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane (230 mg, 0.91 mmol) and KOAc (178 mg, 1.81 mmol) in THF was added f)Cl2 (22 mg, 0.03 mmol). The reaction mixture was heated in a sealed tube at 80 C for 16 h, then was cooled to rt and partitioned between water and EtOAc. The s layer was extracted with EtOAc (3 X mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude boronate product was carried on to the next step without further purification. To a solution of the crude product, 2-(1-methyl (((tetrahydro-2H-pyranyl)oxy)methyl)-1H-1,2,3-triazolyl)(4,4,5,5-tetramethyl- dioxaborolanyl)pyridine (241 mg, 0.603 mmol) in EtOAc (2 mL) was added H2O2 (0.19 mL of a 30% aqueous solution, 6.0 mmol). The reaction mixture was d at rt for 1h, then was cooled to 0 C and quenched by slowly adding sat. aq. Na2S2O3. The aqueous layer was extracted with EtOAc (3 X 20 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed (SiO2, continuous gradient from 0% to 100% EtOAc in Hexanes, min) to give the title compound (150 mg, 86%) as as a white solid. 1H NMR (400M Hz, CDCl3)  8.27 (d, J=2.6 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 7.29 - 7.21 (m, 1H), 5.33 (s, 1H), 5.28 (d, J=2.4 Hz, 2H), 4.76 (s, 1H), 4.18 (s, 3H), 3.90 (s, 1H), 3.63 - 3.48 (m, 1H), 1.72 (s, 2H), 1.65 - 1.51 (m, 2H). LCMS, [M+H]+ = 291.2. 1D. isopropyl )((2-methyl(1-methyl(((tetrahydro-2H-pyran yl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylate To a solution of 1C (1.18 g, 4.06 mmol) and (1S, 3R)-isopropyl 3-hydroxy cyclohexanecarboxylate (synthesized according to the procedure described in US2007/0197788A1, 1.51 g, 8.13 mmol) in toluene (81 mL) was added Bu3P (3.17 mL, 12.2 mmol). To this d mixture was added (E)-diazene-1,2-diylbis(piperidin ylmethanone) (3.08 g, 12.2 mmol) portionwise, and the reaction mixture was heated at 50 °C for 120 min, then was cooled to rt. At this point an LC -MS of the on mixture showed the presence of the desired product. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed (SiO2, continuous gradient from 0% to 100% EtOAc in Hexanes, 20 min) to give the title compound (1.20 g, 2.62 mmol, 64.4 % yield) as a white foam. 1H NMR (400 MHz, CDCl 3)  7.95 (d, J=8.6 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 5.45 - 5.24 (m, 2H), 5.04 (dt, J=12.5, 6.3 Hz, 1H), 4.83 - 4.64 (m, 2H), 4.16 (s, 3H), 3.91 (ddd, , 7.9, 3.1 Hz, 1H), 3.64 - 3.48 (m, 1H), 2.93 - 2.71 (m, 1H), 2.52 (s, 3H), 2.23 - 1.45 (m, 14H), 1.26 (dd, J=6.4, 2.0 Hz, 6H). 1E. isopropyl (1S,3S)((6-(5-(hydroxymethyl)methyl-1H-1,2,3-triazolyl) methylpyridinyl)oxy)cyclohexanecarboxylate To a solution of 1D (1.7 g, 3.71 mmol) in MeOH (37 mL) added pyridinium ptoluenesulfonate (0.932 g, 3.71 mmol). The reaction mixture was heated to 60C for 2h, then was cooled to rt, diluted with water and sat. aq. NaHCO3, then extracted with EtOAc (3 X 10 mL). The combined organic extracts were trated in vacuo and tographed (SiO2; continuous gradient from 0% to 100% EtOAc in Hexanes, 20 min) to give the title compound as a white foam (1.36 g, 3.63 mmol, 98 % yield). 1H NMR (400 MHz, CDCl3)  8.01 (d, J=8.6 Hz, 1H), 7.46 (d, J=5.1 Hz, 1H), 7.27 - 7.15 (m, 1H), 4.96 (dt, J=12.5, 6.3 Hz, 1H), 4.74 (s, 2H), 4.66 - 4.59 (m, 1H), 4.00 (s, 3H), 2.80 - 2.64 (m, 1H), 2.46 (s, 3H), 2.07 - 1.50 (m, 8H), 1.18 (dd, J=6.4, 2.2 Hz, 6H). 1F. isopropyl (1S,3S)((2-methyl(1-methyl((((4- nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane- 1-carboxylate To a solution of 1E (1.36 g, 3.63 mmol) and 4-nitrophenyl chloroformate (2.20 g, .9 mmol) in DCM (36.3 mL) was added pyridine (1.47 mL, 18.2 mmol). The reaction mixture was d at rt for 2 h. LCMS showed the desired product at this point. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed (SiO2, continuous gradient from 0% to 100% EtOAc in Hexanes, 20 min) to afford the title compound as a white solid (1.66 g, 3.08 mmol, 85% yield). 1H NMR (400 MHz, CDCl3)  8.30 (d, J=9.2 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.41 (d, J=9.2 Hz, 2H), 7.25 (d, J=8.6 Hz, 1H), 6.07 (s, 2H), 5.05 (quin, J=6.2 Hz, 1H), 4.72 (br. s., 1H), 4.22 (s, 3H), 2.91 - 2.73 (m, 1H), 2.52 (s, 3H), 2.21 - 1.61 (m, 9H), 1.27 (dd, J=6.3, 1.9 Hz, 6H). 1G. isopropyl (1S,3S)((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylate To a solution of 1F (5 g, 9 mmol) and DIPEA (1.5 L, 9 mmol) in THF (0.5 mL) was added N-methylcyclopentanamine (1 mg, 9 mmol). The reaction mixture was stirred at rt overnight, after which LC-MS showed the desired t. Volatiles were removed in vacuo and the e was dissolved in EtOAc and washed with aq. 1N NaOH (5 x 10 mL) until the yellow color had disappeared. The organic layer was concentrated in vacuo. The residue was used for the next step without purification. LCMS, [M+H]+ = 514.4.
Example 1 To a stirred solution of 1G (4.6 mg, 9 mol) in THF (0.5 mL), MeOH (0.1 mL) and water (0.1 mL) at rt was added aq 2O (0.023 mL of a 2.0 M solution, 0.045 mmol). The reaction mixture was stirred at 50 C for 2h, after which LC-MS showed that all ng material had been consumed. The mixture was acidified to pH = ~1 by dropwise addition of 1M aq. HCl. The mixture was extracted with EtOAc (3 x 15 mL); the combined organic extracts were concentrated in vacuo. The e was purified by preparative HPLC (PHENOMENEX®, Axia 5µ C18 30x100 mm column; detection at 220 nm; flow rate=40 mL/min; continuous gradient from 0% B to 100%B over 10 min+2 min hold time at 100% B, where A=90:10:0.1 H2O:MeOH:TFA and B=90:10:0.1 MeOH:H2O:TFA) (to give the title compound as an oil (3.2 mg, 75%). LCMS, [M+H]+ = 472.3. 1H NMR (500 MHz, DMSO-d 6)  7.84 (d, J=8.2 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), .64 (br. s., 2H), 4.79 (br. s., 1H), 4.10 (s, 3H), 2.66 (br. s., 4H), 2.42 (s, 3H), 2.10 - 1.31 (m, 17H). hLPA1 IC50 = 24 nM. Acute in vivo histamine assay in CD-1 mice : -97% histamine at a 3 mg/kg dose of e 1.
Example 2 (1S,3S)((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid 2A. 3-(5-bromopyridinyl)propynol To a solution of 3,6-dibromopyridine (25.0 g, 100 mmol)) and propynol (8.70 mL, 149 mmol) in MeCN (141 mL) was added Et3N (33.2 mL, 240 mmol). The solution was degassed under Ar (sparged with Ar 3X), after which trans- robis(triphenlyphosphine) palladium (II) de (2.96 g, 4.22 mmol) and CuI (0.804 g, 4.22 mmol) were added. The reaction was stirred at rt under Ar for 14 h; the mixture was ed through a Celite plug, which was washed with EtOAc (3 X 50 mL).
The combined filtrates were concentrated in vacuo. The residue was chromatographed (SiO2; continuous nt from 0% to 100% EtOAc in Hexanes, 20 min) to give the title compound as a white solid (16.6 g, 74 % yield). 1H NMR (400 MHz, CD 3OD)  8.60 (d, J=2.2 Hz, 1H), 7.99 (dd, J=8.4, 2.2 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 4.41 (s, 2H) 2B (4-(5-bromopyridinyl)methyl-1H-1,2,3-triazolyl)methanol To a degassed (sparged with Ar 3X) solution of 2A (1.9 g, 8.40 mmol) in e (42.0 mL) was added chloro(pentamethylcyclopentadienyl)bis (triphenyl-phosphine) ruthenium (II) (0.402 g, 0.504 mmol). The mixture was degassed 3 times under Ar again and TMSCH2N3 (1.87 mL, 12.6 mmol) was added. The reaction was stirred at 50 °C for h under Ar, then cooled to rt and concentrated in vacuo. The oily residue was dissolved in THF (90 mL) and cooled to 0 °C. TBAF (5.40 mL of a 1.0 M solution in THF; 5.40 mmol) was added and the reaction was stirred at 0 °C for 10 min, after which solid NaHCO3 (4 g) was added. The reaction mixture was stirred for 30 min at rt and then filtered. The filtrate was concentrated in vacuo. The residue was chromatographed (SiO2; continuous gradient from 0% to 100% EtOAc in Hexanes, 20 min) to give the title compound (1.30 g, 4.59 mmol, 102 % yield) as a white solid. 1H NMR (500 MHz, CDCl3)  8.49 (dd, J=2.3, 0.7 Hz, 1H), 8.08 (dd, J=8.5, 0.6 Hz, 1H), 7.83 (dd, J=8.5, 2.2 Hz, 1H), 6.16 (t, J=6.9 Hz, 1H), 4.68 (d, J=6.9 Hz, 2H), 3.95 (s, 3H). 2C (4-(5-bromopyridinyl)methyl-1H-1,2,3-triazolyl)methyl (4-nitrophenyl) carbonate To a solution of 2B (1.22 g, 4.31 mmol) in CH2Cl2 (50 mL) was added pyridine (1.74 mL, 21.55 mmol) and ophenyl chloroformate (1.74 g, 8.62 mmol). The reaction was stirred at rt for 1h, then was trated in vacuo. The residual solid was triturated with CH2Cl2 and filtered to give the pure title compound. The filtrate was concentrated in vacuo and the residue was chromatographed (SiO2; continuous gradient from 0% to 100% EtOAc in DCM, 20 min); this ed material was combined with the previously triturated compound to give the title compound as a white solid (1.66 g, 86%).
LCMS, [M+H]+ = 434.1. 2D. (4-(5-bromopyridinyl)methyl-1H-1,2,3-triazolyl)methyl cyclopentyl(methyl)carbamate To a solution of 2C (140 mg, 0.31 mmol) in THF (6.2 mL) was added iPr2NEt (109 L, 0.62 mmol) and 1-cyclobutyl-N-methylmethanamine (31 mg, 0.31 mmol). The reaction was d at rt for 2h, then was concentrated in vacuo. The residue was chromatographed (SiO2; continuous gradient from 0% to 100% EtOAc in Hexanes, 20 min) to give the title compound as a white solid (100 mg, 78%). 1H NMR (400 MHz, CDCl3)  8.66 (dd, J=2.4, 0.7 Hz, 1H), 8.11 (dd, J=8.6, 0.7 Hz, 1H), 7.89 (dd, J=8.6, 2.4 Hz, 1H), 5.74 (s, 2H), 4.15 (s, 3H), 2.88 - 2.59 (m, 3H), 1.87 - 1.38 (m, 9H) 2E. (4-(5-Hydroxypyridinyl)methyl-1H-1,2,3-triazolyl)methyl (cyclobutylmethyl)(methyl)carbamate To a degassed (sparged with Ar 3X) solution of 2D (151 mg, 3.70 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.41 g, 5.55 mmol), and potassium e (1.45 g, 14.8 mmol) in THF (25 mL) was added Pd(dppf)Cl2 (0.271 g, 0.370 mmol) and the reaction was heated at 60 C ght under Ar, then cooled to rt.
Water (10 mL) was added and the mixture was extracted with EtOAc (2 X 20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried (MgSO4) and trated in vacuo. The residual crude boronate product was dissolved in EtOAc (15 mL) and H2O2 (1.62 mL of a 30% aq. solution, 18.5 mmol) was carefully added portionwise at 0C. The reaction was allowed to warm to rt and stirred at rt for 1h, then was cooled 0C and quenched with sat. aq. Na2S2O3 (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (SiO2; continuous gradient from 0% to 100% EtOAc in Hexanes, 20 min) to give the title compound as a white solid (962 mg, 75%). 1H NMR (400 MHz, CD3OD)  8.22 (dd, J=3.0, 0.6 Hz, 1H), 7.87 (dd, J=8.6, 0.7 Hz, 1H), 7.30 (dd, J=8.7, 3.0 Hz, 1H), 5.68 (s, 2H), 4.19 (s, 3H), 2.76 (br. s., 3H), 1.92 - 1.43 (m, 8H). LCMS, [M+H]+ = 332.3. 1G. isopropyl (1S,3S)((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylate To a solution of 2E , 2.79 mmol), (1S,3R)-isopropyl 3-hydroxycyclohexanecarboxylate (934 mg, 5.01 mmol), and Bu3P (1.74 mL, 6.96 mmol) in toluene (55 mL) was added (E)-diazene-1,2-diylbis(piperidinylmethanone) (1.76 g, 6.96 mmol). The reaction was heated at 50 C for 7h, then was cooled to rt. The mixture was diluted with CH2Cl2 (20mL) and filtered through , which was washed with additional CH2Cl2 (3 x 20mL). The combined filtrates were concentrated in vacuo, and the residue was chromatographed (SiO2; continuous gradient from 0% to 100% EtOAc in Hexanes, 20 min) to give the title compound as a white solid (786 mg, 55%). 1H NMR (400 MHz, CDCl3)  8.33 (d, J=2.6 Hz, 1H), 8.12 (d, J=8.6 Hz, 1H), 7.34 (dd, J=8.8, 2.9 Hz, 1H), 5.78 (s, 2H), 5.05 (dt, J=12.5, 6.3 Hz, 1H), 4.77 - 4.66 (m, 1H), 4.16 (s, 3H), 2.95 - 2.64 (m, 4H), 2.12 - 2.08 (m, 1H), 2.03 - 1.87 (m, 4H), 1.82 - 1.41 (m, 12H), 1.29 - 1.19 (m, 6H). LCMS, [M+H]+ = 500.4.
Example 2 To a solution of 2F (786 mg, 1.53 mmol) in THF (3 mL) and MeOH (3 mL) added aq. LiOH (3.06 mL of a 2N solution, 6.12 mmol). The reaction mixture was d at rt overnight, after which the pH was adjusted to ~5 and water (10 mL) was added. The mixture was extracted with EtOAc (3 x 30 mL), washed with water (30 mL) and brine (30 mL), dried (MgSO4) and concentrated in vacuo. The resulting solid was dissolved in 3 mL of EtOAc and allowed to stand overnight to give the title compound as a white crystalline solid (600 mg, 83%). LCMS, [M+H]+ = 458.2. 1H NMR (500 MHz, CD  8.34 (d, J=2.5 Hz, 1H), 8.08 - 8.00 (m, 1H), 7.45 (dd, J=8.8, 2.8 Hz, 1H), 5.66 (s, 2H), 4.88 - 4.73 (m, 1H), 4.11 (s, 3H), 2.87 - 2.77 (m, 1H), 2.72 (br. s., 3H), 2.10 - 2.01 (m, 1H), 1.92 - 1.80 (m, 3H), 1.79 - 1.57 (m, 9H), 1.56 - 1.43 (m, 4H). : RT = 7.99 min, purity = 100%; HPLC-2: RT = 7.81 min, purity = 100%. hLPA1 IC50 = 19 nM.
Example 3 (1S,3S)((6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid 3A. Isopropyl (1S,3S)((6-(1-methyl((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H- 1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylate The title compound was prepared by the same synthetic sequence as for Example 1F, except that 2,5-dibromo-pyridine was used as starting material instead of 2,5- dibromomethyl-pyridine. 1H NMR (400 MHz, CDCl3) δ 8.43 - 8.25 (m, 3H), 8.23 - 8.10 (m, 1H), 7.47 - 7.31 (m, 3H), 6.11- 5.77 (m, 2H), 5.20 - 4.95 (m, 1H), 4.79 - 4.63 (m, 1H), 4.31 - 4.19 (m, 3H), 2.92 - 2.71 (m, 1H), 2.12 - 1.54 (m, 8H), 1.35 - 1.20 (m, 6H).
LCMS, [M+H]+ = 540.2. 3B. isopropyl (1S,3S)((6-(5-((((2-cyclopropylethyl)carbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylate To a solution of Example 3A (10 mg, 9.3 µmol) and iPr2NEt (6.5 µL, 0.037 mmol) in THF (0.5 mL) was added 2-cyclopropyl mine (0.8 mg, 9.3 µmol). The on mixture was stirred at rt overnight, then was concentrated in vacuo. The residue was chromatographed (SiO2; continuous gradient from 0% to 100% EtOAc in Hexanes, min) to give the title compound as a white solid (8 mg, 80%). LCMS, [M+H]+ = 486.4. 3B. isopropyl (1S,3S)((6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl) -1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylate To a solution of 3A (50 mg, 0.103 mmol) and MeI (0.129 mL, 0.257 mmol) in DMF (0.5 mL) was added NaH (10 mg of a 40% suspension in oil, 0.25 mmol). The reaction was stirred at rt for 1h, then was quenched with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried (MgSO4) and concentrated in vacuo to give the crude product, which was used in the next step without further purification. LCMS, [M+H]+ = 500.4.
Example 3 To a stirred solution of 3B (5 mg, 10 µmol) in THF (1.5 mL), MeOH (0.10 mL) and water (0.15 mL) at rt was added aq. LiOH (0.015 mL of a 2 M solution, 0.030 mmol).
The reaction mixture was stirred at 50 °C for 1 h, then was cooled to rt. The mixture was acidified to pH 2.3 by se addition of 1M aq. HCl, then was concentrated in vacuo.
The residue was purified by preparative HPLC (PHENOMENEX®, Axia 5µ C18 30x100 mm column; detection at 220 nm; flow rate=40 mL/min; continuous gradient from 0% B to 100%B over 10 min+2 min hold time at 100% B, where A=90:10:0.1 OH:TFA and B=90:10:0.1 MeOH:H2O:TFA) (to give the title compound as an oil (4.2 mg, 92%). 1H NMR (500 MHz, DMSO- )   (br. s., 1H), 7.78 (d, J=8.2 Hz, 1H), 7.33 (d, J=6.4 Hz, 1H), 5.48 - 5.30 (m, 2H), 4.57 (br. s., 1H), 3.89 (br. s., 3H), 3.09 - 2.88 (m, 2H), 2.56 (d, J=16.8 Hz, 4H), 2.46 (br. s., 1H), 1.80 - 1.53 (m, 5H), 1.51 - 1.25 (m, 5H), 1.20 - 0.93 (m, 4H). LCMS, [M+H]+ = 458.4. HPLC-4: RT = 1.42 min, purity = 100%. hLPA1 IC50 = 19 nM.
Example 4 (rac)-trans(4-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)phenoxy)cyclohexanecarboxylic acid 4A Methyl 4-(4-bromophenyl)-1H-1,2,3-triazolecarboxylate To a stirred solution of obenzaldehyde (1.0 g, 5.40 mmol), methyl 2- cyanoacetate (0.536 g, 5.40 mmol) and Et3N.HCl (2.23 g, 16.2 mmol) in DMF (20 mL) under N2 was added NaN3 (1.12 g, 17.3 mmol) and the reaction mixture was stirred at 70 °C for 16 h, then was cooled to rt. The on mixture was slowly poured into water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was chromatographed (12 g p® SiO2 column, g with 40% EtOAc in n-hexanes) to afford the title compound (0.24 g, 16%) as a yellow solid. LCMS, [M+H]+ = 284.0. 1H NMR (400 MHz, DMSO-d 6)  ppm 15.91 (br. s., 1H), 7.75 - 7.85 (m, 4H), 3.82 (m, 3H). 4B Methyl 4-(4-bromophenyl)methyl-1H-1,2,3-triazolecarboxylate To a stirred solution of 4A (250 mg, 0.886 mmol) in MeCN (5 mL) was added K2CO3 (122 mg, 0.886 mmol) and the reaction mixture was allowed to stir at rt for 30 min. CH3I (0.06 mL, 0.886 mmol) was added and the reaction was stirred at rt under N2 for 16 h. The reaction mixture was diluted with water, ted with EtOAc (3 x 15 mL).
The combined organic extracts were dried (Na2SO4), ed and concentrated in vacuo.
The residue was chromatographed (12 g Redisep® SiO2 column, eluting with 30% EtOAc in n-hexanes) to afford the title compound (200 mg, 70%) as an off white solid. 1H NMR and LCMS showed the presence of a 3:1 ratio of a mixture of triazole regioisomers (with the title compound the as major isomer), which was carried onto the next step without further purification. LC-MS, [M+H]+ = 296.0 . 4C (4-(4-Bromophenyl)methyl-1H-1,2,3-triazolyl)methanol To a solution of mixture of 4B (250 mg, 0.844 mmol) in THF (10 mL) under nitrogen was added dropwise LiAlH (0.93 mL of a 1M solution in THF; 0.93 mmol) at 0 °C and the reaction mixture was allowed to stir at 0 °C for 1h. The reaction was slowly quenched with water (0.5 mL) and aq. NaOH (0.5 mL of a 10% solution). The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (25 mL), dried 4), filtered and trated in vacuo. The residue was chromatographed (12 g Redisep® SiO2 column, eluting with 55 % EtOAc in n-hexanes) to afford the title compound (60 mg, 26%) as an off-white solid. The two regioisomers were separated by preparative HPLC (Column: Symmetry C8 (300 X19)mm 5 m; M.Phase A: 0.1% HCO2H in water; M.Phase B: MeCN, flow rate: 17.0 mL/min; time(min)/%B: 0/45, 35/60;). The desired triazole N- methyl regioisomer 4C was isolated as white solid (60 mg 26%) and structurally identified by proton NMR NOE studies on the N-methyl group. LC-MS, [M+H]+ = 270.0. 1H NMR (300 MHz, DMSO-d6)  ppm 7.80 - 7.60 (m, 4H), 5.59 (t, J = 6.0 Hz, 1H) 4.66 (d, J = 3 Hz, 2H), 4.08 (s, 3H). 4D Bromophenyl)methyl-1H-1,2,3-triazolyl)methyl cyclopentylcarbamate To a stirred solution of cyclopentanecarboxylic acid (63.9 mg, 0.559 mmol) and 4C (150 mg, 0.559 mmol) in toluene (4 mL) were added Et3N (0.10 mL, 0.84 mmol) and Ph2PON3 (0.2 mL, 0.671 mmol), and the resultant solution was d at 110 °C for 20h under N2. The reaction mixture was cooled to rt, volatiles were removed in vacuo and the crude product was chromatographed (12 g Redisep® SiO2 column, g with 38% EtOAc in n-hexanes) to afford the title compound (150 mg, 71%) as an off white solid.
LC-MS, [M+H]+ = 379.0. 1H NMR (400 MHz, CDCl 3)  ppm 7.66 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 5.24 (s, 2H), 4.18 (s, 3H), 3.90 - 4.00 (m, 1H), 2.02 - 1.90 (m, 2H), 1.50 - 1.80 (m, 3H), 1.30 - 1.50 (m, 4H). 4E Bromophenyl)methyl-1H-1,2,3-triazolyl)methyl cyclopentyl(methyl)carbamate To a stirred solution of 4D (200 mg, 0.527 mmol) and DMF (4 mL) was added NaH (19 mg of a 60% suspension in mineral oil, 0.79 mmol) portionwise at 0 °C and the reaction was stirred at 0 °C for 30 min. Iodomethane (0.049 mL, 0.79 mmol) was added at 0 °C and the reaction was allowed to warm to rt and d at rt for 1h. The reaction mixture was slowly quenched with aq. HCl (5 mL of a 1.5 N solution), diluted with water (25 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was tographed (12 g Redisep® SiO2 column, eluting with 40% EtOAc in n-hexanes) to afford the title compound (200 mg, 96%) as a pale yellow oily liquid. LCMS , [M+H]+ = 395.0. 4F (1-Methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)-1H-1,2,3-triazol- -yl)methyl cyclopentyl(methyl)carbamate To a stirred on of 4E (700 mg, 1.78 mmol) and bis(pinacolato)diboron (678 mg, 2.67 mmol) in 1,4-dioxane (7 mL) was added KOAc (349 mg, 3.56 mmol) and the reaction mixture was degassed with N2 for 5 min. 1,1'-Bis(diphenylphosphino) ferrocenepalladium (II) dichloride-toluene adduct (73 mg, 0.089 mmol) was added and the reaction mixture was stirred at 90 °C for 16h under N2. The reaction mixture was cooled to rt, filtered through a Celite pad, washed with EtOAc (50 mL) and the combined organic filtrates were concentrated in vacuo. The residue was chromatographed (24 g Redisep® SiO2 column, eluting with 75% EtOAc in n-hexanes) to afford the title compound (700 mg, 89%) as a pale yellow oily liquid. LC-MS, [M+H]+ = 441.2. 4G (4-(4-Hydroxyphenyl)methyl-1H-1,2,3-triazolyl)methyl cyclopentyl(methyl)carbamate To a solution of 4F (700 mg, 1.590 mmol) in THF (20 mL) and water (7 mL) mixture was added sodium perborate monohydrate (317 mg, 3.18 mmol) and the reaction mixture was d at rt for 30 min. The reaction mixture was diluted with sat’d aq.
NH4Cl (50 mL) and ted with EtOAc (2 x 50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was chromatographed (12 g Redisep® SiO2 column, eluting with 60 % EtOAc in n-hexanes) to afford the title nd (400 mg, 76%) as a white solid. LC-MS, [M+H]+ = 331.2. 1H NMR (300 MHz, DMSO-d6)  ppm 9.63 (s, 1H), 7.55 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 5.26 (s, 2H), 4.20 - 4.50 (m, 1 H), 4.09 (s, 3H), 2.67 (s, 3H), 1.60 - 1.80 (m, 4H), 1.40 - 1.60 (m, 4H). 4H (rac)-trans-Ethyl 3-(4-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl- ,3-triazolyl)phenoxy)cyclohexanecarboxylate To a stirred solution of 4G (300 mg, 0.908 mmol) and di-tert-butyl azodicarboxylate (627 mg, 2.72 mmol) and Ph3P (714 mg, 2.72 mmol) in THF (10 mL) under N2 was added ethyl 3-hydroxycyclohexanecarboxylate (racemic cis ; 313 mg, 1.82 mmol) and the reaction mixture was stirred at 60 °C for 16 h under N2, then was cooled to rt and concentrated in vacuo. The residue was chromatographed (24 g p ® SiO2 column, eluting with 40% EtOAc in n-hexanes) to afford the title compound (260 mg, 56%) as a colorless oil. LC-MS, [M+H]+ = 485.2. 1H NMR (400 MHz, CD3OD)  ppm 7.67 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 5.35 (s, 2H), 4.70 - 4.80 (m, 1H), 4.18 (s, 3H), 4.12 (q, J = 7.2 Hz, 2H), 2.70 - 2.90 (m, 1H), 2.75 (s, 3H), 1.80 - 2.10 (m, 4H), 1.40 - 1.80 (m, 13H), 1.10 - 1.30 (t, J = 7.2 Hz, 3H).
Example 4 (rac)-trans(4-(5-(((Cyclopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)phenoxy)cyclohexanecarboxylic acid To a stirred solution of 4H (260 mg, 0.429 mmol) in THF (4 mL) and MeOH (4 mL) was added a solution of LiOH.H2O (31 mg, 1.29 mmol) in water (4 mL) and the reaction mixture was stirred at rt for 16 h. The mixture was diluted with water (20 mL) and washed with Et2O (20 mL) to remove traces of non-polar impurities. The aqueous layer was neutralized with aq. HCl (2.0 mL of a 1.5N solution) and extracted with 5% MeOH in CHCl3 (25 mL). The organic layer was washed with brine (25 mL), dried 4), filtered and concentrated in vacuo. The crude product was purified by ative HPLC (Column: Symmetry C8 (300 X19)mm 10 m; M.Phase A: 0.1% HCOOH in water; M.Phase B: MeCN, flow rate: 17.0 mL/min; time(min)/%B: 0/30, /100;) to afford the title compound (120 mg, 45%) as a white solid. LC-MS, [M+H]+ = 457.2. 1H NMR (400 MHz, CD 3OD)  7.66 (d, J = 8.40 Hz, 2H), 7.09 (d, J = 8.80 Hz, 2H), 5.37 (s, 2H), 4.75-4.76 (m, 1H), 4.31-4.50 (m, 1H), 4.20 (s, 3H), 2.77-2.81 (m, 4H), 2.07-2.10 (m, 1H), 1.82-1.97 (m, 3H), 1.49-1.79 (m, 12H). hLPA1 IC50 = 18 nM.
Example 5 and Example 6 Individual enantiomers of Example 4 was separated by chiral SFC (Column/ dimensions: pak IC (250 X 21)mm, 5 m; % CO2: 60%; % Co solvent: 40%(0.25% DEA in MeOH); Total Flow: 60 g/min; Back Pressure: 100 bars; Temperature: 25°C; UV: 250 nm;). Example 5 (37 mg, 18%) was isolated as a white solid. LC-MS, [M+H]+ = 457.2. OR []24.8D = 0 (c 0.10, MeOH). 1H NMR (400 MHz, CD 3OD)  ppm 7.66 (d, J = 8.40 Hz, 2H), 7.09 (d, J = 8.40 Hz, 2H), 5.37 (s, 2H), 4.75 - 4.76 (m, 1H), 4.31 - 4.50 (m, 1H), 4.20 (s, 3H), 2.77 - 2.81 (m, 4H), 2.07 - 2.10 (m, 1H), 1.82-1.97 (m, 3H), 1.49 - 1.79 (m, 12H). hLPA1 IC50 = 6 nM. Acute mouse in vivo histamine assay: -90% histamine at a 3 mg/kg dose of Example 5. Example 6 (35 mg, 17%) was isolated as a white solid. LC-MS, [M+H]+= 457.2. OR []25.2D = (-)14.0 (c 0.10, MeOH). 1H NMR (400 MHz, CD3OD)  7.66 (d, J = 8.40 Hz, 2H), 7.09 (d, J = 8.40 Hz, 2H), 5.37 (s, 2H), 4.75 - 4.76 (m, 1H), 4.31 - 4.50 (m, 1H), 4.20 (s, 3H), 2.77 - 2.81 (m, 4H), 2.07 - 2.10 (m, 1H), 1.82 - 1.97 (m, 3H), 1.49 - 1.79 (m, 12H). hLPA1 IC50 = 1314 nM.
Example 7 (1-Methyl(4-(((1S,3S)((methylsulfonyl)carbamoyl)cyclohexyl)oxy)phenyl)-1H- 1,2,3-triazolyl)methyl cyclopentyl(methyl)carbamate To a stirred solution of Example 5 (10 mg, 0.022 mmol) and methane sulfonamide (3 mg, 0.033 mmol) in DCM (0.5 mL) and DMF (0.5 mL) mixture was added 4- dimethylaminopyridine (3.21 mg, 0.026 mmol) and 1-(3-dimethylaminopropyl) ethylcarbodiimide hydrochloride (6.30 mg, 0.033 mmol) and the on mixture was stirred at rt for 16 h under N2. The reaction mixture was concentrated in vacuo and the crude t was purified by preparative HPLC n: Sunfire C18 (150 X19)mm 5 micron; M.Phase A: 0.1% HCO2H in water; M.Phase B: MeCN, flow rate: 16.0 mL/min; time(min)/%B: 0/30, 30/100;) to afford the title compound (4 mg, 33%) as a white solid.
LC-MS, [M+H]+ = 534.4. 1H NMR (400 MHz, CD 3OD)  7.67 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 5.37 (s, 2H), 4.20 (s, 3H), 3.20 (s, 3H), 2.78 - 2.89 (m, 5H), 1.59 - 2.10 (m, 17H). hLPA1 IC50 = 3750 nM.
Example 8 & Example 9 8A 4-(4-Methoxyphenyl)methylH-1,2,3-triazolecarbaxaldehyde To a stirred solution of 4-(4-methoxyphenyl)methyl-1H-1,2,3-triazole (35 g, 185 mmol) in THF (860 mL) under N2 was added n-BuLi (111 mL of a 2.5 M solution in hexanes, 277 mmol) dropwise at -78 °C and the reaction mixture was stirred at -78 °C for 1h. DMF (22 mL, 277 mmol) was added at -78 °C and the reaction mixture was allowed to slowly warm to rt and d for 2h at rt. The reaction mixture was cooled to 0 °C, then was slowly quenched with sat’d aq. NH4Cl and extracted with DCM (3 x 250 mL). The combined organic extracts were washed with brine (500 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was chromatographed (330 g Redisep® SiO2 column, eluting with 20% EtOAc in n-hexanes) to afford the title compound (18.0 g, 48%) as a yellow solid. LC-MS, [M+H]+ = 218.2. 1H NMR (400 MHz, DMSO-d 6)  ppm 10.04 (s, 1H), 7.84 (d, J=9.0 Hz, 2H), 7.10 (d, J=9.0 Hz, 2H), 4.31 (s, 3H), 3.84 (s, 3H). 8B 4-(4-Hydroxyphenyl)methyl-1H-1,2,3-triazolecarbaldehyde To a stirred solution of 8A (8.4 g, 38.7 mmol) in DCM (160 mL) was added dropwise BBr3 (11 mL, 116 mmol) at 0 °C and the reaction mixture was stirred at 0 ° for 1h. The reaction mixture was quenched carefully with ice-cold water and neutralized with % aq. NaHCO3 and ted with DCM (3 x 150 mL). The combined organic extracts were washed with brine (250 mL), dried 4), filtered and trated in vacuo.
The residue was diluted with DCM and the resulting solid that formed was filtered and dried in vacuo to afford the title compound (5.7 g, 73%) as a white solid. 1H NMR (300 MHz, DMSO-d6)  ppm 10.04 (s, 1H), 9.88 (s, 1H), 7.71 (d, J=13.0 Hz, 2H), 6.92 (d, J=13.0 Hz, 2H), 4.28 (s, 3H). 8C 4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)methyl-1H-1,2,3-triazole carbaldehyde To a stirred solution of 8B (1.0 g, 4.92 mmol) and imidazole (0.670 g, 9.84 mmol) in DMF (20 mL) was added TBSCl (0.890 g, 5.91 mmol) and the reaction mixture was stirred at rt for 16 h under N2. Water (100 mL) was added to the mixture, which was extracted with EtOAc (2 x 75 mL). The combined organic extracts were washed with brine (150 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was chromatographed (24 g Redisep® SiO2 column, eluting with 25 % EtOAc in nhexanes ) to afford the title compound (1.2 g, 77%) as a white solid. 1H NMR (300 MHz, CDCl3)  ppm 10.07 (s, 1H), 7.63 (d, J=8.7 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 4.36 (s, 3H), 1.01 (s, 9H), 0.24 (s, 6H). 8D (4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)methyl-1H-1,2,3-triazolyl)methanol To a 0 °C on of 8C (1.25 g, 3.94 mmol) in THF (30 mL) was added NaBH4 (0.223 g, 5.91 mmol) and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was d with water (75 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were washed with brine (150 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude t was chromatographed (24 g Redisep® SiO2 column, eluting with 60 % EtOAc in n-hexanes) to afford the title compound (0.7 g, 56%) as a white solid. LC-MS, [M+H]+= 320.3. 1H NMR (300 MHz, CD 3OD)  ppm 7.59 (d, J=8.7 Hz, 2H), 6.97 (d, J=8.7 Hz, 2H), 4.77 (s, 2H), 4.15 (s, 3H), 1.02 (s, 9H), 0.24 (s, 8E (4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)methyl-1H-1,2,3-triazolyl)methyl (4- nitrophenyl) ate To a stirred solution of 8D (500 mg, 1.565 mmol) and iPr2NEt (0.50 mL, 3.13 mmol) in DCM (10 mL) was added 4-nitrophenyl chloroformate (379 mg, 1.88 mmol) at 0 °C and the resultant pale yellow solution was stirred at rt for 16 h under N2. The reaction e was d with water (50 mL) and extracted with DCM (2 x 50 mL).
The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo.
The crude product was chromatographed (24 g Redisep® SiO2 column, eluting with 40% EtOAc in n-hexanes) to afford the title compound (260 mg, 35%) as a white solid. LC- MS, [M+H]+ = 485.2. 1H NMR (400 MHz, CDCl 3)  ppm 8.30 (d, J=9.0 Hz, 2H), 7.64 (d, J=9.0 Hz, 2H), 7.40 (d, J=9.0 Hz, 2H), 6.96 (d, J=8.5 Hz, 2H), 5.47 (s, 2H), 4.22 (s, 3H), 1.00 (s, 9H), 0.23 (s, 6H). 8F (4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)methyl-1H-1,2,3-triazolyl)methyl isopentylcarbamate To a stirred solution of 8E (240 mg, 0.496 mmol) and Et3N (0.20 mL, 1.49 mmol) in THF (10 mL) was added 3-methylbutanamine (86 mg, 0.991 mmol) and the reaction mixture was stirred at rt for 16 h under N2, then was concentrated in vacuo. The crude product was tographed (12 g p® SiO2 column, eluting with 65% EtOAc in n-hexanes) to afford the title compound (150 mg, 70%) as a pale yellow liquid. LC-MS, [M+H]+ = 433.4. 1H NMR (400 MHz, CDCl 3)  ppm 7.62 (d, J=8.5 Hz, 2H), 6.92 (d, J=8.5 Hz, 2H), 5.24 (s, 2H), 4.72 (br. s., 1H), 4.16 (s, 3H), 3.27 - 3.19 (m, 2H), 1.30 - 1.50 (m, 3H), 0.97 – 1.00 (s, 9H), 0.91 - 0.96 (m, 6H), 0.23 (s, 6H). 8G Hydroxyphenyl)methyl-1H-1,2,3-triazolyl)methyl isopentylcarbamate To a stirred solution of 8F (150 mg, 0.347 mmol) in THF (6 mL) was added TBAF (0.52 mL of a 1M solution in THF; 0.52 mmol,) at 0 °C and the reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was chromatographed (12 g Redisep® SiO2 column, eluting with 85% EtOAc in n-hexanes) to afford the title compound (90 mg, 82%) as a white solid. LC-MS, [M+H]+ = 319.2. 1H NMR (400 MHz, CD3OD)  ppm 7.56 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 5.28 (s, 2H), 4.19 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 1.55 - 1.70 (m, 1H), 1.40 (q, J=7.0 Hz, 2H), 0.94 (d, J= 6.4 Hz, 8H (rac)-trans-(Ethyl 3-(4-(5-(((isopentylcarbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)phenoxy)cyclohexanecarboxylate To a stirred solution of 8G (100 mg, 0.314 mmol), di-tert-butyl arboxylate (217 mg, 0.942 mmol) and Ph3P (247 mg, 0.942 mmol) in THF (10 mL) under N2 was added ethyl 3-hydroxycyclohexanecarboxylate (racemic cis isomer; 135 mg, 0.785 mmol) and the reaction mixture was stirred at 60 °C for 16 h under N2, then was cooled to rt.
The reaction mixture was concentrated in vacuo and the crude product was chromatographed (12 g Redisep® SiO2 column, eluting with 22% EtOAc in n-hexanes) to afford the title compound (90 mg, 60%) as a pale yellow liquid. LC-MS, [M+H]+ = 473.2. 1H NMR (400 MHz, CD 3OD)  ppm 7.66 (d, J=9.0 Hz, 2H), 7.09 (d, J=9.0 Hz, 2H), 5.29 (s, 2H), 4.75 (br. s., 1H), 4.20 (s, 3H), 4.13 (q, J= 6.4 Hz, 2H), 3.15 (t, J=7.3 Hz, 2H), 2.80 - 2.90 (m, 1H), 1.60 - 2.00 (m, 6H), 1.20 - 1.35 (m, 9H), 0.93 (d, J=6.4 Hz, 6H). 8I trans-Ethyl 3-(4-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)phenoxy)cyclohexanecarboxylate To a stirred solution of 8H (90 mg, 0.190 mmol) in DMF (3 mL) under N2 was added NaH (9 mg of a 60% mineral sion, 0.38 mmol) portionwise at 0°C and stirred at 0°C for 30 min. Iodomethane (0.020 mL, 0.29 mmol) was then added and the reaction mixture was allowed to warm to rt & stirred at rt for 1h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 25 mL). The combined organic ts were washed with brine (50 mL), dried (Na2SO4), and filtered. The combined filtrates were concentrated in vacuo. The crude t was purified by combiflash chromatography (12 g Redisep® SiO2 column, eluting with 75% EtOAc in nhexanes ) to afford the title compound (60 mg, 64%) as a pale yellow liquid. LC-MS, [M+H]+ = 487.2.
Example 8 & Example 9 To a stirred solution of 8I (50 mg, 0.103 mmol) in THF (2 mL) and MeOH (2 mL) mixture was added a solution of LiOH.H2O (7.0 mg, 0.308 mmol) in water (2 mL) and the reaction mixture was stirred at rt for 16 h under N2. The reaction mixture was d with water (20 mL) and washed with Et2O (20 mL) to remove non-polar ties. The aqueous layer was neutralized with aq. HCl (2.0 mL of a 1.5 N solution) and extracted with MeOH in CHCl3 (5% of a 25 mL mixture). The organic layer was washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (Column: Sunfire C18 (250 X30)mm 5 m; M.Phase A: 10 mM NH4OAc in water; M.Phase B: MeCN, flow rate: 15.0 mL/min; time(min)/%B: 0/30, 8/40;) followed by tion of individual enantiomers by chiral SFC. Example 8 (17 mg, 28%) was obtained as a gummy solid. LC-MS, [M+H]+ = 459.2. OR []25.1D = (+)10.0 (c 0.10, MeOH). 1H NMR (400 MHz, CD3OD) δ ppm 7.64 - 7.70 (m, 2H), 7.09 (d, J= 8.8 Hz, 2H), 5.36 - 5.38 (m, 2H), 4.72 - 4.75 (m, 1H), 4.21 (s, 3H), 3.23 - 3.26 (m, 1H), 2.82 - 2.90 (m, 4H), 2.06 - 2.11 (m, 1H), 1.92 - 1.94 (m, 3H), 1.57 - 1.80 (m, 4H), 1.31 - 1.45 (m, 4H), 0.82 - 0.96 (m, 6H). hLPA1 IC50 = 87 nM. e 9 (14 mg, 24%) was obtained as a gummy solid. LC-MS, [M+H]+ = 459.2. OR []25.1D = (-)2.0 (c 0.10, MeOH). 1H NMR (400 MHz, CD 3OD)  ppm 7.64 - 7.70 (m, 2H), 7.09 (d, J= 8.4 Hz, 2H), 5.36 - 5.38 (m, 2H), 4.72 - 4.75 (m, 1H), 4.21 (s, 3H), 3.23 - 3.26 (m, 1H), 2.82 - 2.90 (m, 4H), 2.06 -2.11 (m, 1H), 1.92 - 1.94 (m, 3H), 1.57 - 1.80 (m, 4H), 1.31 - 1.45 (m, 4H), 0.82 - 0.96 (m, 6H). hLPA1 IC50 = 65 nM.
Example 10 (1S,3S)(4-(1-Methyl(((methyl(2-methylpentanyl)carbamoyl)oxy)methyl)-1H- 1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid 10A 4-(4-(Benzyloxy)phenyl)methyl-1H-1,2,3-triazolecarbaldehyde To a stirred mixture of compound 8B (5.5 g, 27.1 mmol) and K2CO3 (5.61 g, 40.6 mmol) in MeCN (60 mL) was added benzyl bromide (3.54 mL, 29.8 mmol) at rt and the reaction mixture was stirred at 70 °C for 3 h under N2, then was cooled to rt. The reaction mixture was ed through a Celite pad, which was washed with DCM (200 mL). The combined filtrates was concentrated in vacuo to afford the title compound (7.50 g, 80%) as a pale yellow solid, which was carried onto to the next step without further purification. LC-MS, [M+H]+ = 294.2. 1H NMR (400 MHz, CDCl 3)  ppm 10.06 (s, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.33 - 7.49 (m, 5H), 7.12 (d, J=8.8 Hz, 2H), 5.15 (s, 2H), 4.37 (s, 3H). 10B (4-(4-(Benzyloxy) phenyl)methyl-1H-1,2,3-triazolyl)methanol To a stirred solution of 10A (8 g, 27.3 mmol) in THF (60 mL) and MeOH (60 mL) was added portionwise NaBH4 (1.14 g, 30.0 mmol) at 0 °C under N2 and the reaction mixture was stirred at rt for 1h. The on mixture was diluted with sat’d. aq. NH4Cl (200 mL) and extracted with EtOAc (2 x 200 mL). The ed organic extracts were washed with brine (400 mL), dried 4), filtered and concentrated in vacuo to afford the title compound (7.0 g, 83%) as a white solid. This crude product was carried on to the next step without further purification. LC-MS, [M+H]+ = 296.2. 1H NMR (300 MHz, CDCl3)  ppm 7.57 (d, J=9.0 Hz, 2H), 7.47 - 7.33 (m, 5H), 7.04 (d, J=9.0 Hz, 2H), 5.10 (s, 2H), 4.81 (d, J=4.2 Hz, 2H), 4.08 (s, 3H), 2.77 (t, J=5.4 Hz, 1H). 10C 4-(4-(Benzyloxy) phenyl)(((tert butyldimethylsilyl) oxy) methyl)methyl-1H- 1,2,3-triazole To a d on of 10B (7 g, 23.70 mmol) and imidazole (4.84 g, 71.1 mmol) in DMF (100 mL) was added TBSCl (4.29 g, 28.4 mmol) and the reaction mixture was stirred at rt for 3h under N2. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with brine (400 mL), dried (Na2SO4), filtered and trated in vacuo to afford the title compound (8.0 g, 77%) as a pale yellow solid. This crude product 10c was used in the next step without further purification. LC-MS, [M+H]+ = 410.2. 1H NMR (300 MHz, CDCl3)  ppm 8.03 (s, 1H), 7.61 (d, J=9.0 Hz, 2H), 7.33 - 7.50 (m, 5H), 7.12 (d, J=9.0 Hz, 2H), 5.11 (s, 2H), 4.81 (s, 2H), 4.13 (s, 3H), 0.91 (s, 9H), 0.07 (s, 6H). 10D 4-(5-(((tert-Butyldimethylsilyl) oxy) methyl)methyl-1H-1,2,3-triazolyl)phenol To a degassed (N2 was bubbled in for 10 min) on of 10C (8.0 g, 19.53 mmol) in MeOH (150 mL) was added 10% Pd/C (1 g, 0.940 mmol) at rt. The reaction mixture was degassed with H2 for 5 min. then was stirred at rt under 1 atm of H2 for 5h, then the H2 atmosphere was evacuated and replaced with N2. The reaction mixture was filtered through a Celite pad and washed with MeOH (200 mL). The combined filtrates was concentration in vacuo to afford the title compound (5.0 g, 76 %) as a white solid.
This crude product 10D was used in the next step without further purification. LC-MS, [M+H]+= 320.2. 10E (rac)-trans-Ethyl 3-(4-(5-(((tert-butyldimethylsilyl) oxy)methyl)methyl-1H-1,2,3- triazolyl)phenoxy)cyclohexanecarboxylate To a stirred solution of 10D (2.75 g, 8.61 mmol), di-tert-butyl arboxylate (7.93 g, 34.4 mmol) and Ph3P (9.03 g, 34.4 mmol) in THF (80 mL) was added (rac)-cis- ethyl 3-hydroxycyclohexanecarboxylate (5.93 g, 34.4 mmol) and the reaction mixture was stirred at 60 °C for 16h under N2, then was cooled to rt. The reaction mixture was concentrated in vacuo. The crude product was tographed (120 g Redisep ® SiO2 column, eluting with 40% EtOAc in nes) to afford the title compound (2.7 g, 65%) as a colorless liquid. LC-MS, [M+H]+ = 474.2. 10F (1S,3S)-ethyl 3-(4-(5-(hydroxymethyl)methyl-1H-1,2,3-triazol yl)phenoxy)cyclohexanecarboxylate To a stirred solution 10E (200 mg, 0.211 mmol) in THF (6 mL) was added TBAF (0.317 mL of a 1M solution in THF; 0.317 mmol) at 0 °C and the reaction mixture was stirred at rt under N2 for 30 min. The on mixture was diluted with water (25 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with brine (40 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude t was chromatographed (12 g Redisep® SiO2 column, eluting with 75% EtOAc in n-hexanes).
The racemic product thus obtained was separated by chiral SFC (Luxcellulose-2 (250 X 21.5)mm, 5 m; % CO2: 70%; % Co-solvent: 30% (0.25% DEA in MeOH); Total Flow: 70 g/min; Back Pressure: 100 bars; Temperature: 35°C; UV: 230 nm;). The d S,S enantiomer 10F was isolated (40 mg, 50%) as an off-white solid: LC-MS, [M+H]+ = 360.2. Optical rotation [α]25.2D = (+)30 (c 0.10, MeOH). 1H NMR (400 MHz, CD3OD)  ppm 7.63 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 4.79 (s, 2H), 4.72 - 4.76 (m, 1H), 4.18 (s, 3H), 4.16 (q, J=7.0 Hz, 2H), 2.80 - 2.88 (m, 1H), 2.03 - 2.11 (m, 1H), 1.88 - 1.98 (m, 3H), 1.57 - 1.82 (m, 4H), 1.25 - 1.30 (m, 3H). 10G )-Ethyl(4-(1-methyl((((2-methylpentanyl) carbamoyl)oxy)methyl)- 1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylate To a solution of 10F (50 mg, 0.14 mmol), 2,2-dimethylpentanoic acid (18 mg, 0.139 mmol) and Et3N (0.029 mL, 0.21 mmol) in toluene (3 mL) was added Ph2PON3 (0.036 mL, 0.167 mmol) and the resultant pale yellow solution was d at 110 °C for 16 h under N2, then was cooled to rt. The reaction mixture was concentrated in vacuo and the crude product was chromatographed (12 g Redisep® SiO2 column, eluting with 50% EtOAc in n-hexanes) to afford the title compound (40 mg, 50%) as a white solid. LC-MS, [M+H]+ = 487.2. 1H NMR (400 MHz, CD 3OD)  ppm 7.65 (d, J=9.2 Hz, 2H), 7.08 (d, J=9.2 Hz, 2H), 5.24 (s, 2H), 4.75 (br. s., 1H), 4.19 (s, 3H), 4.16 (q, J=7.2 Hz, 2H), 3.15 (s, 1H), 2.86 (d, J=11.0 Hz, 2H), 2.07 (br. s., 1H), 1.89 - 1.99 (m, 3H), 1.60 - 1.80 (m, 4H), 1.20 - 1.40 (m, 8H), 0.95 - 0.88 (m, 6H). 10H (1S,3S)-Ethyl 3-(4-(1-methyl(((methyl(2-methylpentan yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylate To a stirred solution of 10G (40.0 mg, 0.082 mmol) in DMF (3 mL) under N2 was added NaH (4 mg of a 60% mineral suspension, 0.16 mmol) portionwise at 0 °C and stirred for 30 min. Iodomethane (7.71 µl, 0.123 mmol) was then added and the reaction mixture was stirred at rt for 1h, then was diluted with water (20 mL). The e was extracted with EtOAc (2 x 20 mL) and the combined organic extracts were washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was chromatographed (12 g Redisep® SiO2 column, g with 75% EtOAc in n-hexanes) to afford the title compound (30 mg, 73%) as a pale yellow liquid. LC-MS,[M+H]+ = 501.2.
