triazole-linked carbamoyl cyclohexyl acids as lpa antagonists

专利摘要:
The present invention relates to compounds of Formula (I): (I),or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, where all variables are as defined herein. These compounds are selective inhibitors of the LPA receptor.
公开号:BR112020011776A2
申请号:R112020011776-5
申请日:2018-12-18
公开日:2020-11-17
发明作者:Yan Shi；James R. Corte；Peter Tai Wah Cheng；Ying Wang；Jun Shi；Shiwei Tao；Jun Li；Lawrence J. Kennedy；Robert F. Kaltenbach Iii；Hao Zhang
申请人:Bristol-Myers Squibb Company；
IPC主号:

专利说明:

[001] [001] This claim claims the priority benefit of US Interim Order No. 62 / 607,399, deposited on December 19, 2017; all content of which is incorporated by reference. FIELD OF THE INVENTION
[002] [002] The present invention relates to new substituted triazole compounds, compositions containing them and methods of using them, for example, for the treatment of disorders associated with one or more of the lysophosphatidic acid receptors. BACKGROUND OF THE INVENTION
[003] [003] Lysophospholipids are mediators of membrane-derived bioactive lipids, 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 varying lengths and degrees of saturation (Fujiwara et al., J Biol. Chem., 2005, 280, 35038-35050). The structural skeleton of LPAs is derived from glycerol-based phospholipids, such as phosphatidylcholine (PC) or phosphatidic acid (PA).
[004] [004] LPAs are bioactive lipids (signaling lipids) that regulate several cell signaling pathways by binding to the same class of receptors coupled to the 7-transmembrane G domain (GPCR) protein (Chun, J., Hla, T. , Spiegel, S., Moolenaar, W., Editors, Lyso-phospholipid Receptors: Signaling and Biochemistry, 2013, Wiley; ISBN: 978-0-470-56905-4 & Zhao, Y. et al, Biochim. Biophys. Acta (BBA) -Mol. Cell Biol. De Lipids, 2013, 1831, 86–92). Currently known LPA receptors are referred to as LPA1, LPA2, LPA3,
[005] [005] LPAs have long been known as precursors of phospholipid biosynthesis in eukaryotic and prokaryotic cells, but LPAs have only recently emerged as signaling molecules that are rapidly produced and released by activated cells, notably platelets, to influence target cells, acting on specific cell surface receptors (see, for example, Mooleanar et al., BioEssays, 2004, 26, 870-881, and van Leewen et al., Bio-chem. Soc. Trans., 2003, 31, 1209-1212). In addition to being synthesized and processed into more complex phospholipids in the endoplasmic reticulum, LPAs can be generated through the hydrolysis of pre-existing phospholipids after cell activation; for example, the sn-2 position generally does not have a fatty acid residue due to decylation, leaving only the hydroxyl sn-1 esterified to a fatty acid. In addition, a key enzyme in the production of LPA, the autotaxin (lysosPLD / NPP2), may be the product of an oncogene, since many tumor types over-regulate autotaxin (Brindley, D., J. Cell Biochem. 2004, 92, 900-12). Concentrations of LPAs in plasma & human serum as well as human bronchoalveolar lavage fluid (BALF) have been reported, including determinations 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).
[006] [006] LPA influences a wide range of biological responses, ranging from induction of cell proliferation, stimulation of cell migration and neuritis retraction, closure of gap junctions and even chemotaxis of sludge mold (Goetzl, et al., Scientific World J., 2002, 2, 324-338; Chun, J., Hla, T., Spiegel, S., Moolenaar, W., Editors, Lys-
[007] [007] Fibrosis is the result of an uncontrolled process of tissue healing that leads to excessive accumulation and insufficient resorption of the extracellular matrix (ECM) which, ultimately, results in failure of the final organ (Rockey, DC, et al., New Engl. J. Med., 2015, 372, 1138-1149). The LPA1 receptor has been reported to be overexpressed in patients with idiopathic pulmonary fibrosis (IPF). Knockout mice for the LPA1 receptor were protected against bleomycin-induced pulmonary fibrosis (Tager et al., Nature Med., 2008, 14, 45- 54). The LPA1 antagonist BMS-986020 has been shown to significantly reduce the rate of decline in FVC (forced vital capacity) in a 26-week clinical trial in patients with IPF (Palmer et al., Chest, 2018, 154, 1061-1069) . Inhibitors of the LPA pathway (for example, an LPA1 antagonist) have been shown to be chemopreventive antifibrotic agents in the treatment of hepatocellular carcinoma in a mouse model (Nakagawa et al., Cancer Cell, 2016, 30, 879-890).
[008] [008] Thus, antagonizing the LPA1 receptor can be useful for the treatment of fibrosis, such as pulmonary fibrosis, liver 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.). SUMMARY OF THE INVENTION
[009] [009] The present invention provides new substituted triazole compounds including stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, which are useful as antagonists against one or more of the lysophosphatidic acid receptors, especially the LPA1 receptor.
[0010] [0010] The present invention also provides processes and intermediates for producing the compounds of the present invention.
[0011] [0011] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or pharmaceutically acceptable stereoisomers, tautomers, salts or solvates thereof.
[0012] [0012] The compounds of the invention can be used in the treatment of conditions in which LPA plays a role.
[0013] [0013] The compounds of the present invention can be used in therapy.
[0014] [0014] The compounds of the present invention can be used for the manufacture of a medicament for the treatment of a condition in which inhibition of physiological activity of LPA is useful, such as diseases in which an LPA receptor participates, it is involved in the etiology or pathology of the disease, or is otherwise associated with at least one symptom of the disease.
[0015] [0015] In another aspect, the present invention relates to a method of treating fibrosis of organs (liver, kidney, lung, heart and the like, as well as skin), liver diseases (acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), liver hypofunction, liver blood flow disorder and the like), cell proliferative disease [cancer (solid tumor, solid tumor metastasis, fibroma vascular, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL) and the like) and invasive cancer cell metastasis, and the like], inflammatory disease (psoriasis, nephropathy, pneumonia and the like), gastrointestinal tract (irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), abnormal pancreatic secretion and the like), kidney disease, urinary tract disease (benign prostatic hyperplasia or associated symptoms neuropathic bladder disease, spinal cord tumors, intervertebral disc herniation, spinal canal stenosis, symptoms derived from diabetes, lower urinary tract disease (lower urinary tract obstruction, and the like), inflammatory disease of the lower urinary tract, dysuria, frequent and similar urination), pancreas disease, disease associated with abnormal angiogenesis (arterial obstruction and the like), scleroderma, disease associated with the brain (cerebral infarction, cerebral hemorrhage and the like), neuropathic pain , peripheral neuropathy and the like, eye disease (age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, healing of glaucoma filtration surgery and the like).
[0016] [0016] In another aspect, the present invention relates to a method of treating diseases, disorders or conditions in which the activation of at least one LPA receptor by LPA contributes to the symptomatology or progression of the disease, disorder or condition. These diseases, disorders or conditions can arise from one or more of a genetic, iatrogenic, immunological, infectious, metabolic, oncological, toxic, surgical and / or traumatic etiology.
[0017] [0017] In another aspect, the present invention relates to a method
[0018] [0018] In one aspect, the present invention provides methods, compounds, pharmaceutical compositions and medicaments described herein that comprise LPA receptor antagonists, especially LPA1 antagonists
[0019] [0019] The compounds of the invention may 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).
[0020] [0020] These and other features of the invention will be presented in an expanded form as the disclosure proceeds.
[0021] [0021] In one aspect, the present invention provides, inter alia, compounds of Formula (I): (I),
[0022] [0022] or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, where:
[0023] [0023] X1, X2, X3, and X4 are each independently CR6 or N; since no more than two of X1, X2, X3, or X4 are N;
[0024] [0024] one of Q1, Q2 and Q3 is NR5, and the other two are N; and the dashed circle represents an optional bond forming an aromatic ring;
[0025] [0025] Y1 is O or NR3;
[0026] [0026] Y2 is;
[0027] [0027] Y3 is O or NR4a; provided that (1) Y1 and Y3 are not both O, and (2) when Y2 is C (O), Y1 is not O;
[0028] [0028] L is a covalent or C1-4 alkylene bond substituted by 0 to 4 R7;
[0029] [0029] R1 is (-CH2) to R9;
[0030] [0030] a is an integer of 0 or 1;
[0031] [0031] R2 is each independently halo, cyano, hydroxyl, amino, C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, C1-6 alkylamino, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1- 6 aminoalkyl, C1-6 alkoxy, alkoxyalkyl, haloalkoxyalkyl, or haloalkoxy;
[0032] [0032] n is an integer of 0, 1 or 2;
[0033] [0033] R3 and R4a are each independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, C1-6 alkoxy, or haloalkoxy;
[0034] [0034] R4 is C1-10 alkyl, C1-10 deuterated alkyl (fully or partially deuterated), C1-10 haloalkyl, C1-10 alkenyl, C3-8 cycloalkyl, 6 to 10 membered aryl, 3 to heterocyclyl 8 members, - (C1-6 alkylene) - (C3-8 cycloalkyl), - (C1-6 alkylene) - (aryl of 6 to 10 members), - (C1-6 alkylene) - (heterocyclyl from 3 to 8 members), or - (C1-6 alkylene) - (5- to 6-membered heteroaryl); wherein each of alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, alone or as part of another portion, is independently replaced by 0 to 3 R8; or, alternatively, R3 and R4, taken together with the atoms to which they are attached, form a 4- to 9-membered heterocyclic ring portion that is replaced by 0 to 3 R8;
[0035] [0035] R5 is hydrogen, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy;
[0036] [0036] R6 is hydrogen, halo, cyano, hydroxyl, amino, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy;
[0037] [0037] R7 is halo, oxo, cyano, hydroxyl, amino, C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy;
[0038] [0038] R8 are each independently deuterium, halo, hydroxyl, amino, cyano, C1-6 alkyl, C1-6 deuterated alkyl (fully or partially deuterated), C2-6 alkenyl, C2-6 alkynyl, alkylamino , haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, -CHO, phenyl, or 5- to 6-membered heteroaryl; or alternatively, two R8s, taken together with the atoms to which they are attached, form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring, each of which is independently replaced by 0 to 3 R12;
[0039] [0039] R9 is selected from –CN, –C (O) OR10, –C (O) NR11aR11b,;
[0040] [0040] Re is C1-6 alkyl, C3-6 cycloalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl;
[0041] [0041] R10 is hydrogen or C1-10 alkyl;
[0042] [0042] R11a and R11b are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; and
[0043] [0043] R12 is halo, cyano, hydroxyl, amino, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl, or 5- to 6-membered heteroaryl.
[0044] [0044] In a form of Formula (I), R8 are each independently deuterium, halo, hydroxyl, amino, cyano, C1-6 alkyl, C1-6 deuterated (fully or partially deuterated) alkyl, C2- 6 alkynyl, C2-6 alkynyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl or heteroaryl of 5 to 6 members; or alternatively, two R8s, taken together with the atoms to which they are attached, form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring, each of which is independently replaced by 0 to 3 R12.
[0045] [0045] In an embodiment of Formula (I), X1 is CR6, where R6 is hydrogen or C1-4 alkyl, for example, methyl.
[0046] [0046] In any of the preceding modalities of Formula (I),
[0047] [0047] the portion of is,, or.
[0048] [0048] In any of the preceding modalities of Formula (I),
[0049] [0049] the portion of is selected from, and; and
[0050] [0050] Y4 is O or NH.
[0051] [0051] In any of the preceding modalities of Formula (I), L is a covalent bond or methylene.