Example 10 To a stirred solution of 10H (30.0 mg, 0.060 mmol) in THF (1.5 mL) and MeOH (1.5 mL) was added a solution of LiOH.H2O (4.3 mg, 0.18 mmol) in water (1.5 mL) and the reaction mixture was stirred at rt for 16 h under N2. The on e was diluted with water (20 mL) and washed with Et2O (20 mL) to remove traces of nonpolar impurities. The aqueous layer was neutralized with aq. HCl (2.0 mL of a 1.5 N solution) and extracted with 5% MeOH in CHCl3 (25 mL). The organic layer was washed with brine (25 mL), dried (Na2SO4), ed and concentrated in vacuo. The residual crude product was purified by preparative HPLC (Kinetex Biphenyl 100A (2500 X21.1)mm 5 m; Mobile Phase A: 0.1% HCO2H in water; Mobile Phase B: MeCN, flow rate: 18.0 ; time(min)/%B: 0/40, 32/75, 35/95;) to afford the title compound (8 mg, 28%) as a white solid. LC-MS, [M+H]+ = 473.2. 1H NMR (400 MHz, CD 3OD) δ ppm 7.63 (d, J = 8.80 Hz, 2H), 7.07 (d, J = 8.80 Hz, 2H), 5.31 (s, 2H), 4.83 - 4.89 (m, 1H), 4.18 (s, 3H), 2.85 (s, 3H), 2.72 - 2.76 (m, 1H), 2.06 - 2.10 (m, 1H), 1.82 - 1.95 (m, 3H), 1.40 - 1.77 (m, 6H), 1.29 (s, 6H), 1.11 -1.24 (m, 2H), 0.08 - 0.84 (m, 3H). hLPA1 IC50 = 23 nM.
Example 11 (rac)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)fluorocyclohexanecarboxylic acid Example 11 was prepared according to the procedure of Example 2 by using Intermeidate 1 instead of (1S,3R)-isopropyl 3-hydroxy-cyclohexanecarboxylate in the procedure (Mitsunobu reaction) to synthesize Example 2F. 1H NMR (400 MHz, CDCl 3)  8.15 (d, J=8.8 Hz, 1H), 8.00 - 7.89 (m, 1H), 5.53 - 5.32 (m, 2H), 5.00 (br. s., 1H), 4.21 (d, J=2.4 Hz, 3H), 3.32 (dd, , 7.5 Hz, 2H), 2.92 (d, J=13.6 Hz, 3H), 2.75 (d, J=2.6 Hz, 3H), 2.55 (dt, J=15.5, 7.8 Hz, 1H), 2.47 - 2.27 (m, 1H), 2.24 - 1.77 (m, 10H), 1.76 - 1.58 (m, 3H); 19F NMR (377 MHz, CDCl 3)  -76.0 (s, F from TFA), -154.4 (s, 1F). LC-MS, [M+H]+ = 490.4. hLPA1 IC50 = 12 nM.
Example 12 (1S,3S)(4-(5-(1-(((cyclobutylmethyl)(methyl)carbamoyl)oxy)ethyl) methyl-1H-1,2,3-triazolyl)phenoxy)cyclohexanecarboxylic acid (diastereomeric mixture) 12A 1-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)methyl-1H-1,2,3-triazolyl)ethan- To a -40 °C solution of 8C (279 mg, 0.879 mmol) in THF (18 mL) was added CH3MgBr (439 µL of a 3 M on in THF, 1.32 mmol). The reaction mixture was allowed to warm to rt and stirred at rt for 1 h. Water (15 mL) was added and the mixture was extracted with EtOAc (2 X 30 mL). The combined organic ts were concentrated in vacuo and chromatographed (SiO2; continuous gradient from 0% to 100% EtOAc in Hexanes, 20 min) to give 12A (230 mg, 78%) as an oil. 1H NMR (400 MHz, CDCl3)  7.42 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 5.33 (dd, J=6.8, 3.5 Hz, 1H), 4.23 (s, 3H), 1.96 (d, J=3.3 Hz, 1H), 1.64 (d, J=6.8 Hz, 3H), 1.00 (s, 9H), 0.22 (s, 6H) Example 12 was prepared according to the procedure for the synthesis of Example 8 by using 12A instead of 8D. 1H NMR (500 MHz, DMSO-d 6)  7.57 (br. s., 2H), 7.06 (d, J=6.6 Hz, 2H), 6.19 - 5.87 (m, 1H), 4.69 (br. s., 1H), 4.13 (d, J=5.6 Hz, 3H), 3.21 - 3.09 (m, 2H), 2.76 (d, J=15.7 Hz, 3H), 2.45 - 2.37 (m, 1H), 2.01 - 1.45 (m, 18H). LC-MS, [M+H]+ = 471.0. hLPA1 IC50 = 384 nM.
Example 13 3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)fluorocyclohexanecarboxylic acid (single omer) Example 13 was subjected to chiral SFC n: Chiralpak IC, 21 x 250 mm, 5 micron Mobile Phase: 40%MeOH / 60% CO2 Flow Conditions: 45 mL/min, 150 Bar, 40°C Detector Wavelength: 254 nm Injection Details: 0.5 mL of 5 mg/mL solution in MeOH) to afford Example 13. 1H NMR (500 MHz, CDCl 3)  8.11 - 7.96 (m, 1H), 7.29 (d, J=8.5 Hz, 1H), 5.75 (d, J=9.6 Hz, 2H), 4.79 (d, J=3.3 Hz, 1H), 4.15 (d, J=7.7 Hz, 3H), 3.38 - 3.11 (m, 2H), 2.93 - 2.75 (m, 3H), 2.65 - 2.51 (m, 1H), 2.25 (br. s., 1H), 2.10 - 1.47 (m, 7H). LC-MS, [M+H]+ = 490.4. hLPA1 IC50 = 95 nM.
Example 14 (4-(5-(((1S,3S)carbamoylcyclohexyl)oxy)methylpyridinyl)methyl-1H-1,2,3- triazolyl)methyl (cyclobutylmethyl)(methyl)carbamate To a solution of Example 2 (100 mg, 0.21 mmol) and DMF (0.8 µL, 11 µmol) in CH2Cl2 (2 mL) was slowly added oxalyl chloride (0.21 mL, 0.42 mmol); the mixture was stirred at rt for 30 min. The mixture was concentrated in vacuo to give the acid chloride.
To the acid chloride in CH2Cl2 (1.0 mL) was added ammonia (6.36 mL of a 0.5 N solution in dioxane, 3.18 mmol). The e was d at rt for 30 min, then was trated in vacuo. The residual crude product was chromatographed (SiO2; 12 g; A = DCM, B = EtOAc; 12 min gradient from 0% B to 100% B; flow rate = 30 mL/min) to afford the title compound (77 mg, 0.17 mmol, 89 % yield) as a white solid. LCMS, [M+H]+ = 471.2. 1H NMR (500 MHz, DMSO-d 6) [rotamer, ratio 53:47] [major rotamer– underline; minor rotamer – Italic]:  ppm 7.81 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.35 (s, 1H), 6.72 (s, 1H), 5.62 (s, 2 H), 5.59 (s, 2 H), 4.81 (br-s, 1H), 4.08 (br-s, 3H), 3.21 (br-s, 2H), 3.08 (br-s, 2H), 2.77 – 2.65 (m, 4H), 2.55 (s, 3H), 2.43 (s, 3H), 2.37 – 1.36 (m, 12H). : RT = 1.36 min, purity = 98%. hLPA1 IC50 = 824 nM.
Example 15 (4-(5-(((1S,3S)cyanocyclohexyl)oxy)methylpyridinyl)methyl-1H-1,2,3- triazolyl)methyl (cyclobutylmethyl)(methyl)carbamate A mixture of Example 14 (90 mg, 0.19 mmol) and Burgess reagent (137 mg, 0.57 mmol) in DCM (1 mL) and THF (1 mL) was stirred at rt for 48 h, then was concentrated in vacuo. The residue was chromatographed (SiO 2; 12 g; A = DCM, B = EtOAc; 12 min gradient from 0% B to 100%B; flow rate = 30 mL/min) to afford the title compound (85 mg, 0.18 mmol, 95 % yield) as a white solid. LCMS, [M+H]+ = 453.0. 1H NMR (500 MHz, DMSO-d6) [rotamer, ratio 53:47] [major rotamer – underline; minor rotamer– Italic]:  ppm 7.83 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 5.62 (s, 2 H), 5.58 (s, 2 H), 4.71 (s, 1H), 4.08 (br-s, 3H), 3.22 (br-s, 2H), 3.08 (br-s, 2H), 2.77 – 2.65 (m, 4H), 2.55 (s, 3H), 2.40 (s, 3H), 2.34 – 1.34 (m, 12H). HPLC-6: RT = 1.68 min, purity = 97%. hLPA1 IC50 = 3750 nM.
Example 16 (4-(5-(((1S,3S)(1H-tetrazolyl)cyclohexyl)oxy)methylpyridinyl)methyl-1H- 1,2,3-triazolyl)methyl (cyclobutylmethyl)(methyl)carbamate A mixture of Example 15 (69 mg, 0.15 mmol), TEA (0.32 mL, 2.3 mmol), NaN3 (149 mg, 2.3 mmol) and HOAc (0.13 mL, 2.3 mmol) in toluene (1.0 mL) in a sealed tube was stirred at 100°C for 18 h, then was cooled to rt. The mixture was diluted with EtOAc (5 mL), quenched with sat’d. aq. NaHCO3 (3 mL). The mixture was extracted with EtOAc (5 x 5 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude material was purified by preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5-μm particles; Mobile Phase A: 5:95 MeCN: water with 10 mM NH4OAc; Mobile Phase B: 95:5 MeCN: water with 10 mM ; nt: 10-60% B over 20 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractions containing the desired t were combined and dried via centrifugal evaporation to afford the title compound (54 mg, 70% yield) as a white solid.
LCMS, [M+H]+ = 496.0. 1H NMR (500 MHz, DMSO-d 6) [rotamer, ratio 53:47] [major r – underline; minor rotamer– Italic]:  ppm 7.82 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 5.61 (s, 2 H), 5.57 (s, 2 H), 4.88 (s, 1H), 4.07 (br-s, 3H), 3.37 (m, 1H), 3.20 (br-s, 2H), 3.06 (br-s, 2H), 2.76 – 2.65 (m, 3H), 2.54 (s, 3H), 2.44 (s, 3H), 2.37 – 1.33 (m, 12H). HPLC-6: RT = 1.50 min, purity = 96%. hLPA1 IC50 = 22 nM.
Example 17 (1-methyl(6-methyl(((1S,3S) ((methylsulfonyl)carbamoyl)cyclohexyl)oxy)pyridinyl)-1H-1,2,3-triazolyl)methyl (cyclobutylmethyl)(methyl)carbamate To a clear solution of Example 2 (15 mg, 0.032 mmol) and methanesulfonamide (5 mg, 0.048 mmol) and DMAP (6 mg, 0.048 mmol) in DMF (0.2 mL) and DCM (1 mL) was added EDC (9.4 mg, 0.048 mmol). The mixture was stirred at rt for 62 h, then was d with water (2 mL) and DCM (5mL). The organic layer was washed with brine (5 mL), dried (MgSO4) and concentrated in vacuo to afford a white solid, which was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile Phase A: 5:95 MeCN: water with 10 mM NH4OAc; Mobile Phase B: 95:5 MeCN: water with 10 mM NH4OAc; Gradient: 20-70% B over 20 min, then a 3-min hold at 100% B; Flow: 20 mL/min. Fractions containing the d product were ed and dried via centrifugal evaporation to afford the title compound (14 mg, 78% yield) as a white solid. LCMS, [M+H]+ = 549.3. 1H NMR (500 MHz, DMSO-d6) [rotamer, ratio 53:47] [major – underlined; minor – Italic]:  ppm 7.82 (d, J = 8.6 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 5.62 (s, 2 H), 5.58 (s, 2 H), 4.85 (s, 1H), 4.08 (br-s, 3H), 3.60 (m, 1H), 3.24 – 3.08 (m, 2H), 2.79 – 2.67 (m, 4H), 2.54 (s, 6H), 2.44 (s, 3H), 2.35 – 1.35 (m, 12H). HPLC-6: RT = 1.56 min, purity = 97%. hLPA1 IC50 = 352 nM.
Table 1 Analytical & Biology Method Example Structure & Name LCMS, [M + H]+ = 458.3. 1H NMR (500 MHz, CD3CN)  8.26 (dd, J=3.0, 0.6 Hz, 1H), 8.00 - 7.96 (m, 1H), 7.38 (dd, 18 J=8.8, 2.8 Hz, 1H), 5.58 Example (s, 2H), 4.70 (br. s., 1H), 2 4.03 (s, 3H), 2.79 - 2.69 (m, 1H), 2.64 (br. s., 3H), (rac)((6-(5- 2.01 - 1.93 (m, 2H), 1.84 lopentyl(methyl)carbamoyl)oxy - 1.73 (m, 3H), 1.71 - )methyl)methyl-1H-1,2,3-triazol- 1.49 (m, 8H), 1.48 - 1.36 4-yl)pyridinyl)oxy)cyclohexane (m, 4H) carboxylic acid hLPA1 IC50 = 21 nM.
LCMS, [M + H]+ = 508.2 1H NMR (500 MHz, DMSO-d6) δ 7.83 (br d, J=8.5 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.38 - 6.97 (m, 5H), 5.68 (br s, 2H), 5.36 (br s, 1H), 5.10 (br s, 1H), 4.76 (br s, 1H), 4.14 - 3.98 (m, 2H), Example 3.69 (br d, J=7.7 Hz, 3 1H), 2.63 - 2.55 (m, 2H), (1S,3S)((2-methyl(1-methyl 2.49 - 2.44 (m, 1H), 2.38 (((methyl((R) (br s, 3H), 1.99 (br d, phenylethyl)carbamoyl)oxy)methyl)- J=14.4 Hz, 1H), 1.87 - 1H-1,2,3-triazolyl)pyridin 1.70 (m, 3H), 1.67 - 1.28 yl)oxy)cyclohexanecarboxylic (m, 7H) acid hLPA1 IC50 = 17 nM Analytical & Biology Method Example Structure & Name LCMS, [M + H]+ =486.2. 1H NMR (500 MHz, DMSO-d6) δ 7.83 (br d, J=8.3 Hz, 1H), 7.48 (br d, J=8.6 Hz, 1H), 5.85 - e .43 (m, 2H), 4.77 (br s, 1 1H), 4.28 - 3.96 (m, 3H), (1S,3S)((6-(5-((((1- 2.55 (s, 6H), 2.42 (br d, cyclobutylethyl)(methyl)carbamoyl)o J=8.6 Hz, 3H), 1.97 (br s, xy)methyl)methyl-1H-1,2,3- 1H), 1.87 - 1.17 (m, lyl)methylpyridin 13H), 1.00 - 0.75 (m, 3H) yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 28 nM. (diastereomeric mixture) LCMS, [M+H]+ = 494.4 1H NMR (500 MHz, DMSO-d6) δ 8.43 - 8.29 (m, 1H), 8.07 - 7.94 (m, 1H), 7.66 - 7.51 (m, 1H), 7.42 - 7.04 (m, 5H), 5.78 - 5.57 (m, 2H), 5.45 - Example .03 (m, 1H), 4.87 - 4.73 1 (m, 1H), 4.22 - 3.95 (m, 3H), 2.74 - 2.63 (m, 1H), (1S,3S)((6-(1-methyl 2.60 - 2.56 (m, 3H), 2.00 (((methyl((R) - 1.91 (m, 1H), 1.90 - phenylethyl)carbamoyl)oxy)methyl)- 1.71 (m, 3H), 1.70 - 1.59 1H-1,2,3-triazolyl)pyridin (m, 2H), 1.57 - 1.33 (m, yl)oxy)cyclohexanecarboxylic 5H) acid hLPA1 IC50 = 21 nM. ical & Biology Method Example Structure & Name LCMS, [M+H]+ = 480.1. 1H NMR (500 MHz, DMSO-d6)  8.34 (br. s., 1H), 8.01 (d, J=8.5 Hz, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.41 - 6.96 (m, 5H), Example .77 - 5.56 (m, 2H), 4.78 22 1 (br. s., 1H), 4.50 - 4.25 (m, 2H), 4.18 - 3.91 (m, (1S,3S)((6-(5- 3H), 3.50 (br. s., 1H), (((benzyl(methyl)carbamoyl)oxy)met 2.84 - 2.62 (m, 3H), 2.02 hyl)methyl-1H-1,2,3-triazol - 1.74 (m, 4H), 1.71 - yl)pyridinyl)oxy)cyclohexane 1.45 (m, 4H) carboxylic acid hLPA1 IC50 = 18 nM.
Example LCMS, [M+H]+ = 458.3 1 1H NMR (500 MHz, DMSO-d6)  8.35 (br. s., 1H), 7.99 (d, J=8.5 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 5.62 (d, J=19.2 Hz, 23 2H), 4.77 (br. s., 1H), 4.11 (d, J=6.1 Hz, 3H), (1S,3S)((6-(5- 3.56 - 3.41 (m, 1H), 3.28 ((((cyclobutylmethyl)(methyl)carbam - 3.04 (m, 2H), 2.80 - oyl)oxy)methyl)methyl-1H-1,2,3- 2.67 (m, 3H), 2.02 - 1.40 triazolyl)pyridin (m, 15H) yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 12 nM.
Analytical & Biology Method Example Structure & Name Example LCMS, [M+H]+ = 460.3 1 1H NMR (500 MHz, DMSO-d6) δ 8.44 - 8.29 (m, 1H), 8.07 - 7.95 (m, 1H), 7.55 (br d, J=7.3 Hz, 1H), 5.73 - 5.52 (m, 2H), 4.78 (br s, 1H), 4.20 - 4.03 (m, 3H), 2.70 - (1S,3S)((6-(1-methyl 2.59 (m, 2H), 1.99 - 1.71 (((methyl(pentan (m, 6H), 1.68 - 1.49 (m, yl)carbamoyl)oxy)methyl)-1H-1,2,3- 4H), 1.43 - 1.09 (m, 4H), triazolyl)pyridin 1.06 - 0.78 (m, 6H), 0.82 yl)oxy)cyclohexanecarboxylic - 0.58 (m, 1H) acid hLPA1 IC50 = 47 nM. (diastereomeric mixture) LCMS, [M+H]+ = 458.3 Example 1H NMR (400 MHz, 3 CD3CN)  8.24 (br. s., 1H), 8.12 (d, J=8.1 Hz, 1H), 7.93 (dd, J=9.1, 2.5 Hz, 1H), 5.17 (br. s., 2H), 4.80 - 4.59 (m, 1H), 3.97 (d, J=15.8 Hz, 3H), 3.31 - 3.07 (m, 1H), 2.72 - )((6-(5-(((((R) 2.54 (m, 4H), 2.02 - 1.76 cyclopropylethyl)(methyl)carbamoyl) (m, 3H), 1.70 - 1.33 (m, oxy)methyl)methyl-1H-1,2,3- 5H), 1.09 - 0.87 (m, 3H), triazolyl)pyridin 0.84 - 0.65 (m, 1H), 0.46 yl)oxy)cyclohexanecarboxylic -0.13 (m, 4H) acid hLPA1 IC50 = 20 nM.
Analytical & Biology Method Example Structure & Name Example LCMS, [M+H]+ = 497.3 1 1H NMR (500 MHz, DMSO-d6)  7.73 - 7.41 (m, 2H), 7.38 - 6.98 (m, 6H), 5.43 - 5.26 (m, 2H), 4.72 (br. s., 1H), 4.39 (d, 26 J=8.9 Hz, 2H), 4.20 - 3.95 (m, 3H), 3.67 - 3.42 (m, 3H), 2.69 - 2.60 (m, (1S,3S)(4-(5- 1H), 1.96 (br. s., 1H), zyl(methyl)carbamoyl)oxy)met 1.82 (t, J=11.1 Hz, 3H), hyl)methyl-1H-1,2,3-triazolyl)- 1.69 - 1.45 (m, 5H) 2-fluorophenoxy)cyclohexane hLPA1 IC50 = 34 nM. carboxylic acid Example LCMS, [M+H]+ = 475.1 1H NMR (500 MHz, DMSO-d6)  7.70 - 7.48 (m, 2H), 7.33 (t, J=8.7 Hz, 1H), 5.32 (d, J=7.9 27 Hz, 2H), 4.75 (br. s., 1H), 4.12 (br. s., 3H), 3.65 - 3.44 (m, 4H), 3.26 - 3.07 (1S,3S)(4-(5- (m, 2H), 2.69 - 2.60 (m, ((((cyclobutylmethyl)(methyl)carbam 1H), 2.01 - 1.41 (m, 14H) oyl)oxy)methyl)methyl-1H-1,2,3- hLPA1 IC50 = 14 nM. triazolyl) fluorophenoxy)cyclohexane carboxylic acid Analytical & Biology Method Example Structure & Name LCMS, [M+H]+ = 477.1 Example 1H NMR (500 MHz, 1 DMSO-d6) δ 7.70 - 7.43 (m, 2H), 7.32 (br t, J=8.5 Hz, 1H), 5.33 (br s, 2H), 4.75 (br s, 1H), 4.12 (s, 3H), 3.90 (br s, 1H), 3.52 (br d, J=16.5 Hz, 2H), 2.71 - 2.59 (m, 2H), 1.97 (1S,3S)(2-fluoro(1-methyl (br s, 1H), 1.88 - 1.76 (m, (((methyl(pentan 3H), 1.71 - 1.45 (m, 4H), yl)carbamoyl)oxy)methyl)-1H-1,2,3- 1.43 - 1.18 (m, 2H), 1.14 triazolyl)phenoxy)cyclohexane - 0.91 (m, 5H), 0.82 (br t, ylic acid J=6.9 Hz, 2H), 0.76 - (diastereomeric mixture) 0.66 (m, 1H) hLPA1 IC50 = 25 nM.
LCMS, [M+H]+ = 472.1 Example 1H NMR (500 MHz, 3 DMSO-d6)  7.69 (d, J=8.2 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 5.74 - .34 (m, 2H), 4.64 (br. s., 1H), 3.95 (s, 3H), 3.27 29 (br. s., 1H), 2.67 - 2.44 (m, 4H), 2.27 (s, 3H), )((6-(5-(((((R) 1.88 (d, J=14.0 Hz, 1H), cyclopropylethyl)(methyl)carbamoyl) 1.79 - 1.59 (m, 3H), 1.56 oxy)methyl)methyl-1H-1,2,3- - 1.27 (m, 4H), 1.05 - triazolyl)methylpyridin 0.63 (m, 4H), 0.44 - -0.39 yl)oxy)cyclohexanecarboxylic (m, 4H) acid hLPA1 IC50 = 41 nM.
Analytical & Biology Method Example Structure & Name Example LCMS, [M+H]+ = 494.3 1 1H NMR (500 MHz, DMSO-d6)  7.86 (d, J=8.5 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.39 - 6.97 (m, 5H), 5.79 - 5.63 (m, 2H), 4.79 (br. s., 1H), 4.49 - 4.26 (m, 2H), 4.17 - 3.91 (m, 3H), 2.86 - )((6-(5- 2.69 (m, 3H), 2.68 - 2.59 (((benzyl(methyl)carbamoyl)oxy)met (m, 1H), 2.41 (d, J=14.3 hyl)methyl-1H-1,2,3-triazolyl)- Hz, 3H), 2.07 - 1.98 (m, 2-methylpyridin 1H), 1.92 - 1.74 (m, 3H), yl)oxy)cyclohexanecarboxylic 1.71 - 1.45 (m, 4H) acid hLPA1 IC50 = 16 nM.
Example LCMS, [M+H]+ = 474.3 1 1H NMR (500 MHz, DMSO-d6)  7.84 (d, J=8.2 Hz, 1H), 7.48 (d, J=7.0 Hz, 1H), 5.66 (br. s., 2H), 4.79 (br. s., 1H), 31 4.10 (s, 4H), 2.63 (br. s., (1S,3S)((2-methyl(1-methyl 3H), 2.42 (s, 3H), 2.10 - (((methyl(pentan 1.97 (m, 1H), 1.91 - 1.71 yl)carbamoyl)oxy)methyl)-1H-1,2,3- (m, 4H), 1.67 - 1.10 (m, triazolyl)pyridin 6H), 1.06 - 0.80 (m, 4H), yl)oxy)cyclohexanecarboxylic 0.64 (br. s., 2H) acid hLPA1 IC50 = 36 nM. (diastereomeric mixture) Analytical & Biology Method Example Structure & Name LCMS, [M+H]+ = 460.3 e 1H NMR (500 MHz, 1 DMSO-d6)  7.85 (d, J=8.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.64 (d, J=15.9 Hz, 2H), 4.79 (br. 32 s., 1H), 4.10 (s, 3H), 3.53 - 3.32 (m, 2H), 3.23 - (1S,3S)((6-(5- 3.02 (m, 1H), 2.85 - 2.69 (((butyl(methyl)carbamoyl)oxy)meth (m, 3H), 2.42 (s, 3H), yl)methyl-1H-1,2,3-triazolyl)- 1.81 (br. s., 3H), 1.63 (d, 2-methylpyridin J=9.8 Hz, 6H), 1.31 - yl)oxy)cyclohexanecarboxylic 0.96 (m, 3H), 0.66 (br. s., acid 3H) hLPA1 IC50 = 10 nM.
Example LCMS, [M+H]+ = 472.4 1 1H NMR (400 MHz, CD3CN) δ 7.96 - 7.79 (m, 1H), 7.35 (d, J=8.8 Hz, 1H), 5.67 (br s, 2H), 4.86 - 4.62 (m, 1H), 4.19 33 - 3.97 (m, 4H), 3.39 - (1S,3S)((6-(5- 3.01 (m, 2H), 2.88 - 2.63 ((((cyclobutylmethyl)(methyl)carbam (m, 4H), 2.60 - 2.29 (m, oyl)oxy)methyl)methyl-1H-1,2,3- 4H), 2.18 - 2.04 (m, 1H), triazolyl)methylpyridin 1.91 - 1.44 (m, 12H), yl)oxy)cyclohexanecarboxylic 1.29 - 1.15 (m, 1H) acid hLPA1 IC50 = 7 nM.
Analytical & Biology Method Example Structure & Name LCMS, [M+H]+ = 474.3 Example 1H NMR (500 MHz, 1 DMSO-d6)  7.85 (d, J=8.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.63 (d, J=15.3 Hz, 2H), 4.79 (br. s., 1H), 4.10 (br. s., 3H), 3.44 (br. s., 1H), 3.22 (br. 34 s., 1H), 3.06 (br. s., 1H), 2.84 - 2.69 (m, 3H), 2.63 (1S,3S)((6-(5- (t, J=10.4 Hz, 1H), 2.42 (((isopentyl(methyl)carbamoyl)oxy) (s, 3H), 2.09 - 1.97 (m, methyl)methyl-1H-1,2,3-triazol 2H), 1.92 - 1.70 (m, 2H), yl)methylpyridin 1.70 - 1.42 (m, 4H), 1.40 yl)oxy)cyclohexanecarboxylic - 1.19 (m, 2H), 1.14 (br. acid s., 1H), 0.88 (br. s., 3H), 0.62 (d, J=4.6 Hz, 3H) hLPA1 IC50 = 16 nM.
Example LCMS, [M+H]+ = 528.3 1H NMR (500 MHz, 6)  7.85 (d, J=8.5 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.44 - 6.99 (m, 4H), 5.83 - 5.59 (m, 2H), 4.79 (br. s., 1H), 4.49 - 4.25 (m, 2H), 4.18 - 3.93 (m, 3H), 2.86 - (1S,3S)((6-(5-((((4- 2.68 (m, 3H), 2.67 - 2.60 chlorobenzyl)(methyl)carbamoyl)oxy (m, 1H), 2.45 - 2.29 (m, )methyl)methyl-1H-1,2,3-triazol- 3H), 2.03 (d, J=13.7 Hz, 4-yl)methylpyridin 1H), 1.94 - 1.73 (m, 3H), yl)oxy)cyclohexanecarboxylic 1.71 - 1.44 (m, 4H) acid hLPA1 IC50 = 284 nM.
Analytical & Biology Method Example Structure & Name LCMS, [M+H]+ = 471.3 Example 1H NMR (400 MHz, 3 CD3CN)  7.48 - 7.31 (m, 2H), 6.87 (d, J=8.4 Hz, 1H), 5.11 (s, 2H), 4.62 (br. s., 1H), 3.95 (s, 36 3H), 2.70 - 2.56 (m, 4H), 2.13 (s, 3H), 2.02 - 1.92 (1S,3S)(4-(5-(((((R) (m, 1H), 1.65 - 1.33 (m, cyclopropylethyl)(methyl)carbamoyl) 8H), 0.99 (br. s., 3H), oxy)methyl)methyl-1H-1,2,3- 0.83 - 0.68 (m, 1H), 0.37 lyl) (br. s., 1H), 0.26 - -0.22 methylphenoxy)cyclohexane (m, 3H) carboxylic acid hLPA1 IC50 = 6 nM.
Example LCMS, [M - H]+ = 471.3 1H NMR (500 MHz, DMSO-d6)  7.66 - 7.42 (m, 2H), 7.06 (d, J=8.5 Hz, 1H), 5.28 (br. s., 2H), 37 4.74 (br. s., 1H), 4.10 (br. s., 3H), 3.48 - 3.34 (m, 2H), 2.76 (br. s., 2H), (1S,3S)(4-(5- 2.65 - 2.58 (m, 1H), 2.22 ((((cyclobutylmethyl)(methyl)carbam (br. s., 3H), 2.02 - 1.40 oyl)oxy)methyl)methyl-1H-1,2,3- (m, 15H) triazolyl) hLPA1 IC50 = 14 nM. methylphenoxy)cyclohexane carboxylic acid LCMS, [M - H]+ = 493.0 e 1H NMR (500 MHz, 1 DMSO-d6)  7.65 - 7.39 (m, 2H), 7.37 - 6.94 (m, 7H), 5.32 (d, J=19.5 Hz, 2H), 4.72 (br. s., 1H), 38 4.39 (d, J=13.4 Hz, 2H), 4.18 - 3.95 (m, 3H), 2.89 - 2.70 (m, 3H), 2.62 (br. (1S,3S)(4-(5- s., 1H), 2.24 - 2.10 (m, (((benzyl(methyl)carbamoyl)oxy)met 3H), 2.00 (d, J=11.9 Hz, hyl)methyl-1H-1,2,3-triazolyl)- 1H), 1.90 - 1.71 (m, 3H), 2-methylphenoxy)cyclohexane 1.69 - 1.39 (m, 4H) carboxylic acid hLPA1 IC50 = 32 nM.
Analytical & Biology Method Example Structure & Name Example LCMS, [M+H]+ = 473.3. 1 1H NMR (500 MHz, DMSO-d6)  7.62 - 7.42 (m, 2H), 7.05 (d, J=8.5 Hz, 1H), 5.27 (br. s., 2H), 4.74 (br. s., 1H), 4.09 (s, 39 3H), 3.43 (br. s., 2H), 2.68 - 2.54 (m, 4H), 2.21 (1S,3S)(2-methyl(1-methyl (s, 3H), 2.01 (d, J=13.7 (((methyl(pentan Hz, 1H), 1.88 - 1.71 (m, yl)carbamoyl)oxy)methyl)-1H-1,2,3- 3H), 1.69 - 1.18 (m, 6H), triazolyl)phenoxy)cyclohexane 1.16 - 0.66 (m, 6H) carboxylic acid hLPA1 IC50 = 23 nM. (diastereomeric mixture) LCMS, [M+H]+ = 459.3 Example 1H NMR (500 MHz, 1 6)  7.52 (d, J=13.1 Hz, 2H), 7.05 (d, J=7.6 Hz, 1H), 5.27 (d, J=5.5 Hz, 2H), 4.74 (br. s., 1H), 4.09 (s, 3H), 3.23 40 - 3.04 (m, 2H), 2.77 (d, J=6.4 Hz, 3H), 2.61 (br. (1S,3S)(4-(5- s., 1H), 2.22 (s, 3H), 2.00 (((butyl(methyl)carbamoyl)oxy)meth (d, J=12.8 Hz, 1H), 1.90 methyl-1H-1,2,3-triazolyl)- - 1.69 (m, 3H), 1.67 - 2-methylphenoxy)cyclohexane 1.04 (m, 8H), 0.91 - 0.61 carboxylic acid (m, 3H) hLPA1 IC50 = 28 nM.
Example LCMS, [M+H]+ = 471.3, 1H NMR (500 MHz, 1 DMSO-d6)  7.60 - 7.44 (m, 2H), 7.04 (d, J=8.5 Hz, 1H), 5.28 (s, 2H), 4.74 (br. s., 1H), 4.09 (s, 41 3H), 3.42 (br. s., 1H), 2.72 - 2.58 (m, 4H), 2.27 (1S,3S)(4-(5- - 2.17 (m, 3H), 2.01 (d, (((cyclopentyl(methyl)carbamoyl)oxy J=13.4 Hz, 1H), 1.89 - )methyl)methyl-1H-1,2,3-triazol- 1.71 (m, 3H), 1.69 - 1.32 4-yl)methylphenoxy)cyclohexane- (m, 12H) 1-carboxylic acid hLPA1 IC50 = 14 nM.
Analytical & Biology Method Example Structure & Name LCMS, [M+H]+ = 474.3. Example 1H NMR (500 MHz, 1 DMSO-d6)  8.32 (s, 1H), 7.90 (s, 1H), 5.62 (d, J=18.0 Hz, 2H), 4.88 (br. s., 1H), 4.10 (br. s., 3H), 3.26 - 3.04 (m, 2H), 42 2.76 (d, J=17.7 Hz, 3H), 2.65 (br. s., 1H), 2.28 (s, (1S,3S)((6-(5- 3H), 2.03 (d, J=12.8 Hz, (((isopentyl(methyl)carbamoyl)oxy) 1H), 1.93 - 1.77 (m, 3H), methyl)methyl-1H-1,2,3-triazol 1.70 - 1.06 (m, 7H), 0.88 yl)methylpyridin (d, J=4.6 Hz, 3H), 0.67 yl)oxy)cyclohexanecarboxylic (d, J=5.2 Hz, 3H) acid hLPA1 IC50 = 3750 nM.
LCMS, [M+H]+ = 446.3. Example 1H NMR (500 MHz, 1 DMSO-d6)  8.35 (d, J=2.4 Hz, 1H), 8.00 (d, J=8.9 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 5.62 (d, J=18.0 Hz, 2H), 4.79 (br. 43 s., 1H), 4.11 (s, 3H), 3.24 - 3.04 (m, 2H), 2.82 - 2.62 (m, 4H), 1.98 (d, (1S,3S)((6-(5- J=14.0 Hz, 1H), 1.89 - (((butyl(methyl)carbamoyl)oxy)meth 1.73 (m, 3H), 1.72 - 1.37 yl)methyl-1H-1,2,3-triazol (m, 5H), 1.26 (br. s., 2H), yl)pyridinyl)oxy)cyclohexane 1.05 (br. s., 1H), 0.88 (br. carboxylic acid s., 2H), 0.69 (br. s., 2H) hLPA1 IC50 = 7 nM.
LCMS, [M+H]+ = 475.2 1H NMR (500MHz, DMSO-d6)  7.61 (d, J=12.2 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.35 (t, 44 J=8.5 Hz, 1H), 5.34 (s, 2H), 4.75 (br. s., 1H), (1S,3S)(4-(5- 4.13 (s, 3H), 3.46 - 3.30 (((cyclopentyl(methyl)carbamoyl)oxy (m, 1H), 2.73 - 2.59 (m, )methyl)methyl-1H-1,2,3-triazol- 4H), 2.01 - 1.30 (m, 16H) 4-yl)fluorophenoxy)cyclohexane- hLPA1 IC50 = 6 nM. 1-carboxylic acid Analytical & Biology Method Example Structure & Name LCMS, [M+H]+ = 475.4 Example 1H NMR (500 MHz, 1 6)  7.61 - 7.39 (m, 2H), 7.30 - 7.19 (m, 1H), 5.23 (s, 2H), 4.66 (br. s., 1H), 4.02 (s, 3H), 3.29 (br. s., 1H), 2.65 (br. 45 s., 3H), 2.60 - 2.52 (m, 1H), 1.94 - 1.85 (m, 1H), (1S,3S)(4-(5-((((1- 1.73 (d, J=11.0 Hz, 3H), cyclopropylethyl)(methyl)carbamoyl) 1.56 (d, J=8.5 Hz, 2H), oxy)methyl)methyl-1H-1,2,3- 1.44 (br. s., 2H), 0.98 (d, triazolyl) J=16.2 Hz, 4H), 0.51 - - fluorophenoxy)cyclohexane 0.31 (m, 4H) carboxylic acid hLPA1 IC50 = 20 nM. ereomeric mixture) Example LCMS, [M+H]+ = 463.0 1 1H NMR (500 MHz, DMSO-d6)  7.69 - 7.45 (m, 2H), 7.35 (br. s., 1H), .34 (br. s., 2H), 4.75 (br. 46 s., 1H), 4.13 (s, 3H), 3.23 - 3.06 (m, 2H), 2.78 (d, J=8.9 Hz, 3H), 2.63 (br. (1S,3S)(4-(5- s., 1H), 1.99 - 1.04 (m, (((butyl(methyl)carbamoyl)oxy)meth 12H), 0.93 - 0.70 (m, 3H) yl)methyl-1H-1,2,3-triazolyl)- hLPA1 IC50 = 6 nM. 2-fluorophenoxy)cyclohexane carboxylic acid Example LCMS, [M+H]+ = 477.1 1H NMR (500 MHz, 1 DMSO-d6)  7.77 - 7.43 (m, 2H), 7.33 (br. s., 1H), .34 (d, J=7.9 Hz, 2H), 4.75 (br. s., 1H), 4.13 (br. 47 s., 3H), 3.23 - 3.06 (m, 2H), 2.78 (d, J=14.6 Hz, (1S,3S)(2-fluoro(5- 3H), 2.67 (br. s., 1H), (((isopentyl(methyl)carbamoyl)oxy) 1.98 (br. s., 1H), 1.89 - methyl)methyl-1H-1,2,3-triazol 1.11 (m, 10H), 0.96 - yl)phenoxy)cyclohexane 0.65 (m, 6H) carboxylic acid hLPA1 IC50 = 3 nM.
Analytical & Biology Method Example Structure & Name Example LCMS, [M+H]+ = 471.3 1 1H NMR (400 MHz, CDCl3) δ 7.73 (br s, 2H), 7.04 (br d, J=7.5 Hz, 2H), 5.32 (s, 2H), 4.72 48 (br s, 1H), 4.19 (br s, 3H), 2.94 (br d, J=3.1 Hz, 1H), 2.67 (s, 3H), (1S,3S)(4-(5-((((1- 2.47 - 1.58 (m, 16H), cyclobutylethyl)(methyl)carbamoyl)o 1.02 (br s, 3H) xy)methyl)methyl-1H-1,2,3- hLPA1 IC50 = 8 nM. triazolyl)phenoxy)cyclohexane carboxylic acid (isomer 1) Example LCMS, [M+H]+ = 471.3 1 1H NMR (400 MHz, CDCl3) δ 7.85 - 7.62 (m, 2H), 7.03 (br d, J=3.3 Hz, 2H), 5.32 (br d, 49 J=2.9 Hz, 2H), 4.87 - 4.56 (m, 1H), 4.19 (br s, 3H), 3.07 - 2.86 (m, 1H), (1S,3S)(4-(5-((((1- 2.67 (br s, 3H), 2.49 - cyclobutylethyl)(methyl)carbamoyl)o 1.49 (m, 16H), 1.05 - hyl)methyl-1H-1,2,3- 0.93 (m, 3H) triazolyl)phenoxy)cyclohexane hLPA1 IC50 = 14 nM. carboxylic acid (isomer 2) LCMS, [M+H]+ = 460.2 Example 1H NMR (500 MHz, 1 DMSO-d6)  8.34 (br. s., 1H), 8.09 - 7.93 (m, 1H), 7.55 (d, J=7.9 Hz, 1H), .62 (d, J=16.8 Hz, 2H), 4.78 (br. s., 1H), 4.11 (br. 50 s., 3H), 3.29 - 3.00 (m, 2H), 2.76 (d, J=17.7 Hz, 3H), 2.64 (br. s., 1H), (1S,3S)((6-(5- 1.97 - 1.45 (m, 8H), 1.40 (((isopentyl(methyl)carbamoyl)oxy) - 1.14 (m, 2H), 0.88 (d, methyl)methyl-1H-1,2,3-triazol J=4.9 Hz, 3H), 0.67 (d, idinyl)oxy)cyclohexane J=5.2 Hz, 3H) carboxylic acid hLPA1 IC50 = 12 nM.
Analytical & Biology Method Example Structure & Name LCMS, [M+H]+ = 457.3 Example 1H NMR (400 MHz, 1 CD3CN)  7.64 - 7.44 (m, 2H), 6.89 (d, J=8.8 Hz, 2H), 5.10 (s, 2H), 4.61 - 4.49 (m, 1H), 3.94 (s, 3H), 2.70 - 2.52 (m, 4H), 1.96 - 1.85 (m, 1H), 1.75 - 1.35 (m, 8H), 0.97 (br. s., 3H), 0.75 (br. s., (1S,3S)(4-(5-(((((R) 1H), 0.44 -0.25 (m, 4H) cyclopropylethyl)(methyl)carbamoyl) hLPA1 IC50 = 24 nM. oxy)methyl)methyl-1H-1,2,3- In vivo acute histamine triazolyl)phenoxy)cyclohexane assay : -73% histamine at carboxylic acid a 3 mg/kg dose of Example 51 LCMS, [M+H]+ = 457.2 e 1H NMR (500 MHz, 3 DMSO-d6)  7.54 (d, J=8.2 Hz, 2H), 6.96 (d, J=8.2 Hz, 2H), 5.18 (br. s., 2H), 4.59 (br. s., 1H), 52 3.99 (s, 3H), 2.62 (br. s., 3H), 2.51 (br. s., 1H), (1S,3S)(4-(5-(((((S) 1.74 - 1.31 (m, 8H), 1.06 cyclopropylethyl)(methyl)carbamoyl) - 0.90 (m, 3H), 0.87 - oxy)methyl)methyl-1H-1,2,3- 0.71 (m, 1H), 0.43 - -0.30 triazolyl)phenoxy)cyclohexane (m, 4H) carboxylic acid hLPA1 IC50 = 197 nM.
Example LCMS, [M+H]+ = 445.2 1H NMR (500 MHz, DMSO-d6)  7.68 (br. s., 2H), 7.08 (d, J=8.2 Hz, 2H), 5.31 (s, 2H), 4.72 (br. s., 1H), 4.12 (s, 3H), 3.08 - 2.93 (m, 2H), 2.80 (d, J=15.3 Hz, 3H), 2.67 (1S,3S)(4-(5- (br. s., 1H), 2.03 - 1.48 (((isobutyl(methyl)carbamoyl)oxy)m (m, 9H), 0.88 - 0.64 (m, ethyl)methyl-1H-1,2,3-triazol 6H) yl)phenoxy)cyclohexane hLPA1 IC50 = 440 nM. carboxylic acid ereomeric mixture) Analytical & Biology Method Example Structure & Name LCMS, [M+ H]+ = 471.2 e 1H NMR (400 MHz, 2 CDCl3)  7.60 (t, J=9.4 Hz, 2H), 6.93 (d, J=7.5 Hz, 2H), 5.21 (s, 2H), 4.61 (br. s., 1H), 4.10 (d, J=2.2 Hz, 4H), 3.84 (dd, 54 J=10.3, 6.6 Hz, 1H), 2.98 - 2.76 (m, 1H), 2.69 - (1S,3S)(4-(5-((((1- 2.53 (m, 3H), 2.34 - 2.19 cyclobutylethyl)(methyl)carbamoyl)o (m, 1H), 2.08 (d, J=13.9 xy)methyl)methyl-1H-1,2,3- Hz, 1H), 2.00 - 1.40 (m, triazolyl)phenoxy)cyclohexane 12H), 0.90 (dd, J=17.7, carboxylic acid 6.7 Hz, 3H) (diastereomeric mixture) hLPA1 IC50 = 19 nM.
LCMS, [M+H]+ = 457.2 3 1H NMR (500 MHz, DMSO-d6)  7.80 (br. s., 2H), 7.20 (d, J=7.6 Hz, 2H), 5.43 (br. s., 2H), 4.83 (br. s., 1H), 4.24 (s, 3H), 3.54 - 3.30 (m, 3H), 2.93 (d, J=9.2 Hz, 3H), (rac)-trans(4-(5-((((2- 2.79 (br. s., 1H), 2.17 - cyclopropylethyl)(methyl)carbamoyl) 1.30 (m, 10H), 0.76 - - oxy)methyl)methyl-1H-1,2,3- 0.06 (m, 4H) triazolyl)phenoxy)cyclohexane hLPA1 IC50 = 41 nM. carboxylic acid LCMS, [M+H]+ = 473.2 Example 1H NMR (400 MHz, 2 CD3CN)  7.61 (d, J=15.2 Hz, 2H), 7.05 (br. s., 1H), 5.33 (br. s., 2H), 4.79 (br. s., 1H), 4.14 (s, 56 3H), 3.35 - 3.13 (m, 2H), 2.91 - 2.72 (m, 4H), 2.36 (1S,3S)(4-(5- - 2.26 (m, 3H), 2.14 (d, (((isopentyl(methyl)carbamoyl)oxy) J=13.4 Hz, 1H), 1.89 - methyl)methyl-1H-1,2,3-triazol 1.26 (m, 10H), 1.02 - yl)methylphenoxy)cyclohexane 0.68 (m, 6H) carboxylic acid hLPA1 IC50 = 3 nM.
Analytical & Biology Method e Structure & Name Example LCMS, [M+ H]+ = 459.2 2 1H NMR (500 MHz, DMSO-d6)  7.67 (t, J=9.6 Hz, 2H), 7.16 - 6.98 (m, 2H), 5.31 (s, 2H), 4.72 (br. s., 1H), 4.12 (s, 3H), 2.66 (d, trans(4-(1-methyl J=10.1 Hz, 1H), 2.04 - (((methyl(pentan 1.47 (m, 10H), 1.46 - yl)carbamoyl)oxy)methyl)-1H-1,2,3- 1.28 (m, 3H), 1.19 - 0.65 triazolyl)phenoxy)cyclohexane (m, 9H) carboxylic acid hLPA1 IC50 = 142 nM. (diastereomeric mixture) Example LCMS, [M+H]+ = 459.1 2 1H NMR (500 MHz, 6)  7.70 (d, J=8.2 Hz, 2H), 7.08 (d, J=7.6 Hz, 2H), 5.31 (br. s., 2H), 4.72 (br. s., 1H), 4.12 (s, 3H), 3.23 - 3.08 (m, 2H), 2.79 (d, J=13.7 (rac)-trans(4-(1-methyl Hz, 3H), 2.67 (br. s., 1H), (((methyl(pentyl)carbamoyl)oxy)met 2.03 - 1.01 (m, 14H), hyl)-1H-1,2,3-triazol 0.93 - 0.69 (m, 3H) yl)phenoxy)cyclohexane hLPA1 IC50 = 250 nM. carboxylic acid Example LCMS, [M+H]+ = 431.1 2 1H NMR (500 MHz, DMSO-d6)  7.68 (br. s., 2H), 7.09 (d, J=8.5 Hz, 2H), 5.31 (s, 2H), 4.72 (br. s., 1H), 4.12 (s, 3H), 3.20 - 3.07 (m, 2H), 2.80 (d, J=9.8 Hz, 3H), 2.67 (rac)-trans(4-(1-methyl (br. s., 1H), 2.05 - 1.31 (((methyl(propyl)carbamoyl)oxy)met (m, 10H), 0.84 - 0.65 (m, hyl)-1H-1,2,3-triazol 3H) yl)phenoxy)cyclohexane hLPA1 IC50 = 1880 nM. carboxylic acid Analytical & Biology Method Example Structure & Name Example LCMS, [M+H]+ = 479.2 1H NMR (500 MHz, DMSO-d6)  7.80 - 7.55 (m, 2H), 7.44 - 6.96 (m, 7H), 5.48 - 5.16 (m, 2H), 60 4.70 (br. s., 1H), 4.41 (d, J=12.8 Hz, 2H), 4.21 - 3.94 (m, 3H), 2.90 - 2.73 (rac)-trans(4-(5- (m, 3H), 2.70 - 2.61 (m, zyl(methyl)carbamoyl)oxy)met 1H), 2.04 - 1.48 (m, 8H) hyl)methyl-1H-1,2,3-triazol hLPA1 IC50 = 130 nM. yl)phenoxy)cyclohexane carboxylic acid LCMS, [M+H]+ = 443.2 Example 1H NMR (500 MHz, 1H 2 NMR (500 MHz, DMSO-d6) δ 7.66 - 7.46 (m, 2H), 7.08 - 6.86 (m, 2H), 5.28 - 5.11 (m, 2H), 4.68 - 4.59 (m, 1H), 4.10 - 3.94 (m, 3H), 3.08 - 2.91 (m, 3H), 2.85 - 2.71 (rac)-trans(4-(5- (m, 3H), 2.65 - 2.54 (m, ((((cyclopropylmethyl)(methyl)carba 1H), 1.97 - 1.39 (m, 8H), moyl)oxy)methyl)methyl-1H- 0.96 - 0.67 (m, 1H), 0.46 1,2,3-triazol - 0.22 (m, 2H), 0.16 to yl)phenoxy)cyclohexane -0.08 (m, 2H) carboxylic acid hLPA1 IC50 = 273 nM.
LCMS, [M+H]+ = 459.2 Example 1H NMR (400 MHz, 2 CD3CN) δ 7.80 - 7.65 (m, 2H), 7.12 - 6.96 (m, 2H), 5.35 - 5.24 (m, 2H), 4.78 - 4.70 (m, 1H), 5.07 62 - 4.33 (m, 1H), 4.20 - 4.06 (m, 3H), 3.37 - 3.14 (1R,3R)(4-(5- (m, 2H), 2.93 - 2.72 (m, (((isopentyl(methyl)carbamoyl)oxy) 4H), 2.13 - 2.02 (m, 1H), methyl)methyl-1H-1,2,3-triazol 1.92 - 1.22 (m, 10H), yl)phenoxy)cyclohexane 0.99 - 0.74 (m, 6H) carboxylic acid hLPA1 IC50 = 1290 nM.
Analytical & Biology Method e Structure & Name Example LCMS, [M+H]+ = 473.2 2 1H NMR (400 MHz, CD3CN)  7.65 - 7.46 (m, 2H), 7.04 (d, J=8.4 Hz, 1H), 5.29 (br. s., 2H), 4.78 (br. s., 1H), 4.13 (s, 3H), 3.30 - 3.19 (m, 2H), 2.88 - 2.74 (m, 4H), 2.30 (1R,3R)(4-(5- (s, 3H), 2.18 - 2.09 (m, (((isopentyl(methyl)carbamoyl)oxy) 1H), 1.80 - 1.25 (m, methyl)methyl-1H-1,2,3-triazol 11H), 0.96 - 0.70 (m, 6H) yl)methylphenoxy)cyclohexane hLPA1 IC50 = 701 nM. carboxylic acid Example LCMS, [M+H]+ = 445.2 1 (500 MHz, DMSO-d6) δ 7.76 - 7.57 (m, 2H), 7.17 - 6.94 (m, 2H), 5.42 - .23 (m, 2H), 4.77 - 4.62 (m, 1H), 4.19 - 4.04 (m, 3H), 3.28 - 3.06 (m, 2H), 2.88 - 2.75 (m, 3H), 2.71 (rac)-trans(4-(5- - 2.59 (m, 1H), 2.01 - (((butyl(methyl)carbamoyl)oxy)meth 1.03 (m, 13H), 0.92 - yl)methyl-1H-1,2,3-triazol 0.68 (m, 3H) yl)phenoxy)cyclohexane hLPA1 IC50 = 32 nM. ylic acid Example LCMS, [M+H]+ = 457.2 1 1H NMR (500 MHz, DMSO-d6)  7.54 (d, J=8.5 Hz, 2H), 6.96 (d, J=8.2 Hz, 2H), 5.19 (br. s., 2H), 4.60 (br. s., 1H), 3.99 (s, 3H), 2.63 (br. s., trans(4-(5-((((1- 4H), 2.60 - 2.51 (m, 1H), cyclopropylethyl)(methyl)carbamoyl) 1.95 - 1.34 (m, 8H), 1.06 oxy)methyl)methyl-1H-1,2,3- - 0.71 (m, 4H), 0.47 - triazolyl)phenoxy)cyclohexane 0.29 (m, 4H) carboxylic acid hLPA1 IC50 = 80 nM. (diastereomeric mixture) Analytical & Biology Method Example Structure & Name Example LCMS, [M+H]+ = 457.2 1 1H NMR (500 MHz, 6)  7.70 (d, J=7.9 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 5.31 (br. s., 2H), 4.72 (br. s., 1H), 4.12 (br. s., 3H), 3.31 - 3.13 (m, 2H), 2.78 (d, (rac)-trans(4-(5- J=11.0 Hz, 3H), 2.67 (br. ((((cyclobutylmethyl)(methyl)carbam s., 1H), 2.03 - 1.45 (m, oyl)oxy)methyl)methyl-1H-1,2,3- 15H) triazolyl)phenoxy)cyclohexane hLPA1 IC50 = 68 nM. carboxylic acid Example LCMS, [M+H]+ = 471.2 1H NMR (500 MHz, DMSO-d6)  7.81 - 7.58 (m, 2H), 7.12 - 7.03 (m, 2H), 5.43 - 5.17 (m, 2H), 4.71 (br. s., 1H), 4.12 (d, J=12.2 Hz, 3H), 4.06 - 3.74 (m, 1H), 3.00 (s, trans(4-(5-((((1- 3H), 2.66 (br. s., 1H), cyclobutylethyl)(methyl)carbamoyl)o 2.03 - 1.44 (m, 15H), hyl)methyl-1H-1,2,3- 0.94 - 0.81 (m, 3H) triazolyl)phenoxy)cyclohexane hLPA1 IC50 = 109 nM. carboxylic acid (diastereomeric mixture) Example LCMS, [M+H]+ = 445.2 1 1H NMR (500 MHz, DMSO-d6)  7.75 - 7.60 (m, 2H), 7.08 (d, J=8.9 Hz, 2H), 5.31 (s, 2H), 4.71 (br. s., 1H), 4.11 (s, 3H), 4.05 - 3.73 (m, 1H), (trans)(4-(5-(((sec- 2.73 - 2.57 (m, 4H), 2.02 butyl(methyl)carbamoyl)oxy)methyl) - 1.27 (m, 10H), 1.08 - methyl-1H-1,2,3-triazol 0.92 (m, 3H), 0.76 - 0.57 yl)phenoxy)cyclohexane (m, 3H) carboxylic acid hLPA1 IC50 = 320 nM. (diastereomeric mixture) Analytical & y Method Example Structure & Name Example LCMS, [M+H]+ = 473.0 (using 1H NMR (500 MHz, intermedi DMSO-d6)  7.83 (d, ate 2) J=8.5 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 5.62 (d, 69 J=19.4 Hz, 2H), 4.09 (d, J=7.2 Hz, 3H), 3.33 - 3.04 (m, 2H), 2.82 - 2.67 (3S)((6-(5- (m, 3H), 2.36 (br. s., 3H), ((((cyclobutylmethyl)(methyl)carbam 2.45 - 2.16 (m, 1H), 2.08 oyl)oxy)methyl)methyl-1H-1,2,3- - 1.15 (m, 14H) triazolyl)methylpyridin hLPA1 IC50 = 57 nM. yl)oxy)cyclohexanecarboxylicd acid (homochiral) LCMS, [M+H]+ = 475.3 Example 1H NMR (400MHz, 1 CDCl3)  7.51 - 7.32 (m, 2H), 7.03 (t, J=8.5 Hz, 1H), 5.28 - 5.12 (m, 2H), 4.62 (br. s., 1H), 4.11 (s, 3H), 3.41 (d, J=9.0 Hz, 1H), 3.19 (br. s., 1H), 2.98 - 2.69 (m, 4H), 2.11 )(4-(5-(((((R) (d, J=13.6 Hz, 1H), 2.01 cyclopropylethyl)(methyl)carbamoyl) - 1.67 (m, 4H), 1.65 - oxy)methyl)methyl-1H-1,2,3- 1.49 (m, 3H), 1.11 (d, triazolyl) J=6.6 Hz, 3H), 0.78 (br. fluorophenoxy)cyclohexane s., 1H), 0.57 - -0.15 (m, carboxylic acid 3H) hLPA1 IC50 = 10 nM.
Example LCMS, [M+H]+ = 459.2 2 1H NMR (500 MHz, DMSO-d6)  7.88 - 7.56 (m, 2H), 7.08 (br. s., 2H), .31 (br. s., 2H), 4.71 (br. s., 1H), 4.12 (s, 3H), 3.29 - 3.05 (m, 2H), 2.79 (d, J=17.1 Hz, 3H), 2.70 - (rac)-trans(4-(5- 2.60 (m, 1H), 2.05 - 1.19 (((isopentyl(methyl)carbamoyl)oxy) (m, 11H), 0.93 - 0.69 (m, methyl)methyl-1H-1,2,3-triazol 6H) yl)phenoxy)cyclohexane hLPA1 IC50 = 13 nM. carboxylic acid Analytical & Biology Method Example Structure & Name Example LCMS, [M+H]+ = 534.4 1H NMR (400 MHz, CD3OD)  7.67 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 72 8.8 Hz, 2H), 5.37 (s, 2H), 4.20 (s, 3H), 3.20 (s, 3H), (1-Methyl(4-(((1R,3R) 2.78 - 2.89 (m, 5H), 1.59- ylsulfonyl)carbamoyl)cyclohex 2.10 (m, 17H). yl)oxy)phenyl)-1H-1,2,3-triazol hLPA1 IC50 = 2780 nM. yl)methyl cyclopentyl (methyl)carbamate Example LCMS, [M+H]+ = 443.5 10 1H NMR (400 MHz, CD3OD)  7.64 (d, J = 8.00 Hz, 2H), 7.08 (d, J = 8.00 Hz, 2H), 5.33 (s, 73 2H), 4.72 - 4.74 (m, 1H), 4.18 (s, 3H), 2.78 - 2.84 (1S,3S)(4-(5- (m, 4H), 2.08 - 2.14 (m, (((cyclobutyl(methyl)carbamoyl)oxy) 5H), 1.82 - 1.93 (m, 3H), methyl)methyl-1H-1,2,3-triazol 1.41 - 1.79 (m, 7H). yl)phenoxy)cyclohexane hLPA1 IC50 = 62 nM. carboxylic acid Analytical & Biology Method Example Structure & Name Example LCMS, [M+H]+ = 483.2 1H NMR (400 MHz, CD3OD)  7.66 (d, J = 8.80 Hz, 2H), 7.09 (d, J = 8.80 Hz, 2H), 5.36 (s, 2H), 4.83 - 4.89 (m, 1H), 4.19 (s, 3H), 2.90 - 2.97 74 (1S,3S)(4-(5- (m, 3H), 2.70 - 2.87 (m, 2H), 2.08 - 2.15 (m, 1H), ((((Dicyclopropylmethyl)(methyl)car 1.90 - 1.99 (m, 3H), 1.62 bamoyl)oxy)methyl)methyl-1H- - 1.74 (m, 4H), 1.05 - 1.09 (m, 2H), 0.50 - 0.70 1,2,3-triazol (m, 2H), 0.12 - 0.43 (m, yl)phenoxy)cyclohexanecarboxylic 6H). hLPA1 IC50 = 100 nM.
LCMS, [M+H]+ = 471.2 e 1H NMR (400 MHz, 3 CD3OD) δ 7.70 - 7.80 (m, 1H), 7.60 - 7.70 (m, 1H), 7.08 (m, 2H), 5.30 - .39 (m, 2H), 4.81 - 4.83 (m, 1H), 4.18 - 4.21 (m, 3H), 2.89 (s, 3H), 2.79 - 75 2.82 (m, 1H), 2.06 - 2.12 (m, 1H), 1.80 - 2.00 (m, (1S,3S)(4-(1-methyl 3H), 1.60-1.80 (m, 4H), (((methyl(1- 1.20 - 1.50 (m, 4H), 0.80 propylcyclopropyl)carbamoyl)oxy)m - 0.90 (m, 2H), 0.70 - ethyl)-1H-1,2,3-triazol 0.80 (m, 3H), 0.60 - 0.70 yl)phenoxy)cyclohexane (m, 2H). carboxylic acid hLPA1 IC50 = 20 nM.
Analytical & y Method Example Structure & Name LCMS, [M+H]+ = 459.2 Example 1H NMR (400 MHz, 3 CD3OD) δ 7.60 - 7.70 (m, 2H), 7.10 - 7.00 (m, 2H), 5.37 (s, 2H), 4.70 - 76 4.80 (m, 1H), 4.18 (s, 3H), 2.75 - 2.85 (m, 1H), 2.60 - 2.70 (m, 3H), 2.08 (1S,3S)(4-(1-methyl - 2.15 (m, 1H), 1.90 - (((methyl(pentan 2.00 (m, 3H), 1.60 - 1.75 yl)carbamoyl)oxy)methyl)-1H-1,2,3- (m, 5H), 1.40 - 1.50 (m, triazolyl)phenoxy)cyclohexane 4H), 0.71 - 0.81 (m, 6H). carboxylic acid hLPA1 IC50 = 47 nM.
LCMS, [M+H]+ = 460.4 Example 1H NMR (400 MHz, 1 CD3OD)  8.30 - 8.46 (m, 1H), 7.90 - 7.97 (m, 1H), 7.51 - 7.65 (m, 1H), .70 (d, J = 10.8 Hz, 1H), 4.50 - 4.60 (m, 1H), 4.20 77 (s, 3H), 3.62 - 3.93 (m, 1H), 2.71 - 2.82 (m, 1H), (1S,3S)((6-(1-methyl 2.60 - 2.70 (m, 3H), 1.82 (((methyl(pentan - 2.10 (m, 4H), 1.57 - yl)carbamoyl)oxy)methyl)-1H-1,2,3- 1.79 (m, 4H), 1.36-1.49 triazolyl)pyridin (m, 5H), 0.82 (t, J = 7.2 yl)oxy)cyclohexanecarboxylic Hz, 3H), 0.67 (t, J = 7.6 acid Hz, 3H). hLPA1 IC50 = 242 nM.
Example LCMS, [M+H]+ = 474.4 1 1H NMR (400 MHz, CD3OD)  8.30 - 8.50 (m, 1H), 7.94-8.05 (m, 1H), 7.53 (d, J = 8.40 Hz, 1H), 5.66 (s, 2H), 4.82 - 78 4.86 (m, 1H), 4.20 (s, 3H), 2.75 - 2.90 (m, 4H), (1S,3S)((6-(1-methyl 1.90 - 2.20 (m, 4H), 1.60 (((methyl(2-methylpentan - 1.90 (m, 6H), 1.31 (s, bamoyl)oxy)methyl)-1H-1,2,3- 6H), 1.15 - 1.21 (m, 2H), triazolyl)pyridin 0.80 (t, J = 6.40 Hz, 3H). yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 27 nM.
Analytical & Biology Method Example Structure & Name LCMS, [M+H]+ = 444.2 1 1H NMR (400 MHz, CD3OD)  8.35 - 8.40 (m, 1H), 7.97 (d, J = 9.20 Hz, 1H), 7.53 (dd, J = 8.8 & 2.8 Hz, 1H), 5.70 (s, 79 2H), 4.80 - 4.85 (m, 1H), (1S,3S)((6-(1-methyl 4.21 (d, J = 16.00 Hz, (((methyl(1- 3H), 2.81-2.87 (m, 4H), methylcyclopropyl)carbamoyl)oxy)m 1.91 - 2.11 (m, 4H), 1.63 ethyl)-1H-1,2,3-triazolyl)pyridin- - 1.87 (m, 4H), 1.12 (s, 3-yl)oxy)cyclohexanecarboxylic 3H), 0.56 - 0.87 (m, 4H). acid hLPA1 IC50 = 45 nM.
Example LCMS, [M+H]+ = 484.4 1H NMR (400 MHz, CD3OD) δ 8.32-8.40 (m, 1H), 7.97-8.04 (m, 1H), 7.53 (d, J = 8.00 Hz, 1H), .60 - 5.80 (m, 2H), 4.82- 4.87 (m, 1H), 4.19 (s, 80 3H), 2.91 (d, J = 14.80 )((6-(5- Hz, 3H), 2.79-2.81 (m, 2H), 2.40 - 2.50 (m, 1H), ((((Dicyclopropylmethyl)(methyl)car 1.91-2.10 (m, 4H), 1.63- bamoyl)oxy)methyl)methyl-1H- 1.79 (m, 4H), 0.99-1.07 (m, 2H), 0.51-0.68 (m, 1,2,3-triazolyl)pyridin 2H), 0.13-0.41 (m, 5H). yl)oxy)cyclohexanecarboxylic acid hLPA1 IC50 = 60 nM.
Analytical & Biology Method Example Structure & Name LCMS, [M+H]+ = 472.2 Example 1H NMR (400 MHz, 3 CD3OD) δ 8.31-8.39 (m, 1H), 7.94-8.02 (m, 1H), 7.52 (d, J = 8.40 Hz, 1H), .67 - 5.70 (m, 2H), 4.81 - 4.89 (m, 1H), 4.40 - 81 4.50, m, 1H), 4.20 (d, J = 16.40 Hz, 3H), 2.72 - (1S,3S)((6-(1-methyl 2.87 (m, 3H), 1.85 - 2.10 (((methyl(1- (m, 4H), 1.60 - 1.73 (m, cyclopropyl)carbamoyl)oxy)m 4H), 1.10 - 1.40 (m, 4H), ethyl)-1H-1,2,3-triazolyl)pyridin- 0.84 - 0.90 (m, 2H), 0.65 3-yl)oxy)cyclohexanecarboxylic - 0.76 (m, 4H), 0.56 - acid 0.59 (m, 1H). hLPA1 IC50 = 61 nM.
Example LCMS, [M+H]+ = 460.9 4 1H NMR (500 MHz, DMSO-d6)  8.35 (br. s., 1H), 7.99 (d, J=8.7 Hz, 1H), 7.54 (d, J=6.6 Hz, 1H), 5.85 - 5.40 (m, 2H), 82 4.78 (br. s., 1H), 3.59 - (1S,3S)((6-(5- 2.83 (m, 2H), 2.79 - 2.60 ((((cyclobutylmethyl)(methyl)carbam (m, 4H), 2.03 - 1.36 (m, oyl)oxy)methyl)(methyl-d3)-1H- 14H), 1.16 (t, J=7.2 Hz, 1,2,3-triazolyl)pyridin 1H) yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 28 nM.
Analytical & y Method Example Structure & Name LCMS, [M+H]+ = 474.4 Example 1H NMR (400 MHz, 2 CD3OD)  7.68 (d, J = 8.0 Hz, 1H), 7.35 - 7.40 (m, 1H), 5.55 - 5.65 (m, 2H), 4.20 - 4.30 (m, 1H), 4.07 (s, 3H), 3.75 - 3.90 83 (m, 1H), 3.55 - 3.70 (m, 1H), 2.50 - 2.70 (m, 3H), 2.20 - 2.40 (m, 3H), 1.80 (1S,3S)((2-Methyl(1-methyl - 2.10 (m, 3H), 1.94 (s, (((methyl(pentan 3H), 1.55 - 1.84 (m, 3H), bamoyl)oxy)methyl)-1H-1,2,3- 1.10 - 1.40 (m, 3H), 0.70 triazolyl)pyridin (t, J = 7.6 Hz, 3H), 0.55 yl)oxy)cyclohexanecarboxylic acid (t, J = 7.2 Hz, 3H). hLPA1 IC50 = 92 nM.
LCMS, [M+H]+ = 488.2 Example 1H NMR (400 MHz, 1 CD3OD)  7.70 (d, J = 8.4, 1H), 7.32 (d, J = 8.4 Hz, 1H), 5.56 (s, 2H), 4.07 (s, 3H), 2.74 (s, 3H), 84 2.62 - 2.69 (m, 1H), 2.40 (s, 3H), 1.98 - 2.05 (m, (1S,3S)((2-methyl(1-methyl 1H), 1.80 - 1.90 (m, 3H), (((methyl(2-methylpentan 1.45 - 1.70 (m, 5H), 1.20 yl)carbamoyl)oxy)methyl)-1H-1,2,3- (s, 6H), 1.01 - 1.10 (m, triazolyl)pyridin 3H), 0.71 - 0.79 (m, 1H), yl)oxy)cyclohexanecarboxylic acid 0.60 - 0.70 (m, 3H). hLPA1 IC50 = 69 nM.
LCMS, [M+H]+ = 458.2 Example 1H NMR (400 MHz, 1 CD3OD) δ 7.81 (d, J=8, 1H) 7.44 (d, J=8 Hz, 1 H) 5.71 (s, 2 H) 4.79 - 4.81 (m, 1 H) 4.13-4.26 85 (m, 3H) 2.74-2.88 (m, 4 H) 2.51 (s, 3 H) 2.06 - (1S,3S)((2-methyl(1-methyl 2.18 (m, 1 H) 1.86 - 1.96 (((methyl(1- (m, 3 H) 1.62 - 1.83 (m, methylcyclopropyl)carbamoyl)oxy)m 4 H) 1.11 (br. s., 3 H) ethyl)-1H-1,2,3-triazolyl)pyridin- 0.43 - 0.85 (m, 4 H) 3-yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 58 nM.
Analytical & Biology Method Example Structure & Name Example LCMS, [M+H]+ = 498.3 1 1H NMR (400 MHz, CD3OD)  7.79 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 5.60 - 5.70 (m, 2H), 4.17 (s, 3H), 2.90 (d, J = 13.2 Hz, 3H), 86 2.60 - 2.80 (m, 3H), 2.49 (1S,3S)((6-(5- (s, 3H), 2.40 - 2.55 (m, 3H), 2.05 - 2.15 (m, 1H), ((((Dicyclopropylmethyl)(methyl)car 1.60 - 1.80 (m, 4H), 1.20 bamoyl)oxy)methyl)methyl-1H- - 1.40 (m, 2H), 0.90 - 1.10 (m, 2H), 0.45 - 0.65 1,2,3-triazolyl)methylpyridin (m, 2H), 0.30 - 0.40 (m, yl)oxy)cyclohexanecarboxylic acid 2H), 0.10 - 0.30 (m, 2H). hLPA1 IC50 = 54 nM.
LCMS, [M+H]+ = 486.0 Example 1H NMR (400 MHz, 1 CD3OD)  7.77 - 7.86 (m, 1 H) 7.44 (d, J=8.4 Hz, 1 H) 5.71 (d, J=11.6 Hz, 2H) .84 (m, 1 H), 4.2 (d, J=8.4 Hz, 1 87 H), 2.74 - 2.90 (m, 4H), 2.51(s, 3H), 2.10-2.15(m, (1S,3S)((2-methyl(1-methyl 1H), 1.91 - , 3H), (((methyl(1- 1.66-1.74 (m, 4H), 1.28 - propylcyclopropyl)carbamoyl)oxy)m 1.37(m, 2H), 1.12 - 1.20 ethyl)-1H-1,2,3-triazolyl)pyridin- (m, 2H), 0.84 - 0.93 (m, 3-yl)oxy)cyclohexanecarboxylic 2H), 0.68 - 0.71(m, 5H), acid 0.51 - 0.53 (m, 2H). hLPA1 IC50 = 36 nM.
Analytical & Biology Method Example Structure & Name Example LCMS, [M+H]+ = 490.3 1H NMR (400 MHz, CDCl3)  7.89 (d, J=8.6 Hz, 1H), 7.24 - 7.17 (m, 1H), 5.71 - 5.62 (m, 2H), 88 4.71 (tt, J=6.8, 3.7 Hz, 1H), 4.58 - 4.13 (m, 1H), (rac)-trans((6-(5- 4.07 (s, 3H), 2.65 (br. s., (((cyclopentyl(methyl)carbamoyl)oxy 3H), 2.52 - 2.38 (m, 4H), )methyl)methyl-1H-1,2,3-triazol- 2.24 - 1.32 (m, 15H); 4-yl)methylpyridinyl)oxy) hLPA1 IC50 = 32 nM. cyclohexanecarboxylic acid Example LCMS, [M+H]+ = 476.3 11 1H NMR (500 MHz, CDCl3)  8.46 (d, J=2.5 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.56 (dd, J=8.9, 89 2.6 Hz, 1H), 5.50 (s, 2H), 4.89 - 4.75 (m, 1H), 4.55 (rac)-trans((6-(5- - 4.44 (m, 1H), 4.10 (s, (((cyclopentyl(methyl)carbamoyl)oxy 3H), 2.64 (br. s., 3H), )methyl)methyl-1H-1,2,3-triazol- 2.56 - 2.37 (m, 4H), 2.19 4-yl)pyridinyl)oxy) – 1.37 (m, 15H) cyclohexanecarboxylic acid hLPA1 IC50 = 32 nM.
LCMS, [M+H]+ = 476.3 Example 1H NMR (500 MHz, 11 CDCl3)  8.60 (d, J=2.5 Hz, 1H), 8.18 (d, J=8.5 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 5.56 (s, 2H), 4.92 (br. s., 1H), 4.65 - 90 4.50 (m, 1H), 4.21 (d, J=3.0 Hz, 3H), 2.85 (d, (rac)-trans((6-(5- J=17.1 Hz, 3H), 2.66 - ((((cyclobutylmethyl)(methyl)carbam 2.41 (m, 4H), 2.29 – 1.48 oyl)oxy)methyl)methyl-1H-1,2,3- (m, 15H) triazolyl)pyridinyl)oxy) hLPA1 IC50 = 14 nM. fluorocyclohexanecarboxylic acid Analytical & Biology Method Example Structure & Name Example LCMS, [M+H]+ = 473.4 2 1H NMR (500 MHz, CDCl3)  8.11 (d, J=8.8 Hz, 1H), 7.80 (t, J=8.9 Hz, 1H), 5.70 - 5.42 (m, 91 2H), 4.86 (br. s., 1H), 4.20 (d, J=1.7 Hz, 3H), (rac)-trans((6-(5- 3.39 - 3.26 (m, 3H), 2.90 ((((cyclobutylmethyl)(methyl)carbam (d, J=7.7 Hz, 3H), 2.77 - oyl)oxy)methyl)methyl-1H-1,2,3- 2.69 (m, 3H), 2.19 - 1.63 triazolyl)methylpyridin (m, 15H) yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 18 nM.
Example LCMS, [M+H]+ = 472.3 2 1H NMR (400 MHz, CDCl3)  8.08 (d, J=8.6 Hz, 1H), 7.66 (t, J=8.6 Hz, 1H), 5.72 (d, J=14.5 Hz, 1H), 5.47 (d, J=14.3 92 Hz, 1H), 4.58 (br. s., 1H), 4.21 (s, 3H), 3.40 - 3.19 (rac)-cis((6-(5- (m, 2H), 2.90 (s, 3H), ((((cyclobutylmethyl)(methyl)carbam 2.70 (d, J=2.6 Hz, 3H), oyl)oxy)methyl)methyl-1H-1,2,3- 2.64 - 2.46 (m, 2H), 2.31 lyl)methylpyridin - 1.48 (m, 14H) yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 76 nM.
Example LCMS, [M+H]+ = 475.1 1H NMR (500 MHz, CDCl3)  8.10 (br. s., 1H), 7.87 (br. s., 1H), .90 - 5.21 (m, 2H), 4.21 93 (br. s., 3H), 3.30 (t, J=8.0 Hz, 2H), 2.85 (br. s., 1H), )((6-(5- 2.73 (br. s., 3H), 2.63 - ((((cyclobutylmethyl)(methyl- 2.47 (m, 1H), 2.24 - 1.52 d3)carbamoyl)oxy)methyl)methyl- (m, 16H) 1H-1,2,3-triazolyl) hLPA1 IC50 = 20 nM. methylpyridinyl)oxy)cyclohexane- 1-carboxylic acid Analytical & Biology Method Example Structure & Name Example LCMS, [M+H]+ = 471.3 14 1H NMR (500 MHz, DMSO-d6)  7.58 (br.
S., 2H), 7.05 (d, J=8.0 Hz, 2H), 6.00 (d, J=6.9 94 Hz, 1H), 4.69 (br. S., 1H), 4.40 – 4.22 (m, 1H), (1S,3S)(4-(5-(1- 4.13 (s, 3H), 2.65 (br. S., ((cyclopentyl(methyl)carbamoyl)oxy) 4H), 1.98 – 1.35 (m, methyl-1H-1,2,3-triazol 19H) yl)phenoxy)cyclohexane hLPA1 IC50 = 241 nM. carboxylic acid Example LCMS, [M+H]+ = 472.3 1H NMR (400 MHz, CDCl3)  7.91 (d, J=8.1 Hz, 1H), 7.16 (dd, J=8.3, 3.6 Hz, 1H), 5.74 (br. S., 95 2H), 4.32 – 4.18 (m, 1H), 4.13 (br. S., 3H), 3.35 – 3.11 (m, 2H), 2.92 – 2.75 3-((6-(5- (m, 3H), 2.56 – 2.24 (m, ((((cyclobutylmethyl)(methyl)carbam 5H), 2.17 – 1.35 (m, oyl)oxy)methyl)methyl-1H-1,2,3- 15H) triazolyl)methylpyridin hLPA1 IC50 = 1152 nM. yl)oxy)cyclohexanecarboxylic acid; Enantiomer A Example LCMS, [M+H]+ = 472.3 1H NMR (400 MHz, CDCl3)  7.86 (d, J=8.6 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 5.67 (br. s., 2H), 96 4.23 - 4.12 (m, 1H), 4.06 (br. s., 3H), 3.31 - 3.01 (Cis)((6-(5- (m, 2H), 2.86 - 2.65 (m, ((((cyclobutylmethyl)(methyl)carbam 3H), 2.42 - 2.30 (m, 4H), oyl)oxy)methyl)methyl-1H-1,2,3- 2.16 - 1.31 (m, 15H) triazolyl)methylpyridin hLPA1 IC50 = 20 nM. yl)oxy)cyclohexanecarboxylic Enantiomer B ical & Biology Method Example Structure & Name Example LCMS, [M+H]+ = 472.3 1H NMR (400 MHz, CDCl3) δ 8.03 - 7.90 (m, 1H), 7.23 (d, J=8.6 Hz, 1H), 5.77 (br d, J=5.3 Hz, 2H), 4.72 (br s, 1H), 97 4.16 (br s, 3H), 3.38 - 3.15 (m, 2H), 2.90 (br s, (1R,3R)((6-(5- 3H), 2.80 (br s, 2H), 2.59 ((((cyclobutylmethyl)(methyl)carbam (br s, 1H), 2.45 - 2.36 (m, oyl)oxy)methyl)methyl-1H-1,2,3- 1H), 2.23 - 2.10 (m, 1H), triazolyl)methylpyridin 2.08 - 1.52 (m, 14H) yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 10 nM.
Example LCMS, [M+H]+ = 512.3 1 1H NMR (600 MHz, DMSO-d6)  7.84 (d, J=5.2 Hz, 1H), 7.46 (br. s., 1H), 7.41 - 6.79 (m, 4H), 5.87 - 5.59 (m, 2H), 98 4.78 (br. s., 1H), 4.51 - 4.26 (m, 2H), 4.15 - 3.91 (1S,3S)((6-(5-((((2- (m, 3H), 3.53 - 3.37 (m, fluorobenzyl)(methyl)carbamoyl)oxy 1H), 2.87 - 2.69 (m, 3H), )methyl)methyl-1H-1,2,3-triazol- 2.67 - 2.58 (m, 1H), 2.46 4-yl)methylpyridin - 2.30 (m, 3H), 2.07 - yl)oxy)cyclohexanecarboxylic 1.44 (m, 8H) acid hLPA1 IC50 = 19 nM.
Analytical & Biology Method Example Structure & Name Example LCMS, [M+H]+ = 486.3 1 1H NMR (600 MHz, DMSO-d6)  7.47 (d, J=8.5 Hz, 1H), 6.98 (d, J=9.1 Hz, 1H), 5.65 (br. s., 2H), 4.77 (br. s., 1H), 4.07 (s, 3H), 3.51 (br. s., 99 4H), 2.66 - 2.57 (m, 1H), (1S,3S)((6-(5-((((1- 2.40 (br. s., 3H), 2.29 - cyclobutylpropyl)(methyl)carbamoyl) 2.19 (m, 1H), 2.05 - 1.97 oxy)methyl)methyl-1H-1,2,3- (m, 1H), 1.89 - 1.43 (m, triazolyl)methylpyridin 14H), 1.25 (d, J=7.3 Hz, yl)oxy)cyclohexanecarboxylic 3H), 0.76 (t, J=7.3 Hz, acid 3H) (diastereomeric mixture) hLPA1 IC50 = 144 nM.
Example LCMS, [M+H]+ = 520.0 5 1H NMR (400 MHz, CD3OD)  7.60 - 7.69 (m, 1 H) 7.01 - 7.34 (m, H) 6.78 - 6.88 (m, 1 H) .60 - 5.68 (m, 2 H) 4.08 100 - 4.14 (m, 1 H) 3.76 - 3.86 (m, 3 H) 2.88 - 2.94 )((2-methyl(1-methyl (m, 3 H) 2.80 - 2.83 (m, (((methyl(1- 1 H) 2.32 - 2.44 (m, 3H) phenylcyclopropyl)carbamoyl)oxy)m 1.86 - 1.92 (m, 4 H) 1.54 ethyl)-1H-1,2,3-triazolyl)pyridin- - 1.67 (m, 4 H) 1.18 - 3-yl)oxy)cyclohexanecarboxylic 1.27 (m, 4 H) acid hLPA1 IC50 = 70 nM.
Analytical & Biology Method Example Structure & Name LCMS, [M+H]+ = 500.0 Example 1H NMR (400 MHz, 5 CD3OD)  7.60 - 7.69 (m, 1 H) 7.01 - 7.34 (m, H) 6.78 - 6.88 (m, 1 H) .60 - 5.68 (m, 2 H) 4.08 101 - 4.14 (m, 1 H) 3.76 - 3.86 (m, 3 H) 2.88 - 2.94 (1S,3S)((2-methyl(1-methyl (m, 3 H) 2.80 - 2.83 (m, hyl(3,3,3- 1 H) 2.32 - 2.44 (m, 3H) trifluoropropyl)carbamoyl)oxy)methy 1.86 - 1.92 (m, 4 H) 1.54 l)-1H-1,2,3-triazolyl)pyridin - 1.67 (m, 4 H) 1.18 - yl)oxy)cyclohexanecarboxylic 1.27 (m, 4 H) acid hLPA1 IC50 = 49 nM.
Example LCMS, [M+H]+ = 469.9 1H NMR (500 MHz, DMSO-d6)  7.83 (d, J=8.4 Hz, 1H), 7.48 (d, J=8.6 Hz, 1H), 5.61 (s, 102 2H), 4.87 – 4.69 (m, 1H), (1S,3S)((6-(5- 4.10 (s, 3H), 2.71 (br. S., (((bicyclo[1.1.1]pentan 3H), 2.55 (s, 3H), 2.40 (s, yl(methyl)carbamoyl)oxy)methyl) 3H), 2.07 – 1.47 (m, methyl-1H-1,2,3-triazolyl) 15H) methylpyridinyl)oxy)cyclohexane- hLPA1 IC50 = 53 nM. 1-carboxylic acid Analytical & Biology Method e Structure & Name LCMS, [M+H]+ = 508.2 Example 1H NMR (400 MHz, 5 CD3OD)  7.84 - 7.88 (m, 1 H) 7.46 (br. s., 1 H) 7.12 - 7.31 (m, 4 H) 6.97 - 7.01 (m, 1 H) 5.60 - .73 (m, 2H) 4.80 (br. s., 103 1 H) 4.12 (br. s., 3 H) 3.46 - 3.53 (m, 3 H) 2.74 (1S,3S)((2-methyl(1-methyl - 2.85 (m, 4 H) 2.63 (d, (((methyl(phenethyl)carbamoyl)oxy) J=7.03 Hz, 1 H) 2.46 (br. methyl)-1H-1,2,3-triazol s., 3 H) 2.09 (br. s., 1 H) yl)pyridinyl)oxy)cyclohexane 1.94 (br. s., 3 H) 1.61 - carboxylic acid 1.73 (m, 4 H) hLPA1 IC50 = 119 nM.
Example LCMS, [M+H]+ = 446.1 5 1H NMR (400 MHz, CD3OD)  7.81 (d, J=8.53 Hz, 1 H) 7.44 (d, J=8.53 Hz, 1 H) 5.71 (br. s., 2 H) 4.81 (br. s., 1 H) 104 4.19 (s, 3 H) 3.09 - 3.17 (m, 2 H) 2.81 - 2.90 (m, (1S,3S)((2-methyl(1-methyl 4 H) 2.51 (s, 3 H) 2.14 (((methyl(propyl)carbamoyl)oxy)met (br. s., 1 H) 1.88 - 1.92 hyl)-1H-1,2,3-triazolyl)pyridin (m, 3 H) 1.68 - 1.71 (m, yl)oxy)cyclohexanecarboxylic 4 H) 1.56 (br. s., 2 H) acid 0.88 (d, J=7.03 Hz, 3 H) hLPA1 IC50 = 19 nM Analytical & Biology Method Example Structure & Name Example 105 LCMS, [M+H]+ = 456.3 )((6-(5- hLPA1 IC50 = 576 nM. (((bicyclo[1.1.1]pentan ylcarbamoyl)oxy)methyl)methyl- 1H-1,2,3-triazolyl) methylpyridinyl)oxy)cyclohexane- 1-carboxylic acid Example LCMS, [M+H]+ = 486.1 5 1H NMR (400 MHz, CD3OD)  7.79 (d, J=8.53 Hz, 1 H) 7.44 (d, J=8.53 Hz, 1 H) 5.66 (s, 2 H) 4.19 (s, 3H) 2.68 (d, 106 J=6.02 Hz, 1 H) 2.52 (s, (1S,3S)((6-(5-((((1,3- 3 H) 2.12 (d, J=13.05 Hz, dimethylcyclobutyl)(methyl)carbamo 3 H) 1.94 (br. s., 3H) yl)oxy)methyl)methyl-1H-1,2,3- 1.58 - 1.79 (m, 5H) 1.31 triazolyl)methylpyridin (br. s., 6 H) 1.13 (br. s., 3 yl)oxy)cyclohexanecarboxylic H) 0.93 - 0.96 (m, 3 H) acid hLPA1 IC50 = 67 nM.
Enantiomer A Analytical & Biology Method Example Structure & Name Example LCMS, [M+H]+ = 486.1 5 1H NMR (400 MHz, CD3OD)  ppm 7.79 (d, J=8.53 Hz, 1 H) 7.44 (d, J=8.53 Hz, 1 H) 5.66 (s, 2 H) 4.19 (s, 3H) 2.68 (d, 107 J=6.02 Hz, 1 H) 2.52 (s, (1S,3S)((6-(5-((((1,3- 3 H) 2.12 (d, J=13.05 Hz, dimethylcyclobutyl)(methyl)carbamo 3 H) 1.94 (br. s., 3H) yl)oxy)methyl)methyl-1H-1,2,3- 1.58 - 1.79 (m, 5H) 1.31 triazolyl)methylpyridin (br. s., 6 H) 1.13 (br. s., 3 yl)oxy)cyclohexanecarboxylic H) 0.93 - 0.96 (m, 3 H) acid hLPA1 IC50 = 70 nM.
Enantiomer B Example LCMS, [M+H]+ = 458.0 1H NMR (500 MHz, DMSO-d6)  7.83 (d, J=8.2 Hz, 1H), 7.58 - 7.37 (m, 1H), 7.29 (br. s., 108 1H), 5.64 (s, 2H), 4.77 (br. s., 1H), 4.07 (s, 3H), (1S,3S)((6-(5- 3.01 (t, J=6.0 Hz, 2H), ((((cyclobutylmethyl)carbamoyl)oxy) 2.44 - 2.31 (m, 4H), 2.05 )methyl-1H-1,2,3-triazol - 1.40 (m, 15H) yl)methylpyridin hLPA1 IC50 = 108 nM. yl)oxy)cyclohexanecarboxylic Analytical & Biology Method Example Structure & Name Example LCMS, [M+H]+ = 486.2 5 1H NMR (400 MHz, DMSO-d6)  6.97 - 7.04 (m, 1 H) 6.60 - 6.67 (m, 1 H) 4.89 (s, 2 H) 3.99 - 4.01 (m, 1 H) 3.38 (s, 3 109 H) 2.39 - 2.43 (m, 1 H) 2.26 - 2.30 (m, 1 H) 2.08 (1S,3S)((6-(5- (s, 3 H) 1.70 (s, 3 H) 1.28 ((((cyclopentylmethyl)(methyl)carba - 1.33 (m, 1 H) 1.10 - moyl)oxy)methyl)methyl-1H- 1.19 (m, 4 H) 0.46 - 0.98 1,2,3-triazolyl)methylpyridin (m, 12 H) 0.39 - 0.42 (m, yl)oxy)cyclohexanecarboxylic 1 H) acid hLPA1 IC50 = 22 nM.