[0052] [0052] In any of the preceding modalities of Formula (I), n is 0 or 1.
[0053] [0053] In any of the preceding modalities of Formula (I), R5 is C1-4 alkyl. In one embodiment, R5a is methyl.
[0054] [0054] In any of the preceding modalities of Formula (I), R1 is CO2H.
[0055] [0055] In any of the preceding modalities of Formula (I), R3 and R4, taken together with the N and O to which they are attached, form a 5- to 7-membered heterocyclic ring portion that is replaced by 1 R8; and R8 is benzyl or phenyl.
[0056] [0056] In any of the preceding modalities of Formula (I), R4 is C1-10 alkyl, C1-10 haloalkyl, C3-6 cycloalkyl, - (C1-4 alkylene) - (C3-6 cycloalkyl) , - (C1-4 alkylene) - (C1-6 alkoxy), or - (C1-4 alkylene) - phenyl; wherein each of alkyl, alkylene, cycloalkyl and phenyl, alone or as part of another portion, is independently replaced by 0 to 3 R8; and R8 is each independently halo, hydroxyl, amine, cyano, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; or, alternatively, two R8, taken together with the atom (s) to
[0057] [0057] In any of the preceding modalities of Formula (I), the compound is represented by Formula (IIa), (IIb), (IIc), (IId), (IIe), or (IIf): (IIa ), (IIb), (IIc), (IId),
[0058] [0058] or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, where:
[0059] [0059] each R7a is independently hydrogen, halo, oxo, cyano, hydroxyl, amino, C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy;
[0060] [0060] f is an integer of 0, 1 or 2;
[0061] [0061] R3 is hydrogen or C1-4 alkyl;
[0062] [0062] R4 is C1-10 alkyl, C3-8 cycloalkyl, 6 to 10 membered aryl, - (C1-6 alkylene) - (C3-8 cycloalkyl), or - (C1-6 alkylene) - (6 aryl to 10 members); wherein each of alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, alone or as part of another portion, is independently substituted by 0 to 3 R8; or, alternatively, R3 and R4, taken together with the N and O to which they are attached, form a 4- to 6-membered heterocyclic ring portion which is replaced by 0 to 3 R8;
[0063] [0063] n is 0 or 1; and
[0064] [0064] R1, R2, R5, R5a, R8; X1, X2, X3, X4 and Z are the same as defined above.
[0065] [0065] In a modality of Formula (IIa) or (IIb), the heterocyclic ring formed by R3 and R4 is replaced by 1 phenyl or 1 benzyl.
[0066] [0066] In any of the previous modalities of the Formula
[0067] [0067] In any of the preceding modalities of Formula (IIa) or (IIb), X1 is CR6, where R6 is hydrogen or C1-4 alkyl. In one embodiment, X1 is CH or CCH3.
[0068] [0068] In any of the preceding modalities of Formula (IIa) or (IIb), X3 is N.
[0069] [0069] In any of the preceding modalities of Formula (IIa) or (IIb), X1 is CR6, where each R6 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyalkyl. In another mode, X1, X2, X3, and X4 are CH.
[0070] [0070] In any of the preceding modalities of Formula (IIa) or (IIb),
[0071] [0071] the portion is selected from;
[0072] [0072] R6a is each independently halo, cyano, hydroxyl, amino, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; and
[0073] [0073] d is an integer of 0, 1 or 2.
[0074] [0074] In any of the preceding modalities of Formula (IIa) or (IIb),
[0075] [0075] the portion is selected from; and
[0076] [0076] R6 is each independently hydrogen, halo, cyano, hydroxyl, amino, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy.
[0077] [0077] In any of the preceding modalities of Formula (IIa) or (IIb), f is 0 or 1. In one embodiment, R7a is hydrogen.
[0078] [0078] In any of the preceding modalities of Formula (IIa) or (IIb), the compound is represented by Formula (IIIa) or Formula (IIIb): (IIIa) or (IIIb),
[0079] [0079] or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein:
[0080] [0080] R2a is hydrogen, chlorine, fluorine, or C1-4 alkyl; R3 is hydrogen or C1-6 alkyl; and R1, R4, X1, X2, X3, and X4 are the same as defined above.
[0081] [0081] In a modality of Formula (IIIa) or (IIIb), the portion is selected from.
[0082] [0082] In any of the preceding modalities of Formula (IIIa) or (IIIb), R1 is CO2H.
[0083] [0083] In any of the preceding modalities of Formula (IIIa) or (IIIb),
[0084] [0084] the portion is selected from; and
[0085] [0085] R6 is each independently hydrogen, CH3,
[0086] [0086] In any of the preceding modalities of Formula (IIIb), the compound is represented by Formula (IV): (IV),
[0087] [0087] or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, where:
[0088] [0088] R2a is hydrogen, chlorine, fluorine, or C1-4 alkyl; R3 is hydrogen or C1-6 alkyl; and R6 and R4 are the same as defined above. In one embodiment, R6 is hydrogen, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy. In another embodiment, R6 is methyl or ethyl. In one embodiment, R4 is C1-10 alkyl, - (C1-6 alkylene) 0-1-phenyl, or - (C1-6 alkylene) 0-1- (C3-8 cycloalkyl). In another embodiment, R4 is C1-6 alkyl, - (CH2) 0-2- (C3-6 cycloalkyl), - (CHCH3) - (C3-6 cycloalkyl), - (CH2) 1-2-phenyl, or - (CHCH3) -phenyl.
[0089] [0089] In any of the preceding modalities of Formula (IIIa) or (IIIb), R4 is C3-10 alkyl, C3-10 haloalkyl, C3-6 cycloalkyl, phenyl, - (C1-4 alkylene) - (C1 -3 alkoxy), - (C1-4 alkylene) - (C3-6 cycloalkyl), or benzyl; wherein the alkyl, alkylene, cycloalkyl, and benzyl are each independently replaced by 0 to 3 R8; and R8 is each independently halo, C1-6 alkyl, alkylamino, haloalkyl, hydroxy-alkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; or, alternatively, two R8, taken together with the atoms to which they are attached, form a 3- to 6-membered carbocyclic ring. Alkyl and alkylene are each, independently, straight or branched; and the methylene and phenyl moieties of benzyl are each independently replaced by 0 to 3 R8.
[0090] [0090] In any of the preceding modalities of Formula (IIIa) or (IIIb), R4 is C3-10 alkyl, C3-10 haloalkyl, cyclobutyl, cyclopentyl, - (CH2) 1-2- (C1- 3 alkoxy), - (CHR8a) 1-2-cyclopropyl, - (CHR8a) 1-2-cyclobutyl, or - (CHR8a) 1-2-phenyl; wherein cyclopropyl, cyclobutyl, cyclopentyl and phenyl are each independently replaced by 0 to 3 R8; or, alternatively, two R8, taken together with the atom to which they are attached, form cyclopropyl; R8a is, each independently, hydrogen or methyl; and R8 is each independently halo or C1-4 alkyl.
[0091] [0091] In one embodiment of the present invention, the compound is selected from any of the Examples described in the specification, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof.
[0092] [0092] In another embodiment of the present invention, the compound is selected from Examples 1 to 240, as described in the specification, either a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof.
[0093] [0093] In another embodiment of the present invention, the compound is selected from Examples 1 to 145, as described in the specification, either a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof.
[0094] [0094] In an embodiment of the present invention, the compound is selected from:
[0095] [0095] In an embodiment of the present invention, the compound is selected from:,,,, and; or a pharmaceutically acceptable salt or solvate thereof.
[0096] [0096] In another embodiment of the present invention, the compound is selected from:
[0097] [0097] In another embodiment of the present invention, the compound is selected from:,,, and; or a pharmaceutically acceptable salt or solvate thereof.
[0098] [0098] In another embodiment of the present invention, the compound is selected from:,,,,,,,,, and; or a pharmaceutically acceptable salt or solvate thereof.
[0099] [0099] In another embodiment of the present invention, the compound is selected from:
[00100] [00100] In another embodiment of the present invention, the compound is selected from:,,,,,,
[00101] [00101] In another embodiment of the present invention, the compound is selected from:,,,
[00102] [00102] In another embodiment of the present invention, the compound is selected from:,,,, and; or a pharmaceutically acceptable salt or solvate thereof.
[00103] [00103] In one embodiment, the compounds of the present invention have IC50 values of hLPA1  5000 nM, using the LPA1 functional antagonist assay; in another embodiment, the compounds of the present invention have ICL values of hLPA1  1000 nM; in another embodiment, the compounds of the present invention have ICL values of hLPA1  500 nM; in another embodiment, the compounds of the present invention have ICL values of hLPA1  200 nM; in another embodiment, the compounds of the present invention have IC 50 hLPA1 values  100 nM; in another embodiment, the compounds of the present invention have ICL values of hLPA1  50 nM. II. Other Modalities of the Invention
[00104] [00104] In some embodiments, the compound of Formulas (I), or a pharmaceutically acceptable salt thereof, is an antagonist of at least one LPA receptor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an LPA1 antagonist. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an LPA2 antagonist. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an LPA3 antagonist.
[00105] [00105] In some embodiments, presented in this document are compounds selected from active metabolites, tautomers, salts or pharmaceutically acceptable solvates of a compound of Formula (I).
[00106] [00106] In another embodiment, the present invention 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 solvate thereof.
[00107] [00107] In another embodiment, the present invention 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.
[00108] [00108] In another embodiment, the present invention provides a process for producing a compound of the present invention.
[00109] [00109] In another embodiment, the present invention provides an intermediate to produce a compound of the present invention.
[00110] [00110] In another embodiment, the present invention provides a pharmaceutical composition further comprising additional therapeutic agent (s).
[00111] [00111] In another embodiment, the present invention provides a method for treating a condition associated with LPA receptor-mediated fibrosis, comprising administering to a patient in need of such treatment 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 species of mammal.
[00112] [00112] In another embodiment, the present invention provides a method of treating a disease, disorder or condition associated with dysregulation of lysophosphatidic acid receptor 1 (LPA1) in a patient in need of it, comprising administering a quantity therapeutically effective quality of a compound of the present invention, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof, to the patient. In one modality of the method, the disease, disorder or condition refers to pathological fibrosis, transplant rejection, cancer, osteoporosis, or inflammatory disorders. In one embodiment of the method, pathological fibrosis is pulmonary, hepatic, renal, cardiac, dermal, ocular or pancreatic fibrosis. In a method modality, the disease, disorder or condition is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis
[00113] [00113] In another embodiment, the present invention provides a method of treating fibrosis in a mammal comprising administering a therapeutically effective amount of a compound of the present invention, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof, to the mammal in need of the same. In one modality of the method, fibrosis is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), chronic kidney disease, diabetic kidney disease and systemic sclerosis.
[00114] [00114] In another embodiment, the present invention provides a method of treating pulmonary fibrosis (idiopathic pulmonary fibrosis), asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute kidney injury, chronic kidney disease, liver fibrosis (non-alcoholic steatohepatitis), skin fibrosis, bowel fibrosis, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, bowel cancer, head cancer and neck, melanoma, multiple myeloma, chronic lymphocytic leukemia, cancer pain, tumor metastasis, transplant organ rejection, scleroderma, ocular fibrosis, age-related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atheism rosclerosis, Raynaud's phenomenon or neuropathic pain, comprising administering a therapeutically effective amount of a compound of the present invention, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvat the same, to the mammal in need of it.
[00115] [00115] As used in this document, "treating" or "treatment" covers the treatment of a disease state in a mammal, particularly a human, and includes: (a) inhibiting the disease state, ie it is, holding its development; and / or (b) relieving the disease state, that is, causing regression of the disease state. As used in this document, "treat" or "treatment" also includes protective treatment of a disease state to reduce and / or minimize the risk and / or reduction in the risk of recurrence of a disease state by administering to a patient 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. Patients can be selected for such protective therapy based on factors that are known to increase the risk of suffering a clinical state of disease compared to the general population. For protective treatment, conditions of the clinical condition of the disease may or may not be present yet. Protective treatment can be divided into (a) primary prophylaxis and (b) secondary prophylaxis. Primary prophylaxis is defined as treatment to reduce or reduce the risk of a clinical state of disease in a patient who has not yet had a clinical state of disease, while secondary prophylaxis is defined as minimizing or reducing the risk of recurrence or second occurrence of the same or similar clinical condition.
[00116] [00116] The present invention can be incorporated in other specific ways without departing from the spirit or the essential attributes of it. This invention encompasses all combinations of preferred aspects of the invention mentioned herein. It is understood that all the modalities of the present invention can be taken in conjunction with any other modality or modalities to describe additional modalities. It must also be understood that each individual element of the modalities is its own independent modality. In addition, any element of a modality is intended to be combined with any and all other elements of any modality to describe an additional modality. III. Chemistry
[00117] [00117] Throughout the specification and attached claims, a given formula or chemical name must cover all the stereo and optical isomers and racemates of the same, so that these 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 of these stable isomers are contemplated in the present invention. Geometric cis- and trans- (or E- and Z-) isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms. The present compounds can be isolated in optically active or racemic forms. Optically active forms can be prepared by resolving racemic forms or by synthesis from optically active starting materials. All processes used to prepare the compounds of the present invention and intermediates made therein are considered part of the present invention. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the process conditions, the final products of the present invention are obtained in free (neutral) or salt form. Both the free form and the salts of these final products are within the scope of the invention. If desired, one form of a compound can be converted to another form. A free base or acid can be converted to salt; a salt can be converted to the free compound or another salt; a mixture of isomeric compounds of the present invention can be separated into individual isomers. The compounds of the present invention, free form and salts thereof can exist in various tautomeric 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 in the invention.
[00118] [00118] 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 a pair of molecular species that are mirror images of others and are not overlapping. The term "diastereomer" refers to stereoisomers that are not mirror images. The term "racemate" or "racemic mixture" refers to a composition composed of equimolar amounts of two enantiomeric species, in which the composition is devoid of optical activity.
[00119] [00119] The symbols "R" and "S" represent the configuration of substitutes around a chiral carbon atom. The isomeric descriptors "R" and "S" are used as described in this document to indicate the atom configuration (s) in relation to a core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996 , Pure and Applied Chemistry, 68: 2193-2222 (1996)).
[00120] [00120] The term "chiral" refers to the structural characteristic of a molecule that makes it impossible to superimpose its mirror image. The term "homoquiral" refers to a state of enantiomeric purity. The term "optical activity" refers to the degree to which a homologous molecule or non-racemic mixture of chiral molecules rotates a plane of polarized light.
[00121] [00121] As used herein, the term "alkyl" or "alkylene" is intended to include saturated straight-chain and branched saturated aliphatic hydrocarbon groups with the specified number of carbon atoms. While "alkyl" represents a monovalent saturated aliphatic radical (such as ethyl), "alkylene" represents a bivalent saturated aliphatic radical (such as ethylene). For example, "C1 to C10 alkyl" or "C1-10 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. "C1 to C10 alkylene" or "C1-10 alkylene" is intended to include groups C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkylene. In addition, for example, "C1 to C6 alkyl" or "C1-6 alkyl" represents alkyl having 1 to 6 carbon atoms; and "C1 to C6 alkylene" or "C1-6 alkylene" represents alkylene having 1 to 6 carbon atoms; and "C1 to C4 alkyl" or "C1-4 alkyl" represents alkyl having 1 to 4 carbon atoms; and "C1 to C4 alkylene" or "C1-4 alkylene" represents alkylene having 1 to 4 carbon atoms. Alkyl group can be unsubstituted or replaced by at least one hydrogen being replaced by another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (eg, n-propyl and isopropyl), butyl (eg, n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When "C0 alkyl" or "C0 alkylene" is used, it is intended to represent a direct bond. In addition, the term "alkyl", alone or as part of another group, such as alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, and haloalkoxy, can be an alkyl having 1 to 4 carbon atoms, or 1 to 6 carbon atoms, or 1 to 10 carbon atoms.
[00122] [00122] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms have been replaced by a hetero atom, such as, O, N or S. For example, if the carbon atom of the alkyl group that is attached the parent molecule is replaced by a heteroatom (for example, O, N or S), the resulting heteroalkyl groups are, respectively, an alkoxy group (for example, -OCH3 etc.), an alkylamino (for example , -NHCH3, -N (CH3) 2 etc.), or a thioalkyl group (for example, -SCH3). If a non-terminal carbon atom of the alkyl group that is not attached to the parent molecule is replaced by a heteroatom (for example, O, N or S) and the resulting heteroalkyl groups are, respectively, an alkyl ether (for example , -CH2CH2-O-CH3 etc.), an alkylaminoalkyl (for example, -CH2NHCH3, -CH2N (CH3) 2 etc.), or a thioalkyl ether (for example, -CH2-S-CH3). If a terminal carbon atom of the alkyl group is replaced by a heteroatom (for example, O, N or S), the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (for example, -CH2CH2-OH), a group aminoalkyl (for example, -CH2NH2), or an alkyl thiol group (for example, -CH2CH2-SH). A heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. A C1-C6 heteroalkyl group means a heteroalkyl group having 1 to 6 carbon atoms.
[00123] [00123] "Alkenyl" or "alkenylene" is intended to include straight or branched hydrocarbon chains having the specified number of carbon atoms and one or more, preferably one to two, carbon-carbon double bonds can occur at 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 groups. Examples of alkenyl include, but are not limited to, ethylene, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl ,
[00124] [00124] "Alquinyl" or "alkynylene" is intended to include straight or branched hydrocarbon chains having one or more, preferably one to three, carbon-carbon triple bonds that can occur at any stable point along the chain . For example, "C2 to C6 alkynyl" or "C2˗6 alkynyl" (or alkynylene), is intended to include groups C2, C3, C4, C5, and C6 alkynyl; such as ethinyl, proppinyl, butynyl, pentynyl and hexynyl.
[00125] [00125] As used herein, "arylalkyl" (aka aralkyl), "heteroarylalkyl", "carbocyclylalkyl" or "heterocyclylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms attached to a carbon atom , usually a terminal carbon atom or sp3, is replaced by an aryl, heteroaryl, carbocyclyl or heterocyclyl radical, respectively. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphobenzyl, 2-naphthophenylethane-1 and the like. The arylalkyl, heteroarylalkyl, carbocyclylalkyl or heterocyclylalkyl group can comprise from 4 to 20 carbon atoms and 0 to 5 heteroatoms, for example, the alkyl portion can contain 1 to 6 carbon atoms.
[00126] [00126] The term "benzyl", as used in this document, refers to the metal group, in which one of the hydrogen atoms is replaced by a phenyl group, in which said phenyl group can optionally be replaced by 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. "Benzila" can also be represented by the Formula "Bn".
[00127] [00127] 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
[00128] [00128] The term "alkanoyl" or "alkylcarbonyl", as used herein alone or as part of another group, refers to alkyl attached to a carbonyl group. For example, alkylcarbonyl can be represented by alkyl-C (O) -. "C1 to C6 alkylcarbonyl" (or alkylcarbonyl), is intended to include C1, C2, C3, C4, C5, and C6 alkyl-C (O) - groups.
[00129] [00129] The term "alkylsulfonyl" or "sulfonamide", as used in this document alone or as part of another group, refers to alkyl or amino attached to a sulfonyl group. For example, alkylsulfonyl can be represented by -S (O) 2R ', while sulfonamide can be represented by -S (O) 2NRcRd. R 'is C1 to C6 alkyl; and Rc and Rd are the same as defined below for "amino".
[00130] [00130] The term "carbamate", as used in this document alone or as part of another group, refers to an oxygen attached to a starch group. For example, carbamate can be represented by N (RcRd) -C (O) -O-, and Rc and Rd are the same as defined below for "amino".
[00131] [00131] The term "starch" as used in this document alone or as part of another group refers to an amino attached to a carbon group. For example, starch can be represented by N (RcRd) -C (O) -, and Rc and Rd are the same as defined below for "amino".
[00132] [00132] The term "amino" is defined as -NRc1Rc2, where Rc1 and Rc2 are independently H or C1-6 alkyl; or alternatively, Rc1 and Rc2, taken together with the atoms to which they are attached, form a 3- to 8-membered heterocyclic ring that is optionally substituted by one or more groups selected from halo, cyano, hydroxyl, amino, oxo , C1-6 alkyl, alkoxy and aminoalkyl. When Rc1 or Rc2 (or both) is C1-6 alkyl, the amino group can also be referred to as alkylamino. Examples of the alkylamino group include, without limitation methylamino, ethylamino, propylamino, isopropylamino and the like. In one embodiment, amino is -NH2.
[00133] [00133] The term "aminoalkyl" refers to an alkyl group in which one of the hydrogen atoms is replaced by an amino group. For example, aminoalkyl can be represented by N (Rc1Rc2) -alkylene-. "C1 to C6" or "C1-6" aminoalkyl "(or aminoalkyl), is intended to include C1, C2, C3, C4, C5 and C6 aminoalkyl groups.
[00134] [00134] The term "halogen" or "halo", as used in this document alone or as part of another group, refers to chlorine, bromine, fluorine and iodine, with chlorine or fluorine being preferred.
[00135] [00135] "Haloalkyl" is intended to include straight or branched chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms replaced by one or more halogens. "C1 to C6 haloalkyl" or "C1-6 haloalkyl" (or haloalkyl), is intended to include C1, C2, C3, C4, C5 and C6 haloalkyl groups. 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" which is intended to include straight or branched chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, replaced by 1 or more fluorine atoms. The term "polyhaloalkyl", as used herein, refers to an "alkyl" group as defined above, which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl , preferably F, such as polyfluoroalkyl, for example, CF3CH2, CF3 or CF3CF2CH2.
[00136] [00136] "Haloalkoxy" or "haloalkyloxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms linked via an oxygen bridge. For example, "C1 to C6 haloalkoxy" or "C1-6 haloalkoxy" is intended to include groups C1, C2, C3, C4, C5 and C6 haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorotoxy. Likewise, "haloalkylthio" or "thiohaloalkoxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms linked through a sulfur bridge; for example, trifluoromethyl-S-, and pentafluoroethyl-S-. The term "polyhaloalkyloxy", as used in this document, refers to a "alkoxy" or "alkyloxy" group, as defined above, which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as polyfluoroalkoxy, for example, CF3CH2O, CF3O or CF3CF2CH2O.
[00137] [00137] "Hydroxyalkyl" is intended to include straight and branched saturated aliphatic hydrocarbon groups having the specified number of carbon atoms replaced by 1 or more hydroxyl (OH). "C1 to C6 hydroxyalkyl" (or hydroxyalkyl), is intended to include C1, C2, C3, C4, C5, and C6 hydroxyalkyl groups.
[00138] [00138] The term "cycloalkyl" refers to cyclized alkyl groups, including mono-, bi- or polycyclic 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. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl. Branched cycloalkyl groups, such as 1-methylcyclopropyl and 2-methylcyclopropyl and spiro and bridged cycloalkyl groups are included in the definition of "cycloalkyl".