Example LCMS, [M+H]+ = 447.4 4 1H NMR (500 MHz, DMSO-d6)  8.34 (br. s., 1H), 7.98 (d, J=7.7 Hz, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.36 - 6.86 (m, 1H), 110 6.03 - 5.43 (m, 2H), 4.77 (br. s., 1H), 3.26 - 2.57 (1S,3S)((6-(5- (m, 6H), 2.19 - 1.31 (m, clopropylmethyl)(methyl)carba 8H), 1.07 - 0.65 (m, 1H), moyl)oxy)methyl)(methyl-d3)-1H- 0.62 - -0.21 (m, 4H) 1,2,3-triazolyl)pyridin hLPA1 IC50 = 31 nM. yl)oxy)cyclohexanecarboxylic Analytical & Biology Method Example Structure & Name LCMS, [M+H]+ = 461.2 4 1H NMR (500 MHz, DMSO-d6)  8.33 (d, J=2.4 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.53 (d, J=6.3 Hz, 1H), 5.60 (br. 111 s., 2H), 4.77 (br. s., 1H), 3.59 (br. s., 1H), 2.63 (br. (1S,3S)((6-(5- s., 4H), 1.94 (br. s., 1H), (((cyclopentyl(methyl)carbamoyl)oxy 1.86 - 1.69 (m, 3H), 1.68 )methyl)(methyl-d3)-1H-1,2,3- - 1.25 (m, 12H) triazolyl)pyridin hLPA1 IC50 = 23 nM. yl)oxy)cyclohexanecarboxylic LCMS, [M+H]+ = 449.4 Example 1H NMR (500 MHz, 4 DMSO-d6)  8.34 (d, J=2.3 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 5.83 - .25 (m, 2H), 4.77 (br. s., 112 1H), 3.29 - 2.97 (m, 2H), 2.85 - 2.59 (m, 4H), 1.94 (br. s., 1H), 1.88 - 1.71 (1S,3S)((6-(5- (m, 3H), 1.68 - 1.33 (m, (((butyl(methyl)carbamoyl)oxy)meth 5H), 1.31 - 1.14 (m, 2H), yl)(methyl-d3)-1H-1,2,3-triazol 1.08 - 0.55 (m, 4H) yl)pyridinyl)oxy)cyclohexane hLPA1 IC50 = 17 nM. carboxylic acid Analytical & Biology Method Example Structure & Name Example LC/MS: [M+H]+ = 1 486.1 1H NMR (500 MHz, DMSO-d6) δ 7.99 - 7.72 (m, 1H), 7.48 (br d, J=7.4 113 Hz, 1H), 5.62 (br s, 3H), 4.79 (br s, 1H), 4.10 (br s, 4H), 3.31 - 2.96 (m, 5H), )((6-(5- 2.71 - 2.59 (m, 1H), 2.41 ((((cyclobutylmethyl)(ethyl)carbamo (br s, 3H), 1.97 - 1.77 (m, yl)oxy)methyl)methyl-1H-1,2,3- 6H), 1.59 - 1.34 (m, 6H), triazolyl)methylpyridin 1.07 - 0.76 (m, 4H) yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 15 nM Example LC/MS: [M+H]+ = 1 460.2 1H NMR (500 MHz, DMSO-d6) δ 7.80 (br d, J=8.6 Hz, 1H), 7.45 (br d, 114 J=8.7 Hz, 1H), 5.65 (s, 2H), 4.76 (br s, 1H), 4.06 (s, 2H), 3.93 - 3.84 (m, (1S,3S)((2-methyl(1-methyl 2H), 3.61 - 3.17 (m, 7H), (((morpholine 2.66 - 2.58 (m, 1H), 2.39 carbonyl)oxy)methyl)-1H-1,2,3- (s, 3H), 2.12 - 1.29 (m, triazolyl)pyridin 8H) yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 643 nM Analytical & Biology Method e Structure & Name Example LC/MS: [M+H]+ = 1 458.2 1H NMR (500 MHz, DMSO-d6) δ 7.84 (br d, J=8.2 Hz, 1H), 7.48 (br d, J=7.7 Hz, 1H), 5.86 - 5.45 (m, 2H), 4.78 (br s, 1H), 4.10 (s, 3H), 3.12 - 2.92 (1S,3S)((6-(5- (m, 2H), 2.89 - 2.76 (m, ((((cyclopropylmethyl)(methyl)carba 3H), 2.62 (br s, 1H), 2.41 moyl)oxy)methyl)methyl-1H- (s, 3H), 2.09 - 1.42 (m, 1,2,3-triazolyl)methylpyridin 8H), 0.97 - 0.64 (m, 1H), yl)oxy)cyclohexanecarboxylic 0.55 - -0.10 (m, 4H) acid hLPA1 IC50 = 18 nM LC/MS: [M+H]+ = Example 460.2 1 1H NMR (500 MHz, DMSO-d6) δ 8.03 - 7.74 (m, 1H), 7.47 (br d, J=7.7 Hz, 1H), 6.06 - 5.43 (m, 2H), 4.78 (br s, 1H), 4.10 116 (s, 3H), 3.02 (br d, J=6.8 Hz, 1H), 2.88 (br d, J=6.9 (1S,3S)((6-(5- Hz, 1H), 2.81 - 2.69 (m, (((isobutyl(methyl)carbamoyl)oxy)m 3H), 2.62 (br t, J=10.2 ethyl)methyl-1H-1,2,3-triazol Hz, 1H), 2.41 (s, 3H), yl)methylpyridin 2.12 - 1.42 (m, 9H), 0.81 yl)oxy)cyclohexanecarboxylic (br d, J=6.1 Hz, 3H), 0.62 acid (br d, J=5.8 Hz, 3H) hLPA1 IC50 = 29 nM Analytical & Biology Method Example Structure & Name LC/MS: [M+H]+ = Example 502.1 1 1H NMR (500 MHz, DMSO-d6) δ 7.85 (br d, J=6.1 Hz, 1H), 7.48 (br d, J=8.6 Hz, 1H), 5.73 - .48 (m, 2H), 4.78 (br s, 1H), 4.10 (br d, J=7.7 Hz, 3H), 3.82 (br d, J=8.8 Hz, 1H), 3.62 (br (1S,3S)((2-methyl(1-methyl d, J=12.5 Hz, 1H), 3.24 (((methyl((tetrahydro-2H-pyran (br s, 1H), 3.17 (s, 1H), yl)methyl)carbamoyl)oxy)methyl)- 3.09 (br d, J=6.3 Hz, 1H-1,2,3-triazolyl)pyridin 1H), 3.04 - 2.92 (m, 2H), yl)oxy)cyclohexanecarboxylic 2.84 - 2.72 (m, 3H), 2.41 acid (s, 3H), 2.05 - 1.10 (m, hLPA1 IC50 = 17 nM LC/MS: [M+H]+ = Example 495.0 1 1H NMR (500 MHz, DMSO-d6) δ 8.69 - 7.72 (m, 2H), 7.72 - 7.03 (m, 4H), 5.79 - 5.58 (m, 2H), 4.78 (br s, 1H), 4.45 (s, 118 2H), 4.27 - 3.82 (m, 2H), 3.17 (s, 1H), 2.97 - 2.75 (1S,3S)((2-methyl(1-methyl (m, 3H), 2.63 (br s, 1H), hyl(pyridin 2.44 - 2.29 (m, 3H), 2.02 ylmethyl)carbamoyl)oxy)methyl)- (br d, J=12.7 Hz, 1H), 1H-1,2,3-triazolyl)pyridin 1.93 - 1.40 (m, 7H) yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 211 nM Analytical & Biology Method Example Structure & Name LC/MS: [M+H]+ = Example 432.1 1 1H NMR (500 MHz, DMSO-d6) δ 7.84 (d, J=8.5 Hz, 1H), 7.48 (br d, J=8.6 Hz, 1H), 5.64 (br d, J=13.1 Hz, 2H), 119 4.78 (br s, 1H), 4.09 (s, 3H), 3.31 - 3.04 (m, 2H), 2.84 - 2.70 (m, 3H), 2.62 (1S,3S)((6-(5- (br s, 1H), 2.41 (s, 3H), (((ethyl(methyl)carbamoyl)oxy)meth 2.01 (br d, J=14.1 Hz, yl)methyl-1H-1,2,3-triazolyl)- 1H), 1.92 - 1.72 (m, 3H), 2-methylpyridin 1.69 - 1.43 (m, 4H), 1.08 yl)oxy)cyclohexanecarboxylic - 0.78 (m, 3H) acid hLPA1 IC50 = 878 nM 120 LC/MS: [M+H]+ = 495.1 Example 1H NMR (500 MHz, 1 DMSO-d6) δ 8.64 - 8.27 (m, 2H), 7.85 (d, J=8.6 Hz, 1H), 7.70 - 7.31 (m, 2H), 6.59 (s, 1H), 5.81 - .57 (m, 2H), 4.79 (br s, 1H), 4.52 - 4.27 (m, 2H), 4.20 - 3.96 (m, 2H), 3.39 (1S,3S)((2-methyl(1-methyl (br s, 1H), 2.98 - 2.70 (m, (((methyl(pyridin 3H), 2.63 (br d, J=9.8 ylmethyl)carbamoyl)oxy)methyl)- Hz, 1H), 2.38 (br d, ,3-triazolyl)pyridin J=17.8 Hz, 2H), 2.10 - yl)oxy)cyclohexanecarboxylic 1.96 (m, 1H), 1.91 - 1.04 acid (m, 8H) hLPA1 IC50 = 809 nM Analytical & Biology Method e Structure & Name 121 LC/MS: [M+H]+ = 496.1 Example 1H NMR (500 MHz, 1 DMSO-d6) δ 8.76 (br d, J=4.9 Hz, 1H), 8.61 (d, J=4.9 Hz, 1H), 7.95 - 7.68 (m, 1H), 7.50 - 7.20 (m, 2H), 5.85 - 5.44 (m, 2H), 4.77 (br s, 1H), 4.67 (1S,3S)((2-methyl(1-methyl - 4.49 (m, 2H), 4.13 (s, (((methyl(pyrimidin 1H), 2.95 - 2.75 (m, 4H), ylmethyl)carbamoyl)oxy)methyl)- 2.64 (br s, 1H), 2.44 - 1H-1,2,3-triazolyl)pyridin 2.33 (m, 4H), 2.09 - 1.97 yl)oxy)cyclohexanecarboxylic (m, 1H), 1.91 - 1.74 (m, 4H), 1.68 - 1.48 (m, 4H) hLPA1 IC50 = 1087 nM LC/MS: [M+H]+ = 495.0 Example 122 1H NMR (500 MHz, 1 DMSO-d6) δ 8.85 - 8.33 (m, 1H), 8.06 - 7.72 (m, 1H), 7.58 - 7.39 (m, 2H), 7.37 - 6.99 (m, 2H), 6.04 - 5.53 (m, 2H), 4.87 - 4.31 (m, 2H), 4.23 - 3.84 (1S,3S)((2-methyl(1-methyl (m, 3H), 3.17 (s, 1H), (((methyl(pyridin 2.93 - 2.73 (m, 3H), 2.67 ylmethyl)carbamoyl)oxy)methyl)- - 2.57 (m, 1H), 2.43 - 1H-1,2,3-triazolyl)pyridin 2.29 (m, 3H), 2.02 (br d, yl)oxy)cyclohexanecarboxylic J=13.9 Hz, 1H), 1.90 - acid 1.73 (m, 2H), 1.66 - 1.47 (m, 2H), 1.37 - 1.14 (m, 2H), 1.00 (br d, J=6.1 Hz, 1H), 0.85 (br d, J=6.3 Hz, 1H) hLPA1 IC50 = 873 nM Analytical & Biology Method Example Structure & Name 123 LC/MS: [M+H]+ = 496.1 Example 1H NMR (500 MHz, 1 DMSO-d6) δ 8.63 - 8.51 (m, 1H), 8.47 - 8.30 (m, 1H), 7.96 - 7.59 (m, 1H), 7.56 - 7.27 (m, 1H), 6.05 - 5.37 (m, 2H), 4.77 (br s, 1H), 4.62 - 4.39 (m, 2H), 4.24 - 3.84 (m, 3H), 3.45 (1S,3S)((2-methyl(1-methyl (br s, 1H), 2.98 - 2.76 (m, (((methyl(pyrazinylmethyl) 3H), 2.63 (br s, 1H), 2.41 carbamoyl)oxy)methyl)-1H-1,2,3- - 2.24 (m, 3H), 2.15 - triazolyl)pyridinyl)oxy) 1.35 (m, 8H) cyclohexanecarboxylic acid hLPA1 IC50 = 618 nM 124 LC/MS: [M+H]+ = 498.2 Example 1H NMR (500 MHz, 1 6) δ 7.83 (d, J=8.5 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.41 - 7.12 (m, 1H), 6.14 (br s, 1H), 5.70 (br s, 2H), 5.13 - 3.29 (m, 7H), 2.71 (br s, (1S,3S)((2-methyl(1-methyl 3H), 2.59 - 2.55 (m, 2H), (((methyl((1-methyl-1H-pyrazol 2.39 (s, 3H), 2.14 - 1.31 yl)methyl)carbamoyl)oxy)methyl)- (m, 9H) 1H-1,2,3-triazolyl)pyridin hLPA1 IC50 = 982 nM yl)oxy)cyclohexanecarboxylic Analytical & y Method Example Structure & Name 125 LC/MS: [M+H]+ = 504.0 Example 1H NMR (500 MHz, 1 DMSO-d6) δ 7.83 (br d, J=8.5 Hz, 2H), 7.49 (br d, J=8.5 Hz, 1H), 6.00 - .25 (m, 3H), 4.75 (br s, 2H), 4.10 (br s, 4H), 2.90 - 2.72 (m, 3H), 2.41 (s, 4H), 2.14 - 1.31 (m, 13H) (1S,3S)((2-methyl(1-methyl hLPA1 IC50 = 668 nM (((methyl(morpholin ylmethyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazolyl)pyridin yl)oxy)cyclohexanecarboxylic LC/MS: [M+H]+ = 488.1 Example 126 1H NMR (500 MHz, 1 DMSO-d6) δ 7.94 (br d, J=8.9 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.48 (br d, J=8.5 Hz, 1H), 6.52 (br d, J=8.2 Hz, 1H), .65 (br s, 2H), 4.76 (br (1S,3S)((2-methyl(1-methyl s, 1H), 4.09 (s, 3H), 3.55 (((methyl((tetrahydrofuran - 2.96 (m, 3H), 2.85 - yl)methyl)carbamoyl)oxy)methyl)- 2.70 (m, 3H), 2.60 - 2.56 1H-1,2,3-triazolyl)pyridin (m, 1H), 2.40 (s, 3H), yl)oxy)cyclohexanecarboxylic 2.33 - 2.23 (m, 1H), 2.03 acid - 1.19 (m, 11H) hLPA1 IC50 = 346 nM Analytical & Biology Method Example Structure & Name 127 LC/MS: [M+H]+ = 474.2 Example 1H NMR (500 MHz, 1 DMSO-d6) δ 7.81 (br d, J=8.5 Hz, 1H), 7.44 (br d, J=8.5 Hz, 1H), 5.58 (s, 2H), 4.75 (br s, 1H), 4.08 (s, 3H), 3.23 - 2.91 (m, 4H), 2.60 (br s, 1H), 2.39 (s, 3H), 2.05 - 1.93 (m, (1S,3S)((6-(5- 1H), 1.89 - 1.71 (m, 3H), (((butyl(ethyl)carbamoyl)oxy)methyl) 1.66 - 1.37 (m, 4H), 1.25 methyl-1H-1,2,3-triazolyl) - 1.12 (m, 4H), 1.06 - methylpyridinyl)oxy)cyclohexane- 0.77 (m, 5H), 0.58 (br s, 1-carboxylic acid hLPA1 IC50 = 33 nM 128 LC/MS: [M+H]+ = Example 460.3 3 1H NMR (500 MHz, DMSO-d6) δ 7.83 (br d, J=8.5 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 5.61 (s, 2H), 4.78 (br s, 1H), 4.09 (s, 3H), 3.42 - 3.33 (m, 1H), 3.23 - 2.96 (m, 4H), (1S,3S)((6-(5- 2.62 (br t, J=10.4 Hz, (((ethyl(propyl)carbamoyl)oxy)methy 1H), 2.41 (s, 3H), 2.01 l)methyl-1H-1,2,3-triazolyl) (br d, J=13.7 Hz, 1H), pyridinyl)oxy)cyclohexane- 1.91 - 1.73 (m, 3H), 1.68 1-carboxylic acid - 1.41 (m, 5H), 1.28 (br s, 1H), 1.00 (br d, J=6.1 Hz, 1H), 0.92 - 0.76 (m, 3H), 0.62 (br s, 1H) hLPA1 IC50 = 158 nM Analytical & Biology Method Example Structure & Name 129 LCMS, [M+H]+ = 486 e 1H NMR (500 MHz, 3 DMSO-d6) δ 7.81 (br d, J=8.2 Hz, 1H), 7.46 (br d, J=8.5 Hz, 1H), 5.60 (br s, 2H), 4.78 (br s, 1H), 4.15 - 4.03 (m, 3H), 3.53 (br s, 1H), 2.80 - 2.70 (m, 3H), 2.65 - 2.57 (1S,3S)((6-(5-((((1- (m, 1H), 2.41 (s, 3H), isopropylcyclopropyl)(methyl)carba 2.05 - 1.96 (m, 1H), 1.89 moyl)oxy)methyl)methyl-1H- - 1.72 (m, 3H), 1.66 - 1,2,3-triazolyl)methylpyridin 1.46 (m, 4H), 0.86 - 0.82 yl)oxy)cyclohexanecarboxylic (m, 2H), 0.76 - 0.48 (m, acid 8H) hLPA1 IC50 = 352 nM 130 LCMS, [M+H]+ = 500 1H NMR (500 MHz, Example DMSO-d6) δ 7.82 (br d, 10 J=8.5 Hz, 1H), 7.46 (br d, J=8.5 Hz, 1H), 5.59 (br s, 2H), 4.77 (br s, 1H), 4.15 - 4.02 (m, 3H), 3.59 (br s, 1H), 2.79 - 2.66 (m, 3H), 2.63 - 2.56 (1S,3S)((6-(5-((((1- (m, 1H), 2.39 (s, 3H), isobutylcyclopropyl)(methyl)carbamo 2.04 - 1.94 (m, 1H), 1.88 yl)oxy)methyl)methyl-1H-1,2,3- - 1.71 (m, 3H), 1.66 - triazolyl)methylpyridin 1.44 (m, 4H), 1.15 - 1.08 yl)oxy)cyclohexanecarboxylic (m, 1H), 0.90 - 0.85 (m, acid 2H), 0.83 - 0.32 (m, 9H) hLPA1 IC50 = 243 nM Analytical & y Method Example Structure & Name 131 LCMS, [M+H]+ = 472 1H NMR (500 MHz, Example DMSO-d6) δ 7.80 (br d, 10 J=7.9 Hz, 1H), 7.46 (br d, J=8.2 Hz, 1H), 5.60 (s, 2H), 4.81 - 4.71 (m, 1H), 4.15 - 4.01 (m, 3H), 3.66 (br s, 3H), 2.78 - 2.66 (m, 3H), 2.61 - 2.55 (m, 1H), (1S,3S)((6-(5-((((1- 2.40 (s, 3H), 2.02 - 1.93 ethylcyclopropyl)(methyl)carbamoyl) (m, 1H), 1.85 - 1.73 (m, oxy)methyl)methyl-1H-1,2,3- 3H), 1.64 - 1.44 (m, 5H), triazolyl)methylpyridin 0.85 - 0.76 (m, 1H), 0.67 yl)oxy)cyclohexanecarboxylic - 0.57 (m, 4H), 0.44 (br s, acid 1H) hLPA1 IC50 = 187 nM LCMS, [M+H]+ = 500 1H NMR (500 MHz, Example DMSO-d6) δ 8.01 - 7.78 10 (m, 1H), 7.49 (br d, J=4.6 Hz, 1H), 5.58 (br s, 2H), 4.78 (br s, 1H), 4.09 (br s, 3H), 3.54 - 3.32 (m, 2H), 2.63 - 2.58 (m, 3H), (1S,3S)((2-methyl(1-methyl 2.46 - 2.32 (m, 3H), 2.08 (((methyl(1- - 1.97 (m, 3H), 1.91 - propylcyclobutyl)carbamoyl)oxy)met 1.74 (m, 4H), 1.70 - 1.47 hyl)-1H-1,2,3-triazolyl)pyridin (m, 8H), 1.28 - 1.19 (m, yl)oxy)cyclohexanecarboxylic 1H), 1.07 - 0.79 (m, 3H), acid 0.62 - 0.56 (m, 1H) hLPA1 IC50 = 180 nM Analytical & Biology Method Example Structure & Name 133 LCMS, [M+H]+ = 486 1H NMR (500 MHz, Example DMSO-d6) δ 7.81 (br d, 10 J=7.3 Hz, 1H), 7.48 (br d, J=8.5 Hz, 1H), 5.57 (br s, 2H), 4.82 - 4.73 (m, 1H), 4.08 (s, 3H), 2.64 - 2.57 (m, 3H), 2.41 (s, 3H), 2.23 - 1.74 (m, 9H), (1S,3S)((6-(5-((((1- 1.70 - 1.44 (m, 8H), 0.92 ethylcyclobutyl)(methyl)carbamoyl)o - 0.41 (m, 3H) xy)methyl)methyl-1H-1,2,3- hLPA1 IC50 = 174 nM triazolyl)methylpyridin yl)oxy)cyclohexanecarboxylic LCMS, [M+H]+ = 470 1H NMR (500 MHz, Example 134 DMSO-d6) δ 7.83 (d, 1 J=8.5 Hz, 1H), 7.48 (d, J=8.9 Hz, 1H), 5.62 (s, 2H), 4.77 (br s, 1H), 4.06 (s, 3H), 3.90 (s, 1H), 3.81 (br s, 3H), 2.64 - 2.58 (m, (1S,3S)((6-(5-(((2- 1H), 2.41 (s, 3H), 2.10 - ro[3.3]heptane 1.97 (m, 5H), 1.88 - 1.75 carbonyl)oxy)methyl)methyl-1H- (m, 3H), 1.74 - 1.50 (m, 1,2,3-triazolyl)methylpyridin 6H) yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 76 nM 135 LCMS, [M+H]+ = 484 1H NMR (500 MHz, Example DMSO-d6) δ 7.79 (br d, 1 J=8.2 Hz, 1H), 7.44 (br d, J=8.5 Hz, 1H), 5.62 - .56 (m, 2H), 4.74 (br s, 1H), 4.08 - 4.04 (m, 2H), 3.86 - 3.61 (m, 2H), 3.18 (s, 3H), 3.04 (s, 1H), 2.62 (1S,3S)((6-(5-(((6- - 2.56 (m, 1H), 2.38 (s, azaspiro[3.4]octane 3H), 2.01 - 1.92 (m, 1H), yl)oxy)methyl)methyl-1H- 1.90 - 1.71 (m, 10H), 1,2,3-triazolyl)methylpyridin 1.65 - 1.41 (m, 4H) yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 47 nM Analytical & Biology Method Example Structure & Name 136 LCMS, [M+H]+ = 458 1H NMR (500 MHz, Example CDCl3) δ 7.98 (d, J=8.5 1 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 5.77 (s, 2H), 4.76 - 4.71 (m, 1H), 4.17 - 4.13 (m, 4H), 2.93 - 2.82 (m, 3H), 2.53 (s, 3H), 2.07 (s, 10H), 1.68 (1S,3S)((6-(5- (br s, 5H) (((cyclobutyl(methyl)carbamoyl)oxy) hLPA1 IC50 = 36 nM methyl)methyl-1H-1,2,3-triazol yl)methylpyridin yl)oxy)cyclohexanecarboxylic 137 LCMS, [M+H]+ = 586 1H NMR (500 MHz, Example DMSO-d6) δ 7.83 (br d, 1 J=8.5 Hz, 1H), 7.47 (br d, J=8.9 Hz, 1H), 5.62 (br s, 2H), 4.77 (br s, 1H), 4.09 (s, 3H), 3.30 - 2.86 (m, 4H), 2.61 - 2.57 (m, 1H), 2.41 (s, 3H), (1S,3S)((6-(5-(((3,3- 2.03 - 1.92 (m, 1H), 1.88 ylpiperidine - 1.72 (m, 3H), 1.62 (br carbonyl)oxy)methyl)methyl-1H- d, J=9.2 Hz, 5H), 1.31 - 1,2,3-triazolyl)methylpyridin 1.19 (m, 4H), 0.89 - 0.75 yl)oxy)cyclohexanecarboxylic (m, 3H), 0.73 - 0.60 (m, acid 3H) hLPA1 IC50 = 292 nM Analytical & y Method Example Structure & Name 138 LCMS, [M+H]+ = 446 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (br d, 3 J=8.3 Hz, 1H), 7.48 (br d, J=8.6 Hz, 1H), 5.63 (br s, 2H), 4.79 (br s, 1H), 4.09 (s, 3H), 3.91 - 3.90 (m, 1H), 2.69 - 2.61 (m, 3H), 2.41 (s, 3H), (1S,3S)((6-(5- 1.62 (br s, 9H), 1.03 (br (((isopropyl(methyl)carbamoyl)oxy) s, 3H), 0.93 (br s, 3H) methyl)methyl-1H-1,2,3-triazol hLPA1 IC50 = 98 nM yl)methylpyridin yl)oxy)cyclohexanecarboxylic 139 LCMS, [M+H]+ = 494 1H NMR (500 MHz, Example DMSO-d6) δ 7.85 (d, 10 J=8.2 Hz, 1H), 7.48 (d, J=8.9 Hz, 1H), 5.66 (br s, 2H), 4.78 (br s, 1H), 4.10 (s, 3H), 2.82 - 2.68 (m, 5H), 2.67 - 2.59 (m, 2H), 2.41 (s, 3H), 2.06 - 1.97 (m, 1H), 1.94 - 1.71 (m, (1S,3S)((6-(5-((((3,3- 3H), 1.68 - 1.42 (m, 4H), difluorocyclobutyl)(methyl)carbamoy 1.24 (s, 2H) l)oxy)methyl)methyl-1H-1,2,3- hLPA1 IC50 = 70 nM triazolyl)methylpyridin yl)oxy)cyclohexanecarboxylic Analytical & y Method Example ure & Name LCMS, [M+H]+ = 472 1H NMR (500 MHz, Example 140 DMSO-d6) δ 7.83 (br d, 1 J=8.5 Hz, 1H), 7.47 (br d, J=8.5 Hz, 1H), 5.65 (br d, J=4.6 Hz, 2H), 4.78 (br s, 1H), 4.08 (br d, J=4.6 Hz, 3H), 3.36 - 3.21 (m, 1H), 3.02 (s, (1S,3S)((6-(5-(((3,3- 1H), 2.90 (s, 1H), 2.62 dimethylpyrrolidine (br s, 1H), 2.41 (s, 3H), carbonyl)oxy)methyl)methyl-1H- 2.06 - 1.96 (m, 1H), 1.80 1,2,3-triazolyl)methylpyridin (br s, 3H), 1.57 (br t, yl)oxy)cyclohexanecarboxylic J=7.2 Hz, 6H), 1.23 (s, acid 2H), 0.99 (s, 3H), 0.94 (s, hLPA1 IC50 = 148 nM 141 LCMS, [M+H]+ = 494 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (d, 10 J=8.2 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 5.65 (br s, 2H), 4.45 - 4.38 (m, 1H), 4.10 (s, 3H), 2.79 - 2.74 (m, 4H), 2.70 - 2.62 (m, 1H), 2.49 - 2.40 (m, (1R,3S)((6-(5-((((3,3-difluoro- J=11.7, 11.7 Hz, 2H), cyclobutyl)(methyl)carbamoyl)oxy)m 2.37 - 2.34 (m, 3H), 2.30 ethyl)methyl-1H-1,2,3-triazol - 2.20 (m, 1H), 2.11 - yl)methylpyridinyl)oxy) 2.00 (m, 1H), 1.90 - 1.78 cyclohexanecarboxylic acid; cis (m, 2H), 1.47 - 1.23 (m, isomer from epimerization in final 6H) ester hydrolysis hLPA1 IC50 = 283 nM Analytical & Biology Method Example Structure & Name 142 LCMS, [M+H]+ = 444 1H NMR (500 MHz, Example DMSO-d6) δ 7.83 (br d, 10 J=8.5 Hz, 1H), 7.47 (br d, J=8.2 Hz, 1H), 5.65 (s, 2H), 4.81 - 4.73 (m, 1H), 4.10 (s, 3H), 3.72 - 3.52 (m, 1H), 2.74 (br s, 3H), (1S,3S)((6-(5- 2.65 - 2.57 (m, 1H), 2.41 (((cyclopropyl(methyl)carbamoyl)ox (s, 3H), 2.04 - 1.94 (m, y)methyl)methyl-1H-1,2,3-triazol- 1H), 1.92 - 1.70 (m, 3H), 4-yl)methylpyridin 1.68 - 1.41 (m, 4H), 0.57 yl)oxy)cyclohexanecarboxylic (br s, 2H), 0.48 (br s, 2H) acid hLPA1 IC50 = 252 nM 143 LCMS, [M+H]+ = 480 1H NMR (500 MHz, Example DMSO-d6) δ 7.82 (br d, 1 J=7.6 Hz, 1H), 7.49 (br d, J=7.6 Hz, 1H), 5.70 (s, 2H), 4.75 (br s, 1H), 4.09 (s, 3H), 3.73 - 3.54 (m, 1H), 2.42 - 2.38 (m, 3H), 2.38 - 2.31 (m, 2H), 1.99 (1S,3S)((6-(5-(((3,3-difluoro- - 1.46 (m, 8H), 1.23 (s, pyrrolidinecarbonyl)oxy)methyl)- 2H) 1-methyl-1H-1,2,3-triazolyl) hLPA1 IC50 = 518 nM methylpyridinyl)oxy)cyclohexane- 1-carboxylic acid 144 LCMS, [M+H]+ = 470 1H NMR (500 MHz, Example 6) δ 7.84 (br d, 1 J=8.4 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H), 5.67 (s, 2H), 4.77 (br s, 1H), 4.09 (br s, 3H), 2.72 - 2.60 (m, 1H), 2.43 (s, 3H), 2.08 - (1S,3S)((6-(5-(((5- 1.97 (m, 1H), 1.83 (br d, azaspiro[2.4]heptane J=10.9 Hz, 3H), 1.75 - carbonyl)oxy)methyl)methyl-1H- 1.45 (m, 7H), 1.25 (s, triazolyl)methylpyridin 2H), 0.63 - 0.44 (m, 4H) yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 89 nM Analytical & Biology Method Example Structure & Name 145 LCMS, [M+H]+ = 508 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (br d, 3 J=8.5 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 5.65 (br s, 2H), 4.77 (br s, 1H), 4.10 (s, 3H), 2.79 (br s, 3H), 2.70 - 2.62 (m, 1H), 2.43 (s, 3H), 2.39 - 2.19 (m, (1S,3S)((6-(5-(((((3,3-difluoro- 4H), 2.09 - 1.97 (m, 2H), cyclobutyl)methyl)(methyl)carba- 1.92 - 1.76 (m, 3H), 1.71 xy)methyl)methyl-1H- - 1.60 (m, 2H), 1.59 - 1,2,3-triazolyl)methylpyridin 1.47 (m, 2H), 1.25 (s, yl)oxy)cyclohexanecarboxylic 2H) acid hLPA1 IC50 = 94 nM 146 LCMS, [M+H]+ = 484 1H NMR (500 MHz, Example DMSO-d6) δ 7.83 (d, 3 J=8.2 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 5.98 - .48 (m, 2H), 4.45 - 4.36 (m, 1H), 4.13 (s, 3H), 3.53 - 3.14 (m, 1H), 2.72 (s, 2H), 2.47 - 2.39 (m, (1R,3S)((2-methyl(1-methyl 1H), 2.35 (s, 3H), 2.27 - (((methyl(spiro[2.3]hexan 2.20 (m, 1H), 2.08 - 1.99 yl)carbamoyl)oxy)methyl)-1H-1,2,3- (m, 1H), 1.93 - 1.58 (m, triazolyl)pyridin 7H), 1.50 - 1.20 (m, 6H), yl)oxy)cyclohexanecarboxylic 0.75 - 0.65 (m, 1H), 0.58 acid (cis isomer from ization - 0.50 (m, 1H) in final ester hydrolysis) hLPA1 IC50 = 1816 nM Analytical & Biology Method Example Structure & Name 147 LCMS, [M+H]+ = 458 1H NMR (500 MHz, Example DMSO-d6) δ 7.83 (d, 1 J=8.6 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 5.65 (s, 2H), 4.81 - 4.74 (m, 1H), 4.08 (s, 3H), 3.82 - 3.59 (m, 1H), 3.45 - 3.10 (m, (1S,3S)((2-methyl(1-methyl 3H), 2.81 - 2.66 (m, 1H), (((3-methylpyrrolidine 2.65 - 2.58 (m, 1H), 2.41 carbonyl)oxy)methyl)-1H-1,2,3- (s, 3H), 2.08 - 1.95 (m, triazolyl)pyridin 1H), 1.93 - 1.73 (m, 4H), yl)oxy)cyclohexanecarboxylic 1.67 - 1.33 (m, 5H), 1.26 acid (mixture of diastereomers) - 1.18 (m, 1H), 0.99 - 0.86 (m, 3H) hLPA1 IC50 = 250 nM 148 LCMS, [M+H]+ = 470 1H NMR (500 MHz, Example DMSO-d6) δ 7.85 - 7.78 1 (m, 1H), 7.46 (d, J=8.7 Hz, 1H), 5.67 - 5.54 (m, 2H), 4.77 (br s, 1H), 4.13 - 4.03 (m, 3H), 3.98 - 3.85 (m, 1H), 3.77 - 3.66 (1S,3S)((6-(5-((( (m, 1H), 3.20 - 3.05 (m, yclo[2.2.1]heptane 1H), 2.93 - 2.77 (m, 1H), yl)oxy)methyl)methyl-1H- 2.66 - 2.57 (m, 1H), 2.48 1,2,3-triazolyl)methylpyridin - 2.42 (m, 1H), 2.40 (s, yl)oxy)cyclohexanecarboxylic 3H), 2.04 - 1.96 (m, 1H), acid (mixture of diastereomers) 1.88 - 1.72 (m, 3H), 1.65 - 1.52 (m, 4H), 1.50 - 1.44 (m, 2H), 1.37 - 1.24 (m, 3H) hLPA1 IC50 = 325 nM Analytical & Biology Method Example Structure & Name 149 LCMS, [M+H]+ = 484 1H NMR (500 MHz, Example DMSO-d6) δ 7.83 (br d, 1 J=8.5 Hz, 1H), 7.47 (br d, J=8.5 Hz, 1H), 5.68 - .57 (m, 2H), 4.78 (br s, 1H), 4.13 - 4.06 (m, 3H), 4.04 - 3.86 (m, 1H), 3.58 (1S,3S)((2-methyl(1-methyl - 3.47 (m, 3H), 2.68 - (((octahydrocyclopenta[b]pyrrole 2.57 (m, 2H), 2.41 (s, carbonyl)oxy)methyl)-1H-1,2,3- 3H), 2.05 - 1.96 (m, 1H), triazolyl)pyridin 1.89 - 1.74 (m, 4H), 1.69 yl)oxy)cyclohexanecarboxylic - 1.59 (m, 3H), 1.54 - acid (mixture of diastereomers) 1.45 (m, 4H), 1.26 - 1.22 (m, 2H) hLPA1 IC50 = 180 nM 150 LCMS, [M+H]+ = 498 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (br d, 1 J=8.2 Hz, 1H), 7.48 (br d, J=8.5 Hz, 1H), 5.66 (br s, 2H), 4.82 - 4.75 (m, 1H), 4.09 (s, 3H), 3.63 - 3.33 (m, 1H), 3.32 - 3.08 (1S,3S)((6-(5-(((3- (m, 2H), 2.97 - 2.72 (m, (cyclopropylmethyl)pyrrolidine 1H), 2.68 - 2.60 (m, 1H), carbonyl)oxy)methyl)methyl-1H- 2.42 (s, 3H), 2.20 - 2.08 1,2,3-triazolyl)methylpyridin (m, 1H), 2.07 - 1.98 (m, )cyclohexanecarboxylic 1H), 1.98 - 1.90 (m, 1H), acid re of diastereomers) 1.90 - 1.73 (m, 3H), 1.68 - 1.38 (m, 5H), 1.29 - 1.11 (m, 2H), 0.70 - 0.54 (m, 1H), 0.42 - 0.30 (m, 2H), 0.04 - -0.11 (m, 2H) hLPA1 IC50 = 91 nM Analytical & y Method Example Structure & Name 151 LCMS, [M+H]+ = 500 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (br d, 1 J=8.2 Hz, 1H), 7.47 (br d, J=8.3 Hz, 1H), 5.66 (br s, 2H), 4.80 - 4.74 (m, 1H), 4.10 (s, 3H), 3.64 - 3.33 (m, 1H), 2.86 - 2.77 (1S,3S)((6-(5-(((3- (m, 1H), 2.74 - 2.64 (m, isobutylpyrrolidine 1H), 2.43 (s, 3H), 2.16 - carbonyl)oxy)methyl)methyl-1H- 2.08 (m, 1H), 2.08 - 2.00 1,2,3-triazolyl)methylpyridin (m, 1H), 1.98 - 1.77 (m, yl)oxy)cyclohexanecarboxylic 5H), 1.71 - 1.32 (m, 7H), acid (mixture of diastereomers) 1.29 - 1.12 (m, 2H), 0.92 - 0.81 (m, 6H) hLPA1 IC50 = 101 nM 152 LCMS, [M+H]+ = 471 1H NMR (500 MHz, Example DMSO-d6) δ 7.83 (br s, 1 1H), 7.48 (br d, J=8.5 Hz, 1H), 5.64 (br s, 2H), 4.79 (br s, 1H), 4.09 (br s, 3H), 3.61 - 3.12 (m, 3H), 2.67 - 2.59 (m, 1H), (1S,3S)((6-(5-(((2- 2.42 (s, 3H), 2.06 - 1.94 yrrolidine (m, 1H), 1.92 - 1.42 (m, carbonyl)oxy)methyl)methyl-1H- 12H), 0.86 - 0.75 (m, 1,2,3-triazolyl)methylpyridin 2H), 0.64 - 0.54 (m, 1H) yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 157 nM acid (mixture of diastereomers) 153 LCMS, [M+H]+ = 500 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (br d, 1 J=8.5 Hz, 1H), 7.48 (br d, J=7.3 Hz, 1H), 5.74 - .48 (m, 2H), 4.78 (br s, 1H), 4.10 (br s, 3H), 3.66 (1S,3S)((6-(5-(((2- - 3.11 (m, 3H), 2.41 (br s, ylpyrrolidine 3H), 2.09 - 1.41 (m, carbonyl)oxy)methyl)methyl-1H- 14H), 1.36 - 1.07 (m, 1,2,3-triazolyl)methylpyridin 2H), 0.89 (br s, 3H), 0.59 yl)oxy)cyclohexanecarboxylic - 0.42 (m, 3H) acid (mixture of diastereomers) hLPA1 IC50 = 163 nM Analytical & Biology Method e Structure & Name 154 LCMS, [M+H]+ = 511 1H NMR (500 MHz, Example DMSO-d6) δ 7.83 (br d, 1 J=8.2 Hz, 1H), 7.55 (br d, J=8.5 Hz, 1H), 5.82 - .65 (m, 2H), 4.78 - 4.68 (m, 1H), 4.10 (br s, 3H), 3.29 - 3.13 (m, 3H), 2.39 (1S,3S)((2-methyl(1-methyl (s, 2H), 2.14 - 2.00 (m, (((2-(trifluoromethyl)pyrrolidine 1H), 1.98 - 1.46 (m, 12H) yl)oxy)methyl)-1H-1,2,3- hLPA1 IC50 = 321 nM lyl)pyridin yl)oxy)cyclohexanecarboxylic acid (mixture of diastereomers) 155 LCMS, [M+H]+ = 458 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (br d, 1 J=8.2 Hz, 1H), 7.49 (d, J=8.9 Hz, 1H), 5.64 (s, 2H), 4.79 (br s, 1H), 4.07 (s, 3H), 3.64-3.45 (m, 1H), 3.32-3.09 (m, 1H), (1S,3S)((6-(5-(((3,3- 2.70-2.59 (m, 1H), 2.43 dimethylazetidine (s, 3H), 2.30 - 2.15 (m, carbonyl)oxy)methyl)methyl-1H- 1H), 2.05 - 1.98 (m, 1H), 1,2,3-triazolyl)methylpyridin 1.91-1.73 (m, 3H), 1.67- yl)oxy)cyclohexanecarboxylic 1.45 (m, 4H), 1.16 (s,6H) acid hLPA1 IC50 = 175 nM 156 LCMS, [M+H]+ = 444 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (br d, 1 J=8.5 Hz, 1H), 7.48 (br d, J=8.9 Hz, 1H), 5.64 (s, 2H), 4.79 (br s, 1H), 4.07 (s, 3H), 4.00 - 3.92 (m, (1S,3S)((2-methyl(1-methyl 2H), 3.31 - 3.09 (m, 1H), (((3-methylazetidine 2.68 - 2.58 (m, 2H), 2.43 carbonyl)oxy)methyl)-1H-1,2,3- (s, 3H), 2.02 (br d, triazolyl)pyridin J=13.4 Hz, 1H), 1.94 - yl)oxy)cyclohexanecarboxylic 1.73 (m, 3H), 1.63 (br d, acid J=10.1 Hz, 4H), 1.12 (d, J=6.7 Hz, 3H) hLPA1 IC50 = 231 nM ical & Biology Method Example Structure & Name 157 LCMS, [M+H]+ = 444 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (br d, 1 J=8.5 Hz, 1H), 7.48 (d, J=8.9 Hz, 1H), 5.63 (s, 2H), 4.79 (br s, 1H), 4.08 (s, 3H), 3.81 - 3.69 (m, 2H), 3.64 - 3.50 (m, 1H), )((2-methyl(1-methyl 3.31 - 3.10 (m, 1H), 2.67 (((2-methylazetidine - 2.59 (m, 1H), 2.43 (s, carbonyl)oxy)methyl)-1H-1,2,3- 3H), 2.33 - 2.21 (m, 1H), triazolyl)pyridine 2.12 - 1.96 (m, 1H), 1.64 yl)oxy)cyclohexanecarboxylic (br s, 7H), 1.00 (d, J=6.1 acid (mixture of diastereomers) Hz, 3H) hLPA1 IC50 = 529 nM 158 LCMS, [M+H]+ = 498 1H NMR (500 MHz, Example DMSO-d6) δ 7.83 (d, 10 J=8.2 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.62 (br s, 2H), 4.78 (br s, 1H), 4.09 (s, 3H), 3.32 - 3.12 (m, (1R,3S)((2-methyl(1-methyl 1H), 2.74 - 2.58 (m, 4H), (((methyl(spiro[3.3]heptan 2.41 (s, 3H), 2.10 - 1.70 yl)carbamoyl)oxy)methyl)-1H-1,2,3- (m, 14H), 1.68 - 1.44 (m, triazolyl)pyridin 4H) yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 32 nM 159 LCMS, [M+H]+ = 484 1H NMR (500 MHz, Example DMSO-d6) δ 7.83 (br d, 1 J=8.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.64 (s, 2H), 4.78 (br s, 1H), 4.07 (s, 3H), 3.69 (br s, 3H), (1S,3S)((6-(5-(((2- 3.63 - 3.51 (m, 1H), 3.31 azaspiro[3.4]octane - 3.11 (m, 2H), 2.42 (s, carbonyl)oxy)methyl)methyl-1H- 3H), 1.91 - 1.77 (m, 3H), 1,2,3-triazolyl)methylpyridin 1.71 - 1.58 (m, 6H), 1.57 yl)oxy)cyclohexanecarboxylic - 1.47 (m, 6H) acid hLPA1 IC50 = 162 nM Analytical & Biology Method Example Structure & Name 160 LCMS, [M+H]+ = 486 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (d, 3 J=8.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 5.63 (br s, 2H), 4.49 - 4.36 (m, 1H), 4.10 (s, 3H), 2.77 - 2.69 (m, 3H), 2.48 - 2.39 (m, )((6-(5-((((3,3- 1H), 2.37 (s, 3H), 2.31 - dimethylcyclobutyl)(methyl)carbamo 2.23 (m, 1H), 2.12 - 2.02 yl)oxy)methyl)methyl-1H-1,2,3- (m, 1H), 1.92 - 1.59 (m, triazolyl)methylpyridin 6H), 1.50 - 1.20 (m, 4H), yl)oxy)cyclohexanecarboxylic 1.14 - 0.95 (m, 6H) acid (cis isomer from ization hLPA1 IC50 = 61 nM in final ester hydrolysis step) 161 LCMS, [M+H]+ = 472 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (br d, 1 J=8.5 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 5.65 (s, 2H), 4.77 (br s, 1H), 4.09 (s, 3H), 3.81 - 3.66 (m, 1H), 2.82 - 2.70 (m, 1H), 2.69 - 2.62 (m, 1H), 2.43 (1S,3S)((2-methyl(1-methyl (s, 3H), 2.06 - 1.97 (m, (((3-methylpiperidine 1H), 1.92 - 1.76 (m, 3H), carbonyl)oxy)methyl)-1H-1,2,3- 1.66 (br s, 6H), 1.46 - triazolyl)pyridin 1.18 (m, 3H), 1.03 (s, yl)oxy)cyclohexanecarboxylic 2H), 0.86 - 0.71 (m, 3H) acid (mixture of diastereomers) hLPA1 IC50 = 178 nM Analytical & Biology Method Example Structure & Name 162 LCMS, [M+H]+ = 472 1H NMR (500 MHz, Example DMSO-d6) δ 7.83 (d, 1 J=8.6 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 5.63 (s, 2H), 4.82 - 4.71 (m, 1H), 4.09 (s, 3H), 3.62 - 3.53 (m, 2H), 3.34 - 3.18 (m, 1H), 2.79 (br s, 3H), 2.70 - 2.61 (m, 1H), 2.42 (s, (1S,3S)((6-(5-((((2- 3H), 2.07 - 1.97 (m, 1H), cyclopropylethyl)(methyl)carbamoyl) 1.89 - 1.77 (m, 3H), 1.70 oxy)methyl)methyl-1H-1,2,3- - 1.47 (m, 4H), 1.31 - triazolyl)methylpyridin 1.15 (m, 2H), 0.42 - 0.16 )cyclohexanecarboxylic (m, 2H), 0.03 - -0.26 (m, acid 2H) hLPA1 IC50 = 34 nM 163 LCMS, [M+H]+ = 486 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (br d, 1 J=8.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.66 (br d, J=9.5 Hz, 2H), 4.83 - 4.75 (m, 1H), 4.10 (s, 3H), 3.18 (br s, 1H), 2.93 (1S,3S)((6-(5-(((3- - 2.81 (m, 1H), 2.74 (s, isopropylpyrrolidine 1H), 2.68 - 2.60 (m, 1H), carbonyl)oxy)methyl)methyl-1H- 2.42 (s, 3H), 2.07 - 1.98 1,2,3-triazolyl)methylpyridin (m, 1H), 1.94 - 1.73 (m, )cyclohexanecarboxylic 6H), 1.67 - 1.34 (m, 6H), acid (mixture of diastereomers) 0.93 - 0.75 (m, 6H) hLPA1 IC50 = 104 nM Analytical & Biology Method Example Structure & Name 164 LCMS, [M+H]+ = 484 1H NMR (500 MHz, Example DMSO-d6) δ 7.82 (br d, 1 J=8.5 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 5.65 (br s, 2H), 4.80 - 4.74 (m, 1H), 4.08 (s, 3H), 3.33 - 3.08 (m, 2H), 2.88 (s, 2H), (1S,3S)((6-(5-(((3- 2.65 - 2.58 (m, 1H), 2.40 ropylpyrrolidine (s, 3H), 2.04 - 1.95 (m, carbonyl)oxy)methyl)methyl-1H- 1H), 1.90 (s, 4H), 1.62 1,2,3-triazolyl)methylpyridin (br s, 6H), 0.71 - 0.54 (m, yl)oxy)cyclohexanecarboxylic 1H), 0.42 - 0.26 (m, 2H), acid re of diastereomers) 0.16 - 0.02 (m, 2H) hLPA1 IC50 = 83 nM 165 LCMS, [M+H]+ = 472 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (d, 1 J=8.5 Hz, 1H), 7.49 (d, J=8.9 Hz, 1H), 5.67 (br s, 2H), 4.83 - 4.76 (m, 1H), 4.10 (s, 3H), 3.24 - 3.09 (m, 1H), 2.98 - 2.78 (m, (1S,3S)((6-(5-(((3- 1H), 2.77 - 2.69 (m, 1H), ethylpyrrolidinecarbonyl) 2.67 - 2.61 (m, 1H), 2.42 oxy)methyl)methyl-1H-1,2,3- (s, 3H), 2.06 - 1.79 (m, triazolyl)methylpyridin 6H), 1.67 - 1.23 (m, 8H), yl)oxy)cyclohexanecarboxylic 0.93 - 0.79 (m, 3H) acid (mixture of reomers) hLPA1 IC50 = 102 nM 166 LCMS, [M+H]+ = 486 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (d, 1 J=8.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.66 (br s, 2H), 4.82 - 4.74 (m, 1H), 4.09 (s, 3H), 3.24 - 3.07 (1S,3S)((2-methyl(1-methyl (m, 1H), 2.90 (s, 1H), (((3-propylpyrrolidine 2.76 - 2.67 (m, 1H), 2.67 carbonyl)oxy)methyl)-1H-1,2,3- - 2.60 (m, 1H), 2.42 (s, triazolyl)pyridinyl)oxy) 3H), 2.10 - 1.97 (m, 2H), cyclohexanecarboxylic acid 1.92 (s, 5H), 1.68 - 1.34 (mixture of diastereomers) (m, 5H), 1.32 - 1.19 (m, 4H), 0.92 - 0.80 (m, 3H) hLPA1 IC50 = 109 nM Analytical & y Method Example Structure & Name 167 LCMS, [M+H]+ = 470 1H NMR (500 MHz, Example DMSO-d6) δ 7.85 (d, 1 J=8.5 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 5.64 (s, 2H), 4.79 (br s, 1H), 4.09 (s, 3H), 3.31 - 3.13 (m, 1H), 2.67 - 2.59 (m, 1H), 2.42 (s, 3H), 2.06 - 1.98 (1S,3S)((6-(5-(((azabicyclo (m, 1H), 1.91 - 1.74 (m, [2.2.1]heptanecarbonyl)oxy) 3H), 1.67 - 1.46 (m, 8H), methyl)methyl-1H-1,2,3-triazol 1.39 - 1.33 (m, 4H) yl)methylpyridinyl)oxy) hLPA1 IC50 = 317 nM cyclohexanecarboxylic acid 168 LCMS, [M+H]+ = 486 1H NMR (500 MHz, e DMSO-d6) δ 7.84 (d, 3 J=8.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.63 (br s, 2H), 4.78 (br s, 1H), 4.10 (s, 3H), 2.72 (br s, 3H), (1S,3S)((6-(5-((((3,3-dimethyl- 2.68 - 2.58 (m, 1H), 2.41 cyclobutyl)(methyl)carbamoyl)oxy)m (s, 3H), 2.00 (br s, 1H), ethyl)methyl-1H-1,2,3-triazol 1.93 - 1.71 (m, 6H), 1.64 yl)methylpyridinyl)oxy) (br s, 5H), 1.07 - 0.95 (m, cyclohexanecarboxylic acid 6H) hLPA1 IC50 = 29 nM 169 LCMS, [M+H]+ = 520 1H NMR (500 MHz, Example DMSO-d6) δ 7.91 - 7.81 1 (m, 1H), 7.52 - 7.45 (m, 1H), 7.37 - 7.19 (m, 5H), .72 (br s, 2H), 4.83 - 4.75 (m, 1H), 4.11 (br d, J=13.7 Hz, 3H), 3.81 - (1S,3S)((2-methyl(1-methyl 3.63 (m, 1H), 3.39 - 3.10 (((3-phenylpyrrolidinecarbonyl) (m, 3H), 2.67 - 2.61 (m, oxy)methyl)-1H-1,2,3-triazol 1H), 2.43 (br d, J=4.9 yl)pyridinyl)oxy)cyclohexane Hz, 3H), 2.24 - 2.16 (m, carboxylic acid (mixture of 1H), 2.07 - 1.99 (m, 1H), diastereomers) 1.97 - 1.73 (m, 4H), 1.70 - 1.47 (m, 4H) hLPA1 IC50 = 336 nM Analytical & Biology Method Example ure & Name 170 LCMS, [M+H]+ = 460 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (br d, 1 J=8.5 Hz, 1H), 7.48 (br d, J=8.5 Hz, 1H), 5.60 (s, 2H), 4.79 (br s, 1H), 4.10 (s, 3H), 2.77 (s, 3H), 2.68 - 2.58 (m, 1H), 2.42 (s, (1S,3S)((6-(5-(((tert-butyl 3H), 2.09 - 1.97 (m, 1H), (methyl)carbamoyl)oxy)methyl) 1.93 - 1.73 (m, 3H), 1.69 methyl-1H-1,2,3-triazolyl) - 1.43 (m, 4H), 1.27 (s, methylpyridinyl)oxy)cyclohexane- 9H) 1-carboxylic acid hLPA1 IC50 = 183 nM 171 LCMS, [M+H]+ = 484 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (d, 1 J=8.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.66 (s, 2H), 4.79 (br s, 1H), 4.09 (s, 3H), 3.59 - 3.16 (m, 2H), 2.69 - 2.60 (m, 1H), 2.42 (s, 3H), 2.06 - 1.95 (1S,3S)((6-(5-(((6-azaspiro (m, 1H), 1.91 - 1.71 (m, [2.5]octanecarbonyl)oxy)methyl)- 3H), 1.68 - 1.44 (m, 4H), 1-methyl-1H-1,2,3-triazolyl) 1.31 - 1.11 (m, 4H), 0.28 pyridinyl)oxy)cyclohexane- (s, 4H) 1-carboxylic acid hLPA1 IC50 = 162 nM 172 LCMS, [M+H]+ = 472 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (d, 3 J=8.