[00139] [00139] The term "cycloheteroalkyl" refers to cyclized heteroalkyl groups, including mono-, bi- or polycyclic ring systems. "C3 to C7 cycloheteroalkyl" or "C3-7 cycloheteroalkyl" is intended to include groups C3, C4, C5, C6, and C7 cycloheteroalkyl. Examples of cycloheteroalkyl groups include, but are not limited to, oxetanil, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl. Branched cycloheteroalkyl groups, such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, and pyrazinylmethyl, are included in the definition of "cycloheteroalkyl".
[00140] [00140] As used herein, "carbocycle", "carbocyclyl" or "carbocyclic residue" means any 3-, 4-, 5-, 6-, 7- or 8-membered monocyclic or bicyclic hydrocarbon ring or stable 7-, 8-, 9-, 10-, 11-, 12- or 13-membered tri-cyclic, any of which can be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctenyl octadienyl, [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane (decalin), [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphile (tetralin). As shown above, bridged rings are also included in the definition of carbocycle (for example, [2.2.2] bicyclooctane). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and indanyl. When the term "carbocyclyl" is used, it is intended to include "aryl". A bridged ring occurs when one or more carbon atoms connect two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is observed that a bridge always converts a monocyclic ring to a tricyclic ring. When a ring is bridged, the substituents cited for the ring may also be present on the bridge.
[00141] [00141] Furthermore, the term "carbocyclyl", including "cycloalkyl" and "cycloalkenyl", as used herein alone or as part of another group, includes saturated or partially unsaturated cyclic hydrocarbon groups (containing 1 or 2 double bonds) with - having 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 10 carbons or 3 to 6 carbons, forming the ring and which can be fused to 1 or 2 aromatic rings, as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl, any of these groups can be optionally substituted by 1 to 4 substituents, such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkyl starch, alkanoylamino, oxo, acyl, arylcarbonylamino, nitro, cyano, thiol and / or alkylthio and / or any one of are alkyl substituents.
[00142] [00142] As used in this document, the term "bicyclic carbocyclyl" or "bicyclic carbocyclic group" means 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 that is saturated, partially unsaturated, or unsaturated. The bicyclic carbocyclic group can be attached to its pendant group on any carbon atom which results in a stable structure. The bicyclic carbocyclic group described in this document can be substituted for any carbon if the resulting compound is stable. Examples of a bicyclic carbocyclic group are, but are not limited to, naphthyl, 1,2-dihydrohydronaphthyl, 1,2,3,4-tetra-
[00143] [00143] As used in this document, the term "aryl", as used in this document alone or as part of another group, refers to monocyclic or polycyclic aromatic hydrocarbons (including bicyclic and tricyclic), including, for example, phenyl, naphthyl, anthracenyl and phenanthranil. Aryl portions 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). In one embodiment, the term "aryl" represents aromatic monocyclic and bicyclic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl, including 1-naphthyl and 2-naphthyl). For example, "C6 or C10 aryl" or "C6-10 aryl" refers to phenyl and naphthyl. Unless otherwise specified, "aryl", "C6 or C10 aryl", "C6-10 aryl", or "aromatic residue" may be unsubstituted or substituted by 1 to 5 groups, preferably 1 to 3 groups, selected from - 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.
[00144] [00144] The term "benzyl", as used in this document, refers to a methyl group in which one of the hydrogen atoms is replaced by a phenyl group, in which said phenyl group can optionally be substituted by 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.
[00145] [00145] As used herein, the term "heterocycle", "heterocyclyl" or "heterocyclic group" is intended to mean a stable monocyclic monocyclic heterocyclic ring of 3, 4, 5, 6 or 7 members or 5-membered polycyclic , 6, 7, 8, 9, 10, 11, 12, 13 or 14 members (including bicyclic and tricyclic) which is saturated, or partially unsaturated, and which contains carbon atoms and 1, 2, 3 or 4 hetero atoms selected selected from N, O and S; and including any polycyclic group in which any of the heterocyclic rings defined above is fused to a carbocyclic or aryl ring (for example, benzene). That is, the term "heterocycle", "heterocyclyl" or "heterocyclic group" includes aromatic ring systems, such as heterocycloalkyl and heterocycloalkenyl. The nitrogen and sulfur heteroatoms can optionally be oxidized (ie, N → O and S (O) p, where p is 0, 1 or 2). The nitrogen atom can be substituted or unsubstituted (that is, N or NR, where R is H or another substituent, if defined). The heterocyclic ring can be attached to its pendant group on any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described in this document can be substituted on carbon or on a nitrogen atom, if the resulting compound is stable. A nitrogen in the heterocycle can optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these hetero atoms are not adjacent to each other. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. Examples of heterocyclyl include, without limitation, azetidinyl, piperazinyl, piperidinyl, piperidonyl, pipe-ronil, pyranyl, morpholinyl, tetrahydrofuranyl, tetrahydrogen hydroisoquinolinyl, tetrahydroquinolinyl, morpholinyl, dihydrohydride [2,3-b] tetrahydrofuran.
[00146] [00146] As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclic group" is intended to mean a stable 9 or 10 membered heterocyclic ring system that contains two fused rings and consists of carbon atoms and 1, 2 , 3 or 4 heteroatoms independently selected from N, O and S. Of the two fused rings, a ring is a 5 or 6 membered monocyclic aromatic ring, comprising a 5 membered heteroaryl ring, a 6 membered heteroaryl ring or one benzo ring, each fused to a second ring. The second ring is a 5- or 6-membered monocyclic ring that is saturated, partially unsaturated or unsaturated and comprises a 5-membered heterocycle, a 6-membered heterocycle or a carbo-cycle (provided the first ring is not benzo when the second ring is a carbocycle).
[00147] [00147] The bicyclic heterocyclic group can be attached to its pendant group on any heteroatom or carbon atom that results in a stable structure. The bicyclic heterocyclic group described in this document can 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 hetero atoms are not adjacent to each other. It is preferred that the total number of S and O atoms in the heterocycle does not exceed 1. Examples of a bicyclic heterocyclic group are, but are not limited to, 1,2,3,4-tetrahydroquinolinyl, 1,2, 3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro quinolinyl, 2,3-dihydrohydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydroquinoxalinyl and 1, 2,3,4-tetrahydro-quinazolinyl.
[00148] [00148] Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more atoms (that is, C, O, N or S) connect 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. Note that a bridge always converts a monocyclic ring to a tricyclic ring. When a ring is bridged, the substituents cited for the ring may also be present on the bridge.
[00149] [00149] As used in this document, the term "heteroaryl" is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons (including bicyclic and tricyclic) that include at least one heteroatom ring member, such as sulfur, oxygen or nitro. Heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrole, oxazolyl, benzofuryl, benzothienyl, tyrolazole, benzylazole , indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted or unsubstituted. The nitrogen atom is substituted or unsubstituted (that is, N or NR, where R is H or another substitute, if defined). The nitrogen and sulfur heteroatoms can optionally be oxidized (ie, N → O and S (O) p, where p is 0, 1 or 2).
[00150] [00150] Examples of heteroaryl also include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benzztriazolyl, benztetrazolyl, benzotetrazolyl, benzotetrazolyl, benzotetrazolyl, benzotetrazolyl, benzothetrazol, , 4aH-carbazolyl, carbolinyl, chromanyl, chromanyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, furanilla, furazanil, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazolylin, indidazolylin , indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, oxyazolyl, isoxazolylin, isoxazolylin, isoxazolylid , 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, ox indolyl, pyrimidinyl, phenanthrinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathianyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazininyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyrazolol, pyrazolol, pyrazolyl pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-
[00151] [00151] Examples of 5- to 10-membered heteroaryl include, but are not limited to, pyridinyl, furanyl, thienyl, pyrazolyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolinyl, tiadiazolyl, thiadiazoline, thiadiazoline , triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolin, benzyl, isoil, benzoyl, benzoyl, benzoyl - azolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl. Examples of 5- to 6-membered heteroaryl include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazide, thiadia, thiadia thiazolyl, triazinyl, and triazolyl. In some embodiments, heteroaryl is selected from benzthiazolyl, imidazolpyridinyl, pyrrolopyridinyl, quinolinyl, and indolyl.
[00152] [00152] Unless otherwise indicated, "carbocyclyl" or "heterocyclic" includes one to three additional rings fused to the carbocyclic ring or the heterocyclic ring (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings), for example, O O O,, O, S,, N N N N O,,, O, N O O N N N,,,,
[00153] [00153] When any of the terms alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are used as part of another group, the number of carbon atoms and ring members are the same as the defined in terms for themselves. For example, alkoxy, haloalkoxy, alkylamino, haloalkyl, hydroxy-alkyl, aminoalkyl, haloalkoxy, alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, alkylthio and the like, each independently contains the same number of defined carbon atoms for the term "alkyl", such as 1 to 4 carbon atoms, 1 to 6 carbon atoms, 1 to 10 carbon atoms, etc. Likewise, cycloalkoxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, aralkylamino, arylamino, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy and the like, each independently, contain ring members that are the same as defined for the terms "cycloalkyl", heterocyclyl "," aryl ", and" heteroaryl ", such as 3 to 6 members, 4 to 7 members, 6 to 10 members, 5 to 10 members, 5 or 6 members etc.
[00154] [00154] According to a convention used in the art, a link pointing to a bold line, as used in structural formulas in this document, represents the bond that is the point of attachment of the portion or substituent to the core or structure. skeleton.
[00155] [00155] According to a convention used in the technique, a wavy or scrambled bond in a structural formula, such as, is used to represent a stereogenic center of the carbon atom to which X ', Y', and Z 'are linked and is intended to represent both enantiomers in a single figure. That is, a structural formula with such a wavy bond represents each of the enantiomers individually, such as or, as well as a racemic mixture of them. When a wavy or scrambled bond is bonded to a double bonded portion (such as C = C or C = N), it includes cis- or trans- (or E- and Z-) geometric isomers or a mixture thereof.
[00156] [00156] It is understood in this document that if a carbocyclic or heterocyclic moiety can be attached or otherwise attached to a substrate designated through different ring atoms without representing a specific attachment point, then all the possible points are intended, either through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridyl" means 2-, 3- or 4-pyridyl, the term "thienyl" means 2- or 3- thienyl, and so on.
[00157] [00157] When a link to a substituent is shown crossing
[00158] [00158] One skilled in the art will recognize that substituents and other portions of the compounds of the present invention must be selected to provide a compound that is sufficiently stable to provide a pharmaceutically useful compound that can be formulated into an acceptable stable pharmaceutical composition. Compounds of the present invention that have such stability are contemplated as falling within the scope of the present invention.
[00159] [00159] The term "counterion" is used to represent a negatively charged species, such as chloride, bromide, hydroxide, acetate and sulfate. The term "metal ion" refers to alkali metal ions, such as sodium, potassium or lithium, and alkaline earth metal ions, such as magnesium and calcium, as well as zinc and aluminum.
[00160] [00160] As mentioned in this document, the term "substituted" means that at least one hydrogen atom (attached to the carbon atom or hetero atom) is replaced by a non-hydrogen group, provided that the normal valences are maintained and that the replacement results in a stable compound. When a substituent is oxo (ie, = O), then 2 hydrogens on the atom are replaced. Oxo substituents are not present in aromatic portions. When a ring system (for example, carbocyclic or heterocyclic) is said to be replaced by a carbonyl group or a double bond, it is intended that the carbonyl group or double bond is part (i.e., within) the ring. Double ring bonds, as used in this document, are double bonds that are formed between two adjacent ring atoms (for example, C = C, C = N or N = N). The term "substituted" in reference to alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl and heterocyclyl means alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkylene, aryl, aryl la, heteroaryl, heteroarylalkyl, carbocyclyl and heterocyclyl, respectively, in which one or more hydrogen atoms, which are bonded to carbon or heteroatom, are each independently replaced by one or more non-hydrogen substituents.