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 5.68 - .59 (m, 2H), 5.16 - 4.91 (m, 1H), 4.47 - 4.36 (m, 1H), 4.09 (s, 3H), 3.87 - 3.60 (m, 2H), 2.80 - 2.64 (1R,3S)((2-methyl(1-methyl (m, 3H), 2.45 - 2.39 (m, (((methyl(3-methylbuten 1H), 2.37 (s, 3H), 2.30 - yl)carbamoyl)oxy)methyl)-1H-1,2,3- 2.22 (m, 1H), 2.09 - 2.02 triazolyl)pyridinyl)oxy) (m, 1H), 1.93 - 1.78 (m, cyclohexanecarboxylic acid 3H), 1.72 - 1.49 (m, 4H), (cis isomer from epimerization during 1.47 - 1.28 (m, 5H) final hydrolysis step) hLPA1 IC50 = 312 nM ical & Biology Method Example Structure & Name 173 LCMS, [M+H]+ = 432 1H NMR (500 MHz, Example DMSO-d6) δ 8.35 (d, 1 J=2.4 Hz, 1H), 7.99 (br d, J=8.2 Hz, 1H), 7.58 - 7.52 (m, 1H), 5.67 - 5.58 (m, 2H), 4.79 (br s, 1H), 4.10 (s, 3H), 3.20 - 3.01 (m, 2H), 2.77 (br d, (1S,3S)((6-(1-methyl J=15.9 Hz, 3H), 2.71 - (((methyl(propyl)carbamoyl)oxy)met 2.62 (m, 1H), 2.00 - 1.72 hyl)-1H-1,2,3-triazolyl)pyridin (m, 4H), 1.72 - 1.41 (m, yl)oxy)cyclohexanecarboxylic 5H), 1.40 - 1.28 (m, 1H), acid 0.86 - 0.61 (m, 3H) hLPA1 IC50 = 131 nM 174 LCMS, [M+H]+ = 444 1H NMR (500 MHz, Example DMSO-d6) δ 8.35 (d, 1 J=2.4 Hz, 1H), 8.00 (d, J=8.9 Hz, 1H), 7.55 (dd, J=8.9, 2.7 Hz, 1H), 5.63 (s, 2H), 4.79 (br s, 1H), (1S,3S)((6-(5- 4.57 - 4.17 (m, 1H), 4.10 (((cyclobutyl(methyl)carbamoyl)oxy) (s, 3H), 2.80 - 2.63 (m, methyl)methyl-1H-1,2,3-triazol 4H), 2.12 - 1.94 (m, 4H), yl)pyridinyl)oxy)cyclohexane 1.90 - 1.74 (m, 4H), 1.72 ylic acid - 1.48 (m, 5H) hLPA1 IC50 = 58 nM 175 LCMS, [M+H]+ = 470 1H NMR (500 MHz, Example DMSO-d6) δ 8.43 - 8.26 1 (m, 1H), 8.08 - 7.91 (m, 1H), 7.64 - 7.44 (m, 1H), .63 (br s, 2H), 4.78 (br s, 1H), 4.08 (br s, 3H), 3.30 - 3.11 (m, 3H), 2.71 (1S,3S)((6-(5-(((6- - 2.60 (m, 1H), 2.00 - azaspiro[3.4]octane 1.88 (m, 2H), 1.88 - 1.73 carbonyl)oxy)methyl)methyl-1H- (m, 9H), 1.70 - 1.44 (m, 1,2,3-triazolyl)pyridinyl)oxy) 4H) cyclohexanecarboxylic acid hLPA1 IC50 = 703 nM Analytical & Biology Method Example Structure & Name 176 LCMS, [M+H]+ = 456 1H NMR (500 MHz, Example DMSO-d6) δ 8.35 (d, 1 J=2.4 Hz, 1H), 8.00 (d, J=8.9 Hz, 1H), 7.55 (dd, J=8.7, 2.6 Hz, 1H), 5.60 (s, 2H), 4.79 (br s, 1H), 4.08 (s, 3H), 3.84 (s, 4H), (1S,3S)((6-(5-(((2- 2.72 - 2.63 (m, 1H), 2.13 azaspiro[3.3]heptane - 2.02 (m, 4H), 2.01 - yl)oxy)methyl)methyl-1H- 1.92 (m, 1H), 1.90 - 1.76 1,2,3-triazolyl)pyridinyl)oxy) (m, 3H), 1.76 - 1.60 (m, cyclohexanecarboxylic acid 4H), 1.60 - 1.48 (m, 2H) hLPA1 IC50 = 400 nM 177 LCMS, [M+H]+ = 472 1H NMR (500 MHz, Example 6) δ 7.85 (d, 3 J=8.5 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 5.69 - .61 (m, 2H), 5.17 - 4.91 (m, 1H), 4.78 (br s, 1H), (1S,3S)((2-methyl(1-methyl 4.09 (s, 3H), 3.85 - 3.61 (((methyl(3-methylbuten (m, 2H), 2.80 - 2.66 (m, yl)carbamoyl)oxy)methyl)-1H-1,2,3- 3H), 2.65 - 2.59 (m, 1H), triazolyl)pyridinyl)oxy) 2.41 (s, 3H), 2.06 - 1.96 cyclohexanecarboxylic acid (m, 1H), 1.90 - 1.74 (m, 3H), 1.73 - 1.60 (m, 4H), 1.59 - 1.47 (m, 4H), 1.46 - 1.37 (m, 2H) hLPA1 IC50 = 21 nM 178 LCMS, [M+H]+ = 478 1H NMR (500 MHz, Example DMSO-d6) δ 7.85 (d, 3 J=8.5 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 5.62 (s, 2H), 4.81 - 4.74 (m, 1H), 4.57 (s, 1H), 4.47 (s, 1H), 4.11 (s, 3H), 2.82 (s, 3H), (1S,3S)((6-(5-((((1-fluoro 2.65 - 2.58 (m, 1H), 2.42 methylpropanyl)(methyl) (s, 3H), 2.05 - 1.96 (m, carbamoyl)oxy)methyl)methyl- 1H), 1.89 - 1.74 (m, 3H), 1H-1,2,3-triazolyl)methyl- 1.64 (br s, 4H), 1.28 (br pyridinyl)oxy)cyclohexane s, 6H) carboxylic acid hLPA1 IC50 = 156 nM Analytical & Biology Method Example Structure & Name 179 LCMS, [M+H]+ = 484 1H NMR (500 MHz, Example 6) δ 7.82 (d, 3 J=8.5 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 5.63 (s, 2H), 4.75 (br s, 1H), 4.09 (s, 3H), 2.88 - 2.72 (m, 3H), 2.70 - 2.59 (m, 1H), (1S,3S)((2-methyl(1-methyl 2.41 (s, 3H), 2.38 - 2.28 (((methyl(spiro[2.3]hexan (m, 2H), 2.08 - 1.75 (m, yl)carbamoyl)oxy)methyl)-1H-1,2,3- 7H), 1.70 - 1.45 (m, 4H), triazolyl)pyridinyl)oxy) 0.47 - 0.26 (m, 4H) cyclohexanecarboxylic acid hLPA1 IC50 = 14 nM 180 LCMS, [M+H]+ = 484 1H NMR (500 MHz, Example DMSO-d6) δ 8.34 (br s, 10 1H), 7.99 (br d, J=8.9 Hz, 1H), 7.59 - 7.51 (m, 1H), 5.60 (br s, 2H), 4.82 - 4.74 (m, 1H), 4.09 (s, )((6-(1-methyl 3H), 2.72 - 2.61 (m, 4H), (((methyl(spiro[3.3]heptan 2.05 - 1.70 (m, 15H), yl)carbamoyl)oxy)methyl)-1H-1,2,3- 1.70 - 1.60 (m, 2H), 1.60 triazolyl)pyridinyl)oxy) - 1.44 (m, 2H) cyclohexanecarboxylic acid hLPA1 IC50 = 62 nM 181 LCMS, [M+H]+ = 472 1H NMR (500 MHz, Example DMSO-d6) δ 8.34 (br d, 10 J=2.1 Hz, 1H), 7.98 (br d, J=8.5 Hz, 1H), 7.54 (dd, J=8.9, 2.7 Hz, 1H), .60 (br s, 2H), 4.78 (br (1S,3S)((6-(5-((((3,3- s, 1H), 4.61 - 4.23 (m, dimethylcyclobutyl)(methyl)carbamo 1H), 4.10 (s, 3H), 2.71 (s, yl)oxy)methyl)methyl-1H-1,2,3- 3H), 2.68 - 2.61 (m, 1H), triazolyl)pyridin 2.08 - 1.71 (m, 7H), 1.66 yl)oxy)cyclohexanecarboxylic (br d, J=8.9 Hz, 2H), acid 1.60 - 1.46 (m, 2H), 1.14 - 0.90 (m, 6H) hLPA1 IC50 = 101 nM Analytical & Biology Method Example Structure & Name 182 LCMS, [M+H]+ = 476 1H NMR (500 MHz, Example DMSO-d6) δ 7.83 (d, 10 J=8.5 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 5.63 (s, 2H), 5.17 - 4.99 (m, 1H), 4.79 - 4.71 (m, 1H), 4.09 (s, 3H), 3.69 - 3.51 (m, (1S,3S)((6-(5-((((3- 1H), 3.46 (br s, 1H), 2.75 fluorocyclobutyl)(methyl)carbamoyl) (s, 3H), 2.67 - 2.57 (m, oxy)methyl)methyl-1H-1,2,3- 1H), 2.41 (s, 4H), 2.32 - triazolyl)methylpyridin 2.17 (m, 2H), 2.03 - 1.95 )cyclohexanecarboxylic (m, 1H), 1.88 - 1.75 (m, acid (mixture of diastereomers) 3H), 1.69 - 1.45 (m, 4H) hLPA1 IC50 = 61 nM 183 LCMS, [M+H]+ = 470 1H NMR (500 MHz, Example CHLOROFORM-d) δ 3 8.34 (d, J=2.5 Hz, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.36 (dd, J=8.8, 2.8 Hz, 1H), 5.76 (s, 2H), 4.79 - (1S,3S)((6-(1-methyl 4.69 (m, 1H), 4.16 (s, hyl(spiro[2.3]hexan 3H), 3.01 - 2.82 (m, 4H), yl)carbamoyl)oxy)methyl)-1H-1,2,3- 2.47 - 2.32 (m, 2H), 2.18 triazolyl)pyridin - 1.87 (m, 7H), 1.85 - yl)oxy)cyclohexanecarboxylic 1.56 (m, 4H), 0.61 - 0.27 acid (m, 4H) hLPA1 IC50 = 20 nM Analytical & Biology Method Example Structure & Name 184 LCMS, [M+H]+ = 486 1H NMR (500 MHz, Example DMSO-d6) δ 7.94 - 7.76 3 (m, 1H), 7.55 - 7.40 (m, 1H), 5.75 - 5.53 (m, 2H), 4.77 (br s, 1H), 4.09 (s, 3H), 3.30 - 3.02 (m, 1H), 2.90 - 2.72 (m, 3H), 2.70 (1S,3S)((6-(5-(((((2,2- - 2.58 (m, 1H), 2.45 - dimethylcyclopropyl)methyl)(methyl) 2.32 (m, 3H), 2.06 - 1.94 carbamoyl)oxy)methyl)methyl- (m, 1H), 1.90 - 1.72 (m, 1H-1,2,3-triazolyl) 3H), 1.67 - 1.43 (m, 4H), pyridinyl)oxy)cyclohexane- 1.08 - 0.93 (m, 3H), 0.92 oxylic acid (mixture of - 0.77 (m, 3H), 0.75 - diastereomers) 0.49 (m, 1H), 0.46 - 0.14 (m, 1H), 0.14 to -0.15 (m, 1H) hLPA1 IC50 = 37 nM 185 LCMS, [M+H]+ = 472 1H NMR (500 MHz, Example DMSO-d6) δ 8.34 (br s, 3 1H), 7.99 (br d, J=8.7 Hz, 1H), 7.53 (dd, J=8.6, 2.5 Hz, 1H), 5.63 (s, 2H), 4.84 - 4.73 (m, 1H), 4.11 (s, 3H), 2.82 (br s, 3H), (1S,3S)((6-(5-(((((2,2- 2.73 - 2.63 (m, 1H), 2.03 dimethylcyclopropyl)methyl)(methyl)c - 1.93 (m, 1H), 1.91 - arbamoyl)oxy)methyl)methyl-1H- 1.74 (m, 3H), 1.72 - 1.49 1,2,3-triazolyl)pyridin (m, 4H), 1.26 (s, 1H), yl)oxy)cyclohexanecarboxylic acid 0.97 (br s, 6H), 0.66 (br (mixture of diastereomers) s, 1H), 0.38 (br s, 1H), 0.02 (br s, 1H) hLPA1 IC50 = 86 nM Analytical & Biology Method Example Structure & Name 186 LCMS, [M+H]+ = 480 1H NMR (500 MHz, Example 6) δ 8.34 (d, 3 J=2.3 Hz, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.53 (dd, J=8.7, 2.7 Hz, 1H), 5.64 (br s, 2H), 4.82 - 4.73 (m, 1H), 4.10 (s, 3H), 2.83 (1S,3S)((6-(5-(((((2,2- (br s, 3H), 2.72 - 2.64 (m, difluorocyclopropyl)methyl)(methyl)ca 1H), 2.01 - 1.93 (m, 1H), rbamoyl)oxy)methyl)methyl-1H- 1.90 - 1.73 (m, 4H), 1.71 1,2,3-triazolyl)pyridin - 1.48 (m, 5H), 1.25 (s, yl)oxy)cyclohexanecarboxylic acid 1H), 1.23 - 1.09 (m, 1H) (mixture of diastereomers) hLPA1 IC50 = 67 nM 187 LCMS, [M+H]+ = 492 1H NMR (500 MHz, Example DMSO-d6) δ 7.90 - 7.73 3 (m, 1H), 7.51 - 7.42 (m, 1H), 5.64 - 5.58 (m, 2H), 4.76 (br s, 1H), 4.08 (br s, 3H), 3.81 - 3.74 (m, 2H), 3.31 - 3.22 (m, 1H), (1S,3S)((6-(5-((((3-fluoro 3.15 - 3.09 (m, 1H), 2.66 methylbutyl)(methyl)carbamoyl)oxy) - 2.57 (m, 1H), 2.38 (br s, )methyl-1H-1,2,3-triazol 3H), 1.98 - 1.72 (m, 5H), yl)methylpyridin 1.67 - 1.39 (m, 6H), 1.32 yl)oxy)cyclohexanecarboxylic - 1.24 (m, 3H), 1.09 - 1.01 (m, 3H) hLPA1 IC50 = 50 nM Analytical & Biology Method Example Structure & Name 188 LCMS, [M+H]+ = 478 1H NMR (500 MHz, Example DMSO-d6) δ 8.39 - 8.25 3 (m, 1H), 8.08 - 7.93 (m, 1H), 7.54 (br s, 1H), 5.66 - 5.53 (m, 2H), 4.76 (br s, 1H), 4.09 (br s, 2H), 3.86 - 3.74 (m, 2H), 3.31 - 3.24 (m, 1H), 3.16 - 3.12 (1S,3S)((6-(5-((((3-fluoro (m, 1H), 2.68 - 2.60 (m, methylbutyl)(methyl)carbamoyl)oxy) 1H), 1.97 - 1.73 (m, 5H), methyl)methyl-1H-1,2,3-triazol 1.63 (br s, 6H), 1.33 - yl)pyridinyl)oxy)cyclohexane 1.25 (m, 3H), 1.14 - 1.07 carboxylic acid (m, 3H) hLPA1 IC50 = 32 nM 189 LCMS, [M+H]+ = 490 1H NMR (500 MHz, Example DMSO-d6) δ 7.84 (br d, 3 J=8.4 Hz, 1H), 7.46 (br d, J=8.6 Hz, 1H), 5.69 (s, 2H), 4.77 (br s, 1H), 4.11 (s, 3H), 3.72 - 3.23 (m, 1H), 2.85 (br s, 3H), 2.72 (1S,3S)((6-(5-(((((1- - 2.60 (m, 1H), 2.42 (s, fluorocyclobutyl)methyl)(methyl)car 3H), 2.20 - 1.73 (m, 9H), )oxy)methyl)methyl-1H- 1.65 (br d, J=9.8 Hz, 5H) 1,2,3-triazolyl)methylpyridin hLPA1 IC50 = 120 nM yl)oxy)cyclohexanecarboxylic Analytical & Biology Method Example Structure & Name 190 LCMS, [M+H]+ = 464.1 1H NMR (500 MHz, CDCl3) δ 8.12 (d, J=8.8 Hz, 1H), 7.86 (br t, J=7.8 Hz, 1H), 5.64 - 5.57 (m, 1H), 5.55 - 5.47 (m, 1H), 4.86 (br s, 1H), 4.53 (dt, , 5.4 Hz, 1H), 4.43 (1S,3S)((6-(5-((((3- (dt, J=10.5, 5.3 Hz, 1H), fluoropropyl)(methyl)carbamoyl)oxy) 4.22 (s, 3H), 3.45 (q, methyl)methyl-1H-1,2,3-triazol J=7.1 Hz, 2H), 2.97 (d, yl)methylpyridin J=12.9 Hz, 3H), 2.88 (br yl)oxy)cyclohexanecarboxylic s, 1H), 2.74 (d, J=2.2 Hz, acid 3H), 2.18 - 1.76 (m, 9H), 1.68 (br d, J=6.3 Hz, 1H) 19F-NMR: -221.9 ppm hLPA1 IC50 = 81 nM 191 LCMS, [M+H]+ = 464.1 1H NMR (500 MHz, DMSO-d6) δ 7.84 (d, J=8.5 Hz, 1H), 7.48 (d, J=8.7 Hz, 1H), 7.33 (br t, J=5.6 Hz, 1H), 5.64 (s, 2H), 4.79 (br s, 1H), 4.47 (t, J=6.1 Hz, 1H), 4.37 (t, J=6.0 Hz, 1H), 4.08 (s, (1S,3S)((6-(5-((((4- 3H), 3.02 (q, J=6.0 Hz, fluorobutyl)carbamoyl)oxy)methyl)- 2H), 2.71 - 2.59 (m, 1H), 1-methyl-1H-1,2,3-triazolyl) 2.42 (s, 3H), 2.11 - 1.98 methylpyridinyl)oxy)cyclohexane- (m, 1H), 1.90 - 1.75 (m, 1-carboxylic acid 3H), 1.72 - 1.41 (m, 8H) hLPA1 IC50 = 553 nM Analytical & Biology Method Example Structure & Name 192 LCMS, [M+H]+ = 478.4 1H NMR (400 MHz, CDCl3) δ 11.11 (br s, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 5.58 - 5.39 (m, 2H), 4.90 (br s, 1H), 4.57 - 4.49 (m, 1H), 4.46 - 4.35 (m, 1H), 4.23 (d, J=4.2 (1S,3S)((6-(5-((((4- Hz, 3H), 3.35 (br d, fluorobutyl)(methyl)carbamoyl)oxy) J=7.0 Hz, 2H), 3.03 - methyl)methyl-1H-1,2,3-triazol 2.69 (m, 7H), 2.24 - 1.57 yl)methylpyridin (m, 12H) yl)oxy)cyclohexanecarboxylic 19F NMR: 219 ppm acid hLPA1 IC50 = 36 nM 193 LCMS, [M+H]+ = 446.1 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J=8.6 Hz, 1H), 7.20 (d, J=8.6 Hz, 1H), 5.77 (br d, J=5.3 Hz, 2H), 4.38 - 4.21 (m, 1H), 4.15 (s, 3H), 3.34 - 3.06 (m, 2H), 2.98 - 2.79 (m, 3H), 2.60 (1R,3R)((2-methyl(1-methyl - 2.38 (m, 5H), 2.21 - (((methyl(propyl)carbamoyl)oxy)met 1.94 (m, 3H), 1.81 - 1.66 hyl)-1H-1,2,3-triazolyl)pyridin (m, 1H), 1.63 - 1.33 (m, yl)oxy)cyclohexanecarboxylic 7H), 0.97 - 0.70 (m, 2H) acid hLPA1 IC50 = 1696 nM The following s were synthesized according to the methods described for the preparation of Example 1 except that the intermediate 3 was used ad of Example Intermediate 3 was prepared from 2,5-dibromoethyl-pyridine using the same synthetic sequence as described for the preparation of Example 1. e Structure & Name Analytical & y Data Method LCMS, [M+H]+ = 472.0 1H NMR (500 MHz, DMSO-d δ 7.87 (br d, J=7.9 Hz, 1H), 7.50 (br d, J=8.5 Hz, 1H), 5.69 (br d, J=16.2 Hz, 2H), 4.81 (br s, 1H), 4.14 (s, 3H), 3.56 (br s, Example 1H), 3.10 (br s, 1H), 2.99 (br s, 1 194 1H), 2.89 - 2.78 (m, 5H), 2.10 - 2.02 (m, 1H), 1.90 (br d, J=11.6 (1S,3S)((6-(5- Hz, 1H), 1.86 - 1.78 (m, 2H), ((((cyclopropylmethyl)(methyl) 1.69 - 1.48 (m, 4H), 1.31 - 1.20 carbamoyl)oxy)methyl) (m, 3H), 1.03 - 0.86 (m, 1H), methyl-1H-1,2,3-triazolyl)- 0.85 - 0.66 (m, 1H), 0.45 (br s, 2-ethylpyridin 1H), 0.28 (br s, 1H), 0.22 (br s, yl)oxy)cyclohexane 1H), 0.00 (br s, 1H) carboxylic acid hLPA1 IC50 = 14 nM LCMS, [M+H]+ = 485.9 1H NMR (500 MHz, DMSO-d δ 7.94 - 7.76 (m, 1H), 7.60 - 7.41 (m, 1H), 5.66 (s, 2H), 4.88 - 4.62 (m, 1H), 2.80 (q, J=7.3 195 Hz, 2H), 2.64 (br s, 3H), 2.01 - 1.92 (m, 1H), 1.92 - 1.86 (m, (1S,3S)((6-(5- 1H), 1.85 - 1.72 (m, 4H), 1.67 - (((cyclopentyl(methyl)carbamo 1.58 (m, 5H), 1.54 (br s, 5H), yl)oxy)methyl)methyl-1H- 1.43 (br s, 5H), 1.24 (br t, J=7.4 1,2,3-triazolyl) Hz, 3H) ethylpyridin hLPA1 IC50 = 11 nM yl)oxy)cyclohexane carboxylic acid Example Structure & Name Analytical & Biology Data Method LCMS, [M+H]+ = 486.2 1H NMR (500 MHz, DMSO-d δ 7.83 (br d, J=8.2 Hz, 1H), 7.50 (br d, J=8.6 Hz, 1H), 5.66 (br d, J=16.0 Hz, 2H), 4.75 (br s, 1H), 4.10 (br d, J=9.4 Hz, 196 3H), 2.80 (br d, J=6.4 Hz, 2H), (1S,3S)((6-(5- 2.73 (br d, J=17.7 Hz, 3H), 1.91 ((((cyclobutylmethyl)(methyl)c (br d, J=14.9 Hz, 2H), 1.84 (s, arbamoyl)oxy)methyl) 6H), 1.76 (s, 4H), 1.71 - 1.57 methyl-1H-1,2,3-triazolyl)- (m, 4H), 1.54 (br s, 2H), 1.43 2-ethylpyridin (br d, J=8.1 Hz, 1H), 1.25 (br d, yl)oxy)cyclohexane J=6.8 Hz, 3H) carboxylic acid hLPA1 IC50 = 12 nM LCMS, [M+H]+ = 474.1 1H NMR (500 MHz, DMSO-d δ 7.80 (br t, J=8.1 Hz, 1H), 7.45 (br d, J=8.2 Hz, 1H), 5.63 (br d, J=18.3 Hz, 2H), 4.75 (br s, 1H), 4.08 (br s, 3H), 2.99 (br d, J=7.0 Hz, 1H), 2.85 (br d, J=6.7 197 Hz, 1H), 2.81 - 2.70 (m, 5H), 1.97 (br d, J=13.7 Hz, 1H), 1.86 (1S,3S)((2-ethyl(5- (s, 1H), 1.79 (br d, J=12.5 Hz, (((isobutyl(methyl)carbamoyl) 3H), 1.60 (br d, J=8.9 Hz, 3H), oxy)methyl)methyl-1H- 1.57 - 1.45 (m, 2H), 1.23 (br d, triazolyl)pyridin J=7.6 Hz, 3H), 0.78 (br d, J=5.5 yl)oxy)cyclohexane Hz, 3H), 0.59 - 0.54 (m, 3H) ylic acid hLPA1 IC50 = 27 nM LCMS, [M+H]+ = 494.0 1H NMR (500 MHz, DMSO-d δ 7.84 (br d, J=8.3 Hz, 2H), 7.47 (br d, J=8.5 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.22 (br d, J=7.2 Hz, 3H), 5.69 (s, 2H), 4.76 (br 198 s, 1H), 4.18 (br d, J=5.9 Hz, 2H), 4.08 (s, 3H), 3.50 (br s, 1H), 2.78 (q, J=7.3 Hz, 2H), (1S,3S)((6-(5- 1.98 (br d, J=13.0 Hz, 1H), 1.80 (((benzylcarbamoyl)oxy)methyl (br d, J=11.8 Hz, 3H), 1.61 (br )methyl-1H-1,2,3-triazol s, 2H), 1.54 (br s, 1H), 1.50 (br yl)ethylpyridin s, 1H), 1.22 (br t, J=7.4 Hz, 3H) yl)oxy)cyclohexane hLPA1 IC50 = 46 nM carboxylic acid Example Structure & Name Analytical & Biology Data Method LCMS, [M+H]+ = 474.1 1H NMR (500 MHz, DMSO-d δ 7.83 (br d, J=8.3 Hz, 1H), 7.46 (br d, J=8.3 Hz, 1H), 5.64 (br d, J=12.4 Hz, 2H), 4.76 (br s, 1H), 4.09 (br s, 3H), 3.53 (br s, 1H), 3.17 (br s, 1H), 3.03 (br 199 s, 1H), 2.82 - 2.69 (m, 5H), 1.98 (br d, J=13.8 Hz, 1H), 1.79 (br (1S,3S)((6-(5- d, J=11.0 Hz, 3H), 1.60 (br s, yl(methyl)carbamoyl)oxy) 2H), 1.57 - 1.45 (m, 2H), 1.41 methyl)methyl-1H-1,2,3- (br s, 1H), 1.26 - 1.16 (m, 5H), triazolyl)ethylpyridin 1.01 - 0.93 (m, 1H), 0.86 (br s, yl)oxy)cyclohexane 1H), 0.61 (br s, 2H) carboxylic acid hLPA1 IC50 = 7 nM LCMS, [M+H]+ = 460.1 1H NMR (500 MHz, DMSO-d δ 7.92 - 7.70 (m, 1H), 7.62 - 7.30 (m, 1H), 5.80 - 5.48 (m, 2H), 4.89 - 4.58 (m, 1H), 4.24 - 3.82 (m, 3H), 3.60 - 3.25 (m, 200 1H), 3.21 - 2.93 (m, 2H), 2.85 - 2.67 (m, 5H), 2.66 - 2.56 (m, (1S,3S)((2-ethyl(1- 1H), 2.07 - 1.94 (m, 1H), 1.90 - methyl 1.69 (m, 3H), 1.68 - 1.36 (m, (((methyl(propyl)carbamoyl)ox 5H), 1.33 - 1.14 (m, 3H), 0.86 - y)methyl)-1H-1,2,3-triazol 0.67 (m, 2H), 0.67 - 0.40 (m, yl)pyridin 2H) yl)oxy)cyclohexane hLPA1 IC50 = 11 nM carboxylic acid Example Structure & Name Analytical & Biology Data Method LCMS, [M+H]+ = 474.1 1H NMR (500 MHz, DMSO-d δ 7.83 (br d, J=8.3 Hz, 1H), 7.46 (br d, J=8.3 Hz, 1H), 5.64 (br d, J=12.4 Hz, 2H), 4.76 (br s, 1H), 4.09 (br s, 3H), 3.53 (br s, 1H), 3.17 (br s, 1H), 3.03 (br 201 s, 1H), 2.82 - 2.69 (m, 5H), 1.98 (br d, J=13.8 Hz, 1H), 1.79 (br (1S,3S)((6-(5- d, J=11.0 Hz, 3H), 1.60 (br s, (((benzyl(methyl)carbamoyl)ox 2H), 1.57 - 1.45 (m, 2H), 1.41 y)methyl)methyl-1H-1,2,3- (br s, 1H), 1.26 - 1.16 (m, 5H), triazolyl)ethylpyridin 1.01 - 0.93 (m, 1H), 0.86 (br s, )cyclohexane 1H), 0.61 (br s, 2H) carboxylic acid hLPA1 IC50 = 25 nM LCMS, [M+H]+ = 446.1 1H NMR (500 MHz, DMSO-d δ 7.84 (br d, J=8.5 Hz, 1H), 7.47 (br d, J=8.5 Hz, 1H), 5.66 (br s, 2H), 4.76 (br s, 1H), 4.09 (s, 3H), 3.56 - 3.37 (m, 1H), 202 3.19 (br d, J=18.6 Hz, 1H), 3.11 (br s, 1H), 2.82 - 2.75 (m, 3H), 2.73 (br s, 2H), 2.60 - 2.53 (m, (1S,3S)((2-ethyl(5- 1H), 1.98 (br d, J=13.4 Hz, 1H), (((ethyl(methyl)carbamoyl)oxy) 1.80 (br d, J=11.0 Hz, 2H), 1.61 methyl)methyl-1H-1,2,3- (br s, 2H), 1.53 (br d, J=16.5 triazolyl)pyridin Hz, 2H), 1.24 (t, J=7.5 Hz, 3H), yl)oxy)cyclohexane 1.00 (br d, J=6.1 Hz, 2H), 0.86 carboxylic acid (br s, 2H) hLPA1 IC50 = 160 nM Example ure & Name Analytical & Biology Data Method LCMS, [M+H]+ = 472.1 1H NMR (500 MHz, DMSO-d δ 7.81 (br d, J=8.2 Hz, 1H), 7.46 (br d, J=8.9 Hz, 1H), 5.62 (s, 2H), 4.74 (br s, 1H), 4.07 (s, 203 3H), 3.77 - 3.70 (m, 4H), 2.77 (q, J=7.3 Hz, 2H), 2.70 (br s, (1S,3S)((6-(5- 2H), 2.03 (br s, 1H), 1.93 (br d, (((cyclobutyl(methyl)carbamoyl J=13.1 Hz, 2H), 1.88 - 1.72 (m, )oxy)methyl)methyl-1H- 5H), 1.63 - 1.41 (m, 6H), 1.21 triazolyl) (br t, J=7.3 Hz, 3H) ethylpyridin hLPA1 IC50 = 8 nM yl)oxy)cyclohexane carboxylic acid LCMS, [M+H]+ = 472.1 1H NMR (500 MHz, DMSO-d δ 7.81 (br d, J=8.5 Hz, 1H), 7.46 (br d, J=8.5 Hz, 1H), 5.62 (s, 2H), 4.74 (br s, 1H), 4.05 (s, 204 3H), 3.79 - 3.70 (m, 4H), 2.78 (1S,3S)((6-(5-(((3,3- (q, J=7.3 Hz, 2H), 1.91 (br s, dimethylazetidine 1H), 1.86 - 1.73 (m, 5H), 1.64 - carbonyl)oxy)methyl) 1.44 (m, 4H), 1.22 (t, J=7.5 Hz, methyl-1H-1,2,3-triazolyl)- 3H), 1.13 (s, 6H) 2-ethylpyridin hLPA1 IC50 = 102 nM yl)oxy)cyclohexane carboxylic acid LCMS, [M+H]+ = 470.1 1H NMR (500 MHz, DMSO-d δ 7.82 (br d, J=7.3 Hz, 1H), 7.48 (br s, 1H), 5.62 (br s, 2H), 4.99 - 4.53 (m, 1H), 4.07 (br s, 205 2H), 3.58 (br s, 1H), 3.17 (s, 1H), 2.89 (s, 1H), 2.82 (br s, 1H), 2.73 (s, 1H), 2.35 (br s, (1S,3S)((6-(5- 1H), 2.05 (br s, 1H), 1.90 (br s, (((bicyclo[1.1.1]pentan 7H), 1.64 (br s, 4H), 1.25 (br s, ylcarbamoyl)oxy)methyl) 3H), 1.00 (d, J=6.1 Hz, 1H) methyl-1H-1,2,3-triazolyl)- hLPA1 IC50 = 842 nM 2-ethylpyridinyl)oxy) cyclohexanecarboxylic acid Example Structure & Name Analytical & y Data Method LCMS, [M+H]+ = 484.1 1H NMR (500 MHz, DMSO-d δ 7.88 - 7.75 (m, J=8.2 Hz, 1H), 7.54 - 7.41 (m, J=8.2 Hz, 1H), .63 (s, 2H), 4.88 - 4.67 (m, 1H), 4.09 (s, 2H), 3.69 - 3.53 206 (m, 1H), 3.17 (s, 1H), 2.89 (s, 1H), 2.80 (br d, J=7.3 Hz, 2H), (1S,3S)((6-(5- 2.76 - 2.63 (m, 3H), 2.05 (br s, (((bicyclo[1.1.1]pentan 1H), 1.79 (br s, 8H), 1.61 (br s, yl(methyl)carbamoyl)oxy)meth 4H), 1.22 (br t, J=7.3 Hz, 3H), yl)methyl-1H-1,2,3-triazol- 1.00 (d, J=6.4 Hz, 1H) 4-yl)ethylpyridin hLPA1 IC50 = 34 nM yl)oxy)cyclohexane carboxylic acid LCMS, [M+H]+ = 500.4 1H NMR (500 MHz, DMSO-d δ 7.83 (br d, J=8.5 Hz, 1H), 7.47 (br d, J=8.5 Hz, 1H), 5.64 (br d, J=8.5 Hz, 2H), 4.78 (br s, 1H), 4.12 (s, 2H), 4.08 (br s, 1H), 2.83 - 2.73 (m, 4H), 2.73 - 2.65 (m, 1H), 2.60 (br s, 1H), 207 2.12 - 1.94 (m, 1H), 1.86 (br d, J=12.2 Hz, 1H), 1.82 - 1.70 (m, (1S,3S)((2-ethyl(1- 2H), 1.66 - 1.52 (m, 3H), 1.52 - methyl(((methyl(1- 1.37 (m, 2H), 1.31 - 1.22 (m, propylcyclopropyl) 4H), 1.20 (br s, 1H), 1.06 (br d, carbamoyl)oxy)methyl)-1H- J=8.2 Hz, 1H), 1.00 (d, J=6.1 1,2,3-triazolyl)pyridin Hz, 1H), 0.84 (br s, 1H), 0.74 yl)oxy) cyclohexane (br s, 1H), 0.68 - 0.54 (m, 4H), carboxylic acid 0.44 (br s, 1H) hLPA1 IC50 = 133 nM Example Structure & Name Analytical & Biology Data Method LCMS, [M+H]+ = 488.3 1H NMR (500 MHz, DMSO-d δ 7.89 - 7.77 (m, J=8.5 Hz, 1H), 7.53 - 7.41 (m, J=8.5 Hz, 1H), .64 (br s, 2H), 4.76 (br s, 1H), 4.09 (s, 3H), 3.27 - 3.10 (m, 1H), 3.04 (br s, 1H), 2.89 (s, 1H), 2.82 - 2.67 (m, 5H), 1.98 208 (br d, J=12.8 Hz, 1H), 1.89 (s, 3H), 1.80 (br d, J=11.6 Hz, 2H), )((2-ethyl(5- 1.61 (br d, J=8.5 Hz, 2H), 1.54 (((isopentyl(methyl)carbamoyl) (br s, 1H), 1.49 (br d, J=11.3 oxy)methyl)methyl-1H- Hz, 1H), 1.30 (br d, J=5.8 Hz, 1,2,3-triazolyl)pyridin 1H), 1.24 (br t, J=7.5 Hz, 3H), yl)oxy)cyclohexane 1.12 (br s, 1H), 0.86 (br s, 3H), carboxylic acid 0.60 (br s, 3H) hLPA1 IC50 = 26 nM LCMS, [M+H]+ = 486.4 1H NMR (500 MHz, DMSO-d δ 7.83 (br d, J=7.6 Hz, 1H), 7.46 (br d, J=8.5 Hz, 1H), 5.65 (br d, J=10.7 Hz, 2H), 4.77 (br s, 1H), 4.09 (br s, 3H), 3.24 (br s, 1H), 3.12 (br s, 1H), 2.95 - 209 2.85 (m, 1H), 2.83 - 2.71 (m, 5H), 2.61 (br t, J=10.5 Hz, 1H), (1S,3S)((6-(5-((((2- 2.08 - 1.95 (m, 1H), 1.92 - 1.82 cyclopropylethyl)(methyl)carba (m, 2H), 1.82 - 1.73 (m, 2H), moyl)oxy)methyl)methyl- 1.66 - 1.45 (m, 4H), 1.33 (br s, 1H-1,2,3-triazolyl) 1H), 1.28 - 1.11 (m, 4H), 0.35 ethylpyridin (br s, 1H), 0.16 (br s, 1H), -0.01 yl)oxy)cyclohexane (br s, 1H), -0.27 (br s, 1H) carboxylic acid hLPA1 IC50 = 22 nM Example ure & Name Analytical & Biology Data Method LCMS, [M+H]+ = 484.4 1H NMR (500 MHz, DMSO-d δ 7.83 (d, J=8.5 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 5.64 (s, 2H), 4.77 (br s, 1H), 4.07 (s, 3H), 2.93 - 2.86 (m, 1H), 2.80 (q, 210 J=7.3 Hz, 2H), 2.73 (s, 1H), (1S,3S)((6-(5-(((2- 2.61 (br t, J=10.7 Hz, 1H), 2.09 azaspiro[3.3]heptane - 1.99 (m, 5H), 1.93 - 1.82 (m, carbonyl)oxy)methyl) 3H), 1.82 - 1.67 (m, 4H), 1.65 - methyl-1H-1,2,3-triazolyl)- 1.52 (m, 3H), 1.50 (br s, 1H), 2-ethylpyridin 1.28 - 1.14 (m, 3H) yl)oxy)cyclohexane hLPA1 IC50 = 67 nM carboxylic acid LCMS, [M+H]+ = 484.4 1H NMR (500 MHz, DMSO-d δ 7.87 - 7.80 (m, 1H), 7.46 (br d, J=8.9 Hz, 1H), 5.69 (br d, J=5.8 Hz, 2H), 4.77 (br s, 1H), 4.09 (br d, J=15.3 Hz, 3H), 3.15 (s, 1H), 3.07 (s, 1H), 2.89 (s, 211 1H), 2.80 (q, J=7.6 Hz, 2H), (1S,3S)((6-(5-(((5- 2.73 (s, 1H), 2.61 (br t, J=10.5 azaspiro[2.4]heptane Hz, 1H), 2.16 - 1.96 (m, 1H), carbonyl)oxy)methyl) 1.91 - 1.74 (m, 3H), 1.70 (t, methyl-1H-1,2,3-triazolyl)- J=6.9 Hz, 2H), 1.65 - 1.45 (m, 2-ethylpyridin 4H), 1.29 - 1.14 (m, 3H), 0.55 yl)oxy)cyclohexane (br s, 1H), 0.53 - 0.45 (m, 3H) carboxylic acid hLPA1 IC50 = 47 nM The following analogs were synthesized according to the s described for the preparation of Example 1 except that the intermediate 4 was used (instead of Example Intermediate 3 was prepared from bromo-pyrazine using the same synthetic sequence as described for the preparation of Example 1. e Structure & Name Analytical & Biology Data Method LCMS, [M+H]+ = 447.1 1H NMR (500 MHz, DMSO-d 6) Example δ 8.77 (s, 1H), 8.34 (s, 1H), 1 .53 (br d, J=15.0 Hz, 2H), 5.36 (br s, 1H), 4.12 (s, 3H), 3.16 (br s, 1H), 3.06 (br s, 1H), 2.74 (br 212 d, J=11.6 Hz, 3H), 2.66 (br t, J=10.1 Hz, 1H), 2.07 (br d, (1S,3S)((5-(5- J=13.1 Hz, 1H), 1.87 - 1.79 (m, (((butyl(methyl)carbamoyl)oxy) 3H), 1.66 (br t, J=13.0 Hz, 2H), methyl)methyl-1H-1,2,3- 1.60 - 1.48 (m, 2H), 1.41 (br s, triazolyl)pyrazin 1H), 1.22 (br s, 2H), 1.06 - 0.99 yl)oxy)cyclohexane (m, 1H), 0.86 (br s, 1H), 0.68 carboxylic acid (br s, 2H) hLPA1 IC50 = 40 nM LCMS, [M+H]+ = 445.1 1H NMR (500 MHz, DMSO-d 6) Example δ 8.80 - 8.73 (m, 1H), 8.37 - 1 8.30 (m, 1H), 5.54 (br d, J=13.1 Hz, 2H), 5.40 - 5.31 (m, 1H), 4.12 (s, 3H), 3.12 - 3.02 (m, 1H), 3.02 - 2.92 (m, 1H), 2.83 213 (br s, 3H), 2.70 - 2.60 (m, 1H), 2.12 - 2.01 (m, 1H), 1.86 - 1.79 (1S,3S)((5-(5- (m, 3H), 1.71 - 1.61 (m, 2H), ((((cyclopropylmethyl)(methyl) 1.59 - 1.48 (m, 2H), 0.98 - 0.85 carbamoyl)oxy)methyl) (m, 1H), 0.85 - 0.70 (m, 1H), methyl-1H-1,2,3-triazol 0.49 - 0.36 (m, 1H), 0.36 - 0.23 yl)pyrazinyl)oxy) (m, 1H), 0.23 - 0.09 (m, 1H), cyclohexanecarboxylic acid 0.09 - -0.07 (m, 1H) hLPA1 IC50 = 1070 nM Example ure & Name Analytical & Biology Data Method LCMS, [M+H]+ = 459.0 1H NMR (500 MHz, DMSO-d 6) Example δ 8.75 (s, 1H), 8.33 (br s, 1H), 1 .51 (br d, J=16.5 Hz, 2H), 5.34 (br s, 1H), 4.12 (br s, 3H), 3.56 (br s, 1H), 3.18 (br d, J=10.4 214 Hz, 1H), 3.08 (br d, J=5.5 Hz, 1H), 2.71 (br d, J=9.5 Hz, 3H), (1S,3S)((5-(5- 2.64 (br s, 1H), 2.34 - 2.19 (m, ((((cyclobutylmethyl)(methyl)c 1H), 2.08 - 2.02 (m, 1H), 1.90 arbamoyl)oxy)methyl) (br s, 1H), 1.86 - 1.78 (m, 3H), methyl-1H-1,2,3-triazol 1.75 (br s, 1H), 1.71 (br s, 1H), yl)pyrazinyl)oxy) 1.64 (br d, J=13.4 Hz, 3H), 1.59 cyclohexanecarboxylic acid - 1.46 (m, 3H), 1.40 (br s, 1H) hLPA1 IC50 = 68 nM LCMS, [M+H]+ = 459.3 Example 1H NMR (500 MHz, DMSO-d 6) 1 δ 8.76 (s, 1H), 8.34 (s, 1H), .54 (s, 2H), 5.35 (br s, 1H), 4.47 - 4.22 (m, 1H), 4.11 (s, 215 3H), 3.53 - 3.31 (m, 1H), 2.63 (br s, 4H), 2.10 - 2.03 (m, 1H), (1S,3S)((5-(5- 1.87 - 1.76 (m, 3H), 1.73 - 1.60 (((cyclopentyl(methyl)carbamo (m, 3H), 1.57 (br s, 3H), 1.51 yl)oxy)methyl)methyl-1H- (br d, J=12.2 Hz, 2H), 1.43 (br 1,2,3-triazolyl)pyrazin s, 4H) yl)oxy)cyclohexane hLPA1 IC50 = 84 nM carboxylic acid Example 216 )((3-methyl(1-methyl(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3- triazolyl)pyrazinyl)oxy)cyclohexanecarboxylic acid 216A. Methyl 3-bromo(3-hydroxypropynyl)pyrazinecarboxylate A e of methyl 3,6-dibromopyrazinecarboxylate (16.5 g, 55.8 mmol), propargyl alcohol (3.33 mL, 55.8 mmol), and TEA (46.6 mL, 335 mmol) in MeCN (100 mL) was degassed with N2 and then CuI (0.531 g, 2.79 mmol) and bis(triphenylphosphine)Palladium(II) chloride (1.96 g, 2.79 mmol) were successively added. The reaction mixture was degassed with N2 for 3 cycles & stirred at rt for 18 h, then was filtered through a pad of Celite. The filtrate was concentrated in vacuo. The crude oil was chromatographed (120 g SiO2 eluted with EtOAc/hexane using a uous gradient from 0% to 80% over 25 min) to give the title product (5.40 g, 19.9 mmol, 35.7 % yield) as a brownish oil. 1H NMR (500 MHz, CDCl 3)  8.53 (s, 1H), 4.56 (d, J=6.3 Hz, 2H), 4.04 (s, 3H), 2.09 - 2.00 (m, 1H) 216B. Methyl 3-bromo(5-(hydroxymethyl)methyl-1H-1,2,3-triazolyl)pyrazine carboxylate To a solution of Example 216A (2.7 g, 9.96 mmol) in 1,4-dioxane (100 mL) were successively added added TMSCH2N3 (1.48 mL, 9.96 mmol), chloro(pentamethylcyclopenta-dienyl)bis(triphenylphosphine)Ruthenium(II) (0.397 g, 0.498 mmol), and CuI (0.095 g, 0.498 mmol). The e was degassed with N2 for 3 cycles. The resulting homogenous mixture was then heated at 50°C (oil bath) for 16h, then was cooled to rt and concentrated in vacuo. The residue was ved in THF (40 mL) and cooled to 0 °C; TBAF (19.9 mL of a 1 M solution in THF, 19.9 mmol) was added at 0 °C. The reaction mixture was allowed to warm to rt and stirred at rt for 60 min, after which sat. aq. NaHCO3 s solution (20 mL) was added. The e was stirred for 1 h and filtered. The filtrate was concentrated in vacuo. The crude brown oily product was chromatographed (SiO2; 80 g; elution with EtOAc/Hexane - continuous gradient from 0% to 80% over 25 min) to give title product (1.5 g, 4.57 mmol, 45.9 % yield) as a light brownish solid. 1H NMR (400 MHz, CDCl 3)  9.42 (s, 1H), 4.90 - 4.85 (m, 3H), 4.15 (s, 3H), 4.07 (s, 3H) 216C. Methyl 3-bromo(1-methyl(((tetrahydro-2H-pyranyl)oxy)methyl)-1H- 1,2,3-triazolyl)pyrazinecarboxylate p-TsOH.H2O (0.087 g, 0.457 mmol) was added to a solution of Example 216B (3.0 g, 9.14 mmol) and 3,4-dihydro-2H-pyran (2.502 mL, 27.4 mmol) in DCM (10 mL) at 0oC. The reaction mixture was stirred overnight at rt and neutralized with satd aq.
NaHCO3 to pH 7 at 0oC. The mixture was partitioned n CH2Cl2 (10 mL) and water (10 mL), and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude oil was chromatographed (40 g SiO2; elution with EtOAc/Hexane - continuous gradient from 0% to 50% over 25 min) to give the title compound (3.50 g, 8.49 mmol, 93 % yield) as light brownish oil.
[M – THP + H] + = 328.1/330.1; 1H NMR (400 MHz, CDCl 3) δ 9.31 (s, 1H), 5.28 - 5.09 (m, 2H), 4.75 - 4.71 (m, 1H), 4.19 (s, 3H), 4.03 (s, 3H), 3.82 - 3.75 (m, 1H), 3.53 - 3.45 (m, 1H), 1.85 - 1.44 (m, 6H) 216D. 3-Bromo(1-methyl(((tetrahydro-2H-pyranyl)oxy)methyl)-1H-1,2,3- triazolyl)pyrazinecarboxylic acid A solution of LiOH.H2O (0.484 g, 11.53 mmol) in water (6 mL) was added dropwise to a stirred solution of Example 216C (1.0 g, 2.43 mmol) in THF (6 mL) at 0 oC. The reaction mixture was allowed to warm to rt and stirred at rt for 60 min, then was quenched carefully with 1N aq. HCl to pH ~5 at 0 °C and extracted with DCM (20 × 5 mL). The combined organic extracts were washed with brine and dried over .
Volatiles were removed in vacuo to afford the title compound (0.80 g, 2.01 mmol, 83 % yield) as a light ish solid.
[M – THP + H] + = 313.9/315.9; 1H NMR (500 MHz, CDCl3) δ 9.46 (s, 1H), 5.42 (d, J=13.5 Hz, 1H), 4.90 (d, J=13.8 Hz, 1H), 4.24 (s, 3H), 3.87 (td, J=10.9, 2.6 Hz, 1H), 3.73 (d, J=11.3 Hz, 1H), 1.93 - 1.50 (m, 7H) 217E. 3-Bromo(1-methyl(((tetrahydro-2H-pyranyl)oxy)methyl)-1H-1,2,3-triazol- 4-yl)pyrazinecarbonyl chloride A mixture of Example 217D (228 mg, 0.573 mmol) and 1-chloro-N,N,2- trimethylpropenamine (0.114 mL, 0.859 mmol) in DCM (2 mL) was stirred at rt for 1 h. The reaction mixture was trated in vacuo to give the title compound (239 mg, 0.574 mmol, 100 % yield) as yellowish oil which was used in the next reaction t further purification. 218F. (3-Bromo(1-methyl(((tetrahydro-2H-pyranyl)oxy)methyl)-1H-1,2,3- triazolyl)pyrazinyl)methanol A solution of Example 218E (3.14 g, 7.54 mmol) in THF (20 mL) was added dropwise to a suspension of NaBH4 (0.656 g, 17.33 mmol) in EtOH (20 mL) at -78 °C.
The reaction was d at -78 °C for 1 h. Aq. HCl (9.80 mL of a 1.0 N solution, 9.80 mmol) was added cautiously to the reaction to make it weakly acidic at -78 °C. The mixture was then basified with sat’d aq. NaHCO3 to pH ~ 8 and ted with EtOAc (4 x 20 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo.
The crude oily product was chromatographed (40 g SiO2; elution with EtOAc/Hexane (continuous gradient from 0% to 80% over 25 min) to give the title compound (2.50 g, 6.51 mmol, 86 % yield) as a light yellowish solid. 1H NMR (500 MHz, CDCl 3) δ 9.13 (s, 1H), 5.47 (d, J=13.2 Hz, 1H), 4.98 (d, J=13.2 Hz, 1H), 4.89 - 4.85 (m, 2H), 4.76 (t, J=2.9 Hz, 1H), 4.69 (t, J=5.6 Hz, 1H), 4.19 (s, 3H), 3.93 - 3.81 (m, 1H), 3.62 (dt, J=10.9, 3.9 Hz, 1H), 1.86 - 1.47 (m, 6H) 218G. 2-Bromo(chloromethyl)(1-methyl(((tetrahydro-2H-pyran yl)oxy)methyl)-1H-1,2,3-triazolyl)pyrazine To a solution of Example 218F (190 mg, 0.494 mmol) in CHCl3 (3 mL) was added methanesulfonyl chloride (0.057 mL, 0.74 mmol), iPr2NEt (0.259 mL, 1.48 mmol) and DMAP (6.0 mg, 0.049 mmol) at 0 °C. After the addition was te, the reaction mixture was stirred at rt for 30 min. after which LiCl (105 mg, 2.472 mmol) and DMF (3 mL) were successively added. The mixture was d at rt for 1 h and then concentrated in vacuo. The e was partitioned between water and EtOAc (10 mL each). The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude oily product was chromatographed (12 g SiO2; n with EtOAc/Hexane (continuous gradient from 0% to 50% over 10 min) to give the title compound (175 mg, 0.435 mmol, 88 % yield) as a white solid. 1H NMR (400MHz, CDCl 3) δ 9.14 (s, 1H), 5.33 - 5.19 (m, 2H), 4.84 (s, 2H), 4.75 (t, J=3.4 Hz, 1H), 4.19 (s, 3H), 3.88 - 3.75 (m, 1H), 3.59 - 3.47 (m, 1H), 1.87 - 1.46 (m, 6H) 218H. 2-Bromomethyl(1-methyl(((tetrahydro-2H-pyranyl)oxy)methyl)-1H- 1,2,3-triazolyl)pyrazine To a 0 °C solution of NaBH4 (286 mg, 7.55 mmol) in EtOH (20 mL) was added dropwise a solution of Example 218G (760 mg, 1.89 mmol) in THF (20 mL). After the addition was te, the reaction was stirred at rt for 6 h. LCMS indicated the reaction was still not complete, so additional NaBH4 (286 mg, 7.55 mmol) was added and the reaction mixture was stirred for 3 days, then usly quenched with water at 0 °C. The mixture was ted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude oily product was chromatographed (24 g SiO2; elution with EtOAc/Hexane (continuous gradient from 0% to 50% over 10 min) to give the title compound (600 mg, 1.63 mmol, 86 % yield) as a white solid. 1H NMR (500 MHz, CDCl 3) δ 9.04 (s, 1H), 5.29 - 5.20 (m, 2H), 4.75 (t, J=3.4 Hz, 1H), 4.20 (s, 3H), 3.86 (ddd, J=11.3, 8.3, 3.0 Hz, 1H), 3.59 - 3.50 (m, 1H), 2.72 (s, 3H), 1.85 - 1.49 (m, 6H) 218I. 3-Methyl(1-methyl(((tetrahydro-2H-pyranyl)oxy)methyl)-1H-1,2,3-triazol- 4-yl)pyrazinol A mixture of Example 218H (600 mg, 1.63 mmol), KOH (1.00 mL of a 7 M aq. solution, 7.0 mmol) in water (5 mL) and dioxane (5 mL) was degassed under N2 and then tBuXphos (83 mg, 0.196 mmol) and Pd2(dba)3 (44.8 mg, 0.049 mmol) were added. The reaction mixture was ed under N2 again and then stirred at 80 °C overnight. The reaction was cooled to rt, then was acidified to pH 5 with 1N aq. HCl at 0 °C and partitioned between water and EtOAc. The organic phase was separated, dried (MgSO4), and trated in vacuo. The crude oily product was chromatographed (12 g SiO2; elution with EtOAc/Hexane (continuous gradient from 0% to 100% over 7 min) to give the title compound (340 mg, 1.11 mmol, 68.3 % yield) as a light yellowish solid.
[M – THP + H] + = 222.2; 1H NMR (500 MHz, CDCl 3) δ 8.04 (s, 1H), 5.24 - 5.15 (m, 2H), 4.88 - 4.72 (m, 1H), 4.16 (s, 3H), 3.90 (ddd, J=11.2, 8.2, 3.2 Hz, 1H), 3.72 - 3.52 (m, 1H), 2.55 (s, 3H), 1.90 - 1.44 (m, 7H) 218J. Isopropyl (1S,3S)((3-methyl(1-methyl(((tetrahydro-2H-pyran yl)oxy)methyl)-1H-1,2,3-triazolyl)pyrazinyl)oxy)cyclohexanecarboxylate To a e of Example 218I (340 mg, 1.11 mmol)), ((1S,3R)-isopropyl 3- ycyclo-hexane carboxylate (373 mg, 2.00 mmol) in THF (5 mL) were successively added n-Bu3P (0.556 mL, 2.227 mmol) and (E)-diazene-1,2-diylbis(piperidin ylmethanone) (562 mg, 2.23 mmol). The reaction mixture was then stirred at 80 °C for 18 h, then was cooled to rt and trated in vacuo. The crude oily product was chromatographed (24 g SiO2; elution with EtOAc/Hexane (continuous gradient from 0% to 50% over 10 min) to give the title compound (527 mg, 1.11 mmol, 100 % yield) as a clear oil.
[M + H] + = 474.2 218K. pyl (1S,3S)((5-(5-(hydroxymethyl)methyl-1H-1,2,3-triazolyl) methylpyrazinyl)oxy)cyclohexanecarboxylate A mixture of Example 218J (527 mg, 1.11 mmol) and pyridinium ptoluenesulfonate (28 mg, 0.11 mmol) in MeOH (10 mL) was stirred at rt for 3 days and then concentrated in vacuo. The crude oily product was chromatographed (24 g SiO2; elution with EtOAc/Hexane (continuous nt from 0% to 100% over 10 min) to give the title compound (277 mg, 0.711 mmol, 63.9 % yield) as a clear oil.
[M + H] + = 390.2; 1H NMR (500 MHz, CDCl 3) δ 8.89 (s, 1H), 5.54 (br s, 1H), 5.04 (dt, J=12.4, 6.3 Hz, 1H), 4.83 (s, 2H), 4.16 - 4.10 (m, 3H), 2.74 (tt, J=11.1, 3.9 Hz, 1H), 2.56 (s, 3H), 2.23 (br d, J=14.0 Hz, 1H), 2.01 (br dd, J=8.8, 4.1 Hz, 2H), 1.89 (ddd, J=13.9, 11.4, 2.8 Hz, 1H), 1.82 - 1.47 (m, 5H), 1.26 (dd, J=6.3, 2.8 Hz, 6H) 218L. Isopropyl (1S,3S)((3-methyl(1-methyl((((4- nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazolyl)pyrazinyl)oxy)cyclohexane- 1-carboxylate A solution of 4-nitrophenyl chloroformate (172 mg, 0.854 mmol) in DCM (1 mL) was added dropwise to a solution of Example 218K (277 mg, 0.711 mmol) and pyridine (0.288 mL, 3.56 mmol) in DCM (5 mL) over 1 h at 0oC. The reaction was then stirred at rt for 18 h, then was concentrated in vacuo. The crude oily product was chromatographed (12 g SiO2; elution with EtOAc/Hexane (continuous gradient from 0% to 50% over 10 min) to give the title compound (366 mg, 0.66 mmol, 93 % yield) as a light yellowish oil.
[M + H] + = 555.2; 1H NMR (500 MHz, CDCl3) δ 8.79 (s, 1H), 8.33 - 8.28 (m, 2H), 7.44 - 7.37 (m, 2H), 6.02 - 5.94 (m, 2H), 5.52 (br s, 1H), 5.03 (dt, J=12.6, 6.2 Hz, 1H), 4.23 (s, 3H), 2.74 (tt, J=11.1, 3.9 Hz, 1H), 2.52 (s, 3H), 2.22 (br d, J=14.0 Hz, 1H), 2.03 - 1.96 (m, 2H), 1.93 - 1.83 (m, 1H), 1.81 - 1.52 (m, 4H), 1.30 - 1.22 (m, 6H) e 218.
To a solution of Example 218L (8 mg, 0.014 mmol) in DCM (1 mL) was added N-methyl propanamine (1.8 µL; 0.017 mmol) and DIPEA (7.6 µL, 0.043 mmol). The reaction mixture was stirred at rt for 2 h, then was concentrated in vacuo. The crude oil was (4 g SiO2; elution with EtOAc/Hexane (continuous gradient from 0% to 30% over 10 min) to give the corresponding ate-isopropyl ester e as a clear oil. This ester intermediate was stirred with 1N aq. NaOH (0.2 mL) in THF (1 mL) and MeOH (0.2 mL) at rt for 18 h and then ied to pH = ~2 with TFA. The reaction mixture was purified by preparative HPLC (Sunfire C18 30 x 100 mm-regenerated column; detection at 220 nm; flow rate = 40 mL/min; continuous nt from 20% B to 100% B over 10 min + 2 min hold time at 100% B, where A = 90:10:0.1 H2O:MeCN:TFA and B = 90:10:0.1 MeCN:H2O:TFA) to give Example 218 (5 mg, 11.0 µmol, 76 % yield) as a clear oil.
[M + H] + = 447.3; 1H NMR (500 MHz, CDCl 3) δ 8.72 (s, 1H), 5.69 (br d, J=7.4 Hz, 2H), .53 (br s, 1H), 4.18 (s, 3H), 3.26 (br t, J=7.2 Hz, 1H), 3.13 (br t, J=7.2 Hz, 1H), 2.97 - 2.79 (m, 4H), 2.52 (s, 3H), 2.32 (br d, J=14.0 Hz, 1H), 2.16 - 1.99 (m, 2H), 1.93 - 1.37 (m, 7H), 0.98 - 0.71 (m, 3H). hLPA IC50 = 194 nM Example Structure & Name Analytical & Biology Data Method LCMS, [M + H] + = 461.4; 1H NMR (500 MHz, CDCl 3) Example δ 8.69 (s, 1H), 5.68 (br. s., 218 2H), 5.53 (br. s., 1H), 4.19 (s, 3H), 3.36 - 3.10 (m, 2H), 219 2.97 - 2.79 (m, 4H), 2.53 (s, 3H), 2.32 (d, J=14.0 Hz, 1H), 2.14 - 1.97 (m, 2H), (1S,3S)((5-(5-(((butyl 1.94 - 1.12 (m, 9H), 1.02 - (methyl)carbamoyl)oxy)methyl) 0.74 (m, 3H) methyl-1H-1,2,3-triazol yl) hLPA1 IC50 = 21 nM pyrazinyl)oxy) cyclohexanecarboxylic acid LCMS, [M+H]+ = 458.9. 1H NMR (500 MHz, Example DMSO-d6): δ 8.57 (s, 1H), 218 .54 (d, J = 19.1 Hz, 2H), .38 (s, 1H), 4.10 (s, 3H), 3.05 (br s, 1H), 2.93 (br s, 220 1H), 2.85 – 2.76 (m, 2H), 2.54 (s, 3H), 2.44 (s, 3H), (1S,3S)((5-(5-((((cyclopropyl- 2.41 – 2.12 (m, 8H). 0.40 )(methyl)carbamoyl) (br s, 1H), 0.24 (br s, 1H), oxy)methyl)methyl-1H-1,2,3- 0.16 (br s, 1H), -0.04 (br s, triazolyl)methyl- pyrazin 1H). yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 149 nM LCMS, [M+H]+ = 473.2. 1H NMR (500 MHz, Example CDCl3): δ 8.66 (s, 1H), 5.64 218 (br s, 2H), 5.51 (s, 1H), 4.17 (s, 3H), 3.31 (d, J = 7.5 Hz, 221 1H), 3.17 (d, J = 7.3 Hz, 1H), 2.91 – 2.77 (m, 4H), (1S,3S)((5-(5- 2.61 – 2.35 (m, 1H), 2.50 (s, ((((cyclobutylmethyl)(methyl)carba 3H), 2.29 (d, J = 14.1 Hz, moyl)oxy)methyl)methyl-1H- 1H), 2.10 – 1.50 (m, 13H). 1,2,3-triazolyl)methylpyrazin- hLPA1 IC50 = 23 nM 2-yl)oxy)cyclohexanecarboxylic Example Structure & Name Analytical & Biology Data Method LCMS; [M + H] + = 475.4; 1H NMR (500 MHz, Example DMSO-d6) δ 8.58 (br s, 1H), 218 .54 (br d, J=13.0 Hz, 2H), .38 (br s, 1H), 4.12 (br s, 222 3H), 3.18 (br d, J=9.2 Hz, 1H), 3.03 (br s, 1H), 2.80 - 2.58 (m, 4H), 2.44 (br s, (1S,3S)((5-(5-(((isopentyl 3H), 2.09 (br d, J=13.6 Hz, (methyl)carbamoyl)oxy)methyl) 1H), 1.94 - 1.03 (m, 10H), methyl-1H-1,2,3-triazolyl) 0.92 - 0.55 (m, 6H) methylpyrazinyl)oxy) hLPA1 IC50 = 19 nM cyclohexanecarboxylic acid LCMS; [M + H] + = 475.4; 1H NMR (500 MHz, Example DMSO-d6) δ 8.58 (s, 1H), 218 .54 (br d, J=15.9 Hz, 2H), .37 (br s, 1H), 4.11 (br s, 2H), 3.22 - 2.99 (m, 2H), 223 2.80 - 2.67 (m, 3H), 2.62 - 2.53 (m, 4H), 2.44 (s, 2H), 2.13 - 1.96 (m, 1H), 1.90 - (1S,3S)((3-methyl(1-methyl- 0.59 (m, 15H) -(((methyl(pentyl)carbamoyl) hLPA1 IC50 = 56 nM oxy)methyl)-1H-1,2,3-triazol yl)pyrazinyl)oxy)cyclohexane carboxylic acid LCMS; [M + H] + = 461.2; 1H NMR (500 MHz, Example CDCl3): δ 8.72 (s, 1H), 5.69 218 (br d, J=14.3 Hz, 2H), 5.53 (br s, 1H), 4.18 (s, 3H), 3.12 (br d, J=7.4 Hz, 1H), 3.03 - 224 2.77 (m, 6H), 2.53 (s, 3H), 2.32 (br d, J=14.0 Hz, 1H), 2.18 - 1.53 (m, 7H), 0.99 - )((5-(5- 0.74 (m, 6H) (((isobutyl(methyl)carbamoyl)oxy) hLPA1 IC50 = 121 nM methyl)methyl-1H-1,2,3-triazol- 3-methylpyrazinyl)oxy) cyclohexanecarboxylic acid Example Structure & Name Analytical & Biology Data Method LCMS; [M + H] + = 473.4; 1H NMR (500 MHz, Example 6) δ 8.57 (s, 1H), 218 .54 (br d, J=14.4 Hz, 2H), .38 (br s, 1H), 4.11 (br s, 3H), 3.29 - 3.07 (m, 2H), 225 2.82 - 2.70 (m, 3H), 2.57 (br d, J=11.3 Hz, 1H), 2.43 (s, 3H), 2.16 - 1.97 (m, 1H), (1S,3S)((5-(5-((((2- 1.93 - 1.01 (m, 9H), 0.70 - cyclopropylethyl)(methyl)carbamo 0.12 (m, 3H), 0.06 - -0.40 yl)oxy)methyl)methyl-1H-1,2,3- (m, 2H) triazolyl)methylpyrazinyl) hLPA1 IC50 = 70 nM oxy)cyclohexanecarboxylic acid LCMS; [M + H] + = 473.5; 1H NMR (500 MHz, Example DMSO-d6) δ 8.56 (s, 1H), 218 .53 (s, 2H), 5.38 (br s, 1H), 4.10 (s, 3H), 3.64 (br s, 1H), 2.62 (br s, 4H), 2.44 (s, 3H), 226 2.19 - 2.02 (m, 1H), 1.95 - 1.24 (m, 15H) hLPA1 IC50 = 49 nM (1S,3S)((5-(5- (((cyclopentyl(methyl)carbamoyl)o xy)methyl)methyl-1H-1,2,3- triazolyl)methylpyrazin yl)oxy)cyclohexanecarboxylic LCMS; [M + H] + = 487.5; 1H NMR (500 MHz, e DMSO-d6) δ 8.58 (s, 1H), 218 .61 - 5.48 (m, 2H), 5.40 (br s, 1H), 4.12 (br s, 3H), 3.20 - 2.91 (m, 2H), 2.84 - 2.69 227 (m, 3H), 2.64 (br s, 1H), 2.48 - 2.42 (m, 3H), 2.10 (br d, J=13.1 Hz, 1H), 1.96 - (1S,3S)((5-(5- 1.07 (m, 15H), 0.89 (br s, ((((cyclopentylmethyl)(methyl)carb amoyl)oxy)methyl)methyl-1H- hLPA1 IC50 = 18 nM 1,2,3-triazolyl)methylpyrazin- 2-yl)oxy)cyclohexanecarboxylic Example Structure & Name Analytical & Biology Data Method LCMS; [M + H] + = 495.3; 1H NMR (500 MHz, DMSO-d6) δ 8.56 (br s, 1H), 7.38 - 7.04 (m, 4H), 6.96 (br s, 1H), 5.68 - 5.47 (m, 2H), .37 (br s, 1H), 4.47 - 4.21 228 (m, 2H), 4.19 - 3.97 (m, 3H), 2.83 - 2.66 (m, 3H), 2.62 (br t, J=11.0 Hz, 1H), (1S,3S)((5-(5- 2.46 - 2.32 (m, 3H), 2.13 - (((benzyl(methyl)carbamoyl)oxy)m 2.04 (m, 1H), 1.95 - 1.40 ethyl)methyl-1H-1,2,3-triazol (m, 7H) yl)methylpyrazinyl)oxy) hLPA1 IC50 = 60 nM cyclohexanecarboxylic acid LCMS; [M + H] + = 459.0; 1H NMR (500 MHz, DMSO-d6) δ 8.58 - 8.57 (m, 1H), 5.54 (br s, 2H), 5.39 (br s, 1H), 4.10 (s, 4H), 2.82 - 2.57 (m, 4H), 2.47 - 2.39 229 (m, 3H), 2.18 - 1.31 (m, hLPA1 IC50 = 76 nM (1S,3S)((5-(5- (((cyclobutyl(methyl)carbamoyl)ox yl)methyl-1H-1,2,3- triazolyl)methylpyrazinyl) oxy)cyclohexanecarboxylic acid LCMS; [M + H] + = 465.4; 1H NMR (500 MHz, DMSO-d6) δ 8.58 (s, 1H), .56 (br s, 2H), 5.39 (br s, 1H), 4.54 - 4.17 (m, 2H), 4.11 (s, 3H), 3.39 - 3.14 (m, 230 2H), 2.89 - 2.69 (m, 3H), 2.64 (br t, J=10.8 Hz, 1H), 2.45 (s, 3H), 2.10 (br d, (1S,3S)((5-(5-((((3- J=13.7 Hz, 1H), 1.94 - 1.41 fluoropropyl)(methyl)carbamoyl)ox (m, 9H) y)methyl)methyl-1H-1,2,3- hLPA1 IC50 = 390 nM triazolyl)methylpyrazinyl) oxy)cyclohexanecarboxylic acid Example Structure & Name Analytical & Biology Data Method LCMS; [M + H] + = 475.2; 1H NMR (500 MHz, CHLOROFORM-d) δ 8.71 (s, 1H), 5.68 (br d, J=12.1 Hz, 2H), 5.54 (br s, 1H), 4.23 - 4.16 (m, 3H), 3.14 (s, 231 1H), 3.04 - 2.96 (m, 3H), 2.93 - 2.81 (m, 2H), 2.53 (s, 3H), 2.32 (br d, J=14.0 Hz, (1S,3S)((3-methyl(1-methyl- 1H), 2.16 - 1.97 (m, 2H), -(((methyl(neopentyl)carbamoyl) 1.94 - 1.84 (m, 1H), 1.83 - oxy)methyl)-1H-1,2,3-triazol 1.55 (m, 4H), 1.04 - 0.72 yl)pyrazinyl)oxy)cyclohexane (m, 9H) carboxylic acid hLPA1 IC50 = 88 nM LCMS; [M + H] + = 479.2; 1H NMR (500 MHz, CDCl3): δ 8.67 (s, 1H), 5.80 - 5.57 (m, 2H), 5.54 (br s, 1H), 4.26 - 4.16 (m, 3H), 3.57 - 3.27 (m, 2H), 3.10 - 232 2.77 (m, 4H), 2.59 - 2.46 (m, 3H), 2.32 (br d, J=13.8 Hz, 1H), 2.13 - 1.97 (m, (1S,3S)((5-(5-((((2-fluoro 2H), 1.95 - 1.53 (m, 5H), methylpropyl)(methyl)carbamoyl)o 1.42 - 1.13 (m, 6H); 19F xy)methyl)methyl-1H-1,2,3- NMR (471 MHz, CDCl3): δ triazolyl)methylpyrazinyl) -139.12 (s, 1F) clohexanecarboxylic acid hLPA1 IC50 = 191 nM LCMS; [M + H] + = 491.2; 1H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 5.69 (br d, J=5.1 Hz, 2H), 5.51 (br s, 1H), 4.16 (s, 3H), 3.72 - 3.34 (m, 2H), 3.04 - 2.75 233 (m, 4H), 2.49 (br d, J=4.6 Hz, 3H), 2.33 - 1.49 (m, (1S,3S)((5-(5-(((((1-fluoro- 14H); 19F NMR (377 MHz, utyl)methyl)(methyl)carbam CDCl3): δ -130.34 (br s, 1F) oyl)oxy)methyl)methyl-1H- hLPA1 IC50 = 122 nM 1,2,3-triazolyl)methylpyrazin- 2-yl)oxy)cyclohexanecarboxylic Example Structure & Name Analytical & Biology Data Method LCMS; [M + H] + = 505.2; 1H NMR (400 MHz, CDCl3): δ 8.64 (s, 1H), 5.71 - 5.61 (m, 2H), 5.52 (br s, 1H), 4.19 (s, 3H), 3.68 - 3.37 (m, 2H), 3.07 - 2.91 (m, 3H), 2.84 (tt, J=11.2, 234 3.7 Hz, 1H), 2.51 (d, J=3.5 (1S,3S)((5-(5-(((((1- Hz, 3H), 2.29 (br d, J=13.9 cyclopentyl)methyl)(methyl)c Hz, 1H), 2.12 - 1.96 (m, arbamoyl)oxy)methyl)methyl- 2H), 1.94 - 1.35 (m, 13H); 1H-1,2,3-triazolyl) 19F NMR (377 MHz, methylpyrazin : δ -139.45 to - yl)oxy)cyclohexanecarboxylic 147.94 (m, 1F) acid hLPA1 IC50 = 72 nM LCMS; [M + H] + = 473.0; 1H NMR (500 MHz, CDCl3): δ 8.72 (s, 1H), 5.82 - 5.56 (m, 2H), 5.53 (br s, 1H), 4.17 (s, 3H), 3.29 - 2.80 (m, 6H), 2.52 (s, 3H), 235 2.31 (br d, J=14.0 Hz, 1H), 2.14 - 1.97 (m, 2H), 1.91 - (1S,3S)((3-methyl(1-methyl- 1.54 (m, 5H), 1.10 - 0.90 -(((methyl(((1R,2R) (m, 3H), 0.75 - 0.11 (m, 4H) methylcyclopropyl)methyl)carbamo hLPA1 IC50 = 70 nM yl)oxy)methyl)-1H-1,2,3-triazol yl)pyrazinyl)oxy)cyclohexane carboxylic acid LCMS; [M + H] + = 473.0; 1H NMR (500 MHz, CDCl3): δ 8.72 (s, 5H), 5.69 (br d, J=6.9 Hz, 2H), 5.52 (br s, 1H), 4.17 (s, 3H), 3.28 - 2.80 (m, 6H), 2.58 - 2.46 236 (m, 3H), 2.31 (br d, J=13.8 Hz, 1H), 2.12 - 1.97 (m, (1S,3S)((3-methyl(1-methyl- 2H), 1.93 - 1.54 (m, 5H), -(((methyl(((1S,2S)methyl 1.10 - 0.89 (m, 3H), 0.74 - cyclopropyl)methyl)carbamoyl)oxy 0.11 (m, 4H) )methyl)-1H-1,2,3-triazol hLPA1 IC50 = 46 nM yl)pyrazinyl)oxy)cyclohexane carboxylic acid Example 237. (1S,3S)((5-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)(trifluoromethyl)pyridinyl)oxy)cyclohexanecarboxylic acid 237A. Isopropyl (1S,3S)((5-bromo(trifluoromethyl)pyridinyl)oxy)cyclohexane- 1-carboxylate To a shed, 50 mL round bottom flask was added (E)-diazene-1,2-diylbis (piperidinylmethanone) (2.11 g, 8.35 mmol), toluene (15 mL) and n-Bu3P (2.1 mL, 8.35 mmol); the dark orange solution became a light yellow solution after the addition of . The solution was stirred at rt for 30 min, then 5-bromo (trifluoromethyl)pyridinol (1.01 g, 4.17 mmol) and (1S,3R)-isopropyl 3- hydroxycyclohexanecarboxylate (1.40 g, 7.51 mmol) were successively added. The reaction mixture was heated to 80 °C for 16 h, then was cooled to rt. EtOAc (10 mL) and water (5 mL) were added, and the mixture was d for 10 min and the organic layer was separated. The aqueous layer was back-extracted with EtOAc (2 x 10 mL). The combined organic ts were washed with brine (10 mL), dried (MgSO4), and concentrated in vacuo to give the crude product. This crude material was chromatographed (SiO2, 120g; elution with EtOAc/hexanes (continuous gradient from 0 to 100%) to afford the title compound (1.7 g, 4.14 mmol, 99 % yield) as a colorless oil. 1H NMR (500 MHz, CDCl 3): δ 8.32 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 2.5 Hz, 1H), 5.52 (br s, 1H), 5.06 – 4.94 (m, 1H), 2.69 (tt, J = 11.6, 3.9 Hz, 1H), 2.23 – 2.17 (m, 1H), 2.03 – 1.93 (m, 2H), 1.82 – 1.43 (m, 5H), 1.22 (d, J = 6.3 Hz, 6H ). LCMS, [M+H]+ = 410. 237B. Isopropyl (1S,3S)((5-(3-hydroxypropynyl)(trifluoromethyl)pyridin )cyclohexanecarboxylate To a 100 mL round bottom flask containing Example 237A (1.7 g, 4.1 mmol) and propynol (0.70 g, 12.4 mmol) in MeCN (21 ml) was added Et3N (2.89 mL, 20.7 mmol). The solution was quickly degassed (evacuation under vacuum, then refill with N2 (3x)). Trans-dichlorobis (triphenylphosphine) palladium (II) chloride (0.29 g, 0.41 mmol) and CuI (0.039 g, 0.21 mmol) were added. The solution degassed (evacuation under vacuum, then refill with N2 (3x)). The reaction was heated to reflux at 80 °C for 24 h, then was cooled to rt. The reaction mixture was filtered through a Celite® plug, which was washed with EtOAc (2 x 10 mL). The combined filtrates were trated in vacuo and the e was chromatographed (40 g SiO2; continuous gradient from 0% to 100% EtOAc in Hexanes for 20 min) to give the title compound as a white solid (1.13 g, 2.93 mmol, 71 % yield). 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 2.5 Hz, 1H), 5.58 (br s, 1H), 5.06 - 4.97 (m, 1H), 4.50 (d, J = 6.2 Hz, 2H), 2.70 (tt, J = 11.6, 3.9 Hz, 1H), 2.24 – 2.17 (m, 1H), 2.03 – 1.93 (m, 2H), 1.82 – 1.43 (m, 5H), 1.22 (d, J = 6.3 Hz, 6H ). LCMS, [M+H]+ = 386.2. 237C. Isopropyl (1S,3S)((5-(5-(hydroxymethyl)methyl-1H-1,2,3-triazolyl) (trifluoromethyl)pyridinyl)oxy)cyclohexanecarboxylate To a solution of Example 237B (1.13 g, 2.9 mmol) in 1,4-dioxane (20 mL) was added TMSCH2N3 (0.68 g, 5.3 mmol), chloro(pentamethylcyclopentadienyl)bis(triphenyl- phosphine)Ruthenium(II) (0.12 g, 0.15 mmol), and CuI (0.028 g, 0.15 mmol). The mixture was quickly ted and backfilled with N2 (this sequence was ed three times). The ing homogenous e was then heated in a 50°C oil bath for 16 h (when the external and internal temp. are between 49 to 50°C), then was cooled to rt and concentrated on a rotary evaporator to dryness (the waste trap content was collected, labeled as containing hazardous waste and disposed accordingly). The resid ue was dissolved in THF (20 mL). TBAF (5.86 mL of a 1 M solution in THF, 5.86 mmol) was added and the e was stirred at rt for 60 min. The reaction was quenched with sat’d aq. NaHCO3 (20 mL) and extracted with EtOAc (4 x 20 mL). The combined c extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude was chromatographed (continuous gradient from 0% to 70% EtOAc/hexanes over 27 min, then gradient from 70 to 100% in 8 min; 80 g Gold ISCO SiO2 column) and then preparative HPLC under the following conditions: Column: Phenomenex Luna 5u C18 100A 30 x 250 mm; Mobile Phase A: 10:90 MeCN:H2O with 0.1% TFA; Mobile Phase B: 90:10 MeCN:H2O with 0.1% TFA; Gradient: 0-100% B over 20 min, then a 5-min hold at 100% B; Flow: mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (0.50 g, 1.13 mmol, 38.5 % yield) (the later eluting fraction). 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 2.5 Hz, 1H), 8.25 (d, J = 2.5 Hz, 1H), 5.62 (br s, 1H), 5.06 – 4.99 (m, 1H), 4.86 (s, 2H), 4.18 (s, 3H), 2.73 (tt, J = 11.5, 3.8 Hz, 1H), 2.28 – 2.22 (m, 1H), 2.05 – 1.98 (m, 2H), 1.85 – 1.45 (m, 5H), 1.22 (d, J = 6.2 Hz, 6H). The regiochemistry of this desired product was determined by 1D-NoE NMR experiments. LCMS, [M+H]+ = 443.2. 237D. Isopropyl (1S,3S)((5-(1-methyl((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H- triazolyl)(trifluoromethyl)pyridinyl)oxy)cyclohexanecarboxylate To a on of Example 237C (116 mg, 0.26 mmol) and 4-nitrophenyl chloroformate (106 mg, 0.52 mmol) in DCM (3 mL) was added pyridine (0.085 mL, 1.05 mmol) at rt. A white solid was formed. The reaction mixture was stirred at rt for 16 h, after which the solid was filtered off and washed with DCM. The combined filtrate and washes were evaporated in vacuo. The crude product was chromatographed (12 g SiO2, elution with continuous nt from 0 to 100% EtOAc in DCM) to give the title compound (114 mg, 0.19 mmol, 71.6 % yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J = 2.2 Hz, 1H), 8.35 (d, J = 2.1 Hz, 1H), 8.31 (d, J = 9.1 Hz, 2H), 7.40 (d, J = 9.1 Hz, 2H), 5.64 (br s, 1H), 5.45 (s, 2H), 5.06 – 4.99 (m, 1H), 4.25 (s, 3H), 2.74 (t, J = 11.7 Hz, 1H), 2.29 – 2.22 (m, 1H), 2.05 – 1.98 (m, 2H), 1.86 – 1.45 (m, 5H), 1.22 (d, J = 6.2 Hz, 6H). LCMS, [M+H]+ = 608.3.
Example 237 To a solution of Example 237D (5.4 mg, 8.9 µmol) and 1-cyclopropyl-N- methylmethanamine (2.0 µL, 0.018 mmol) in THF (0.4 mL) was added N-ethyl-N- isopropyl-propanamine (5 µL, 0.027 mmol). The mixture was stirred at rt for 1 h, after which a solution of LiOH.H2O (3.7 mg, 0.088 mmol) in water (0.4 mL) and MeOH (0.2 mL) was added. The reaction mixture was stirred at rt for 48 h, then was ied to pH = 4 with 1N aq. HCl and extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified via preparative LC/MS with the ing conditions: Column: XBridge C18, 19 x 200 mm, 5-μm particles; Mobile Phase A: 5:95 MeCN: H2O with 10 mM NH4OAc; Mobile Phase B: 95:5 MeCN:H2O with 10 mM NH4OAc; Continuous gradient: 20-60% B over min, then a 4-min hold at 100% B; Flow: 20 mL/min. ons containing the desired product were ed and dried via centrifugal evaporation to afford the title compound (2.4 mg, 51% yield).
The following compounds were prepared by the general synthetic scheme for Example 237.
Analytical & Biology Method Example Structure & Name LCMS, [M + H]+ = 512.0. 1H NMR (500 Example MHz, DMSO-d6)  8.75 237 (s, 1H), 8.32 (s, 1H), 5.55 (br s, 1H), 5.33 (s, 2H), 4.12 (s, 3H), 2.71 (s, 3H), 237 2.66 – 2.58 (m, 1H), 2.54 (s, 2H), 2.41 – 2.12 (m, (1S,3S)((5-(5- 9H). 0.41 (br s, 1H), 0.25 ((((cyclopropylmethyl)(methyl)carba (br s, 1H), 0.18 (br s, moyl)oxy)methyl)methyl-1H-1,2,3- 1H), -0.01 (br s, 1H). triazolyl) hLPA1 IC50 = 2400 nM (trifluoromethyl)pyridin yl)oxy)cyclohexanecarboxylic acid LCMS, [M + H]+ = 526.0. 1H NMR (500 MHz, DMSO-d6)  8.56 (s, 1H), 8.12 (s, 1H), 5.32 (br s, 1H), 5.15 (s, 1H), .11 (s, 1H), 3.91 (s, 3H), 238 3.0 – 2.85 m, 3H), 2.50 (s, 3H), 1.88 – 1.13 (m, 15H). (1S,3S)((5-(5- hLPA1 IC50 = 174 nM (((cyclopentyl(methyl)carbamoyl)oxy) methyl)methyl-1H-1,2,3-triazol yl)(trifluoromethyl)pyridin yl)oxy)cyclohexanecarboxylic acid Analytical & Biology Method Example Structure & Name LCMS, [M + H]+ = 512.5. 1H NMR (500M Hz, DMSO-d6)  8.76 (s, 1H), 8.34 (s, 1H), 5.55 (br s, 1H), 5.33 (s, 2H), 4.12 (s, 3H), 2.71 (s, 3H), 239 2.54 (s, 2H), 2.12 – 1.36 (m, 14H). hLPA1 IC50 = 440 nM (1S,3S)((5-(5- ((((cyclobutylmethyl)(methyl)carbamo yl)oxy)methyl)methyl-1H-1,2,3- triazolyl) (trifluoromethyl)pyridin yl)oxy)cyclohexanecarboxylic acid LCMS, [M + H]+ = 526.0. 1H NMR (500 MHz, DMSO-d6)  8.79 (s, 1H), 8.36 (s, 1H), 5.57 (br s, 1H), 5.37 (br s, 240 2H), 4.14 (s, 3H), 2.64 (s, 3H), 2.59 – 2.52 (m, 2H), 2.15 – 1.32 (m, 16H). (1S,3S)((5-(5- hLPA1 IC50 = 1207 nM lobutyl(methyl)carbamoyl)oxy) methyl)methyl-1H-1,2,3-triazol (trifluoromethyl)pyridin yl)oxy)cyclohexanecarboxylic acid Example 241 (1S,3S)((6-(5-(2-(((Cyclobutylmethyl)(methyl)carbamoyl)oxy)ethyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid 241A. Methyl (1S,3S)((6-(5-formylmethyl-1H-1,2,3-triazolyl)methylpyridin- 3-yl)oxy)cyclohexanecarboxylate To a d solution of methyl (1S,3S)((6-(5-(hydroxymethyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylate (3.28 g, 9.10 mmol) in CH2Cl2 (45.5 ml) were added NaHCO3 (3.82 g, 45.5 mmol) and Dess-Martin periodinane (4.63 g, 10.9 mmol) and the reaction mixture was stirred at rt for 1 h. The white solid was filtered off through Celite® and rinsed with EtOAc. The combined filtrates were washed with sat. aq. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was chromatographed (120 g Redisep® SiO2 column; isocratic 60% EtOAc in Hex) to afford the title compound as a clear, colorless oil (3.10 g, 95 %). LC-MS, [M+H]+ = 359.1. 1H NMR (500 MHz, CDCl 3) δ 10.96 (s, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 4.77 - 4.72 (m, 1H), 4.36 (s, 3H), 3.70 (s, 3H), 2.87 - 2.80 (m, 1H), 2.51 (s, 3H), 2.20 - 2.08 (m, 1H), 2.02 - 1.91 (m, 3H), 1.80 - 1.59 (m, 4H). 241B Methyl (1S,3S)((2-methyl(1-methylvinyl-1H-1,2,3-triazolyl)pyridin yl)oxy)cyclohexanecarboxylate To a cooled (0°C) suspension of triphenylphosphonium bromide (3.77 g, 10.55 mmol) in THF (70.3 mL) was added KOtBu (0.947 g, 8.44 mmol), and the reaction mixture was stirred at 0°C for 30 min. To this reaction mixture was added a solution of Example 241A (2.52 g, 7.03 mmol) in THF (10 mL). The reaction was stirred at 0°C for min, then was allowed to warm to rt. After 1 h at rt, the reaction was quenched with sat. aq. NH4Cl, then was diluted with EtOAc. The aqueous layer was extracted with EtOAc (2 X 25 mL). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude t was chromatographed (220 g Redisep® SiO2 column; continuous gradient from 0-60% EtOAc in Hex) to afford the title compound as a white gum (2.2 g, 88 %). LC-MS, [M+H]+ = 357.0. 1H NMR (500 MHz, CDCl3) δ 7.91 (d, J=8.5 Hz, 1H), 7.42 (dd, J=18.3, 12.0 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 5.93 - 5.88 (m, 1H), 5.70 - 5.66 (m, 1H), 4.71 (br s, 1H), 4.15 (s, 3H), 3.70 (s, 3H), 2.84 (tt, J=10.5, 3.9 Hz, 1H), 2.53 (s, 3H), 2.16 (br d, J=13.8 Hz, 1H), 2.02 - 1.87 (m, 3H), 1.87 - 1.71 (m, 1H), 1.71 - 1.54 (m, 3H). 241C Methyl (1S,3S)((6-(5-(2-hydroxyethyl)methyl-1H-1,2,3-triazolyl) methylpyridinyl)oxy)cyclohexanecarboxylate To a cooled (0 °C) solution of Example 241B (1.45 g, 4.07 mmol) in THF (13.6 ml) was added dropwise 9-BBN (17.9 mL of a 0.5M solution in THF; 8.95 mmol). The ice bath was then removed and the reaction was warmed to 65 oC. After 4 h at 65 oC, the on mixture was cooled to 0 °C and a solution of sodium perborate ydrate (2.50 g, 16.3 mmol) in water (10 mL) was added. The reaction was then warmed to rt and stirred at rt for 18 h; water was then added. The s layer was extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed (120 g Redisep® SiO2 column; continuous gradient from 0-100% EtOAc in Hex) to afford the title compound as a colorless oil (0.37 g, 24 %). LC-MS, [M+H]+ = 375.1. 1H NMR (400 MHz, CDCl 7.92 (d, J=8.6 Hz, 1H), 7.30 - 7.25 (m, 1H), 6.71 - 6.42 (m, 1H), 4.74 - 4.68 (m, 1H), 4.06 - 3.98 (m, 5H), 3.70 (s, 3H), 3.26 (td, J=5.6, 1.4 Hz, 2H), 2.83 (tt, , 3.9 Hz, 1H), 2.51 (s, 3H), 2.14 (dt, J=13.9, 4.3 Hz, 1H), 2.02 - 1.87 (m, 3H), 1.82 - 1.56 (m, 4H). 241D. Methyl (1S,3S)((2-methyl(1-methyl(2-(((4- henoxy)carbonyl)oxy)ethyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane carboxylate To a solution of Example 241C (370 mg, 0.988 mmol) and 4-nitrophenyl chloroformate (299 mg, 1.48 mmol) in THF (9.9 mL) was added pyridine (0.24 mL, 2.96 mmol). The reaction mixture was stirred at rt for 3 h, then was concentrated in vacuo.
The crude product was tographed (120 g Redisep® SiO2 column; continuous gradient from 0-100% EtOAc in Hex) to afford the title compound as a white solid (387 mg, 72.6 %). LC-MS, [M+H]+ = 540.1. 1H NMR (500 MHz, CDCl 3) δ 8.30 (d, J=9.4 Hz, 2H), 8.03 (d, J=8.5 Hz, 1H), 7.34 (d, J=9.4 Hz, 2H), 7.24 (d, J=8.5 Hz, 1H), 4.75 - 4.69 (m, 3H), 4.14 (s, 3H), 3.72 (s, 3H), 3.66 (t, J=6.3 Hz, 2H), 2.89 - 2.83 (m, 1H), 2.50 (s, 3H), 2.17 (br d, J=14.0 Hz, 1H), 2.04 - 1.89 (m, 3H), 1.87 - 1.72 (m, 1H), 1.70 - 1.59 (m, 3H). e 241 To a solution of Example 241D (11 mg, 0.020 mmol) and iPr2NEt (7.1 µl, 0.041 mmol) in THF (1 mL) was added 1-cyclobutyl-N-methylmethanamine (2.0 mg, 0.020 mmol). The reaction was stirred at rt for 1 h. Water (0.5 mL) was added, followed by aq.
LiOH.H2O (0.05 mL of a 2N solution, 0.10 mmol). The reaction was stirred at rt for 18 h, then was acidified with 1N aq. HCl to pH ~4 and extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude material was purified by preparative HPLC (Column: XBridge C18, 19 x 200 mm, 5-μm particles; Mobile Phase A: 5:95 MeCN: water with 10 mM NH4OAc; Mobile Phase B: 95:5 MeCN: water with 10 mM NH4OAc; continuous gradient: 15-55% B over 25 min, then a 4-min hold at 100% B; Flow: 20 mL/min). Fractions containing the d product were combined and dried via centrifugal evaporation to afford the title compound (5.7 mg, 58.7 %). LC-MS, [M+H]+ = 486.0. 1H NMR (500 MHz, DMSO-d δ 7.84 (br s, 1H), 7.48 (br d, J=8.5 Hz, 1H), 4.76 (br s, 1H), 4.30 (br s, 2H), 4.02 (s, 3H), 3.53 (br s, 2H), 3.21 - 3.11 (m, 1H), 3.03 - 2.93 (m, 1H), 2.71 (br s, 3H), 2.63 – 2.56 (m, 1H), 2.42 (s, 3H), 2.33 – 2.24 (m, 1H), 2.02 - 1.37 (m, 14H). hLPA1 IC50 = 41 nM.
The following examples were prepared according to the synthetic scheme bed for Example 241.
Analytical & Biology Method Example ure & Name LC-MS, [M+H]+ = 460.2 1H NMR (500 MHz, Example DMSO-d6) δ 7.83 (d, 241 J=8.5 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 4.78 (br s, 1H), 4.30 (br s, 2H), 4.03 242 (s, 3H), 3.56- 3.46 (m, 2H), 3.11 - 2.85 (m, 2H), 2.76 - 2.61 (m, 4H), 2.43 (1S,3S)((2-Methyl(1-methyl (s, 3H), 2.06 – 1.99 (m, (2-((methyl(propyl)carbamoyl)oxy)- 1H), 1.92 - 1.74 (m, 3H), ethyl)-1H-1,2,3-triazolyl)pyridin 1.69 - 1.20 (m, 6H), 0.86 yl)oxy)cyclohexanecarboxylic acid, - 0.57 (m, 3H).
TFA salt hLPA1 IC50 = 319 nM Analytical & Biology Method Example Structure & Name Example LC-MS, [M+H]+ = 486.0 1H NMR (500 MHz, 241 DMSO-d6) δ 7.83 (d, J=8.5 Hz, 1H), 7.46 (br d, J=8.7 Hz, 1H), 4.73 (br s, 1H), 4.32 (br t, J=6.1 Hz, 2H), 4.23 - 4.11 (m, 1H), 4.01 (s, 3H), 3.53 (br t, J=6.0 Hz, (1S,3S)((6-(5-(2-((Cyclopentyl- 2H), 2.60 - 2.55 (m, 4H), (methyl)carbamoyl)oxy)ethyl) 2.42 (s, 3H), 1.99 - 1.22 methyl-1H-1,2,3-triazolyl) (m, 16H). methylpyridinyl)oxy)cyclohexanehLPA1 IC50 = 72 nM. 1-carboxylic acid LC-MS, [M+H]+ = 508.0 1H NMR (500 MHz, e DMSO-d6) δ 7.82 (br d, 241 J=8.2 Hz, 1H), 7.48 (br d, J=4.9 Hz, 1H), 7.36 - 7.24 (m, 3H), 7.15 (br d, J=5.2 Hz, 1H), 7.04 (br s, 1H), 4.74 (br s, 1H), 4.43 - 4.30 (m, 3H), 4.17 (br s, 1H), 4.05 - 3.92 (m, 3H), (1S,3S)((6-(5-(2-((Benzyl(methyl)- 3.56 - 3.49 (m, 2H), 2.71 oyl)oxy)ethyl)methyl-1H- (s, 3H), 2.60 – 2.54 (m, 1,2,3-triazolyl)methylpyridin 1H), 2.44 – 2.36 (m, 3H), yl)oxy)cyclohexanecarboxylic acid 1.98 - 1.48 (m, 8H). hLPA1 IC50 = 54 nM.
LC-MS, [M+H]+ = 474.2 Example 1H NMR (500 MHz, 241 DMSO-d6) δ 7.83 (br d, J=8.5 Hz, 1H), 7.46 (br d, J=8.6 Hz, 1H), 4.75 245 (br s, 1H), 4.31 (br s, 2H), 4.02 (s, 3H), 3.56 - 3.47 (m, 2H), 2.93 - 2.55 (1S,3S)((6-(5-(2-((Isobutyl- (m, 7H), 2.43 (s, 3H), (methyl)carbamoyl)oxy)ethyl) 2.04 - 1.48 (m, 8H), 0.71 methyl-1H-1,2,3-triazolyl) (br d, J=10.8 Hz, 6H). methylpyridinyl)oxy)cyclohexane- hLPA1 IC50 = 69 nM. 1-carboxylic acid ical & Biology Method Example Structure & Name LC-MS, [M+H]+ = 458.3 Example 1H NMR (500 MHz, DMSO-d6) δ 7.84 (br s, 1H), 7.45 (br d, J=8.6 Hz, 1H), 4.75 (br s, 1H), 4.31 (t, J=6.1 Hz, 2H), 4.03 (s, 3H), 3.51 (br t, J=6.0 Hz, 2H), 3.21 – 2.62 (m, 5H), 2.42 (br s, (1S,3S)((2-Methyl(1-methyl 3H), 2.08 - 1.95 (m, 1H), (2-((pyrrolidinecarbonyl)oxy)- 1.91 - 1.74 (m, 3H), 1.72 ethyl)-1H-1,2,3-triazolyl)pyridin - 1.50 (m, 8H). yl)oxy)cyclohexanecarboxylic acid, hLPA1 IC50 = 210 nM.
TFA salt LC-MS, [M+H]+ = 472.1 Example 1H NMR (500 MHz, 241 6) δ 7.83 (d, J=8.5 Hz, 1H), 7.44 (d, J=8.6 Hz, 1H), 4.75 (br s, 1H), 4.31 (br t, J=6.2 Hz, 2H), 4.02 (s, 3H), 3.52 (br t, J=5.7 Hz, 2H), 3.24 – 3.15 (m, 1H), 2.68 - (1S,3S)((6-(5-(2- 2.56 (m, 4H), 2.43 (s, ((Cyclobutyl(methyl)carbamoyl)oxy)e 3H), 2.08 - 1.38 (m, thyl)methyl-1H-1,2,3-triazolyl)- 14H). 2-methylpyridinyl)oxy)cyclo- hLPA1 IC50 = 41 nM. hexanecarboxylic acid, TFA salt Example LC-MS, [M+H]+ = 472.1 241 1H NMR (500 MHz, DMSO-d6) δ 7.49 (br s, 1H), 7.01 (br s, 1H), 4.75 (br s, 1H), 4.29 (br s, 2H), 4.02 (s, 3H), 3.54 - 3.24 (m, 2H), 3.00 - 2.94 (m, 2H), 2.71 - 2.63 (m, (1S,3S)((6-(5-(2-(((Cyclobutyl- 2H), 2.35 (br s, 3H), 2.09 methyl)carbamoyl)oxy)ethyl) - 1.45 (m, 14H). methyl-1H-1,2,3-triazolyl) hLPA1 IC50 = 144 nM. methylpyridinyl)oxy)cyclohexane- 1-carboxylic acid, TFA salt Example 249 (1S,3S)((6-(5-(3-((Benzyl(methyl)carbamoyl)oxy)propyl)methyl-1H-1,2,3-triazol yl)methylpyridinyl)oxy)cyclohexanecarboxylic acid 249A (2-(Benzyloxy)ethyl)triphenylphosphonium bromide Benzyl 2-bromoethyl ether (0.78 mL, 4.96 mmol) was added to a solution of Ph3P (1 g, 3.81 mmol) in toluene (7.63 mL) and the reaction was stirred at 105 °C for 18 h, then was cooled to rt. Diethyl ether (50 mL) was added, and the mixture was stirred for 15 min at rt; the itated product was collected by filtration, rinsed with ether and air-dried to afford the title product (1.46 g, 80 %) as a white solid. LC-MS, [M]+ = 397.1. 1H NMR (500 MHz, CDCl3) δ 7.87 - 7.73 (m, 9H), 7.63 (td, J=7.8, 3.3 Hz, 6H), 7.27 - 7.19 (m, 3H), 6.92 (d, J=6.6 Hz, 2H), 4.36 (dt, J=11.7, 5.7 Hz, 2H), 4.27 (s, 2H), 4.11 - 4.01 (m, 2H). 249B. Methyl )((6-(5-(3-(benzyloxy)propenyl)methyl-1H-1,2,3-triazol- 4-yl)methylpyridinyl)oxy)cyclohexanecarboxylate In a sealed tube was placed Example 249A (0.116 g, 0.243 mmol), Example 241A (0.058 g, 0.162 mmol), K2CO3 (0.067 g, 0.485 mmol), and THF (1.6 mL). The reaction was d at 115 °C for 2 h, then was cooled to rt. The mixture was diluted with EtOAc, washed with brine, dried (MgSO4), and concentrated in vacuo. The crude product was chromatographed (12 g Redisep® SiO2 column, eluting with 0-100% EtOAc in Hex) to afford the title compound as a yellow solid (35 mg, 45 %) as a mixture of cis/trans isomers. 249C Methyl (1S,3S)((6-(5-(3-(benzyloxy)propyl)methyl-1H-1,2,3-triazolyl) methyl pyridineyl)oxy)cyclohexanecarboxylate.
To a solution of Example 249B (35 mg, 0.073 mmol) in MeOH (20 mL) under Ar was added 20% Pd(OH)2 on carbon (10.31 mg, 0.015 mmol) and ammonium formate (93 mg, 1.47 mmol). The reaction mixture was stirred in a sealed tube at 65 °C for 18 h, then was cooled to rt. The on was filtered through a pad of Celite®, rinsed with MeOH, and the filtrate was concentrated in vacuo. The crude material was purified by ative HPLC using the ing conditions: Column: Sunfire Prep C18 OBD 5um 30 x 100mm; Mobile Phase A: 10:90 MeCN: water with 0.1% TFA; Mobile Phase B: 90:10 MeCN: water with 0.1% TFA; Gradient: 20-100% B over 12 min; Flow: 40 mL/min. Fractions containing the d product were combined and dried via centrifugal evaporation to afford the title compound (40 mg, 92 %) as a yellow solid. LC-MS, [M+H]+ = 479.3. 249D. Methyl (1S,3S)((6-(5-(3-hydroxypropyl)methyl-1H-1,2,3-triazolyl) methyl-pyridinyl)oxy)cyclohexanecarboxylate.
To a solution of e 249C (40 mg, 0.067 mmol) in EtOH (2 mL) and AcOH (1 mL) was added 10% Pd/C (7.2 mg, 6.8 µmol), and H2 gas was bubbled through the reaction mixture for a few minutes; the reaction was then stirred under H2-balloon for 72 h. The on mixture was filtered through a pad of Celite®, rinsed with MeOH, and the combined te/rinses were concentrated in vacuo. The crude material was purified by preparative HPLC using the following conditions: Column: Sunfire Prep C18 OBD 5u 30 x 100mm; Mobile Phase A: 10:90 MeCN: water with 0.1% TFA; Mobile Phase B: 90:10 MeCN: water with 0.1% TFA; Gradient: 20-100% B over 12 min; Flow: 40 mL/min.
Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound 246D (23 mg, 68 %) as a colorless solid. LC-MS, [M+H]+ = 389.2. 1H NMR (500 MHz, CD 3OD) δ 8.10 - 7.98 (m, 2H), 5.02 - 4.96 (m, 1H), 4.15 (s, 3H), 3.71 (s, 3H), 3.62 (br t, J=5.6 Hz, 2H), 3.18 (br t, J=7.2 Hz, 2H), 2.91 - 2.83 (m, 1H), 2.71 (s, 3H), 2.20 - 2.10 (m, 1H), 2.07 - 1.90 (m, 5H), 1.85 - 1.65 (m, 4H). 249E Methyl (1S,3S)((2-methyl(1-methyl(3-(((4- nitrophenoxy)carbonyl)oxy)propyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane- 1-carboxylate To a solution of e 249D (21 mg, 0.042 mmol) and 4-nitrophenyl chloroformate (12.6 mg, 0.063 mmol) in THF (1 mL) was added pyridine (10 µl, 0.13 mmol). The reaction was stirred at rt for 18 h, then was concentrated in vacuo. The crude product was chromatographed (4 g Redisep® SiO2 column, g with 0-100% EtOAc in Hex) to afford the title compound (10 mg, 43 %) as a white solid. LC-MS, [M+H]+ = 554.2.
Example 249 To a solution of Example 249E (10 mg, 0.018 mmol) and DIEA (6.31 µl, 0.036 mmol) in THF (1 mL) was added N-methylphenylmethanamine (2.2 mg, 0.018 mmol).
After 1 h, water (0.5 mL) was added, followed by aq. LiOH (0.070 mL of a 2M solution, 0.139 mmol). The reaction mixture was stirred at rt for 18 h, after which the pH was adjusted with 1N aq. HCl to ~4 and the mixture was extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude material was purified by preparative HPLC using the following conditions: Column: Sunfire Prep C18 OBD 5u 30 x 100mm; Mobile Phase A: 10:90 MeCN: water with 0.1% TFA; Mobile Phase B: 90:10 MeCN: water with 0.1% TFA; nt: % B over 12 min; Flow: 40 mL/min. Fractions containing the desired product were combined and dried via centrifugal ation, then re-purified by preparative HPLC using the following conditions: Column: Sunfire Prep C18 OBD 5u 30 x 100mm; Mobile Phase A: 10:90 MeOH: water with 0.1% TFA; Mobile Phase B: 90:10 MeOH: water with 0.1% TFA; Gradient: 20-100% B over 12 min; Flow: 40 mL/min.
Fractions containing the d product were combined and dried via centrifugal evaporation to afford the title compound (2.1 mg, 18 %) as a white solid. LC-MS, [M+H]+ = 522.3. 1H NMR (400 MHz, 60 oC, CD 3OD) δ 7.65 (br d, J=8.4 Hz, 1H), 7.32 (br d, J=8.8 Hz, 1H), 7.23 - 7.05 (m, 5H), 4.69 - 4.61 (m, 1H), 4.30 (s, 2H), 4.09 (t, J=5.6 Hz, 2H), 3.90 (br s, 3H), 3.16 - 3.08 (m, 2H), 2.75 - 2.63 (m, 4H), 2.39 (s, 3H), 2.04 - 1.89 (m, 3H), 1.89 - 1.75 (m, 3H), 1.72 - 1.49 (m, 4H). hLPA1 IC50 = 122 nM. sis of amine intermediate for the preparation of Example 250: Intermediate 5. N-methylpropoxyethanamine Intermediate 5A. yl-N-methylpropoxyethanamine To a solution of 2-(benzyl(methyl)amino)ethanol (1 mL, 6.15 mmol) in dry DMF (5 mL) was added 60% NaH in mineral oil (0.369 g, 9.23 mmol) at 0 °C. After 1 h, 1-chloropropane (0.813 mL, 9.23 mmol) was added. The reaction mixture was stirred overnight at rt, then was quenched with ice water and extracted with EtOAc. The organic phase was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The crude oily t was chromatographed (24 g SiO2; elution with EtOAc/ Hexane (continuous gradient from 0% to 100% over 10 min)) to give the free amine as an oil.
This oil was treated with 2.0 M HCl in ether to give N-benzyl-N-methyl propoxyethanamine HCl salt (1.2 g, 4.92 mmol, 80 % yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.67 - 7.61 (m, 2H), 7.47 - 7.43 (m, 3H), 4.34 - 4.20 (m, 2H), 4.04 - 3.93 (m, 2H), 3.46 (t, J=6.6 Hz, 2H), 3.34 - 3.27 (m, 1H), 3.14 - 3.06 (m, 1H), 2.74 (d, J=5.1 Hz, 3H), 1.65 - 1.59 (m, 2H), 0.93 (t, J=7.4 Hz, 3H) Intermediate 5 A mixture of Intermediate 5A (1.2 g, 4.92 mmol) and 20% Pd(OH)2-C (0.346 g, 2.461 mmol) in EtOH (5 mL) was stirred at 60 oC under 1 atmosphere H 2 for 2 h, then was filtered and concentrated in vacuo to provide the title intermediate as the HCl salt (0.72 g, 4.69 mmol, 95 % yield) as a white solid. 1H NMR (500 MHz, CDCl 3) δ 9.41 (br s, 2H), 3.81 (t, J=4.8 Hz, 2H), 3.44 (t, J=6.6 Hz, 2H), 3.24 - 3.11 (m, 2H), 2.77 (br t, J=5.0 Hz, 3H), 1.60 (sxt, J=7.1 Hz, 2H), 0.90 (t, J=7.4 Hz, 3H). sis of amine ediate 6 for Examples 254 & 255: Intermediate 6. 2-fluoro-N-methylbutanamine Intermediate 6A. 1-(benzyl(methyl)amino)butanol A on of N-methylphenylmethanamine (6.09 mL, 46.4 mmol) and 1,2- epoxybutane (1.0 mL, 11.6 mmol) in EtOH (50 mL) was stirred under reflux for 8 h, then was cooled to rt and concentrated in vacuo. The crude residue was chromatographed (80 g SiO2; elution with CM (continuous gradient from 0% to % over 20 min) to give the title compound (500 mg, 2.59 mmol, 22.3 % yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.35 - 7.24 (m, 5H), 3.72 - 3.41 (m, 4H), 2.42 - 2.32 (m, 2H), 2.23 (s, 3H), 1.50 - 1.36 (m, 2H), 0.97 (t, J=7.6 Hz, 3H); [M + H] + = 194.3 Intermediate 6B. N-benzylfluoro-N-methylbutanamine DAST (0.697 mL in THF, 5.28 mmol) was added to a solution of Intermediate 6A (0.51 g, 2.64 mmol) in DCM (3 mL) at -78 °C and the reaction was stirred for 5 h at - 78 °C and for 18 h at rt. Volatiles were concentrated in vacuo and the residue was carefully quenched with water (2 mL). The aqueous solution containing product was purified by prepHPLC (Sunfire C18 30 x 100 mm-regenerated column; detection at 220 nm; flow rate = 40 mL/min; continuous gradient from 0% B to 100% B over 10 min + 2 min hold time at 100% B, where A = 90:10:0.1 H2O:MeCN:TFA and B = 90:10:0.1 MeCN:H2O:TFA) and appropriate fractions were concentrated to obtain an oil. The e was treated with 2.0 M HCl in ether (3.61 mL, 7.22 mmol) to give the HCl salt of the title compound (0.22 g, 1.127 mmol, 42.7 % yield) as a clear oil. 1H NMR (500 MHz, CD3OD) δ 7.54 (s, 5H), 5.12 - 4.91 (m, 1H), 4.68 - 4.22 (m, 2H), 3.56 - 3.41 (m, 2H), 3.01 - 2.83 (m, 3H), 1.84 - 1.60 (m, 2H), 1.06 (q, J=7.7 Hz, 3H); 19F NMR (471 MHz, METHANOL-d4) δ -186.78 (s), -188.25(s); [M + H] + = 196.3 ediate 6.
A mixture of Intermediate 6B (0.22 g, 0.95 mmol) and 20% Pd(OH)2-C (0.067 g, 0.475 mmol) in EtOH (5 mL) was stirred at 60 oC under 1 atmosphere of H 2 for 2 h. The mixture was filtered and concentrated in vacuo to provide the title compound as the HCl salt (0.099 g, 9.41 mmol, 99 % yield) as a white solid. 1H NMR (400 MHz, CDCl 3) δ .06 - 9.40 (m, 2H), 5.34 - 4.94 (m, 1H), 3.38 - 3.02 (m, 2H), 2.81 (br s, 3H), 1.75 (br d, J=1.5 Hz, 2H), 1.04 (br t, J=6.2 Hz, 3H); 19F NMR (377 MHz, CDCl 3) δ: -185.22 (br s, F).