[00161] [00161] In cases where nitrogen atoms (eg, amines) exist in the compounds of the present invention, they can be converted to N-oxides by treatment with an oxidizing agent (eg, mCPBA and / or hydrogen peroxides) to generate other compounds of this invention. Thus, the nitrogen atoms presented and claimed are considered to cover both the nitrogen shown and its N-oxide derivative (NO).
[00162] [00162] When any variable occurs more than once in any constituent or formula for a compound, its definition in each occurrence is independent of its definition in all other occurrences. Thus, for example, if a group is shown to be replaced by 0, 1, 2 or 3 R groups, then that group is unsubstituted when it is replaced by 0 R group, or it is replaced by up to three R groups, and in each occurrence R is selected regardless of the definition of R.
[00163] [00163] In addition, combinations of substituents and / or variables are allowed only if such combinations result in stable compounds.
[00164] [00164] As used in this document, the term "tautomer" refers to each of two or more isomers of a compound that exist together in equilibrium, and are easily exchanged by the migration of an atom or group within the molecule. For example, one skilled in the art would readily understand that a 1,2,3-triazole exists in two tautomechanical forms, as defined above:.
[00165] [00165] Thus, this disclosure is intended to cover all possible tautomers, even when a structure has only one of them.
[00166] [00166] The phrase "pharmaceutically acceptable" is used in this document to refer to compounds, materials, compositions and / or dosage forms that, within the scope of good medical judgment, are suitable for use in contact with tissues of human and animal beings without excessive toxicity, irritation, allergic response and / or other problem or complication, proportional to a reasonable benefit / risk ratio.
[00167] [00167] The compounds of the present invention can be present as salts, which are also within the scope of this invention. Pharmaceutically acceptable salts are preferred. As used herein, the phrase "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, wherein the parent compound is modified to produce acidic or basic salts thereof. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic portion by conventional chemical methods. Generally, these salts can be prepared by reacting the acid or base free forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Lis-
[00168] [00168] If the compounds of the present invention have, for example, at least one basic center, they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example, sulfuric acid, phosphoric acid or a hydrohalic acid, with organic carboxylic acids, such as alkanocarboxylic acids of 1 to 4 carbon atoms, for example. example, acetic acid, which are unsubstituted or substituted, for example, by halogen such as chloroacetic acid, such as saturated or unsaturated dicarboxylic acids, for example, oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid , such as hydroxycarboxylic acids, for example, ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids (for example, aspartic or glutamic acid or lysine or arginine), or benzoic acid or with organic sulfonic acids, such as (C1-C4) alkyl or arylsulfonic acids, which are unsubstituted or substituted, for example, by halogen, for example, methyl- or p-toluenesulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds of the present invention having at least one acid group (for example, COOH) can also form salts with bases. Suitable base salts are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example, sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine , piperidine, pyrrolidine, a lower mono-, di- or trialkylamine, for example, ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethylpropylamine, or a lower mono-, di- - or trihydroxy, for example, mono-, di- or tri-
[00169] Preferred salts of the compounds of Formula (I) that contain a basic group include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate, nitrate or acetate.
[00170] Preferred salts of the compounds of Formula (I) that contain an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.
[00171] [00171] In addition, compounds of Formula (I) can 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 invention. Various forms of prodrug are well known in the art. For examples of such prodrug derivatives, see: a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder, K. et al., Eds., Methods in Enzymology, 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) Bundgaard, H. et al., J. Pharm. Sci., 77: 285 (1988); and e) Kakeya, N. et al., Chem. Pharm. Bull., 32: 692 (1984).
[00172] [00172] The compounds of the present invention contain a carboxy group that can form physiologically hydrolyzable esters that serve as prodrugs, that is, "prodrug esters", being hydrolyzed.
[00173] [00173] The 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 Society of Chemistry, Cambridge, UK (1994); Testa, B. et al., Hidrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, Academic Press, San Diego, CA (1999).
[00174] [00174] The present invention is intended to apply all isotopes of atoms that occur in the present compounds. Isotopes include those atoms having the same atomic number, but different mass numbers. As a general example and without limitation, hydrogen isotopes include deuterium and tritium. Deuterium has a proton and a neutron in its nucleus and it has twice the mass of common hydrogen. Deuterium can be represented by symbols like "2H" or
[00175] [00175] The isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described here, using an appropriate isotopically labeled reagent in place of the unlabeled reagent employed elsewhere. way. Such compounds have a variety of potential uses, for example, as standards and reagents to determine the ability of a potential pharmaceutical compound to bind to proteins or target receptors, or to imagine compounds of this invention bound to biological receptors in vivo. or in vitro.
[00176] [00176] "Stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust to survive isolation with a useful degree of purity from a mixture of reaction and formulation into an effective therapeutic agent. It is preferred that the compounds of the present invention do not contain an N-halo, S (O) 2H or S (O) H group.
[00177] [00177] The term "solvate" means a physical association of a compound of this invention with one or more solvent molecules, organic or inorganic. This physical association includes hydrogen bonding. In certain cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystalline matrix of the crystalline solid. The solvent molecules in the solvate can be present in a regular arrangement and / or in an unordered arrangement. The solvate may comprise a stoichiometric or non-stoichiometric amount of the solvent molecules. "Solvate" encompasses both solvates in solution and isolable phase.
[00178] [00178] The abbreviations used in this document are defined as follows: "1 x" for one time, "2 x" for two times, "3 x" for three times, "ºC" for degrees Celsius, "eq" for equivalent or equivalent, "g" for grams or grams, "mg" for milligrams or milligrams, "L" for liter or liters, "ml" for milliliters or milliliters, "μL" for microliters or microliters, "N" for normal , "M" for molar, "mmol" for millimol or millimoles, "min" for minute or minutes, "h" for hour or hours, "rt" for room temperature, "TA" for retention time ", RBF" for round-bottom flask "," atm "for atmosphere," psi "for pounds per square inch," conc. "for concentrate," RCM "for ring closure 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 mass spectroscopy mass by electropul ionization verification, "HR" for high resolution mass spectrometry, "LCMS" for liquid chromatography mass spectrometry, "HPLC for" high pressure liquid chromatography, "RP HPLC" for HPLC of reverse phase, "TLC" or "tlc" for thin layer chromatography, "NMR" for nuclear magnetic resonance spectroscopy, "nOe" for nuclear overhauser spectroscopy, "1H" for proton, "δ" for delta, "s" for singletO, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" for broad, "Hz" for hertz, and "α", " β ","  "," R "," S "," E "and" Z "are stereochemical designations familiar to one skilled in the art. Methylate me
[00179] [00179] Lysophospholipids are mediators of bioactive lipids derived from membrane. Lysophospholipids include, but are not limited to, lysophosphatidic acid (1-acyl-2-hydroxy-sn-glycero-3-phosphate; LPA), sphingosine 1-phosphate (S1P), lysophosphatidylcholine (LPC) and sphingosylphosphonylcholine ( SPC). Lysophospholipids affect fundamental cellular functions that include proliferation, differentiation, survival, migration, adhesion, invasion and cell morphogenesis. These functions influence many biological processes that include neurogenesis, angiogenesis, wound healing, immunity and carcinogenesis.
[00180] [00180] The LPA acts through specific sets of receptors coupled to the G protein (GPCRs) in an autocrine and paracrine manner. The binding of LPA to its cognate GPCRs (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) activates intracellular signaling pathways to produce a variety of biological responses.
[00181] [00181] Lysophospholipids, such as LPA, are quantitatively smaller lipid species compared to their main phospholipid counterparts (for example, phosphatidylcholine, phosphatidylethanolamine and sphingomyelin). LPA has a role as a biological effector molecule, and has several physiological actions, such as, but not limited to, effects on blood pressure, platelet activation, smooth muscle contraction, and a variety of cellular effects, which include cell growth, cell rounding, neuronal retraction and fiber formation due to actin stress and cell migration. The effects of LPA are predominantly mediated by receptors.
[00182] [00182] The activation of LPA receptors (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) with LPA mediates a series of downstream signaling cascades. These include, but are not limited to, activation of mitogen-activated protein kinase (MAPK), adenylyl cyclase (AC) inhibition / activation, phospholipase C (PLC) Ca2 + activation / mobilization, arachidonic acid release , activation of Akt / PKB, and 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), serine / threonine protein Raf proto-oncogene kinase (c-RAF), Src proto-oncogene tyrosine kinase (c-src), extracellular signal regulated kinase (ERK), focal adhesion kinase (FAK), nucleotide exchange factor of guanine (GEF), glycogen synthase kinase 3b (GSK3b), c-junction amino-terminal kinase (JNK), MEK, myosin light chain II (MLC II), kB nuclear factor (NF-kB), N receptor activation -methyl-D- aspartate (NMDA), phosphatidylinositol 3-kinase (PI3K), protein kinase A (PKA), protein kinase C (PKC), substrate 1 of ras-related botulinum toxin C3 (RAC1). The actual route and the end point performed depend on a range of variables that include use of the receptor, cell type, expression level of a receptor or signaling protein, and LPA concentration. Almost all mammalian cells, tissues and organs coexpress various subtypes of LPA receptors, indicating that LPA receptors signal cooperatively. LPA1, LPA2 and LPA3 share high amino acid sequence similarity.
[00183] [00183] LPA is produced from activated platelets, activated adipocytes, neuronal cells and other types of cells. Serum LPA is produced by multiple enzymatic pathways that involve monoacyl glycerol kinase, phospholipase A1, secretory phospholipase A2 and lysophospholipase
[00184] [00184] LPA1 (formerly called VZG-1 / EDG-2 / mrec1.3) is coupled to three types of proteins G, Gi / o, Gq and G12 / 13. Through the activation of these G proteins, LPA induces a range of cell responses through LPA1, including, but not limited to: cell proliferation, activation of the serum response element (SRE), activation of protein kinase activated by mitogen (MAPK), inhibition of adenylyl cyclase (AC), activation of phospholipase C (PLC), mobilization of Ca2 +, activation of Akt and activation of Rho.
[00185] [00185] Wide expression of LPA1 is observed in adult mice, with a clear presence in the testicles, brain, heart, lung, small intestine, stomach, spleen, thymus and skeletal muscle. Likewise, human tissues also express LPA1; it is present in the brain, heart, lung, placenta, colon, small intestine, prostate, testis, ovary, pancreas, spleen, kidney, skeletal muscle and thymus.
[00186] [00186] LPA2 (EDG-4) is also coupled to three types of proteins
[00187] [00187] LPA3 (EDG-7) is different 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 acyl chains saturated. LPA3 can mediate LPA-induced pleiotropic signaling that includes PLC activation, Ca2 + mobilization, AC inhibition / activation and MAPK activation. Overexpression of LPA3 in neuroblastoma cells leads to neuritis elongation, whereas LPA1 or LPA2 results in neurite retraction and cell rounding when stimulated.
[00188] [00188] LPA4 (p2y9 / GPR23) is of divergent sequence compared to LPA1, LPA2 and LPA3 with a closer similarity to the platelet activating factor receptor (PAF). LPA4 mediates LPA-induced Ca2 + mobilization and cAMP accumulation, and functional coupling to Gs of protein G for AC activation, as well as coupling to other G proteins. The LPA4 gene is expressed in ovary, pancreas, thymus, kidney and skeletal muscle.