Intermediate 7. 4-fluoro-N-methylpentanamine (for the synthesis of Example 256) 7A. ylhydroxy-N-methylpentanamide N-methylphenylmethanamine (5.78 mL, 44.9 mmol) was added to a mixture of 5-methyl dihydrofuran-2(3H)-one (1.426 mL, 14.98 mmol) and toluene (20 mL), and NaOMe solution (sodium (1.033 g, 44.9 mmol) added to MeOH (15 mL)) was added dropwise at 20 to 30°C, ed by stirring for 18 h at rt. The reaction was quenched by addition of ice water (20 mL) and HOAc (3.43 mL, 60 mmol) was added dropwise. The aqueous layer was extracted with EtOAc (2 X 20 mL). The combined organic extracts were washed with water and concentrated in vacuo. The crude oily product was chromatographed (40 g SiO2; elution with EtOAc/Hexane nuous gradient from 0% to 100% over 10 min)) to give the title compound (1.5 g, 6.78 mmol, 45.2 % yield) as a clear oil. 1H NMR (400 MHz, , CDCl 3) δ 7.41 - 7.13 (m, 5H), 4.63 - 4.53 (m, 2H), 3.85 (dddd, J=14.0, 8.0, 6.2, 4.2 Hz, 1H), 3.02 (dd, J=7.4, 4.5 Hz, 1H), 2.98 - 2.91 (m, 3H), 2.66 - 2.45 (m, 2H), 1.97 - 1.70 (m, 2H), 1.21 (dd, , 6.4 Hz, 3H) ); [M + H] + = 222.2. 7B. 5-(benzyl(methyl)amino)pentanol Intermediate 7A (1.5 g, 6.78 mmol) was added to a suspension of LAH (4.07 mL of a 2.0 M solution in THF; 8.13 mmol) in THF (50 mL). The mixture was heated at reflux for 18 h, then was cooled to 0° C. Brine (~1 mL) was lly added until no more gas was generated. The solids were filtered off, and the filtrate was concentrated in vacuo. The crude residue was chromatographed (12 g SiO2; elution with MeOH/DCM (continuous nt from 0% to 10% over 20 min) to give the title compound (1.35 g, 6.51 mmol, 96 % yield) as a clear oil. 1H NMR (500 MHz, CDCl 3) δ 7.40 - 7.25 (m, 5H), 3.84 - 3.73 (m, 1H), 3.56 (q, J=12.7 Hz, 2H), 2.59 - 2.51 (m, 1H), 2.49 - 2.39 (m, 1H), 2.18 (s, 3H), 1.82 - 1.67 (m, 3H), 1.50 - 1.40 (m, 1H), 1.22 (d, J=6.3 Hz, 3H); [M + H] + = 208.3. 7C. N-benzylfluoro-N-methylpentanamine DAST (1.03 mL in THF, 7.81 mmol) was added to a solution of Intermediate 7B (0.81 g, 3.91 mmol) in DCM (3 mL) at -78 °C and the reaction was stirred for 5 h at -78 °C and for 18 h at rt. The reaction was concentrated in vacuo and carefully quenched with water (2 mL). The aqueous solution was ed by preparative HPLC (Sunfire C18 30 x 100 mm-regenerated column; ion at 220 nm; flow rate = 40 mL/min; continuous gradient from 0% B to 100% B over 10 min + 2 min hold time at 100% B, where A = 0.1 H2O:MeCN:TFA and B = 90:10:0.1 MeCN:H2O:TFA) and appropriate fractions were concentrated to give an oil. The residue was treated with 2.0 M HCl in ether (3.61 mL, 7.22 mmol) to give the title compound as the HCl salt (0.12 g, 0.488 mmol, 12.50 % yield) as a clear oil. 1H NMR (400 MHz, CDCl 3) δ 12.21 (br s, 1H), 7.62 (br s, 2H), 7.50 - 7.41 (m, 3H), 4.80 - 4.55 (m, 1H), 4.32 - 4.15 (m, 2H), 3.23 - 2.83 (m, 2H), 2.81 - 2.64 (m, 3H), 2.21 - 1.94 (m, 2H), 1.78 - 1.55 (m, 2H), 1.40 - 1.27 (m, 3H); 19F NMR (377 MHz, CDCl + = 210.2 3) δ -173.65 (d, J=38.9 Hz, F); [M + H] Intermediate 7 A mixture of Intermediate 7C (0.12 g, 0.488 mmol) and 20% Pd(OH)2-C (0.034 g, 0.24 mmol) in EtOH (5 mL) was stirred at 60 oC under 1 atmosphere H 2 for 2 h. The reaction was filtered and concentrated in vacuo to provide the title compound as the HCl salt (0.05 g, 0.321 mmol, 65.8 % yield) as a white solid. 1H NMR (500 MHz, CDCl 3) δ 9.51 (br s, 2H), 4.83 - 4.62 (m, 1H), 3.01 (br s, 2H), 2.70 (br s, 3H), 2.13 - 1.94 (m, 2H), 1.81 - 1.65 (m, 2H), 1.41 - 1.29 (m, 3H); 19F NMR (471 MHz; CDCl3) δ -173.53 (s, 1F).
Example Structure & Name Analytical & Biology Data Method LCMS; [M + H] + = 490.3; 1H NMR (500 MHz, Example DMSO-d6) δ 7.85 (br s, 1 1H), 7.47 (d, J=8.6 Hz, 1H), 5.66 (br s, 2H), 4.77 (br s, 1H), 4.10 (s, 3H), 250 2.83 (br s, 3H), 2.71 - 2.61 (m, 1H), 2.43 (s, 3H), 2.08 (1S,3S)((2-methyl(1-methyl - 1.98 (m, 1H), 1.91 - 1.76 (((methyl(2- (m, 3H), 1.72 - 1.34 (m, yethyl)carbamoyl)oxy)methyl 6H), 0.79 (br s, 3H), 6 )-1H-1,2,3-triazolyl)pyridin protons are in water yl)oxy)cyclohexanecarboxylic suppression area acid LPA1 IC50 = 314 nM LCMS; [M + H] + = 458.1; 1H NMR (500 MHz, Example CDCl3) δ 8.64 (d, J=2.5 3 Hz, 1H), 8.24 (d, J=8.8 Hz, 1H), 7.89 - 7.79 (m, 1H), .54 (s, 2H), 4.84 (br s, 1H), 4.23 (br s, 3H), 3.23 - 251 3.15 (m, 1H), 3.14 - 2.98 (m, 1H), 2.94 (br s, 4H), (1S,3S)((6-(1-methyl 2.19 - 2.01 (m, 2H), 1.98 - (((methyl(((1R,2R) 1.75 (m, 5H), 1.73 - 1.61 methylcyclopropyl)methyl)carbamo (m, 1H), 1.03 (br s, 3H), yl)oxy)methyl)-1H-1,2,3-triazol 0.70 - 0.51 (m, 2H), 0.42 - yl)pyridinyl)oxy)cyclohexane 0.22 (m, 2H) ylic acid LPA1 IC50 = 27 nM LCMS; [M + H] + = 458.1; 1H NMR (500 MHz, Example CDCl3) δ 8.64 (d, J=1.9 3 Hz, 1H), 8.23 (d, J=8.8 Hz, 1H), 7.82 (br d, J=8.0 Hz, 1H), 5.54 (s, 2H), 4.84 (br 252 s, 1H), 4.23 (br s, 3H), 3.24 - 3.14 (m, 1H), 3.14 - 2.97 (1S,3S)((6-(1-methyl (m, 1H), 2.93 (br s, 4H), (((methyl(((1S,2S) 2.19 - 2.00 (m, 2H), 1.98 - methylcyclopropyl)methyl)carbamo 1.61 (m, 6H), 1.02 (br s, yl)oxy)methyl)-1H-1,2,3-triazol 3H), 0.69 - 0.50 (m, 2H), yl)pyridinyl)oxy)cyclohexane 0.42 - 0.20 (m, 2H) carboxylic acid LPA1 IC50 = 29 nM Example Structure & Name ical & Biology Data Method LCMS; [M + H] + = 478.1; 1H NMR (500 MHz, e DMSO-d6) δ 7.84 (br d, 1 J=8.5 Hz, 1H), 7.47 (br d, J=8.6 Hz, 1H), 5.67 (br s, 4H), 4.77 (br s, 2H), 4.10 (s, 4H), 2.86 (br s, 2H), 2.65 (br t, J=10.1 Hz, 1H), 2.42 (s, 3H), 2.08 - 1.99 (1S,3S)((6-(5-((((2-fluoro (m, 1H), 1.91 - 1.75 (m, methylpropyl)(methyl)carbamoyl)ox 3H), 1.73 - 1.44 (m, 4H), y)methyl)methyl-1H-1,2,3- 1.37 - 0.97 (m, 6H) triazolyl)methylpyridin 3 protons are in water yl)oxy) cyclohexanecarboxylic suppression area acid LPA1 IC50 = 134 nM LCMS; [M + H] + = 479.1; 1H NMR (500 MHz, DMSO-d6) δ 8.59 (s, 1H), .71 - 5.48 (m, 2H), 5.39 (br s, 1H), 4.73 - 4.21 (m, 1H), 4.11 (s, 3H), 3.57 - 3.19 (m, 2H), 2.90 - 2.74 (m, 3H), 2.64 (br t, J=11.1 Hz, 1H), 2.45 (s, 3H), 2.19 (1S,3S)((5-(5-((((2- - 2.04 (m, 1H), 1.96 - 1.72 fluorobutyl)(methyl)carbamoyl)oxy) (m, 3H), 1.70 - 1.24 (m, methyl)methyl-1H-1,2,3-triazol- 6H), 0.97 - 0.60 (m, 3H); 19F NMR (471 MHz, 4-yl)methylpyrazin yl)oxy)cyclohexanecarboxylic DMSO-d6) δ -73.42 (br s, acid; mixture of diastereomers TFA), -185.33 (br d, J=97.1 Hz, F) LPA1 IC50 = 132 nM LCMS; [M + H] + = 478.2; 1H NMR (500 MHz, Example DMSO-d6) δ 7.85 (br s, 1 1H), 7.47 (br d, J=8.2 Hz, 1H), 5.76 - 5.51 (m, 2H), 4.77 (br s, 1H), 4.69 - 4.20 (m, 1H), 4.09 (s, 3H), 3.60 - 3.20 (m, 2H), 2.94 - 2.73 (1S,3S)((6-(5-((((2- (m, 3H), 2.62 (br s, 1H), fluorobutyl)(methyl)carbamoyl)oxy) 2.40 (br s, 3H), 2.07 - 1.19 )methyl-1H-1,2,3-triazol- (m, 10H), 0.98 - 0.55 (m, 4-yl)methylpyridin 3H); 19F NMR (471 MHz, yl)oxy)cyclohexanecarboxylic DMSO-d6) δ -73.54 (s, acid; mixture of diastereomers TFA), -185.49 (s) LPA1 IC50 = 57 nM Example Structure & Name Analytical & Biology Data Method LCMS; [M + H] + = 492.3; 1H NMR (500 MHz, e DMSO-d6) δ 7.83 (br d, 1 J=8.5 Hz, 1H), 7.45 (br d, J=8.5 Hz, 1H), 5.62 (br d, J=13.7 Hz, 2H), 4.85 - 4.29 (m, 2H), 4.08 (s, 3H), 3.25 - 3.03 (m, 2H), 2.83 - 2.68 (m, 3H), 2.62 (br t, J=10.2 Hz, 1H), 2.40 (s, 3H), 1.99 (1S,3S)((6-(5-((((4- (br d, J=13.7 Hz, 1H), 1.90 fluoropentyl)(methyl)carbamoyl)oxy - 0.97 (m, 11H), 0.84 (br t, )methyl)methyl-1H-1,2,3-triazol- J=7.2 Hz, 3H); 19F NMR 4-yl)methylpyridin (471 MHz, DMSO-d6) δ - yl)oxy)cyclohexanecarboxylic 73.75 (s, TFA), 9 (br acid d, J=65.9 Hz, F) LPA1 IC50 = 17 nM Example 257 (1S,3S)((2-methyl(1-methyl(((methyl(((1R,2R)methylcyclopropyl)methyl) carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexane carboxylic acid 257A. (E)-N-benzylbutenamide EDC (36.7 g, 192 mmol) was added portionwise to a solution of crotonic acid (15.0 g, 174 mmol), benzyl amine (21.0 mL, 192 mmol) and DIPEA (33.5 mL, 192 mmol) in DCM (300 mL). The reaction mixture was stirred overnight and then poured onto 10% aq. KHS04 (250 mL) and extracted with EtOAc (100 mL). The organic layer was washed once again with 10% aq. KHS04 followed by brine (150 mL), dried (Na2SO4) and trated in vacuo to give the title compound as a white solid (25 g, 143 mmol, 82 % yield). [M + H] + = 176.2; 1H NMR (500 MHz, CDCl3) δ 7.40 - 7.20 (m, 5H), 6.98 - 6.82 (m, 1H), 5.84 (br dd, J=15.1, 1.7 Hz, 2H), 4.52 (d, J=5.8 Hz, 2H), 1.87 (dd, J=6.9, 1.7 Hz, 3H) 257B. N-benzylmethylcyclopropanecarboxamide In an Erlenmeyer flask containing Et2O (50 mL) and aq. 40% KOH (5 mL) was added N-methyl-N'-nitro-N-nitrosoguanidine (504 mg, 3.42 mmol) portionwise (with vigorous stirring) over 15 min at 0 °C. Upon complete addition, stirring was d and the aqueous layer was separated. The ether layer was dried with KOH pellets and allowed to stand for 5 min, then decanted into a third flask with KOH s and then poured onto a THF solution (2 mL) containing Example 257A (300 mg, 1.712 mmol). Pd(OAc)2 (3.84 mg, 0.017 mmol) was subsequently added and the reaction d to warm to rt and stirred for 1 h at rt. The reaction was concentrated in vacuo, and the crude oil was chromatographed (12 g SiO2; elution with EtOAc/Hexane (continuous gradient from 0% to 50% over 20 min) to give the title compound (310 mg, 1.61 mmol, 94 % yield) as a white solid. [M + H] + = 190.2; 1H NMR (400 MHz, CDCl 3) δ 7.37 - 7.26 (m, 5H), 5.82 (br s, 1H), 4.44 (dd, J=5.6, 2.3 Hz, 2H), 1.46 - 1.32 (m, 1H), 1.22 - 1.15 (m, 1H), 1.12 - 1.03 (m, 4H), 0.57 (ddd, J=7.9, 6.2, 3.7 Hz, 1H) 257C (1R,2R)-N-benzylmethylcyclopropanecarboxamide and 257D (1S,2S)-N- benzylmethylcyclopropanecarboxamide Example 257B (2.0 g, 10.6 mmol) was separated by chiral preparative HPLC (Instrument: Berger MG II (CTR-L409-PSFC1), Column: Chiralpak ID, 21 x 250 mm, 5 micron, Mobile Phase: 15% IPA / 85% CO2, Flow Conditions: 45 mL/min, 150 Bar, 40°C, Detector Wavelength: 220 nm, Injection Details: 0.25 mL of an ~200 mg/mL in IPA) to give Example 257C (0.9 g, 4.76 mmol, 45.0 % yield, 99.0% ee) and Example 257D (0.9 g, 4.76 mmol, 45.0 % yield, 99.0% ee) as white . The te stereochemistry of these two isomers was previously determined in the literature reference Bioorg. Med. Chem. Lett. 2007, 17, 1788. 257E. N-benzyl((1R,2R)methylcyclopropyl)methanamine, To a solution of Example 257C (0.90 g, 4.76 mmol) in THF (50 mL) was added BH3.THF (23.8 mL of a 1M solution in THF, 23.8 mmol) dropwise. Upon completion of the addition (10 min), the mixture was heated at reflux for 5 h, then cooled to rt and quenched via successive addition of MeOH (2 mL) and 1N aq. HCl dropwise (10 mL).
The ing solution was stirred at 50 °C for 1 h and then partitioned between water and Et2O (50 mL each). The aqueous layer was neutralized with 7N aq. KOH and extracted with DCM (3 x 10 mL). The organic layers were dried (Na2SO4) and concentrated in vacuo. The oily product was diluted with EtOAc and d with HCl gas. The resulting solids were filtered, washed with hexane and dried to give the title compound (HCl salt; 0.9 g, 4.25 mmol, 89 % yield) as a white solid.
[M + H] + = 176.2; 1H NMR (400 MHz, CD 3OD) δ 7.56 - 7.43 (m, 5H), 4.21 (s, 2H), 3.02 - 2.90 (m, 2H), 1.12 (d, J=5.5 Hz, 3H), 0.93 - 0.73 (m, 2H), 0.59 (dt, J=8.0, 5.0 Hz, 1H), 0.50 (dt, J=7.8, 5.3 Hz, 1H) 257F. N-benzyl-N-methyl((1R,2R)methylcyclopropyl)methanamine A solution of Example 257E (0.90 g, 5.13 mmol), 36% aq. formaldehyde solution (1.97 mL, 25.7 mmol), and HOAc (3 mL, 52.4 mmol) in MeOH (10 mL) was d at rt for 5 min. NaBH(OAc)3 (2.177 g, 10.27 mmol) was then added. The reaction mixture was stirred at rt for 20 min and then concentrated in vacuo and the residue was partitioned between DCM (20 mL) and 1N NaOH (50 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was treated with 2.0 M HCl in ether (3 mL, 6.0 mmol) to give the title compound (HCl salt; 0.97 g, 4.30 mmol, 84 % yield) as a white solid. [M + H] + = 176.2; 1H NMR (400 MHz, CD 3OD) δ 7.55 - 7.51 (m, 5H), 4.49 (dd, J=13.0, 7.3 Hz, 1H), 4.24 (br d, J=13.2 Hz, 1H), 3.22 - 3.14 (m, 1H), 3.02 (dt, J=13.3, 7.8 Hz, 1H), 2.85 (d, J=5.9 Hz, 3H), 1.15 (d, J=5.7 Hz, 3H), 0.94 - 0.79 (m, 2H), 0.66 - 0.53 (m, 2H) 257G. yl((1R,2R)methylcyclopropyl)methanamine A mixture of Example 257F HCl salt (0.97 g, 4.30 mmol) and 20% Pd(OH)2-C (0.1 g, 0.712 mmol) in EtOH (40 mL) was d at 60 oC under 1 atmosphere of H 2 for 2 h. The on was filtered and concentrated in vacuo to provide the title compound (HCl salt, 0.54 g, 3.98 mmol, 93 % yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 2.91 (d, J=7.3 Hz, 2H), 2.71 (s, 3H), 1.12 (d, J=5.9 Hz, 3H), 0.92 - 0.75 (m, 2H), 0.59 (dt, J=8.4, 4.9 Hz, 1H), 0.48 (dt, J=8.0, 5.1 Hz, 1H) Example 257 To a solution of Example 1F (30 mg, 0.054 mmol) in DCM (1 mL) was added Example 257G HCl salt (7.4 mg, 0.054 mmol) and DIPEA (0.028 mL, 0.163 mmol). The reaction mixture was stirred at rt for 2 h and then concentrated in vacuo. The residue was stirred with 1.0 M aq. NaOH (0.54 mL, 0.54 mmol) in THF (1 mL)/MeOH (0.2 mL) at rt for 18 h, then concentrated in vacuo and purified by preparative HPLC (Xbridge C18 5u OBD 19X100mm column; detection at 220 nm; flow rate = 20 mL/min; continuous gradient from 15% B to 100% B over 10 min + 2 min hold time at 100% B, where A = 90:10:0.1 H2O:MeCN:TFA and B = 0.1 MeCN:H2O:TFA) to give the title compound (TFA salt; 26 mg, 0.044 mmol, 81 % yield) as a yellowish oil.
[M + H] + = 472.1; 1H NMR (400 MHz, CDCl 3) δ 8.05 (d, J=8.8 Hz, 1H), 7.66 (br t, J=9.9 Hz, 1H), 5.67 - 5.53 (m, 2H), 4.80 (br s, 1H), 4.18 (s, 3H), 3.28 - 2.91 (m, 5H), 2.86 (br s, 1H), 2.66 (s, 3H), 2.15 - 1.56 (m, 8H), 1.01 (br dd, J=12.1, 5.1 Hz, 3H), 0.72 - 0.46 (m, 2H), 0.43 - 0.13 (m, 2H); 19F NMR (377 MHz, CDCl 3) δ -75.88 (s, TFA). hLPA1 IC50 = 18 nM Example 258. (1R,3S)((2-methyl(1-methyl(((methyl(((1S,2S)methylcyclopropyl)methyl) carbamoyl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic 258A. N-methyl((1S,2S)methylcyclopropyl)methanamine The same synthetic sequence to prepare Example 257G (from Example 257C) was used to prepare e 258A from Example 257D (HCl salt; 0.53 g, 3.91 mmol, 91 % yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 2.91 (d, J=7.3 Hz, 2H), 2.75 - 2.70 (m, 3H), 1.12 (d, J=5.7 Hz, 3H), 0.95 - 0.76 (m, 2H), 0.59 (dt, J=8.5, 4.9 Hz, 1H), 0.48 (dt, J=8.2, 5.1 Hz, 1H) Example 258.
To a solution of e 1F (30 mg, 0.054 mmol) in DCM (1 mL) added Example 258A HCl salt (7.35 mg, 0.054 mmol) and DIPEA (0.028 mL, 0.163 mmol).
The reaction mixture was stirred at rt for 2 h, then was concentrated in vacuo. The residue was stirred with 1.0 M aq. NaOH (0.542 mL, 0.542 mmol) in THF (1 mL)/MeOH (0.2 mL) at rt for 18 h and then purified by preparative HPLC ge C18 5u OBD 19X100mm column; detection at 220 nm; flow rate = 20 mL/min; continuous gradient from 30% B to 100% B over 10 min + 2 min hold time at 100% B, where A = 90:10:0.1 H2O:MeCN:TFA and B = 90:10:0.1 MeCN:H2O:TFA) to give the title compound (TFA salt, 27 mg, 0.046 mmol, 84 % yield) as a yellowish oil. [M + H] + = 472.1; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=8.8 Hz, 1H), 7.63 (br t, J=9.6 Hz, 1H), 5.72 - 5.51 (m, 2H), 4.79 (br d, J=3.1 Hz, 1H), 4.18 (s, 3H), 3.29 - 2.80 (m, 6H), 2.65 (s, 3H), 2.11 - 1.98 (m, 2H), 1.97 - 1.56 (m, 6H), 1.01 (br dd, J=13.4, 5.1 Hz, 3H), 0.69 - 0.16 (m, 4H). hLPA1 IC50 = 19 nM Example 259 (1S,3S)((6-(5-((((2,2-difluoropropyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid 259A. N-benzyl-2,2-difluoro-N-methylpropanamine To a solution of 1-(benzyl(methyl)amino)propanone (1.28 g, 7.22 mmol) and DAST (2.86 mL, 21.66 mmol) in DCM (12 ml) was added CsF (0.329 g, 2.166 mmol) portionwise, followed by a few drops of TFA at rt. The reaction mixture was stirred for 18 h at rt, then was ed with satd aq. NaHCO3. The aqueous layer was extracted with DCM (50 mL X 3). The combined organic extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo. The crude oily product was chromatographed (12 g SiO2; elution with EtOAc/Hexane (continuous nt from 0% to 50% over 10 min) and then further ed by preparative HPLC to give a clear oil. This material was treated with 2.0 M HCl in ether (3.61 mL, 7.22 mmol) to give the title compound (HCl salt, 334 mg, 1.417 mmol, 19.6 % yield) as a white solid.
[M + H] + = 482.3; 1H NMR (400 MHz, CDCl 3) δ 7.68 (dt, J=3.8, 2.8 Hz, 2H), 7.55 - 7.38 (m, 3H), 4.56 - 4.18 (m, 2H), 3.65 - 3.15 (m, 2H), 2.94 (s, 3H), 1.80 (t, J=19.3 Hz, 3H); 19F NMR (377 MHz, CDCl 3) δ -87.77 to -91.55 (m, F) 259B. 2,2-difluoro-N-methylpropanamine A mixture of e 259A (HCl salt; 0.33 g, 1.40 mmol) and 20% Pd(OH)2-C (0.10 g, 0.712 mmol) in EtOH (40 mL) was stirred at 60 oC under 1 atmosphere H 2 for 2 h. Filtration and concentration in vacuo provided 2,2-difluoro-N-methylpropanamine (HCl salt, 200 mg, 1.37 mmol, 98 % yield) as a white solid. 1H NMR (500 MHz, CD 3OD) δ 3.63 (t, J=14.9 Hz, 2H), 2.81 (s, 3H), 1.79 (t, J=19.1 Hz, 3H); 19F NMR (471 MHz, CD3OD) δ -98.01 (s) Example 259.
To a solution of Example 1F (30 mg, 0.054 mmol) in DCM (1 mL) added Example 259B (HCl salt; 15.78 mg, 0.108 mmol) and DIPEA (0.047 mL, 0.271 mmol).
The reaction mixture was stirred at 50 °C for 18 h and then concentrated in vacuo. The residue was stirred with 1.0 M aq. NaOH (0.271 mL, 0.271 mmol) in THF (1 mL)/MeOH (0.2 mL) at rt for 18 h and then purified by preparative LC/MS (Column: XBridge C18, 19 x 200 mm, 5-μm particles; Mobile Phase A: 5:95 MeCN:H2O with 10-mM NH4OAc; Mobile Phase B: 95:5 MeCN:H2O with 10-mM NH4OAc; Gradient: 15-55% B over 20 min, then a 4-min hold at 100% B; Flow: 20 ) to give the title compound (TFA salt; 9.3 mg, 0.015 mmol, 27.4 % yield) as a ish oil. [M + H] + = 482.3; 1H NMR (500 MHz, DMSO-d6) δ 7.85 (br d, J=7.9 Hz, 1H), 7.49 (br d, J=8.5 Hz, 1H), 5.70 (br d, J=18.3 Hz, 2H), 4.79 (br s, 1H), 4.11 (br s, 3H), 3.76 - 3.52 (m, 1H), 2.95 - 2.78 (m, 3H), 2.64 (br t, J=10.4 Hz, 1H), 2.42 (s, 3H), 2.03 (br d, J=13.7 Hz, 1H), 1.92 - 1.74 (m, 3H), 1.69 - 1.34 (m, 8H); 19F NMR (471 MHz, DMSO-d 6) δ -73.67 (s, TFA), -93.07 (br d, J=64.2 Hz). hLPA1 IC50 = 134 nM e 260. (1S,3S)((6-(5-((((3-fluorobutyl)(methyl)carbamoyl)oxy)methyl)methyl-1H-1,2,3- triazolyl)methylpyridinyl)oxy)cyclohexanecarboxylic acid 260A. 4-(benzyl(methyl)amino)butanone A mixture of N-methylphenylmethanamine (2.57 mL, 20 mmol), paraformaldehyde (0.901 g, 30.0 mmol) and conc. HCl (1.67 mL, 20.0 mmol) in iPrOH (2 mL) and acetone (50 mL) was stirred under reflux overnight and then concentrated in vacuo. The residue was diluted with water, basified to pH 14 with 1 N aq. NaOH solution (33.4 mL, 33.4 mmol) and extracted with ether. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound (4.0 g, 20.9 mmol, 94 % yield), which was used directly in the next reaction. [M + H] + = 192.2; 1H NMR (400 MHz, CDCl3) δ 7.34 - 7.22 (m, 5H), 3.49 (s, 2H), 2.74 - 2.67 (m, 2H), 2.66 - 2.58 (m, 2H), 2.19 (s, 3H), 2.14 (s, 3H) 260B. 4-(benzyl(methyl)amino)butanol NaBH4 (2.37 g, 62.7 mmol) was added to a solution of e 260A (4.0 g, 20.9 mmol) in MeOH (90 mL) at 0°C under N2. The reaction mixture was stirred for 1 h at 0°C; water was then added at 0°C and the mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with water, dried (Na2SO4) and concentrated in vacuo.
The residue was chromatographed (SiO2; elution with isocratic 10% EtOH/CHCl3) to give the title compound (3.5 g, 18.11 mmol, 87 % yield) as a light yellowish oil.
[M + H] + = 194.2; 1H NMR (400 MHz, CDCl 3) δ 7.35 - 7.27 (m, 5H), 3.99 - 3.86 (m, 1H), 3.72 - 3.31 (m, 2H), 2.76 (td, J=12.0, 3.3 Hz, 1H), 2.59 - 2.48 (m, 1H), 2.22 (s, 3H), 1.72 - 1.61 (m, 1H), 1.54 - 1.45 (m, 1H), 1.15 (d, J=6.2 Hz, 3H) 260C. N-benzylfluoro-N-methylbutanamine DAST (1.367 mL, 10.35 mmol) was added to a solution of Example 260B (1.0 g, .17 mmol) in DCM (5 mL) at -78 °C and the reaction was stirred for 5 h at -78 °C and 18 h at rt, after which it was quenched with sat. aq. NaHCO3 (50 mL). The aqueous layer was extracted with DCM (20 mL x 3), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude oil was purified by preparative HPLC (Sunfire C18 30 x 100 mm-regenerated ; detection at 220 nm; flow rate = 40 mL/min; continuous gradient from 0% B to 100% B over 10 min + 2 min hold time at 100% B, where A = 90:10:0.1 H2O:MeCN:TFA and B = 90:10:0.1 2O:TFA) and appropriate fractions were concentrated in vacuo to give an oil. This product was d with 2.0 M HCl in ether (3.61 mL, 7.22 mmol) to give the title nd (HCl salt; 0.15 g, 0.647 mmol, 12.5 % yield) as a white solid. [M + H] + = 196.2; 1H NMR (400 MHz, CDCl3) δ 7.69 - 7.54 (m, 2H), 7.50 - 7.34 (m, 3H), 4.97 - 4.57 (m, 1H), 4.39 - 3.96 (m, 2H), 3.38 - 3.21 (m, 1H), 3.08 - 2.88 (m, 1H), 2.77 - 2.64 (m, 3H), 2.57 - 1.96 (m, 2H), 1.54 - 1.29 (m, 3H); 19F NMR (377 MHz, CDCl3) δ -176.04 (s), -176.11 (s) 260D.
A mixture of Example 260C (HCl salt; 0.15 g, 0.647 mmol) and 20% Pd(OH)2-C (0.045 g, 0.324 mmol) in EtOH (5 mL) was stirred at 60 oC under 1 atmosphere H 2 for 2 h. Filtration and concentration in vacuo provided the title compound (HCl salt; 0.075 g, 0.530 mmol, 82 % yield) as a white solid. 1H NMR (400 MHz, CDCl 3) δ 5.01 - 4.71 (m, 1H), 3.13 (br s, 2H), 2.72 (br s, 3H), 2.33 - 2.06 (m, 2H), 1.53 - 1.25 (m, 3H); 19F NMR (377 MHz, CDCl 3) δ -175.47 (s, 1F) Example 260 To a on of Example 1F (30 mg, 0.054 mmol) in DCM (1 mL) was added Example 260D (HCl salt; 15.4 mg, 0.11 mmol) and DIPEA (0.047 mL, 0.271 mmol). The reaction mixture was stirred at rt for 1 h, then was concentrated in vacuo. The residue was stirred with 1.0 M aq. NaOH (0.271 mL, 0.271 mmol) in THF (1 mL)/MeOH (0.2 mL) at rt for 18 h and then was purified by preparative HPLC (Sunfire C18 30 x 100 mmregenerated column; detection at 220 nm; flow rate = 40 mL/min; uous gradient from 30% B to 100% B over 10 min + 2 min hold time at 100% B, where A = 90:10:0.1 H2O:MeCN:TFA and B = 90:10:0.1 MeCN:H2O: TFA) to give the title compound (TFA salt; 24 mg, 0.040 mmol, 73.4 % yield) as a yellowish oil.
[M + H] + = 478.1; 1H NMR (500 MHz, CDCl 3) δ 8.18 (br d, J=8.5 Hz, 1H), 8.00 (br d, J=8.0 Hz, 1H), 5.57 - 5.42 (m, 2H), 4.90 (br s, 1H), 4.78 - 4.51 (m, 1H), 4.23 (s, 3H), 3.55 - 3.41 (m, 2H), 3.04 - 2.93 (m, 3H), 2.91 - 2.82 (m, 1H), 2.82 - 2.75 (m, 4H), 2.23 - 2.06 (m, 1H), 2.06 - 1.95 (m, 1H), 1.95 - 1.77 (m, 6H), 1.69 (br s, 1H), 1.42 - 1.31 (m, 3H); 19F NMR (471 MHz, CDCl3) δ -76.03 (br s, TFA), 2 (dd, J=135.2, 9.3 Hz, F). hLPA1 IC50 = 50 nM.
Example Structure & Name Analytical & Biology Data Method LCMS; [M + H] + = 464.0; 1H NMR (500 MHz, CDCl3) δ Example 8.18 - 8.05 (m, 1H), 7.82 - 1 7.68 (m, 1H), 5.73 - 5.46 (m, 2H), 4.96 - 4.69 (m, 2H), 4.22 (br d, J=12.9 Hz, 3H), 3.03 (br d, J=7.2 Hz, 3H), 2.96 - 2.84 (m, 1H), 2.78 - 2.63 (m, (1S,3S)((6-(5-((((2- 3H), 2.21 - 1.53 (m, 9H), 1.41 fluoropropyl)(methyl)carbamoyl) - 1.22 (m, 4H); 19F NMR (471 oxy)methyl)methyl-1H-1,2,3- MHz, CDCl3) δ -75.91 (br s, triazolyl)methylpyridin TFA), yl)oxy)cyclohexanecarboxylic -175.36 to -181.71 (m, 1F) acid LPA1 IC50 = 145 nM LCMS; [M + H] += 472.2; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=8.8 Hz, 1H), 7.94 (br d, J=9.0 Hz, 1H), 5.57 - .40 (m, 2H), 4.87 (br s, 1H), 4.21 (d, J=6.4 Hz, 3H), 3.27 - 262 3.06 (m, 2H), 3.04 - 2.94 (m, (1S,3S)((2-methyl(1- 3H), 2.86 (br d, J=3.5 Hz, (((methyl((2-methyl 1H), 2.76 (d, J=4.6 Hz, 3H), cyclopropyl)methyl)carbamoyl)o 2.20 - 1.56 (m, 8H), 1.09 - xy)methyl)-1H-1,2,3-triazolyl) 1.01 (m, 3H), 0.73 - 0.23 (m, pyridinyl)oxy)cyclohexane 4H) carboxylic acid; e of LPA1 IC50 = 29 nM diastereomers LCMS; [M + H] + = 474.3; 1H NMR (500 MHz, DMSO-d6) δ 7.83 (br d, J=8.5 Hz, 1H), 7.46 (br d, J=8.9 Hz, 1H), .64 (br s, 2H), 4.77 (br s, 1H), 4.09 (s, 3H), 3.18 - 2.95 (m, 2H), 2.90 - 2.72 (m, 3H), 2.63 (br d, J=10.4 Hz, 1H), (1S,3S)((2-methyl(1-methyl 2.40 (s, 3H), 2.05 - 1.40 (m, (((methyl((1-methylcyclo- 8H), 0.97 - 0.66 (m, 3H), 0.43 propyl)methyl)carbamoyl)oxy)me - 0.07 (m, 4H) thyl)-1H-1,2,3-triazolyl) LPA1 IC50 = 76 nM pyridinyl)oxy)cyclohexane carboxylic acid Example Structure & Name Analytical & Biology Data Method LCMS; [M + H] + = 474.4; 1H NMR (500 MHz, DMSO-d6) δ 7.84 (br s, 1H), 7.48 (br s, 1H), 5.63 (br d, J=17.1 Hz, 2H), 4.79 (br s, 1H), 4.11 (s, 3H), 3.57 (br dd, J=12.1, 6.0 264 Hz, 2H), 3.26 (dd, J=10.4, 5.8 Hz, 1H), 3.20 - 3.11 (m, 1H), 3.06 (br s, 1H), 2.93 (br s, )((2-methyl(1- 1H), 2.90 - 2.76 (m, 3H), 2.63 methyl(((methyl(neopentyl) (br s, 1H), 2.09 - 1.43 (m, carbamoyl)oxy)methyl)-1H-1,2,3- 8H), 0.92 - 0.64 (m, 9H) triazolyl)pyridinyl)oxy) LPA1 IC50 = 76 nM exanecarboxylic acid Example 265 (1S,3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)(hydroxymethyl)pyridinyl)oxy)cyclohexanecarboxylic acid 265A. 3,6-dibromo(((tetrahydro-2H-pyranyl)oxy)methyl)pyridine A solution of ethyl 3,6-dibromopicolinate (3.0 g, 9.71 mmol) in THF (50 mL) was stirred at 0 °C, then LiBH4 (7.28 mL of a 2M solution in THF, 14.57 mmol) was added portionwise over 5 - 10 min. Vigorous gas evolution ensued. The reaction mixture was stirred at rt overnight, then was quenched with 1N aq. HCl slowly, adjusting the pH to ~7. The mixture was partitioned between EtOAc and water (50 mL each) and ted with EtOAc (3X). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (24 g SiO2) to provide 3,6- dibromopyridinyl)methanol (1.89 g, 7.08 mmol, 72.9 % yield).
To a solution of (3,6-dibromopyridinyl)methanol (2.46 g, 9.22 mmol) in CH2Cl2 (12 mL) was added 3,4-dihydro-2H-pyran (2.52 mL, 27.6 mmol) and pyridinium p-toluenesulfonate (0.116 g, 0.461 mmol). The reaction was stirred overnight at rt, then quenched with water and ted with DCM, washed with water, brine, dried (MgSO4) and concentrated in vacuo. The e was chromatographed (24 g SiO2, uous gradient from 0-100% EtOAc/hexanes over 20 min) to give the title compound (3.4 g, 9.40 mmol, 100 % . 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J=8.53 Hz, 1H), 7.32 (d, J=8.25 Hz, 1H), 4.94 (d, J=11.83 Hz, 1H), 4.88 (t, J=3.30 Hz, 1H), 4.69 (d, J=11.83 Hz, 1H), 3.94-4.09 (m, 1H), 3.49-3.70 (m, 1H), 1.49-2.00 (m, 8H) 265B. 3-(5-Bromo(((tetrahydro-2H-pyranyl)oxy)methyl)pyridinyl)propyn To a solution of e 265A (3.4 g, 9.69 mmol) and -ynol (0.677 mL, 11.62 mmol) in MeCN (30 mL) was added Et3N (6.00 mL). The solution was degassed with N2 for 5 mins, after which Pd(Ph3)2Cl2 (0.340 g, 0.484 mmol) and CuI (0.092 g, 0.484 mmol) were added. The reaction mixture was degassed with N2 for 5 min, then was stirred at rt for 16 h under N2. LCMS indicated at this time indicated that the reaction was complete. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (4 x 30 mL). The filtrate was concentrated in vacuo and the residue was chromatographed (80 g SiO2, elution by continuous gradient from 0% to 100% EtOAc/Hex over 80 min at 35 mL/min) to give the title compound (2.90 g, 8.89 mmol, 92 % yield). 1H NMR (500 MHz, CDCl 3) δ 7.86 (d, J=8.25 Hz, 1H), 7.26 (d, J=8.25 Hz, 1H), 4.98 (d, J=11.55 Hz, 1H), 4.88 (t, J=3.30 Hz, 1H), 4.69 (d, J=11.55 Hz, 1H), 4.53 (d, J=6.05 Hz, 2H), 3.99 (dt, J=2.75, 10.45 Hz, 1H), .65 (m, 1H), 1.47-1.95 (m, 6H) 265C. (4-(5-Bromo(((tetrahydro-2H-pyranyl)oxy)methyl)pyridinyl) ((trimethylsilyl)methyl)-1H-1,2,3-triazolyl)methanol To a solution of Example 265B (2.9 g, 8.89 mmol) in dioxane (40 mL) was added CuI (0.068 g, 0.356 mmol), chloro(pentamethylcyclopentadienyl)bis(triphenylphosphine)Ruthenium(II) (0.283 g, 0.356 mmol). The resulting sion was degassed with N2 for 3 min, after which trimethylsilylmethyl azide (1.404 g, 9.78 mmol) was added. The mixture was degassed with N2 for another 5 min, then was heated in an oil bath at 50°C for 20 h under N2, then was cooled to rt. The mixture was filtered through Celite; the filtrate was concentrated in vacuo, and chromatographed (120 g SiO2; elution with continuous gradient from 0 to 60% EtOAc/Hex over 65 min at 120 mL/min) to give the title compound (2.30 g, 5.05 mmol, 56.8 % . 1H NMR (500 MHz, CDCl 3) δ 8.10 (d, J=8.25 Hz, 1H), 7.97 (d, J=8.53 Hz, 1H), 6.41 (t, J=7.57 Hz, 1H), 5.05 (d, 0 Hz, 1H), 4.86 (t, J=3.30 Hz, 1H), 4.80 (dd, J=1.38, 7.43 Hz, 2H), 4.76 (d, J=14.03 Hz, 1H), 3.86-3.97 (m, 1H), 3.83 (s, 2H), 3.53- 3.64 (m, 1H), 1.51-2.02 (m, 8H), 0.18-0.27 (m, 9H) 265D. (4-(5-Bromo(((tetrahydro-2H-pyranyl)oxy)methyl)pyridinyl)methyl- 1H-1,2,3-triazolyl)methyl (cyclobutylmethyl)(methyl)carbamate TBAF (5.56 mL of a 1M solution in THF, 5.56 mmol) was added dropwise to a solution of Example 265C (2.3 g, 5.05 mmol) in THF (15 mL) and the reaction mixture was d at rt ght, then was ed with satd aq. NaHCO3 (50 mL) and stirred for 20 min at rt. The mixture was extracted with EtOAc (2 x 100 mL); the combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo. The crude product was chromatographed (40 g SiO2; continuous gradient from 0% to 100% EtOAc over 30 min, at 20 mL/min) to give (4-(5-bromo(((tetrahydro-2H-pyran )methyl)pyridinyl)methyl-1H-1,2,3-triazolyl)methanol (1.69 g, 4.41 mmol, 87 % yield). To a solution of this material (0.41 g, 1.07 mmol) and pyridine (0.433 mL, .35 mmol) in DCM (5 mL) was added 4-nitrophenyl chloroformate (0.431 g, 2.140 mmol) in DCM (2 mL). The reaction mixture was stirred at rt overnight, then (cyclobutylmethyl)methylamine (0.318 g, 3.21 mmol) was added, followed by Et3N (1.49 mL, 10.7 mmol). The reaction was stirred at rt for 3 h, then was partitioned between DCM and sat’d aq. NaHCO3. The organic layer was washed with brine and concentrated in vacuo. The residue was chromatographed (40 g SiO2; continuous gradient from 0% to 100% EtOAc over 30 min, at 20ml/min) to give the title compound (0.52 g, 0.921 mmol, 86 % yield). 1H NMR (500 MHz, CDCl 3) δ 8.05 (d, J=8.3 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 5.83 (br d, J=16.0 Hz, 2H), 5.01 (d, J=11.8 Hz, 1H), 4.93 (t, J=3.2 Hz, 1H), 4.77 (d, J=12.1 Hz, 1H), 4.10-4.24 (m, 3H), .07 (m, 1H), .70 (m, 1H), 3.10-3.42 (m, 2H), 2.70-2.98 (m, 3H), 1.46-2.05 (m, 13H) 265E. (4-(5-hydroxy(((tetrahydro-2H-pyranyl)oxy)methyl)pyridinyl)methyl- 1H-1,2,3-triazolyl)methyl (cyclobutylmethyl)(methyl)carbamate To a degassed solution of Example 265D (510 mg, 1.00 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (509 mg, 2.01 mmol) and KOAc (295 mg, 3.01 mmol) in THF (4013 µl) was added PdCl2(dppf) (36.7 mg, 0.050 mmol). The vial was purged with N2, sealed and stirred at 80 °C overnight, then was cooled to rt. The mixture was diluted with EtOAc and filtered; the filtrate was concentrated in vacuo, re-dissolved in THF (5 mL) and this crude l boronate product was used in the next step without further purification. To the solution of this crude pinacol boronate product in THF (5 mL) was added aq. NaOH (2.01 mL of a 1 M on, 2.01 mmol), followed by aq. H2O2 (0.830 mL, 10.03 mmol). The reaction mixture was stirred at rt for 2 h, after which satd. aq. Na2S2O3 (1 mL) was added; the mixture was stirred at rt for 10 min, then was extracted with EtOAc (3 x 10 mL). The ed organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed (24 g SiO2; continuous nt from 0 to 100% EtOAc/Hex over 20 min at 20 ) to give the title compound (379 mg, 0.851 mmol, 85 % yield). 1H NMR (500 MHz, CDCl 3) δ 8.22 (br s, 1H), 8.07 (d, J=8.53 Hz, 1H), 7.30 (d, J=8.53 Hz, 1H), 5.73 (br d, J=9.08 Hz, 2H), 5.14 (d, J=12.93 Hz, 1H), 4.92 (d, J=12.65 Hz, 1H), 4.77-4.86 (m, 1H), 4.15 (br d, J=5.23 Hz, 3H), 3.96-4.06 (m, 1H), 3.60-3.73 (m, 1H), 3.34 (br d, J=7.43 Hz, 1H), 3.18 (br d, J=6.88 Hz, 1H), 2.74-2.99 (m, 3H), 1.60-1.98 (m, 13H) 265E. Isopropyl (1S,3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)- 1-methyl-1H-1,2,3-triazolyl)(hydroxymethyl)pyridinyl)oxy)cyclohexane carboxylate To a solution of Example 265D (275 mg, 0.617 mmol), Example 1F (610 mg, 1.54 mmol) in t-AmOH (5 mL) was added Cs2CO3 (603 mg, 1.85 mmol); the reaction was stirred at 65 °C for 24 h. Then more Example 1F (244 mg, 0.617 mmol) and Cs2CO3 (241 mg, 0.741 mmol) were added to the reaction, which was heated at 65 °C for another 24 h, then cooled to rt. Water (5 mL) was added and the mixture was stirred at rt for 10 min, then was extracted with EtOAc (3 x 10 mL). The combined organic ts were dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed (24 g SiO2, continuous gradient from 0 to 100% EtOAc/Hex over 18 min at 15 ) to give (1S,3S)-isopropyl (5-((((cyclobutylmethyl) (methyl)carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl)(((tetrahydro-2H-pyranyl)oxy)methyl)pyridin yl)oxy)cyclohexanecarboxylate (290 mg, 0.402 mmol, 65.1 % yield).
A mixture of this THP ether (330 mg, 0.468 mmol) and PPTS (23.5 mg, 0.094 mmol) in MeOH (4 mL) was heated at 60 oC overnight, then was cooled to rt. Volatiles were d in vacuo and the residue was partitioned between DCM and satd aq.
. The organic extract was dried (Na 2SO4) was concentrated in vacuo. The crude product was chromatographed (24 g SiO2; continuous gradient from 0 to 100% EtOAc/Hex over 20 min at 20 mL/min and then at 100% EtOAc for 10 min) to give the title compound (274 mg, 0.491 mmol, 100 % yield). 1H NMR (500 MHz, CDCl 3) δ 8.13 (br dd, J=3.71, 8.12 Hz, 1H), 7.32 (d, J=8.53 Hz, 1H), 5.70 (s, 2H), 4.99-5.14 (m, 1H), 4.78-4.90 (m, 1H), 4.75 (br s, 1H), 4.24 (s, 3H), 3.20-3.34 (m, 2H), 2.82-2.96 (m, 3H), 2.67-2.79 (m, 1H), 2.33-2.63 (m, 1H), 1.46-2.15 (m, 16H), 1.07-1.32 (m, 6H) Example 265.
To a solution of 265E (17 mg, 0.032 mmol) in THF (0.5 mL) was added 4 drops of MeOH at rt, after which LiOH.H2O (0.080 mL, 0.321 mmol) was added. The reaction mixture was stirred at rt overnight, then was ed by preparative HPLC ((PHENOMENEX®, Axia 5µ C18 30 x 100 mm column; detection at 220 nm; flow rate = 40 mL/min; continuous gradient from 0% B to 100%B over 10 min + 2 min hold time at 100% B, where A=90:10:0.1 H2O:MeOH:TFA and B=90:10:0.1 MeOH:H2O:TFA)) to give the title compound (15 mg, 0.024 mmol, 75 % yield). 1H NMR (500 MHz, CDCl3) δ 8.19 (br d, J=8.25 Hz, 1H), 7.65 (br d, J=8.53 Hz, 1H), 5.51-5.66 (m, 2H), 4.90-5.12 (m, 2H), 4.84 (br s, 1H), 4.24 (s, 3H), 3.29 (br dd, J=7.15, 16.78 Hz, 2H), 2.88 (br s, 4H), 2.38-2.68 (m, 1H), 1.49-2.22 (m, 15H). LCMS, [M+H]+ = 488.3. hLPA1 IC50 = 68 nM Example 266. (1S,3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- triazolyl)(fluoromethyl)pyridinyl)oxy)cyclohexanecarboxylic acid To a solution of Example 265E (50 mg, 0.094 mmol) in DCM (1 mL) at 0°C, was added bis(2-methoxyethyl)aminosulfur trifluoride (0.061 mL, 0.283 mmol) dropwise under N2. The reaction mixture was gradually warmed to rt and stirred at rt for 2 h, then was slowly quenched by on of satd aq. NaHCO3 followed by DCM. The organic layer was dried using a stream of N2 and the crude product (1S,3S)-isopropyl (5- ((((cyclobutylmethyl)(methyl) carbamoyl)oxy)methyl)methyl-1H-1,2,3-triazolyl) (fluoromethyl)pyridinyl)oxy) cyclohexanecarboxylate) was used in the next step without further purification. To a solution of the crude pyl ester (50 mg, 0.094 mmol) in THF (0.5 mL) was added 4 drops of MeOH at rt, followed by aq. LiOH (0.235 mL, 0.941 mmol). The reaction mixture was stirred at rt overnight, then was filtered.
The crude product was purified by preparative HPLC (PHENOMENEX®, Axia 5µ C18 30x100 mm column; detection at 220 nm; flow rate=40 mL/min; continuous gradient from 0% B to 100%B over 10 min+2 min hold time at 100% B, where A=90:10:0.1 H2O:MeOH:TFA and B=90:10:0.1 MeOH:H2O:TFA to give the title compound (25 mg, 0.039 mmol, 41.8 % yield). 1H NMR (500 MHz, CDCl 3) δ 8.19 (br d, J=8.53 Hz, 1H), 7.62-7.71 (m, 1H), 5.49-5.77 (m, 4H), 4.84 (br s, 1H), 4.22 (br d, J=4.40 Hz, 3H), 3.16- 3.44 (m, 2H), 2.80-2.98 (m, 4H), 1.26-2.68 (m, 16H). LCMS, [M+H]+ = 490.3. hLPA1 IC50 = 27 nM.
Example 267. (1S,3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)(difluoromethyl)pyridinyl)oxy)cyclohexanecarboxylic acid To a mixture of Example 265E (80 mg, 0.151 mmol) and 75 mg of Celite in DCM (1.5 mL) was added pyridinium dichromate (73.9 mg, 0.196 mmol). The reaction mixture was stirred at rt for 90 min, after which more pyridinium dichromate (73.9 mg; 0.196 mmol) was added, and the reaction was stirred overnight at rt. EtOAc was added and the mixture was filtered through Celite. The filtrate was concentrated in vacuo, and the crude product was chromatographed (4 g SiO2, continuous gradient from 0 to 100% EtOAc/Hex over 12 min at 8 mL/min) to give (1S,3S)-isopropyl (5- ((((cyclobutylmethyl)(methyl)carbamoyl)oxy) methyl)methyl-1H-1,2,3-triazolyl) formylpyridinyl)oxy)cyclohexanecarboxylate (15 mg, 0.028 mmol, 18 % . To a RT solution of the above aldehyde (15 mg, 0.028 mmol) in DCM (0.3 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (0.032 mL, 0.148 mmol) in one portion. The mixture was stirred at rt for 2h; volatiles were d via an N2 , and the crude difluoromethyl product (1S,3S)-isopropyl 3-((6-(5-((((cyclobutylmethyl)(methyl) carbamoyl)oxy)methyl)methyl-1H-1,2,3-triazolyl)(difluoromethyl)pyridin ) cyclohexanecarboxylate was directly in the next step without further cation.
To a solution of this isopropyl ester (13 mg, 0.024 mmol) in THF (0.5 mL) was added aq.