[00189] [00189] LPA5 (GPR92) is a member of the GPCR purinocluster and is structurally more related to LPA4. LPA5 is expressed in the heart, placenta, spleen, brain, lung and human intestine. LPA5 also shows very high expression in the CD8 + lymphocyte compartment of the gastrointestinal tract.
[00190] [00190] LPA6 (p2y5) is a member of the GPCR purinocluster and is structurally more related to LPA4. LPA6 is an LPA receptor coupled to the G12 / 13-Rho signaling pathways and is expressed in the inner root sheaths of human hair follicles. Illustrative Biological Activity Wound Healing
[00191] [00191] Normal wound healing occurs through a highly coordinated sequence of events, in which cellular, soluble factors and matrix components act together to repair the injury. The healing response can be described as occurring in four broad and overlapping phases - hemostasis, inflammation, proliferation and remodeling. Many growth factors and cytokines are released at a wound site to initiate and perpetuate wound healing processes.
[00192] [00192] When injured, damaged blood vessels activate platelets. Activated platelets play key roles in subsequent repair processes, releasing bioactive mediators to induce cell proliferation, cell migration, blood clotting and angiogenesis. LPA is one of these mediators that is released from activated platelets; this induces platelet aggregation together with mitogenic / migratory effects on surrounding cells, such as endothelial cells, smooth muscle cells, fibroblasts and keratinocytes.
[00193] [00193] The topical application of LPA to cutaneous wounds in mice promotes repair processes (wound closure and increase in neoepithelial thickness), increasing cell proliferation / migration without affecting secondary inflammation.
[00194] [00194] The activation of dermal fibroblasts by growth factors and cytokines leads to the subsequent migration of the wound edges to the provisional matrix formed by the fibrin clot, when the fibroblasts proliferate and begin to restore the dermis, secreting and organizing the extracellular matrix dermal characteristic (ECM). The increasing number of fibroblasts within the wound and the continuous precipitation of ECM increase the stiffness of the matrix by applying small tensile forces to the newly formed granulation tissue. The increase in mechanical stress, together with the transforming growth factor β (TGFβ), induces the expression of α smooth muscle actin (α-SMA) and the subsequent transformation of fibroblasts into myofibroblasts. Myofibroblasts facilitate the remodeling of granulation tissue through myofibroblastic contraction and through the production of ECM components.
[00195] [00195] LPA regulates many important functions of fibroblasts in wound healing, including proliferation, migration, differentiation
[00196] [00196] Tissue injury initiates a complex series of healing responses from the host; if successful, these responses restore normal tissue function and structure. Otherwise, these responses can lead to tissue fibrosis and loss of function.
[00197] [00197] For most organs and tissues, the development of fibrosis involves a multitude of events and factors. Molecules involved in the development of fibrosis include proteins or peptides (pro-fibrotic cytokines, chemokines, metalloproteinases, etc.) and phospholipids. Phospholipids involved in the development of fibrosis include platelet activation factor (PAF), phosphatidyl choline, sphingosine-1 phosphatide (S1P) and lysophosphatidic acid (LPA).
[00198] [00198] Several muscular dystrophies are characterized by progressive weakness and loss of muscle, and by extensive fibrosis. LPA treatment of cultured myoblasts has been shown to induce significant expression of connective tissue growth factor (CTGF). Subsequently, the CTGF induces the expression of collagen
[00199] [00199] CTGF expression by gingival epithelial cells, which are involved in the development of gingival fibromatosis, has been exacerbated by treatment with LPA (A. Kantarci, et al., J. Pathol. 210 (2006) 59-66) .
[00200] [00200] LPA is associated with the progression of liver fibrosis. In vitro, LPA induces proliferation of stellate cells and hepatocytes. These activated cells are the main cell type responsible for the accumulation of ECM in the liver. In addition, plasma LPA levels increase during CCl4-induced liver fibrosis in rodents, or in hepatitis C virus-induced liver fibrosis in humans (N. Watanabe, et al., Lysophosphatidic acid plasma level and serum activity of autotaxin increase liver damage in rats in relation to their severity, Life Sci. 81 (2007) 1009–1015; N. Watanabe, et al., J. Clin. Gastroenterol. 41 (2007) 616–623).
[00201] [00201] An increase in phospholipid concentrations in bronchoalveolar lavage fluid in rabbits and rodents injected 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) 91–102).
[00202] [00202] LPA is associated with heart disease and myocardial remodeling. Serum LPA levels increase after myocardial infarction in patients and LPA stimulates the proliferation of cardiac fibroblasts in rats and the production of collagen (Chen et al. FEBS Lett.
[00203] [00203] In the lung, aberrant responses to wound healing contribute to the pathogenesis of fibrotic lung diseases. Fibrotic lung diseases, such as idiopathic pulmonary fibrosis (IPF), are associated with high morbidity and mortality.
[00204] [00204] LPA is an important mediator of fibroblast recruitment in pulmonary fibrosis. LPA and LPA1 play important pathogenic roles in pulmonary fibrosis. The chemoattractive activity of fibroblasts plays an important role in the lungs in patients with pulmonary fibrosis. The pro-fibrotic effects of LPA1 receptor stimulation are explained by the vascular leakage mediated by the LPA1 receptor and the increased recruitment of fibroblasts, both pro-fibrotic events. The LPA-LPA1 pathway plays a role in mediating fibroblast migration and vascular leak in IPF. The end result is the aberrant healing process that characterizes this fibrotic condition.
[00205] [00205] The LPA1 receptor is the most highly expressed LPA receptor in fibroblasts obtained from patients with IPF. In addition, BAL obtained from patients with IPF induced chemotaxis of human fetal lung fibroblasts that were blocked by the dual LPA1-LPA3 receptor antagonist Ki16425. In an experimental mouse model with bleomycin-induced lung injury, LPA levels were shown to be high in bronchoalveolar lavage samples compared to unexposed controls. Knockout mice for LPA1 are protected from fibrosis after the challenge with bleomycin, with reduced accumulation of fibroblasts and vascular leakage. In human subjects with IPF, high levels of LPA were observed in samples of bronchoalveolar lavage compared to healthy controls. The increase in the chemotactic activity of
[00206] [00206] The LPA-LPA1 pathway is crucial in the recruitment of fibroblasts and vascular leakage in pulmonary fibrosis.
[00207] [00207] The activation of latent TGF-β by the integrin v6 plays a critical role in the development of fibrosis and lung injury (Munger et al. Cell, vol. 96, 319-328, 1999). LPA induces v6-mediated TGF-β activation in human lung epithelial cells (Xu et al. Am. J. Pathology, 2009, 174, 1264-1279). Activation of TGF-β mediated by v6 induced by LPA is mediated by the LPA2 receptor. Expression of the LPA2 receptor is increased in epithelial cells and mesenchymal cells in areas of pulmonary fibrosis in patients with IPF compared to normal human lung tissue. The LPA-LPA2 pathway contributes to the activation of the TGF-β pathway in pulmonary fibrosis. In some embodiments, compounds that inhibit LPA2 show efficacy in the treatment of pulmonary fibrosis. In some modalities, compounds that inhibit LPA1 and LPA2 show improved efficacy in the treatment of pulmonary fibrosis compared to compounds that inhibit only LPA1 or LPA2.
[00208] [00208] The LPA1 antagonist BMS-986020 has been shown to significantly reduce the rate of decline in FVC (forced vital capacity) in a 26-week clinical trial in patients with IPF (Palmer et al., Chest, 2018, 154, 1061-1069 ). Renal Fibrosis
[00209] [00209] LPA and LPA1 are involved in the etiology of renal fibrosis. LPA has effects on both the proliferation and contraction of glomerular mesangial cells and has thus been implicated in proliferative glomerulonephritis (C.N. Inoue, et al., Clin. Sci. (Colch.) 1999, 96, 431-436). In an animal model of renal fibrosis [unilateral ureteral obstruction
[00210] [00210] In mice in which the LPA1 receptor was exterminated (LPA1 (- / -), the development of renal fibrosis was significantly attenuated. Mice with UUO treated with the LPA receptor antagonist Ki16425 closely resembled the mouse profile LPA1 (- / -).
[00211] [00211] LPA can participate in the intraperitoneal accumulation of monocytes / macrophages and LPA can induce the expression of the pro-fibrotic cytokine CTGF in primary cultures of human fibroblasts (JS Koh, et al., J. Clin. Invest., 1998, 102, 716-727).
[00212] [00212] LPA treatment of a mouse epithelial renal cell line, MCT, induced a rapid increase in the expression of the pro-fibrotic cytokine CTGF. CTGF plays a crucial role in UUO-induced tubulointerstitial fibrosis (TIF), and is involved in the pro-fibrotic activity of TGFβ. This induction was almost completely suppressed by co-treatment with the LPA receptor antagonist Ki16425. In one aspect, the pro-fibrotic activity of LPA in the kidney results from a direct action of LPA on renal cells, while
[00213] [00213] LPA is involved in liver disease and fibrosis. Plasma levels of LPA and serum autotaxin (enzyme responsible for the production of LPA) are elevated in patients with hepatitis and in animal models of liver injury in correlation with increased fibrosis. LPA also regulates the function of liver cells. The LPA1 and LPA2 receptors are expressed by the hepatic stellate cells of mice and the LPA stimulates the migration of hepatic myofibroblasts. Ocular Fibrosis
[00214] [00214] LPA is involved in wound healing in the eye. LPA1 and LPA3 receptors are detectable in normal rabbit corneal epithelial cells, keratocytes and endothelial cells and the expression of LPA1 and LPA3 increases in corneal epithelial cells after injury.
[00215] [00215] The LPA and its counterparts are present in the aqueous humor and in the fluid of the lacrimal gland of the rabbit's eye and these levels increase in a model of rabbit corneal injury.
[00216] [00216] LPA induces the formation of actin stress fibers in the endothelial and epithelial cells of the rabbit cornea and promotes the contraction of corneal fibroblasts. LPA also stimulates the proliferation of pigmented epithelial cells in the human retina Cardiac Fibrosis
[00217] [00217] LPA is implicated in myocardial infarction and cardiac fibrosis. Serum LPA levels are elevated in patients after myocardial infarction (MI) and LPA stimulates the proliferation and production of collagen (fibrosis) by cardiac fibroblasts in rats. Both LPA1 and LPA3 receptors are highly expressed in human heart tissue.
[00218] [00218] In one aspect, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used to treat or prevent fibrosis in a mammal. In one aspect, a compound of Formulas (I), or a pharmaceutically acceptable salt thereof, is used to treat fibrosis of an organ or tissue in a mammal. In one aspect it is a method of preventing a condition of fibrosis in a mammal, the method comprising the mammal at risk of developing one or more conditions of fibrosis, a therapeutically effective amount of a compound of Formulas (I) , or a pharmaceutically acceptable salt thereof. In one aspect, the mammal has been exposed to one or more environmental conditions that are known to increase the risk of fibrosis of an organ or tissue. In one aspect, the mammal has been exposed to one or more environmental conditions that are known to increase the risk of fibrosis of the lung, liver or kidney. In one aspect, the mammal has a genetic predisposition for the development of fibrosis of an organ or tissue. In one aspect, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a mammal to prevent or minimize scarring after injury. In one aspect, the injury includes surgery.
[00219] [00219] The terms "fibrosis" or "fibrosing disorder", as used in this document, refer to conditions that are associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased recruitment of fibroblasts and include, but are not limited to, fibrosis of individual organs or tissues, such as heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.
[00220] [00220] Examples of diseases, disorders or conditions involving fibrosis include, but are not limited to: pulmonary diseases associated with fibrosis, for example, idiopathic pulmonary fibrosis, fibrosis
[00221] [00221] In one aspect, a mammal suffering from one of the following exemplary non-limiting diseases, disorders or conditions will benefit from therapy with a compound of Formula (I), or a pharmaceutically acceptable salt thereof: atherosclerosis, thrombosis, heart disease, vasculitis, scar tissue formation, restenosis,
[00222] [00222] In one aspect, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a mammal with fibrosis of an organ or tissue or with a predisposition to develop 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 immunosuppressants. In one aspect, the one or more agents include B cell antagonists. In one aspect, the one or more agents include uteroglobin.
[00223] [00223] In one aspect, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used to treat dermatological disorders in a mammal. The term "dermatological disorder", as used in this document, refers to a skin disorder. Such dermatological disorders include, but are not limited to, inflammatory or proliferative skin disorders, such as atopic dermatitis, bullous disorders, collagenosis, psoriasis, scleroderma, psoriasis lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea , wound healing, scars, hypertrophic scars, keloids, Kawasaki disease, rosacea, Sjogren-Larsso syndrome, urticaria. In one aspect, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used to treat systemic sclerosis. Ache
[00224] [00224] Since LPA is released after tissue injury, LPA1 plays an important role in the onset of neuropathic pain. LPA1, unlike LPA2 or LPA3, is expressed in neurons of the dorsal root ganglion (DRG) and dorsal root. Using oligodeoxin-
[00225] [00225] In one aspect, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used to treat pain in a mammal. In one aspect, the pain is acute pain or chronic pain. In another aspect, the pain is neuropathic pain.
[00226] [00226] In one aspect, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used in the treatment of fibrililage. In one aspect, fibromyalgia results from the formation of fibrous scar tissue in the contractile (voluntary) muscles. Fibrosis binds tissue and inhibits blood flow, resulting in pain. Cancer
[00227] [00227] Lysophospholipid receptor signaling plays a role in the etiology of cancer. Lysophosphatitic acid (LPA) and its receptors coupled to protein G (GPCRs) LPA1, LPA2 and / or LPA3
[00228] [00228] The LPA signals through its own GPCRs, leading to the activation of several effector pathways downstream. Such effector pathways downstream play a role in cancer. LPA and its GPCRs are linked to cancer through the main oncogenic signaling pathways.
[00229] [00229] LPA contributes to tumorigenesis by increasing cell motility and invasiveness. LPA has been implicated in the initiation or progression of ovarian cancer. LPA is present in significant concentrations (2–80 μM) in the ascitic fluid of patients with ovarian cancer. Ovarian cancer cells constitutively produce larger amounts of LPA compared to normal ovarian surface epithelial cells, the precursor to ovarian epithelial cancer. Elevated levels of LPA are also detected in the plasma of patients with early-stage ovarian cancer compared to controls. LPA receptors (LPA2 and LPA3) are also over-expressed in ovarian cancer cells compared to epithelial cells on the normal ovarian surface. LPA stimulates Cox-2 expression through transcriptional activation and post-transcriptional enhancement of Cox-2 mRNA in ovarian cancer cells. The prostaglandins produced by Cox-2 have been implicated in several human cancers and the pharmacological inhibition of Cox-2 activity reduces the development of colon cancer and decreases the size and number of adenomas in patients with adenomatous polyposis. familiar. APL 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. Biochem, 73, 321-354, 2004; Mills et al., Nat. Rev. Cancer, 3, 582-591, 2003; Murph et al., Biochemistry et Biophysica Acta, 1781, 547-557, 2008).
[00230] [00230] Cellular responses to LPA are mediated by lysophosphatidic acid receptors. For example, LPA receptors mediate migration and invasion by pancreatic cancer cell lines: an LPA1 and LPA3 antagonist (Ki16425) and LPA1 specific siRNA effectively blocked migration in vitro in response to LPA and peritoneal fluid (ascites) of patients with pancreatic cancer; in addition, Ki16425 blocked the invasion activity induced by LPA and induced by ascites from a highly peritoneal metastatic pancreatic cancer cell line (Yamada et al., J. Biol. Chem., 279, 6595-6605, 2004).
[00231] [00231] 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 plays a role in the pathogenesis of thyroid cancer. LPA3 was originally cloned from prostate cancer cells, agreeing with LPA's ability to induce
[00232] [00232] LPA has stimulating roles in cancer progression in many types of cancer. LPA is produced from and induces the proliferation of prostate cancer cell lines. LPA induces the proliferation, migration, adhesion and secretion of DLD1 cells from human colon carcinoma and angiogenic factors through LPA1 signaling. In other human colon carcinoma cell lines (HT29 and WiDR), LPA increases cell proliferation and secretion of angiogenic factors. In other colon cancer cell lines, activation of the LPA2 and LPA3 receptor results in the proliferation of cells. Genetic or pharmacological manipulation of LPA metabolism, specific blocking of receptor signaling and / or inhibition of downstream signal transduction pathways, represent approaches for cancer therapies.
[00233] [00233] It has been reported that LPA and other phospholipids stimulate the expression of interleukin-8 (IL-8) in ovarian cancer cell lines. In some modalities, high concentrations of IL-8 in ovarian cancer correlate with low initial response to chemotherapy and poor prognosis, respectively. In animal models, the expression of IL-8 and other growth factors, such as vascular endothelial growth factor (VEGF), is associated with increased tumorigenicity, ascites formation, angiogenesis and invasion of ovarian cancer cells. In some ways, IL-8 is an important modulator of cancer progression, drug resistance and prognosis in ovarian cancer. In some embodiments, a compound of Formula (I) inhibits or reduces the expression of IL-8 in ovarian cancer cell lines.
[00234] [00234] In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used in the treatment of cancer. In one aspect, a compound of Formula (I), or a pharmaceutical salt
[00235] [00235] The term "cancer", as used in this document, refers to an abnormal growth of cells that tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread). Types of cancer include, but are not limited to, solid tumors (such as bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas, or other endogenous organ) crino (thyroid), prostate, skin (melanoma or basal cell cancer) or haematological tumors (such as leukemia) at any stage of the disease with or without metastases.
[00236] [00236] Other non-limiting examples of cancer include: acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical thyroid / rhabdoid tumor, basal cell carcinoma, cancer of the basal cell bile duct, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt's lymphoma, cervical cancer, chronic lymphocytic leukemia,
[00237] [00237] Increased concentrations of vesicle LPA in ascites of patients with ovarian cancer and breast cancer effusions 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, 582-591, 2003; Sutphen et al., Cancer Epidemiol. Biologist Markers Prev. 13, 1185-1191, 2004). LPA concentrations are consistently higher in ascites samples than in the corresponding plasma samples. Respiratory and Allergic Disorders
[00238] [00238] In one aspect, the LPA is a contributor to the pathogenesis of respiratory diseases. In one aspect, 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 show responses to LPA. LPA induces the secretion of IL-8 from human bronchial epithelial cells. IL-8 is found in increased concentrations in the BAL fluids of patients with asthma, chronic obstructive pulmonary disease, pulmonary sarcoidosis and acute respiratory distress syndrome. IL-8 has been shown to exacerbate airway inflammation and airway remodeling. All LPA1, LPA2 and LPA3 receptors have been shown to contribute to LPA-induced IL-8 production. Cloning studies of several LPA-activated GPCRs have allowed the demonstration of the presence of mRNA for LPA1, LPA2 and LPA3 in the lung (J. J. A. Contos, et al., Mol. Pharmacol. 58, 1188-1196, 2000).
[00239] [00239] The release of LPA from activated platelets at the lesion site and its ability to promote the proliferation and contraction of fibroblasts are characteristics of LPA as a mediator of wound repair. In the context of airway disease, asthma is an inflammatory disease, in which inadequate airway "repair" processes lead to structural airway "remodeling" processes. In asthma, airway cells are subject to continuous 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.
[00240] [00240] In one aspect, in the asthmatic individual, the release of normal repair mediators, including APL, is exaggerated or the actions of repair mediators are inadequately prolonged, leading to an inadequate remodeling of the airways. The main structural features of the remodeled airways seen in asthma involve a thick reticular lamina (the basal membrane-like structure just below the airway epithelial cells), increased number and activation of myofibroblasts, thickening of the muscle layer smooth, increased number of mucous glands and mucus secretions and changes in connective tissue and capillary bed along the airway wall. In one respect, LPA contributes to these structural changes in the airways. In one aspect, LPA is involved in acute airway hyperresponsiveness in asthma. The lumen of the remodeled asthmatic airways is narrower due to the thickening of the airway wall, which
[00241] [00241] In addition to cellular responses mediated by LPA, several of the components of the LPA signaling pathway that lead to these responses are relevant to asthma. Positive regulation of the EGF receptor is induced by LPA and is also observed in asthmatic airways (M. Amishima, et al., Am. J. Respir. Crit. Care Med. 157, 1907– 1912, 1998). Chronic inflammation contributes to asthma and several transcription factors that are activated by LPA are known to be involved in inflammation (Ediger et al., Eur Respir J 21: 759-769, 2003).
[00242] [00242] In one aspect, the proliferation and contraction of fibroblasts and the secretion of extracellular matrix stimulated by LPA contribute to the fibroproliferative characteristics of other diseases of the airways, such as peribronchiolar fibrosis present in chronic bronchitis, emphysema and disease interstitial lung. Emphysema is also associated with mild fibrosis of the alveolar wall, a characteristic that is believed to represent an attempt to repair alveolar damage. In another aspect, LPA plays a role in fibrotic interstitial lung diseases and obliterative bronchiolitis, in which collagen and myofibroblasts increase. In another aspect, LPA is involved in several of the syndromes that constitute chronic obstructive pulmonary disease.
[00243] [00243] The administration of LPA in vivo induces airway hyperresponsiveness, itch responses, infiltration and activation of eosinophils and neutrophils, vascular remodeling and nociceptive flexor responses. LPA also induces the release of histamines
[00244] [00244] The term "respiratory disease", as used in this document, refers to diseases that affect the organs involved in breathing, such as nose, throat, larynx, Eustachian tube, trachea, bronchi, lungs, muscles related (eg, diaphragm and intercostal) and nerves. Respiratory diseases include, but are not limited to, asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, severe acute asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma,
[00245] [00245] The term "asthma" used in this document refers to any pulmonary disorder characterized by variations in the flow of pulmonary gases associated with constriction of the airways by any cause (intrinsic, extrinsic or both; allergic or non-allergic). The term asthma can be used with one or more adjectives to indicate the cause.
[00246] [00246] In one aspect, the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the treatment or prevention of chronic obstructive pulmonary disease in a mammal is presented in this document comprising administering to the mammal at least once an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof. In addition, chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and / or airway inflammation and cystic fibrosis. Nervous system
[00247] [00247] The nervous system is a major locus for the expression of LPA1; there, it is spatially and temporally regulated throughout the brain's development. Oligodendrocytes, the myelinating cells of the central nervous system (CNS), express LPA1 in mammals. In addition, Schwann cells, the myelinating cells of the peripheral nervous system, also express LPA1, which is involved in the regulation of Schwann cell survival and morphology.
[00248] [00248] The exposure of cell lines of the peripheral nervous system to LPA produces a rapid retraction of its processes, resulting in cell rounding, which was, in part, mediated by the 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 show retraction responses to LPA exposure through Rho activation and actomyosin interactions. In one aspect, LPA is associated with post-ischemic neural damage (J. Neurochem. 61, 340, 1993; J. Neurochem., 70:66, 1998).