LiOH (0.118 mL, 0.473 mmol) and 4 drops of MeOH. The reaction mixture was stirred at rt for 2 days, filtered and the crude product was purified by preparative HPLC, (PHENOMENEX®, Axia 5µ C18 30x100 mm column; detection at 220 nm; flow rate=40 mL/min; continuous nt from 0% B to 100%B over 10 min+2 min hold time at 100% B, where A=90:10:0.1 H2O:MeOH:TFA and B=90:10:0.1 MeOH:H2O:TFA) to give the title compound (2 mg, 3.19 µmol, 13.5 % yield). 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=8.80 Hz, 1H), 7.37-7.65 (m, 1H), 6.62-7.05 (m, 1H), 5.71 (br s, 2H), 4.80 (br d, J=2.64 Hz, 1H), 4.17 (br d, J=7.92 Hz, 3H), 3.09-3.45 (m, 2H), 2.72-3.02 (m, 4H), 1.36- 2.65 (m, 15H). LCMS, [M+H]+ = 508.2. hLPA IC50 = 30 nM atively, the title compound can also be sized as follows. 267A. (3,6-Dibromopyridinyl)methanol To a 0 °C solution of ethyl 3,6-dibromopicolinate (5.0 g, 16.2 mmol) in THF (30 mL) was added LiBH4 in THF (12.14 mL of a 2 M solution, 24.28 mmol) portionwise over 10 min. us gas evolution ensued. After 1 h at rt, the reaction mixture was slowly ed with satd aq., stirred for 10 min, then was extracted with EtOAc. The pH of the aqueous phase was adjusted to 7-8 by addition of 1N aq. HCl, then was extracted again with EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude material was chromatographed (40 g SiO2; EtOAc/Hexane; continuous gradient from 0% to 100% EtOAc over 30 min, at 20 mL/min) to give the title compound (3.0 g, 11.24 mmol, 69.4 % yield), 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J=7.98 Hz, 1H), 7.35 (d, J=7.98 Hz, 1H), 4.77 (d, J=4.95 Hz, 2H), 3.78 (t, J=5.09 Hz, 1H) 267B. 3,6-Dibromo(difluoromethyl)pyridine Anhydrous DMSO (4.04 mL, 56.9 mmol) was added dropwise to a solution of (COCl)2 (2.277 mL, 26.0 mmol) in DCM (25 mL) at -78oC. After stirring at -78oC for 15 min, a on of Example 267A (2.17 g, 8.13 mmol) in DCM (25 mL) was added dropwise. After stirring for 15 min at -78oC, TEA (10.2 mL, 73.2 mmol) was added dropwise. The reaction was allowed to warm to rt over 1 h (the reaction e became cloudy); more DCM (50 mL) was added and the e was stirred for 2h at rt. The reaction was quenched with brine (20 mL) and extracted with DCM (2 x 50 mL). The combined c extracts were dried (Na2SO4) and concentrated in vacuo. The crude oil was chromatographed (80 g SiO2; elution with EtOAc/ Hexane (continuous gradient from 0% to 60% over 20 min) to give 3,6-dibromopicolinaldehyde (1.92 g, 7.25 mmol, 89 % yield) as a light yellowish oil. To a solution of the 3,6-dibromopicolin -aldehyde (1.5 g, .66 mmol) in DCM (6 mL) at rt was added bis(2-methoxyethyl)aminosulfur trifluoride (1.46 mL, 6.79 mmol) in one portion. The mixture was stirred at rt for 1 h, then was lly quenched with sat’d aq. NaHCO3, adjusted to pH=7-8 and extracted with DCM (2X). The combined organic ts were concentrated in vacuo. The residue was chromatographed (EtOAc/Hexane; continuous gradient from 0% to 100% EtOAc over 20 min, at 15 mL/min) to give the title compound (1.48 g, 5.16 mmol, 91 % yield). 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J=8.53 Hz, 1H), 7.51 (d, J=8.53 Hz, 1H), 6.65-7.00 (m, 1H) Example 267B can then be used as the starting material for the synthesis of Example 267. The tic sequence is analogous to that used for the sis of Example 1 (i.e. regioselective Sonogashira coupling of the less hindered bromide of Example 267B with propargyl alcohol, followed by Ru-mediated [3+2] cycloaddition with trimethylsilyl azide to form the 1,2,3-triazole, etc.).
Example 267: 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=8.80 Hz, 1H), 7.37-7.65 (m, 1H), 6.62-7.05 (m, 1H), 5.71 (br s, 2H), 4.80 (br d, J=2.64 Hz, 1H), 4.17 (br d, J=7.92 Hz, 3H), 3.09-3.45 (m, 2H), 2.72-3.02 (m, 4H), 1.36-2.65 (m, 15H). LCMS, [M+H]+ = 508.2 hLPA1 IC50 = 30 nM Example 268. (1S,3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)(methoxymethyl)pyridinyl)oxy)cyclohexanecarboxylic acid 268A. bromo(methoxymethyl)pyridine A solution of ibromopyridinyl)methanol (1.67 g, 6.26 mmol) in ous THF (29 mL) was slowly added to a stirring suspension of NaH (0.30 g, 7.51 mmol) in anhydrous THF (5 ml) at 0-5°C under N2. After gas evolution stopped, MeI (0.587 mL, 9.38 mmol) was added slowly dropwise and the reaction was warmed to rt over 1 h. Brine (10 mL) was added slowly to the reaction, which was then extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude al was chromatographed (24 g SiO2; EtOAc/Hexane; continuous gradient from 0% to 100% EtOAc over 30 min, at 10 mL/min) to give the title compound (1.70 g, 6.05 mmol, 97 % yield). 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J=8.25 Hz, 1H), 7.34 (d, J=8.25 Hz, 1H), 4.66 (s, 2H), 3.52 (s, 3H).
Example 268B was then used for the synthesis of Example 268. The synthetic sequence is analogous to that used for the synthesis of Example 1 (i.e. regioselective shira coupling of the less hindered bromide of Example 268B with propargyl alcohol, followed by Ru-mediated [3+2] cycloaddition with trimethylsilyl azide to form the 1,2,3-triazole, etc.).
Example 268: 1H NMR (500 MHz, DMSO-d6)  7.95 (br d, J=8.24 Hz, 1H), 7.60 (br d, J=8.85 Hz, 1H), 5.63 (br d, 2 Hz, 2H), 4.81 (br s, 1H), 4.53 (br s, 2H), 4.10 (br s, 3H), 3.03-3.27 (m, 2H), 2.68-2.82 (m, 3H), 2.59 (br d, J=10.38 Hz, 1H), 2.56 (s, 3H), 1.32-2.36 (m, 16H); LCMS, [M+H]+ = 502.3; hLPA1 IC50 = 103 nM Example 269. (1S,3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)(trifluoromethyl)pyridinyl)oxy)cyclohexanecarboxylic acid Example 269 was synthesized using commercially available 3,6-dibromo (trifluoromethyl) pyridine, using the same synthetic sequence as for the preparation of Example 1.
Example 269: 1H NMR (500 MHz, CDCl 3) δ 8.39 (br d, J=8.80 Hz, 1H), 7.54 (d, J=9.08 Hz, 1H), 5.71 (br s, 1H), 4.86 (br s, 1H), 4.21 (br d, J=13.76 Hz, 3H), 3.12-3.40 (m, 2H), 2.89-2.99 (m, 1H), .89 (m, 3H), 2.35-2.66 (m, 1H), 2.17-2.37 (m, 1H), 1.42-2.29 (m, 14H) LCMS, [M+H]+ = 526.2; hLPA1 IC50 = 10 nM.
Example 270. (1S,3S)((2-cyano(1-methyl(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3- triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid 270A. 3,6-Dibromopicolinonitrile To a suspension of bromopicolinic acid (0.5 g, 1.780 mmol), NH4Cl (0.381 g, 7.12 mmol) and Et3N (1.985 ml, 14.24 mmol) in THF (7.12 mL) was added 1- propanephosphonic anhydride (4.24 mL, 7.12 mmol) dropwise at 0 oC. The reaction was slowly warmed to rt, then was heated to 80 oC for 48 h, then was cooled to rt. The mixture was ioned between water and EtOAc (10 mL each) and extracted with EA (2 x 10 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed (40 g SiO2; EtOAc/Hexane; continuous gradient from 0% to 100% EtOAc over 30 min, at 20 mL/min) to give the title compound (0.32 g, 1.22 mmol, 68.6 % yield) as a white solid. 1H NMR (500 MHz, CDCl 3) δ 7.88 (d, J=8.53 Hz, 1H), 7.60 (d, J=8.53 Hz, 1H).
Example 270 was synthesized using e 270A, using the same synthetic sequence as for the preparation of Example 1 (except that N-methyl, N-propylamine was used to generate the carbamate of Example 270 rather than the N-methyl, N- utylmethylamine that was used in Example 1).
Example 270: 1H NMR (500 MHz, DMSO-d 6) δ 8.30 (d, J=9.16 Hz, 1H), 7.98 (d, J=9.16 Hz, 1H), 5.54 (br d, J=19.53 Hz, 2H), 5.01 (br s, 1H), 4.14 (s, 3H), 3.00-3.25 (m, 2H), 2.77 (br d, J=9.16 Hz, 3H), 2.63 (br t, J=10.22 Hz, 1H), 1.15-2.21 (m, 10H), 0.58-0.96 (m, 3H) LCMS, [M+H]+ = 457.1; hLPA1 IC50 = 11 nM Example 271. (1S,3S)((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)methyl-1H- 1,2,3-triazolyl)(2-hydroxypropanyl)pyridinyl)oxy)cyclohexanecarboxylic 271A. Ethyl 3-bromo(1-methyl(((tetrahydro-2H-pyranyl)oxy)methyl)-1H-1,2,3- lyl)picolinate This compound was synthesized from commercially available ethyl 3,6- dibromopicolinate , using the same synthetic sequence as for Example 265. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J=8.53 Hz, 1H), 8.05 (d, J=8.53 Hz, 1H), 5.26-5.40 (m, 2H), 4.76 (t, J=3.44 Hz, 1H), 4.50 (q, J=7.15 Hz, 2H), 4.19 (s, 3H), 3.83 (ddd, J=3.03, 8.05, 11.21 Hz, 1H), 3.46-3.62 (m, 1H), 1.51-1.88 (m, 6H), 1.48 (t, J=7.15 Hz, 3H) 271B. Ethyl 3-hydroxy(1-methyl(((tetrahydro-2H-pyranyl)oxy)methyl)-1H- 1,2,3-triazolyl)picolinate To a degassed solution of Example 271A (433 mg, 1.02 mmol), ,4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (517 mg, 2.036 mmol) and KOAc (300 mg, 3.05 mmol) in THF (4.07 mL) was added PdCl2(dppf) (37.2 mg, 0.051 mmol). The vial was purged with N2, sealed and d at 80 °C overnight, then was cooled to rt. The mixture was filtered and the filtrate (crude pinacol boronate) was used directly in the next step without further purification To a solution of the above crude te product (397 mg, 1.018 mmol) in EtOAc (7 mL) and THF (2 mL) was added H2O2 (0.946 mL, 10.2 mmol). The reaction was stirred at rt for 3 h, then was extracted with EtOAc. To the aqueous phase was added satd aq. Na2S2O3 (3 mL) and 2 drops of 1N aq. NaOH; the mixture was stirred for 5 min and extracted again with EtOAc (2 X 5 mL). The combined organic ts were concentrated in vacuo. The residue was chromatographed (40 g SiO2; EtOAc/Hexane - continuous gradient from 0% to 100% EtOAc over 30 min, at 20 mL/min) to give the title compound (328 mg, 88 % yield). 1H NMR (500 MHz, CDCl 3) δ 10.74 (s, 1H), 8.35 (d, J=8.80 Hz, 1H), 7.46 (d, J=8.80 Hz, 1H), 5.22-5.57 (m, 2H), 4.81 (t, J=3.58 Hz, 1H), 4.52 (dq, J=2.06, 7.11 Hz, 2H), 4.19 (s, 3H), 3.93 (br s, 1H), 3.84 (ddd, J=2.61, 8.32, 11.07 Hz, 1H), 3.43-3.60 (m, 1H), 1.48-2.06 (m, 9H) 271C. 2-(2-hydroxypropanyl)(1-methyl(((tetrahydro-2H-pyran yl)oxy)methyl)-1H-1,2,3-triazolyl)pyridinol To a solution of Example 271B (0.3g, 0.828 mmol) in THF (7 mL) was added dropwise r (1.95 mL of a 3.5 M solution in THF, 6.62 mmol) at 0oC. The resulted mixture was allowed to warm to rt and d at rt for 3 h. Satd aq. NH4Cl was then carefully added to quench the reaction, which was extracted with EtOAc. The aqueous layer was carefully adjusted to pH 6 by using 1 N aq. HCl, then ted again with EtOAc (2X). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was chromatographed (24 g SiO2; EtOAc/Hexane - uous gradient from 0% to 100% EtOAc over 30 min, at 10 mL/min) to give the title compound (110 mg, 0.316 mmol, 38.1 % yield).
Example 271.
Example 271C was converted to Example 271 by a similar sequence used to convert Example 1C to Example 1. 1H NMR (500 MHz, DMSO-d6) δ 7.96 (d, J=8.54 Hz, 1H), 7.59 (br d, J=8.54 Hz, 1H), .49 (s, 2H), 4.85 (br s, 1H), 4.13 (br s, 2H), 3.79 (br d, J=16.78 Hz, 1H), 3.07-3.26 (m, 2H), 2.88 (s, 1H), 2.68-2.75 (m, 2H), 2.55 (s, 3H), 1.19-2.16 (m, 20H). LCMS, [M+H]+ = 516.3. hLPA1 IC50 = 225 nM Example 272. (1S,3S)((2-Methoxy(1-methyl(((methyl(propyl)carbamoyl)oxy)methyl)-1H- 1,2,3-triazolyl)pyridinyl)oxy)cyclohexanecarboxylic acid Example 272 was synthesized from 3,6-dibromo(methoxy)pyridine using the same tic sequence as for the preparation of Example 1 from bromopyridine.
LCMS, [M+H]+ = 462.1; 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J=8.0 Hz, 1H), 7.33 - 7.30 (m, 1H), 5.79 (br s, 2H), 4.72 - 4.67 (m, 1H), 4.18 (s, 3H), 4.04 (s, 3H), 3.25 (br t, J=7.3 Hz, 1H), 3.18 - 3.07 (m, 1H), 3.06 - 2.95 (m, 1H), 2.92 (s, 1.5H), 2.83 (s, 1.5H), 2.16 - 2.07 (m, 2H), 2.05 - 1.83 (m, 4H), 1.79 - 1.68 (m, 2H), 1.68 - 1.52 (m, 2H), 1.50 - 1.33 (m, 1H), 0.95 - 0.85 (m, 1.5H), 0.76 (br t, J=7.2 Hz, 1.5H) hLPA1 IC50 = 4 nM The following examples were synthesized according to the procedures described above.
Example Structure & Name Analytical & Biology Data Method LCMS, [M+H]+ = 512.4 1H NMR (500 MHz, DMSO- Example d6) δ 8.33 (br d, J=8.85 Hz, 269 1H), 7.87-8.11 (m, 1H), 5.62 (br d, 9 Hz, 2H), 5.06 (br s, 1H), 4.18 (s, 2H), 2.69- 3.38 (m, 6H), 2.11 (br d, J=13.43 Hz, 1H), 1.78-2.02 (1S,3S)((6-(5- (m, 3H), 1.44-1.76 (m, 3H), ((((cyclopropylmethyl)(methyl)ca .35 (m, 1H), 1.05 (d, rbamoyl)oxy)methyl)methyl- J=6.10 Hz, 1H), 0.71-0.97 (m, 1H-1,2,3-triazolyl) 1H), 0.47 (br s, 1H), 0.30 (br (trifluoromethyl)pyridin s, 2H), 0.13-0.26 (m, 1H) yl)oxy)cyclohexanecarboxylic hLPA1 IC50 = 7 nM. 1H NMR (500 MHz, DMSO- d6) δ 8.27 (br d, J=8.54 Hz, Example 1H), 7.95 (br d, J=8.85 Hz, 269 1H), 5.57 (br d, J=13.43 Hz, 2H), 5.01 (br s, 1H), 4.13 (s, 2H), 2.97-3.21 (m, 2H), 2.93 274 (q, J=7.22 Hz, 2H), 2.65-2.79 (m, 3H), 1.21-2.13 (m, 8H), (1S,3S)((6-(1-methyl 1.17 (t, J=7.17 Hz, 3H), 0.50- (((methyl(propyl)carbamoyl)oxy) 0.85 (m, 2H) methyl)-1H-1,2,3-triazolyl) LCMS, [M+H]+ = 499.9 (trifluoromethyl)pyridinyl) hLPA1 IC50 = 28 nM. oxy)cyclohexanecarboxylic 1H NMR (500 MHz, DMSO- d6) δ 8.27 (br d, J=8.85 Hz, Example 1H), 7.94 (br d, J=8.85 Hz, 269 1H), 5.55 (br d, J=12.82 Hz, 2H), 5.00 (br s, 1H), 4.13 (br s, 3H), 2.99-3.23 (m, 2H), 275 2.92 (q, J=7.32 Hz, 1H), 2.74 (br s, 1H), 2.70 (br s, 2H), (1S,3S)((6-(5- 1.33-2.13 (m, 10H), 1.08-1.27 (((butyl(methyl)carbamoyl)oxy)m (m, 3H), 0.91-1.00 (m, 1H), methyl-1H-1,2,3-triazol- 0.85 (br s, 1H), 0.61 (br s, 2H) 2-(trifluoromethyl)pyridin- LCMS, [M+H]+ = 514.1 3-yl)oxy)cyclohexane hLPA1 IC50 = 5.6 nM. carboxylic acid Example Structure & Name Analytical & Biology Data Method 1H NMR (500 MHz, DMSO- d6) δ 8.27 (d, J=8.84 Hz, 1H), Example 7.96 (d, J=9.00 Hz, 1H), 5.56 269 (br s, 2H), 5.01 (br s, 1H), 4.13 (s, 3H), 3.65 (m, 1H), 2.54-2.70 (m, 4H), 1.73-2.14 276 (m, 4H), 1.25-1.71 (m, 12H) LCMS, [M+H]+ = 526.5 (1S,3S)((6-(5- hLPA1 IC50 = 15 nM. (((cyclopentyl(methyl)carbamoyl) oxy)methyl)methyl-1H-1,2,3- triazolyl)(trifluoro methyl)pyridinyl)oxy) exanecarboxylic acid 1H NMR (500 MHz, DMSO- d6) δ 8.16 (br d, J=8.24 Hz, Example 1H), 7.82 (br d, J=8.85 Hz, 267 1H), 7.01-7.34 (m, 1H), 5.62 (br d, J=13.12 Hz, 2H), 4.94 (br s, 1H), 4.13 (s, 3H), 2.95- 277 3.22 (m, 2H), 2.75 (br d, (1S,3S)((2-(difluoromethyl) J=16.78 Hz, 3H), 2.66 (br t, (1-methyl J=10.68 Hz, 1H), 2.06 (br d, (((methyl(propyl)carbamoyl)oxy) J=13.43 Hz, 1H), 1.39-1.95 methyl)-1H-1,2,3-triazol (m, 8H), 1.18-1.34 (m, 2H), idinyl)oxy)cyclohexane- .88 (m, 3H) 1-carboxylic acid LCMS, [M+H]+ = 482.2 hLPA1 IC50 = 35 nM 1H NMR (500 MHz, DMSO- d6) δ 8.16 (d, J=8.85 Hz, 1H), Example 7.82 (br d, J=8.85 Hz, 1H), 267 6.87-7.22 (m, 1H), 5.62 (br d, 9 Hz, 2H), 4.93 (br s, 1H), 4.13 (br s, 3H), 2.96- 278 3.29 (m, 2H), 2.61-2.87 (m, 4H), 0.52-2.18 (m, 15H) (1S,3S)((6-(5- (((butyl(methyl)carbamoyl)oxy)m LCMS, [M+H]+ = 496.2 ethyl)methyl-1H-1,2,3-triazol- hLPA1 IC50 = 22 nM 4-yl)(difluoromethyl)pyridin- 3-yl)oxy)cyclohexane carboxylic acid Example Structure & Name Analytical & Biology Data Method 1H NMR (500 MHz, DMSO- d6) δ 8.16 (d, J=8.75 Hz, 1H), Example 7.80 (d, J=8.92 Hz, 1H), 6.84- 267 7.23 (m, 1H), 5.63 (s, 2H), 4.92 (br s, 1H), 4.13 (s, 3H), 2.83 (s, 2H), 2.61-2.74 (m, 279 1H), 2.55 (s, 3H), 2.01-2.17 (m, 1H), 1.40-1.95 (m, 7H), (1S,3S)((6-(5- 1.25 (s, 1H), -0.16-0.98 (m, clopropylmethyl)(methyl)ca 5H) rbamoyl)oxy)methyl)methyl- LCMS, [M+H]+ = 494.2 1H-1,2,3-triazolyl) hLPA1 IC50 = 21 nM (difluoromethyl)pyridinyl)oxy) cyclohexanecarboxylic acid 1H NMR (500 MHz, DMSO- d6) δ 8.16 (d, J=8.75 Hz, 1H), Example 7.80 (d, J=8.92 Hz, 1H), 6.89- 267 7.22 (m, 1H), 5.62 (s, 2H), 4.92 (br s, 1H), 2.74 (s, 3H), 2.60-2.72 (m, 1H), 2.55 (s, 280 3H), 1.79 (d, J=123.19 Hz, (1S,3S)((6-(5- LCMS, [M+H]+ = 494.2 (((cyclobutyl(methyl)carbamoyl)o hLPA1 IC50 = 22 nM xy)methyl)methyl-1H-1,2,3- triazolyl)(difluoromethyl) nyl)oxy)cyclohexane carboxylic acid 1H NMR (500 MHz, DMSO- d6) δ 8.16 (d, J=8.85 Hz, 1H), Example 7.82 (br d, J=8.85 Hz, 1H), 267 6.88-7.19 (m, 1H), 5.62 (br d, J=10.99 Hz, 2H), 4.93 (br s, 1H), 4.02-4.24 (m, 3H), 2.97- 281 3.34 (m, 2H), .85 (m, 4H), -0.24-2.48 (m, 16H) (1S,3S)((6-(5- LCMS, [M+H]+ = 508.2 (((cyclopentyl(methyl)carbamoyl) hLPA1 IC50 = 35 nM oxy)methyl)methyl-1H-1,2,3- triazolyl)(difluoromethyl) pyridinyl)oxy)cyclohexane carboxylic acid Example Structure & Name Analytical & Biology Data Method 1H NMR (500 MHz, DMSO- d6) δ 8.16 (br d, J=8.75 Hz, Example 1H), 7.80 (br d, J=8.84 Hz, 267 1H), 6.85-7.47 (m, 6H), 5.69 (br s, 2H), 4.91 (br s, 1H), 4.37 (br s, 2H), 4.07 (br d, 282 J=14.22 Hz, 3H), 2.61-2.89 (m, 4H), 1.42-2.16 (m, 8H) (1S,3S)((6-(5- LCMS, [M+H]+ = 530.9 (((benzyl(methyl)carbamoyl)oxy) hLPA1 IC50 = 19 nM methyl)methyl-1H-1,2,3- triazolyl) (difluoromethyl)pyridin yl)oxy)cyclohexanecarboxylic 1H NMR (500 MHz, DMSO- d6) δ 7.97 (br d, J=7.02 Hz, Example 1H), 7.61 (br d, J=8.54 Hz, 268 1H), 5.66 (br d, J=8.54 Hz, 2H), 4.84 (br s, 2H), 4.54 (br d, J=2.75 Hz, 2H), 4.11 (s, 283 3H), 3.34 (s, 1H), .22 (m, 2H), 2.71-2.86 (m, 3H), .70 (m, 1H), 1.23-2.13 (1S,3S)((2-(methoxymethyl)- (m, 10H), 1.01 (d, J=6.41 Hz, 6-(1-methyl(((methyl(propyl) 1H), 0.56-0.87 (m, 3H) carbamoyl)oxy)methyl)-1H-1,2,3- LCMS, [M+H]+ = 476.2 lyl)pyridinyl)oxy) hLPA1 IC50 = 475 nM cyclohexanecarboxylic acid 1H NMR (500 MHz, DMSO- d6) δ 7.98 (br d, J=8.85 Hz, Example 1H), 7.61 (br d, J=8.85 Hz, 268 1H), 5.66 (br d, J=8.85 Hz, 2H), 4.84 (br s, 1H), 4.54 (d, J=2.44 Hz, 2H), 4.11 (s, 3H), 284 3.00-3.28 (m, 2H), 2.61-2.85 (m, 4H), 0.57-2.16 (m, 18H) LCMS, [M+H]+ = 490.3 (1S,3S)((6-(5-(((butyl(methyl) hLPA1 IC50 = 48 nM carbamoyl)oxy)methyl) methyl-1H-1,2,3-triazolyl) (methoxymethyl)pyridinyl) oxy)cyclohexanecarboxylic Example ure & Name Analytical & Biology Data Method 1H NMR (500 MHz, DMSO- d6) δ 7.98 (br d, J=8.54 Hz, Example 1H), 7.60 (br d, J=8.54 Hz, 268 1H), 5.66 (br d, J=12.82 Hz, 2H), 4.82 (br s, 1H), 4.42- 4.65 (m, 2H), 4.12 (s, 3H), 285 2.92-3.22 (m, 2H), 2.61-2.89 (m, 4H), 0.64-2.16 (m, 14H), -0.11-0.53 (m, 4H) (1S,3S)((6-(5-((((cyclopropyl LCMS, [M+H]+ = 488.3 methyl)(methyl)carbamoyl)oxy)m hLPA1 IC50 = 1008 nM ethyl)methyl-1H-1,2,3-triazol- 4-yl)(methoxymethyl)pyridin- 3-yl)oxy)cyclohexane ylic acid 1H NMR (500 MHz, DMSO- d6) δ 7.96 (br d, J=8.54 Hz, Example 1H), 7.60 (br d, J=8.85 Hz, 268 1H), 5.63 (s, 2H), 4.82 (br s, 1H), 4.52 (br s, 2H), 4.09 (s, 3H), 3.32 (s, 3H), .81 286 (m, 4H), 1.26-2.24 (m, 15H) LCMS, [M+H]+ = 488.3 hLPA1 IC50 = 92 nM (1S,3S)((6-(5-(((cyclobutyl (methyl)carbamoyl)oxy)methyl)- 1-methyl-1H-1,2,3-triazolyl)- 2-(methoxymethyl) pyridinyl) oxy)cyclohexanecarboxylic 1H NMR (500 MHz, DMSO- d6) δ 7.98 (d, J=8.54 Hz, 1H), Example 7.61 (d, J=8.85 Hz, 1H), 5.66 268 (s, 2H), 4.84 (br s, 1H), 4.54 (d, J=2.75 Hz, 2H), 4.11 (s, 3H), 3.91 (s, 1H), 2.73-2.92 287 (m, 1H), 2.65 (br s, 3H), 2.56 (s, 1H), 1.24-2.12 (m, 17H) (1S,3S)((6-(5- LCMS, [M+H]+ = 502.3 (((cyclopentyl(methyl)carbamoyl) hLPA1 IC50 = 118 nM oxy)methyl)methyl-1H-1,2,3- triazolyl)(methoxymethyl) pyridinyl)oxy)cyclohexane carboxylic acid Example Structure & Name Analytical & Biology Data Method 1H NMR (500 MHz, CDCl3) δ 8.12 (br d, J=8.53 Hz, 1H), Example 7.95 (br s, 1H), 5.39-5.59 (m, 93 2H), 4.87 (br s, 1H), 4.20 (br s, 3H), 3.23 (br s, 2H), 2.84 (br s, 1H), 2.68-2.79 (m, 3H), 1.46-2.19 (m, 10H), 0.88 (br s, 3H) )((2-methyl(1- LCMS, [M+H]+ = 449.1 methyl((((methyl-d3)(propyl) hLPA1 IC50 = 29 nM carbamoyl)oxy)methyl)-1H-1,2,3- triazolyl)pyridinyl)oxy) cyclohexanecarboxylic acid 1H NMR (500 MHz, DMSO- d6) δ 8.29 (d, J=8.85 Hz, 1H), Example 7.98 (br d, J=9.16 Hz, 1H), 270 .45-5.65 (m, 2H), 4.99 (br s, 1H), 4.12 (s, 3H), 2.91-3.14 (m, 2H), 2.83 (br s, 3H), 2.56- 289 2.69 (m, 1H), 1.41-2.04 (m, 8H), 0.71-1.03 (m, 1H), -0.08- (1S,3S)((2-cyano(5- 0.50 (m, 4H) ((((cyclopropylmethyl)(methyl)ca LCMS, [M+H]+ = 469.1 rbamoyl)oxy)methyl)methyl- hLPA1 IC50 = 40 nM 1H-1,2,3-triazolyl)pyridin yl)oxy)cyclohexanecarboxylic 1H NMR (500 MHz, DMSO- d6) δ 8.30 (br s, 1H), 7.92 (br Example d, J=9.77 Hz, 1H), 6.91-7.38 270 (m, 5H), 5.47-5.72 (m, 2H), .00 (br s, 1H), .50 (m,3H), 3.94-4.20 (m, 2H), 290 .88 (m, 4H), 1.37-2.18 (m, 8H) (1S,3S)((6-(5- LCMS, [M+H]+ = 505.3 (((benzyl(methyl)carbamoyl)oxy) hLPA1 IC50 = 2 nM methyl)methyl-1H-1,2,3- triazolyl)cyanopyridin yl)oxy)cyclohexanecarboxylic Example Structure & Name ical & Biology Data Method 1H NMR (500 MHz, DMSO- d6) δ 8.30 (br d, J=8.85 Hz, e 1H), 7.98 (d, J=9.16 Hz, 1H), 270 .40-5.65 (m, 2H), 5.00 (br s, 1H), 4.13 (br s, 3H), 2.99- 3.29 (m, 2H), 2.70-2.83 (m, 291 3H), 2.62 (br t, J=9.92 Hz, 1H), 0.59-2.17 (m, 15H) (1S,3S)((6-(5- LCMS, [M+H]+ = 471.3 (((butyl(methyl)carbamoyl)oxy)m hLPA1 IC50 = 15 nM methyl-1H-1,2,3-triazol- 4-yl)cyanopyridin yl)oxy)cyclohexanecarboxylic 1H NMR (500 MHz, DMSO- d6) δ 8.24-8.45 (m, 1H), 8.30 Example (br d, J=8.67 Hz, 1H), 7.97 270 (br d, J=9.09 Hz, 1H), 5.43- .68 (m, 2H), 5.01 (br s, 1H), 4.05-4.22 (m, 3H), 3.56 (br s, 292 1H), 3.05-3.30 (m, 2H), 2.66- 2.83 (m, 3H), 1.09-2.37 (m, (1S,3S)((2-cyano(5- 15H) ((((cyclobutylmethyl)(methyl)car LCMS, [M+H]+ = 483.2 bamoyl)oxy)methyl)methyl- hLPA1 IC50 = 20 nM 1H-1,2,3-triazolyl)pyridin yl)oxy)cyclohexanecarboxylic 1H NMR (500 MHz, DMSO- d6) δ 8.30 (d, J=9.16 Hz, 1H), Example 7.97 (br d, J=9.16 Hz, 1H), 270 .52 (br s, 2H), 5.00 (br s, 1H), 4.12 (s, 3H), 3.40-3.67 (m, 1H), 2.74 (br s, 3H), 2.57- 293 2.66 (m, 1H), 1.29-2.22 (m, (1S,3S)((2-cyano(5- LCMS, [M+H]+ = 469.3 (((cyclobutyl(methyl)carbamoyl)o hLPA1 IC50 = 23 nM xy)methyl)methyl-1H-1,2,3- triazolyl)pyridin yl)oxy)cyclohexanecarboxylic Example Structure & Name Analytical & Biology Data Method 1H NMR (500 MHz, DMSO- d6) δ 8.29 (d, J=8.85 Hz, 1H), Example 7.97 (br d, J=9.16 Hz, 1H), 270 .52 (br s, 2H), 5.00 (br s, 1H), 4.12 (s, 3H), .69 (m, 1H), 2.65 (br s, 3H), 2.60 294 (br s, 1H), 1.22-2.11 (m, 16H) LCMS, [M+H]+ = 483.3 (1S,3S)((2-cyano(5- hLPA1 IC50 = 15 nM (((cyclopentyl(methyl)carbamoyl) oxy)methyl)methyl-1H-1,2,3- triazolyl)pyridinyl)oxy) cyclohexanecarboxylic acid

Claims (38)

WHAT IS D IS:
1. A compound according to Formula (I): 10 or stereoisomers, tautomers, a pharmaceutically acceptable salts, or solvates thereof, wherein R2 is independently selected from H and C1-4 alkyl substituted with 1-5 R9; R13 is independently selected from H, D, and C1-4 alkyl substituted with 1-3 R9; R3 and R4 are independently selected from H, C1-7 alkyl substituted with 1-3 R9, 15 -(CR7R7)r-C3-8 cycloalkyl tuted with 1-3 R8, -(CR7R7)r-aryl substituted with 1-3 R8, C2-7alkenyl tuted with 1-3 R9, 7)r6 membered cyclic ring substituted with 1-3 R8, -(CR7R7)r6 membered heteroaryl ring substituted with 1-3 R8, or R3 and R4 combine with the N to which they are attached to form a 4-9 membered heterocyclic ring substituted with 1-3 R8; 20 X1, X2, X3, and X4 are independently selected from CR5 and N; provided no more than two of X1, X2, X3, or X4 are N; R5 is independently selected from H, F, Cl, OR7, CN, N(R7)2, C1-4 alkyl substituted with 1-5 R9, C1-4 alkoxy substituted with 1-5 R9, and C1-4 heteroalkyl substituted with 1-5 R9; R6 is C3-8 cycloalkyl which is substituted with R10 and (–CH2)0-1R11; R7 is independently selected from H, C1-4 alkyl, and C3-6 cycloalkyl; or R7 and R7, together with the carbon atom to which they both attach, form a C3-6 cycloalkyl ring; R8 is independently selected from H, D, C1-6 alkyl substituted with 1-5 R9, C2-6 alkenyl, 5 C2-6 alkynyl, phenyl, -(CH2)r-C3-6 cycloalkyl, F, Cl, Br, CN, COOH, and C1-4 alkoxy; R9 is independently selected from H, D, F, Cl, NH2, OH, OC1-5alkyl, C1-5alkyl, C1-5 heteroalkyl C3-6 cycloalkyl, and phenyl, wherein when R9 is Cl, NH2 or OH it is not substituted on C1 of the the alkyl to which it is attached; R10 is independently selected from H, D, C1-4 alkyl, F, Cl, Br, OR7, )OR7, and 10 NHC(=O)OR7; R11 is independently ed from H, CN, –C(=O)R12, tetrazolyl, , and R12 is ndently selected from OH, OC1-4 alkyl, NH2, NHCH2CH2SO3H, and NHSO2C1-4alkyl; 15 r is independently selected from zero, 1, 2, 3, and 4, and n is slected from 1, 2, 3, or 4.
2. The compound of claim 1, wherein R3 and R4 are independently selected from H, C1-7 alkyl substituted with 1-3 R9, 20 -(CR7R7)r-C3-8 lkyl substituted with 1-3 R8, -(CR7R7)r-aryl substituted with 1-3 R8, C2-7alkenyl substituted with 1-3 R9, -(CR7R7)r6 membered heterocyclic ring substituted with 1-3 R8, -(CR7R7)r6 membered heteroaryl ring substituted with 1-3 R8, and R3 and R4 combine with the N to which they are attached to form the following: , , , , , , , , , 5 , , or , each of which may be substituted with 1-3 R8, and n equals 1 or 2.
3. The nd according to claim 1 wherein, 10 R3 and R4 are independently selected from H, C1-7 alkyl substituted with 1-3 R9, -(CR7R7)r-C3-8 cycloalkyl substituted with 1-3 R8, -(CR7R7)r-aryl substituted with 1-3 R8, C2-7alkenyl substituted with 1-3 R9, , , , , , , , , , 5 each of which can be substituted with 1-3 R8, and R3 and R4 combine with the N to which they are attached to form a 4-9 ed heterocyclic ring substituted with 1-3 R8; and n equals 1 or 2. 10
4. A compound according to claim 1 of Formula (II): or an enantiomer, a diastereomer, a stereoisomer, a ceutically acceptable salt thereof, wherein R2 is independently selected from H and C1-4 alkyl substituted with 1-5 R9; 15 R13 is independently selected from H, D, and C1-4 alkyl substituted with 1-3 R9; R3 and R4 are independently selected from H, C1-7 alkyl substituted with 1-3 R9, -(CR7R7)r-C3-6 cycloalkyl substituted with 1-3 R8, and -(CR7R7)r-aryl substituted with 1-3 R8; X1, X2, X3, and X4 are independently selected from CR5 and N; ed no more than 5 two of X1, X2, X3, or X4 are N; R5 is independently selected from H, F, Cl, OR7, CN, , C1-4 alkyl substituted with 1-5 R9, C1-4 alkoxy substituted with 1-5 R9, and C1-4 heteroalkyl substituted with 1-5 R9; 10 R6 is ; R7 is independently selected from H, C1-4 alkyl, and C3-6 cycloalkyl; or R7 and R7, together with the carbon atom to which they both attach, form a C3-6 cycloalkyl ring; R8 is independently selected from H, C1-6 alkyl substituted with 1-5 R9, C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3-6 cycloalkyl, F, Cl, Br, CN, and COOH; 15 R9 is independently selected from H, F, Cl, NH2, OH, lkyl, C1-5alkyl, C1-5 heteroalkyl C3-6 cycloalkyl, and phenyl wherein when R9 is Cl, NH2 or OH it is not substituted on C1 of the the alkyl to which it is attached; R10 is independently ed from H, D, C1-4 alkyl, F, Cl, Br, OR7, NHC(=O)OR7, and NHC(=O)OR7; 20 R11 is ndently selected from CN, –C(=O)R12, tetrazolyl, , and R12 is independently selected from OH, OC1-4 alkyl, NH2, NHCH2CH2SO3H, and NHSO2C1-4alkyl; r is independently selected from zero, 1, 2, 3, and 4.
5. The compound of claim 4 having Formula (III): (III) or an enantiomer, a diastereomer, a stereoisomer, a pharmaceutically acceptable salt thereof, wherein R2 is independently ed from CH3 and CD3; 5 R13 is independently selected from H and C1-4 alkyl; R3 is independently selected from H and C1-4 alkyl; R4 is independently selected from C1-6 alkyl substituted with 1-3 R9, -(CR7R7)r-C3-6 cycloalkyl substituted with 1-3 R8, and -(CR7R7)r-aryl substituted with 1-3 R8; R5 is independently selected from H, F, Cl, CN and C1-4 alkyl; provided one of R5 is H; 10 R6 is ; R7 is independently ed from H, C1-4 alkyl, and C3-6 cycloalkyl; or R7 and R7, together with the carbon atom to which they both attach, form a C3-6 cycloalkyl ring; R8 is independently selected from H, C1-6 alkyl substituted with 1-5 R9, C3-6 cycloalkyl, F, Cl, Br, CN, =O, and COOH; 15 R9 is independently selected from H, F, Cl, NH2, OH, OC1-5alkyl, C1-5alkyl, C3-6 lkyl, and phenyl wherein when R9 is Cl, NH2 or OH it is not substituted on C1 of the the alkyl to which it is attached; R10 is ndently selected from H, D, C1-4 alkyl, and F; R11 is independently selected from CN, –C(=O)R12, and tetrazolyl; 20 R12 is independently selected from OH, OC1-4 alkyl, NH2, and NHSO2C1-4alkyl; and r is independently selected from zero, 1, 2, 3, and 4.
6. The compound of claim 5, having Formula (IV): or an enantiomer, a diastereomer, a stereoisomer, a pharmaceutically able salt thereof, wherein 5 R2 is independently selected from CH3 and CD3; R13 is independently selected from H and C1-4 alkyl; R3 is independently selected from H and C1-4 alkyl; R4 is independently selected from C1-6 alkyl, , , , 10 , and ; R5 is independently selected from H, F, Cl, and C1-4 alkyl; provided one of R5 is H; R7 is independently selected from H, C1-4 alkyl, and C3-6 cycloalkyl; R8 is independently selected from H, C1-6 alkyl substituted with 1-5 R9, C3-6 cycloalkyl, F, Cl, Br, CN, =O, and COOH; 15 R9 is independently selected from H, F, Cl, NH2, OH, OC1-5alkyl, kyl, C3-6 cycloalkyl, and phenyl wherein when R9 is Cl, NH2 or OH it is not substituted on C1 of the the alkyl to which it is ed; R10 is independently selected from H, D, C1-4 alkyl, and F; R11 is independently selected from CN, –C(=O)R12, and ; and R12 is independently selected from OH and NHSO2C1-4alkyl.
7. The compound of claim 6 or an omer, a diastereomer, a 5 stereoisomer, a pharmaceutically acceptable salt f, wherein R4 is independently selected from , , , , , , , , , , , , , , , , , 10 , , , , , , and ; and R8 is independently selected from H, F, Cl, Br, CN, and C1-4 alkyl.
8. The compound of claim 7 having Formula (V): or an enantiomer, a diastereomer, a stereoisomer, a pharmaceutically acceptable salt thereof, wherein R2 is independently selected from CH3 and CD3; 5 R13 is ndently selected from H and CH3; R3 is independently selected from H and CH3; R4 is independently selected from , , , , , , , , , , , , 10 , , , , , , , , , , , and ; and R5 is independently selected from H, F, and C1-4 alkyl; R8 is independently selected from H, F, Cl, Br, CN, and C1-4 alkyl; R10 is independently selected from H, D, and F; and R11 is independently selected from–C(=O)OH, and –C(=O)NHSO2Me. 5
9. The compound of claim 7 having Formula (VI): or an enantiomer, a diastereomer, a stereoisomer, a pharmaceutically able salt thereof, wherein R2 is ndently selected from CH3 and CD3; 10 R13 is independently selected from H and CH3; R3 is independently selected from H and CH3; R4 is independently selected from , , , , , , , , , , , 15 , , and ; R5 is independently selected from H and CH3; and R8 is independently selected from H, F, Cl, Br, CN, and C1-4 alkyl.
10. The nd of claim 4 having Formula (VII): (VII) 5 or an enantiomer, a diastereomer, a stereoisomer, a pharmaceutically acceptable salt thereof, wherein R2 is independently selected from CH3 and CD3; R13 is independently selected from H and C1-4 alkyl; R3 is independently selected from H and C1-4 alkyl; 10 R4 is independently selected from C1-6 alkyl tuted with 1-3 R9, (CR7R7)r-C3-6 cycloalkyl substituted with 1-3 R8, and -(CR7R7)r-aryl substituted with 1-3 R8; R5 is independently selected from H, F, Cl, CN, and C1-4 alkyl; R6 is ; R7 is independently selected from H, C1-4 alkyl, and C3-6 cycloalkyl; or R7 and R7, together 15 with the carbon atom to which they both attach, form a C3-6 cycloalkyl ring; R8 is independently selected from H, C1-6 alkyl substituted with 1-5 R9, C3-6 cycloalkyl, F, Cl, Br, CN, =O, and COOH; R9 is independently selected from H, F, Cl, NH2, OH, OC1-5alkyl, kyl, C3-6 cycloalkyl, and phenyl, n when R9 is Cl, NH2 or OH it is not substituted on 20 C1 of the the alkyl to which it is attached; R10 is independently selected from H, C1-4 alkyl, and F; R11 independently selected from–C(=O)R12 and tetrazolyl; R12 is independently selected from OH and 1-4alkyl; and r is independently selected from zero, 1, 2, 3, and 4.
11. The compound of claim 10, or an enantiomer, a diastereomer, a stereoisomer, a ceutically acceptable salt thereof, wherein R2 is ndently selected from CH3 and CD3; R13 is independently selected from H and CH3; 10 R3 is independently selected from H and CH3; R4 is independently selected from C1-6 alkyl, , , , , and ; R5 is independently selected from H, F, Cl, and C1-4 alkyl; 15 R6 is R7 is independently selected from H, C1-4 alkyl, and C1-6 cycloalkyl; and R8 is independently selected from H, F, Cl, Br, CN, and C1-4 alkyl. 20
12. The compound of claim 10 having Formula (VIII): (VIII) or an enantiomer, a diastereomer, a stereoisomer, a pharmaceutically acceptable salt thereof, wherein R2 is independently selected from CH3 and CD3; 5 R13 is independently selected from H and CH3; R3 is independently selected from H and CH3; R4 is independently ed from , , , , , , , , , , , , 10 , , , , , , , , , , , and ; R5 is independently selected from H, F, and CH3; and R8 is independently selected from H, F, Cl, Br, CN, and C1-4 alkyl.
13. The compound of claim 4 having Formula (IX): 5 or an enantiomer, a diastereomer, a stereoisomer, a pharmaceutically acceptable salt thereof, wherein R2 is ndently ed from CH3 and CD3; R13 is independently selected from H and C1-4 alkyl; R3 is ndently selected from H and C1-4 alkyl; 10 R4 is independently selected from C1-6 alkyl substituted with 1-3 R9, (CR7R7)r-C3-6 cycloalkyl substituted with 1-3 R8, and -(CR7R7)r-aryl substituted with 1-3 R8; R5 is independently selected from H, F, Cl, CN, and C1-4 alkyl; R6 is ; R7 is independently selected from H, C1-4 alkyl, and C3-6 cycloalkyl; or R7 and R7, together 15 with the carbon atom to which they both attach, form a C3-6 cycloalkyl ring; R8 is independently selected from H, C1-6 alkyl tuted with 1-5 R9, C3-6 cycloalkyl, F, Cl, Br, CN, =O, and COOH; R9 is independently selected from H, F, Cl, NH2, OH, OC1-5alkyl, C1-5alkyl, C3-6 cycloalkyl, and phenyl, wherein when R9 is Cl, NH2 or OH it is not substituted on 20 C1 of the the alkyl to which it is attached; R10 is independently ed from H and F; R11 is independently selected from–C(=O)R12 and tetrazolyl; R12 is independently selected from OH and –C(=O)NHSO2Me; and r is independently selected from zero, 1, 2, 3, and 4.
14. The compound of claim 4, wherein said compound is selected from the group of: , , , 10 , , , , , , , , , , , , , or an omer, a diastereomer, a stereoisomer, or a 5 pharmaceutically acceptable salt thereof.
15. The compound of claim 4, wherein said compound is selected from the group of: , , , , , , , , and , or an enantiomer, a diastereomer, a stereoisomer, or a pharmaceutically acceptable salt thereof.
16. The compound of any one of claims 1-8, wherein said compound has the formula: , an enantiomer, a diastereomer, a stereoisomer, or a ceutically acceptable salt thereof.
17. The compound of any one of claims 1-8, wherein said compound has the formula: 10 , an omer, a diastereomer, a isomer, or a pharmaceutically acceptable salt thereof.
18. The compound of any one of claims 1-8, wherein said compound has the formula: , an enantiomer, a diastereomer, a stereoisomer, or a ceutically acceptable salt thereof.
19. The compound of any one of claims 1-8, wherein said compound has the formula: 5 , an enantiomer, a diastereomer, a stereoisomer, or a pharmaceutically acceptable salt thereof.
20. The compound of any one of claims 1-8, wherein said compound has the a: , an enantiomer, a diastereomer, a stereoisomer, or a 10 pharmaceutically acceptable salt f.
21. The compound of any one of claims 1-8, wherein said compound has the formula: , an enantiomer, a diastereomer, a stereoisomer, or a pharmaceutically acceptable salt f.
22. The compound of any one of claims 1-8, wherein said compound has the formula: , an enantiomer, a diastereomer, a stereoisomer, or a pharmaceutically acceptable salt thereof.
23. The nd of any one of claims 1-8, wherein said compound has the formula: , or an enantiomer, a diastereomer, a stereoisomer, or a pharmaceutically acceptable salt thereof.
24. The nd of any one of claims 1-8, wherein said compound has the formula: , an enantiomer, a reomer, a stereoisomer, or a pharmaceutically acceptable salt thereof.
25. The compound of any one of claims 1-8, wherein said compound has the formula: , an enantiomer, a diastereomer, a stereoisomer, or a pharmaceutically acceptable salt thereof.
26. A compound of Formula (X): 10 (X) or an enantiomer, a diastereomer, or a stereoisomer f, wherein R20 is independently C1-6 alkyl or H; R21 is independently C1-6 alkyl or H; X5 and X6 are independently CH or N; and X7 is Br. 5
27. The compound of claim 26 having Formula (XI): (XI), or an enantiomer, a diastereomer, or a stereoisomer f.
28. A pharmaceutical composition comprising one or more compounds ing to any one of claims 1-25 and a ceutically acceptable carrier or diluent.
29. A compound according to any one of claims 1-25 for use in therapy.
30. A method of treating fibrosis in a mammal comprising stering a therapeutically effective amount of a compound according to any one of claims 1-25 or a pharmaceutically acceptable salt thereof to the mammal in need thereof, wherein the mammal is not a human.
31. A method of treating lung fibrosis (idiopathic pulmonary fibrosis), asthma, chronic ctive pulmonary disease (COPD), renal fibrosis, acute kidney injury, chronic kidney e, liver fibrosis (non-alcoholic steatohepatitis), skin fibrosis, fibrosis of the gut, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, bowel cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, cancer pain, tumor metastasis, lant organ rejection, derma, ocular fibrosis, age related macular degeneration (AMD), ic retinopathy, collagen vascular e, atherosclerosis, Raynaud’s enon, or 5 neuropathic pain in a mammal comprising administering a therapeutically effective amount of a compound according to any one of claims 1-25 or a pharmaceutically acceptable salt thereof to the mammal in need thereof, wherein the mammal is not a human. 10
32. Use of a compound according to any one of claims 1-25 or a ceutically able salt thereof in the manufacture of a medicament for treating fibrosis in a mammal.
33. Use of a compound ing to any one of claims 1-25 or a 15 pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating lung fibrosis (idiopathic pulmonary fibrosis), asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute kidney injury, chronic kidney e, liver fibrosis (non-alcoholic steatohepatitis), skin fibrosis, fibrosis of the gut, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon , bowel 20 , head and neck cancer, melanoma, multiple myeloma, chronic cytic leukemia, cancer pain, tumor metastasis, transplant organ rejection, scleroderma, ocular fibrosis, age related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atherosclerosis, Raynaud’s phenomenon, or neuropathic pain in a mammal. 25
34. A compound according to claim 1, 4, or 26, substantially as herein described with reference to any example thereof.
35. A pharmaceutical composition according to claim 28, substantially as 30 herein described with reference to any example thereof.
36. A compound for use according to claim 29, substantially as herein described with nce to any example thereof.
37. A method according to claim 30 or 31, substantially as herein described with reference to any example thereof.
38. Use according to claim 32 or 33, substantially as herein described with 5 reference to any e thereof.
NZ750013A 2016-06-21 2017-06-20 Carbamoyloxymethyl triazole cyclohexyl acids as lpa antagonists NZ750013B2 (en)

Applications Claiming Priority (3)

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US201662352792P 2016-06-21 2016-06-21
US62/352,792 2016-06-21
PCT/US2017/038216 WO2017223016A1 (en) 2016-06-21 2017-06-20 Carbamoyloxymethyl triazole cyclohexyl acids as lpa antagonists

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NZ750013B2 true NZ750013B2 (en) 2022-06-28

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