[00249] [00249] In one aspect, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment or prevention of disorders of the nervous system in a mammal. The term "nervous system disorder", as used in this document, refers to conditions that alter the structure or function of the brain, spinal cord or peripheral nervous system, including, but not limited to, Alzheimer's disease, edema cerebral, cerebral ischemia, stroke, multiple sclerosis, neuropathies, Parkinson's disease, those found after blunt or surgical trauma (including post-surgical cognitive dysfunction and spinal cord or brainstem injury), as well as aspects neurological disorders such as degenerative disc disease and sciatica.
[00250] [00250] In one aspect, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided for use in treating or preventing a CNS disorder in a mammal. The dis-
[00251] [00251] Cardiovascular phenotypes observed after targeted exclusion 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 capillary networks from pre-existing vasculature, is normally invoked in wound healing, tissue growth and myocardial angiogenesis after ischemic injury. Peptide growth factors (eg, vascular endothelial growth factor (VEGF)) and lysophospholipids control the coordinated proliferation, migration, adhesion, differentiation and assembly of vascular endothelial cells (VECs) and adjacent vascular smooth muscle cells (VSMCs). In one aspect, the deregulation of the mediating processes of angiogenesis leads to atherosclerosis, hypertension, tumor growth, rheumatoid arthritis and diabetic retinopathy (Osborne, N. and Stainier, DY Annu. Rev. Physiol. 65, 23-43, 2003 ).
[00252] [00252] Downstream signaling pathways evoked by lysophospholipid receptors include formation of Rac-dependent lamellipods (eg, LPA1) and formation of Rho-dependent tension fibers (eg, LPA1), which is important in migration and ce adhesion - lular. Dysfunction of the vascular endothelium can change the balance of vasodilation to vasoconstriction and lead to hypertension and vascular remodeling, which are risk factors for atherosclerosis (Malaria).
[00253] [00253] LPA contributes to atherosclerosis both in the initial phase (barrier function and monocyte adhesion to the endothelium) and in the late phase (platelet activation and formation of intra-arterial thrombus), in addition to its general progression. In the initial phase, the LPA from numerous sources accumulates in the lesions and activates its cognate GPCRs (LPA1 and LPA3) expressed in the platelets (Siess, W. Biochim. Biophys. Acta 1582, 204-215, 2002; Rother, E et al. Circulation 108, 741-747, 2003). This triggers changes in platelet form and aggregation, leading to the formation of intra-arterial thrombus and, potentially, myocardial infarction and stroke. In support of its atherogenic activity, LPA can also be a mitogen and a motogen for VSMCs and an activator of endothelial cells and macrophages. In one aspect, mammals with cardiovascular diseases benefit from antagonists of the LPA receptors that prevent the formation of thrombus and neointima plaques.
[00254] [00254] In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used to treat or prevent cardiovascular diseases in mammals.
[00255] [00255] The term "cardiovascular disease", as used in this document, refers to diseases that affect the heart or blood vessels or both, including but not limited to: arrhythmia (atrial or ventricular or both) ; atherosclerosis and its sequelae; angina; heart rhythm disorders; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, organ or tissue; reperfusion injury after 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
[00256] [00256] In one aspect, methods are provided in this document to prevent or treat vasoconstriction, atherosclerosis and its sequelae, myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and stroke comprising administering at least once to mammal an effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition or medicament that includes a compound of formula (I), or a pharmaceutically acceptable salt thereof.
[00257] [00257] In one aspect, methods are provided in this document to reduce cardiac reperfusion injuries after myocardial ischemia and / or endotoxic shock, comprising administering at least once to the mammal an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof.
[00258] [00258] In one aspect, methods are provided in this document to reduce blood vessel constriction in a mammal which comprises administering to the mammal at least once an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt the same.
[00259] [00259] In one aspect, methods are provided in this document to decrease or prevent the increase in the blood pressure of a mammal comprising administering to the mammal at least once an effective amount of at least one compound of Formula (I) , or a pharmaceutically acceptable salt thereof. Inflammation
[00260] [00260] The LPA has been shown to regulate immune responses through the modulation of activities / functions of immune cells, such as T / B lymphocytes and macrophages. In activated T cells, LPA activates the production
[00261] [00261] In one aspect, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used to treat or prevent inflammation in a mammal. In one aspect, LPA1 and / or LPA3 antagonists find use in the treatment or prevention of inflammatory / immunological disorders in a mammal. In one aspect, the LPA1 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof.
[00262] [00262] Examples of inflammatory / immunological disorders include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, eczema, graft rejection allogeneic or xenogenic transplantation (organ, bone marrow, stem cells and other cells and tissues), graft versus host disease, lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (for example, Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, relapsing chronic hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis. Other Diseases, Disorders or Conditions
[00263] [00263] According to one aspect, they are methods to treat, prevent, reverse, stop or slow the progression of diseases or conditions dependent on LPA or mediated by LPA, once they become clinically evident, or to treat the associated symptoms or related to diseases or conditions mediated by LPA or dependent on LPA, administering to the mammal a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In certain modalities, the individual already has a disease or condition dependent on APL or mediated by APL at the time of administration, or is at risk of developing an illness or condition dependent on APL or mediated by APL.
[00264] [00264] In certain respects, the activity of LPA1 in a mammal is directly or indirectly modulated by administering (at least once) a therapeutically effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof . This modulation includes, but is not limited to, reducing and / or inhibiting LPA1 activity. In additional aspects, LPA activity in a mammal is directly or indirectly modulated, including reduction and / or inhibition, by administering (at least once) a therapeutically effective amount of at least one compound of Formula (I ), or a pharmaceutically acceptable salt thereof. This modulation includes, but is not limited to, reducing and / or inhibiting the quantity and / or activity of an LPA receptor. In one aspect, the LPA receptor is LPA1.
[00265] [00265] In one aspect, LPA has a contraction action on smooth bladder muscle cells, isolated from the bladder, and promotes the growth of prostate-derived epithelial cells (J. Urology,
[00266] [00266] In certain respects, they are methods to prevent or treat eosinophils and / or basophils and / or dendritic cells and / or neutrophils and / or monocytes and / or recruitment of T cells comprising administering at least once to the mammal an effective amount of at least a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
[00267] [00267] In certain respects, they are methods for the treatment of cysts, including, for example, interstitial cystitis, comprising administering to the mammal at least once a therapeutically effective amount of at least one compound of Formula (I ), or a pharmaceutically acceptable salt thereof.
[00268] [00268] According to one aspect, the methods described in this document can be used to diagnose or determine whether a patient is suffering from an LPA-mediated or dependent disease or to administer to the individual a therapeutically effective amount of a compound of formula ( I), or a pharmaceutically acceptable salt thereof, and determine whether or not the patient responds to treatment.
[00269] [00269] In one aspect, compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs and pharmaceutically acceptable solvates thereof, which are LPA1 antagonists, are provided and are used to treat sick patients suffering from one or more diseases or conditions mediated by LPA or dependent on LPA, including, but not limited to, pulmonary 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, cancer, pain, proliferative disorders and inflammatory conditions. In some modalities, conditions or diseases dependent on APL include those that absolute or relative excess APL is present and / or is observed.
[00270] [00270] In any of the aspects mentioned above, diseases or conditions dependent on LPA or mediated by LPA include, but are not limited to, organ fibrosis, asthma, allergic disorders, chronic obstructive pulmonary disease, pulmonary hypertension , pulmonary or pleural fibrosis, peritoneal fibrosis, arthritis, allergy, cancer, cardiovascular disease, respiratory distress syndrome, myocardial infarction, aneurysm, stroke and cancer.
[00271] [00271] In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used to improve the decrease in corneal sensitivity caused by corneal operations, such as laser-assisted local keratomileuse ( LASIK) or cataract operation, decreased corneal sensitivity caused by corneal degeneration, and dry eye symptom caused by it.
[00272] [00272] In one aspect, the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the treatment or prevention of ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis and papillary conjunctivitis is presented in this document. mammal comprising administering to the mammal at least once an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof.
[00273] [00273] In one aspect, the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the treatment or prevention of Sjögren's disease or inflammatory disease with dry eyes in a mammal is presented in this document understanding
[00274] [00274] In one aspect, LPA and LPA receptors (eg, LPA1) are involved in the pathogenesis of osteoarthritis (Kotani et al., Hum. Mol. Genet., 2008, 17, 1790-1797). In one aspect, the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the treatment or prevention of osteoarthritis in a mammal is disclosed in this document, comprising administering at least once to the mammal a effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof.
[00275] [00275] In one aspect, LPA receptors (eg, LPA1, LPA3) contribute to the pathogenesis of rheumatoid arthritis (Zhao et al., Mol. Pharmacol., 2008, 73 (2), 587-600). In one aspect, the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the treatment or prevention of rheumatoid arthritis in a mammal is presented in this document, which comprises administering at least once to the mammal a effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof.
[00276] [00276] In one aspect, LPA receptors (eg, LPA1) contribute to adipogenesis. (Simon et al., J. Biol. Chem., 2005, vol. 280, n. 15, p, 14656). In one aspect, this document presents the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in promoting the formation of adipose tissue in a mammal that comprises administering at least once to the mammal an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof. The. In Vitro Tests
[00277] [00277] The effectiveness of the compounds of the present invention as inhibitors of LPA1 can be determined in an LPA1 functional antagonist assay as follows:
[00278] [00278] Chinese hamster ovary cells that overexpress human LPA1 were plated overnight (15,000 cells / well) in 384-well microplates coated with poly-D-lysine (Greiner bio-one, Cat # 781946) in DMEM / F12 medium (Gibco, Cat # 11039). After nocturnal culture, the cells were loaded with calcium indicator dye (AAT Bioquest Inc, Cat # 34601) for 30 minutes at 37ºC. The cells were then equilibrated at room temperature for 30 minutes before the assay. Test compounds soaked in DMSO were transferred to non-bonding surface plates of 384 wells (Corning, Cat # 3575) using the Labcyte Echo acoustic buffer 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 (Hamamat-su), in final concentrations ranging from 0.08 nM to 5 µM and were then incubated for 20 minutes at room temperature, where the LPA in time ( Avanti Polar Lipids Cat # 857130C) was added in final concentrations of 10 nM to stimulate cells. The IC50 value of the compound was defined as the concentration of the test compound that inhibited 50% of the calcium flow induced by LPA alone. IC50 values were determined by adjusting the data to a 4-parameter logistic equation (GraphPad Prism, San Diego CA). B. In Vivo Trials Challenge with LPA with plasma histamine evaluation
[00279] [00279] The compound is dosed orally p.o. 2 hours for female CD-1 mice before the LPA challenge. The mice are then dosed via the tail vein (IV) with 0.15 ml of LPA in 0.1% BSA / PBS (2 μg / µL). Exactly 2 minutes after the challenge with LPA, the mice are sacrificed by decapitation and the blood from the trunk is collected. These samples are centrifuged collectively and individual 75 μl samples are frozen at -20ºC until the time of the histamine test.
[00280] [00280] Plasma histamine analysis was performed using standard EIA (Enzyme Immunoassay) methods. Plasma samples were thawed and diluted 1:30 in 0.1% BSA in PBS. The EIA protocol for histamine analysis was followed, as described by the manufacturer (Histamine EIA, Oxford Biomedical Research, EA # 31).
[00281] [00281] The LPA used in the test is formulated as follows: LPA (1-oleoyl-2-hydroxy-sn-glycero-3-phosphate (sodium salt), 857130P, Polar Lipids Avanti) is prepared in 0.1% of BSA / PBS for a total concentration of 2 μg / µL. 13 mg of LPA is weighed and 6.5 ml of 0.1% BSA is added, vortexed and sonicated for ~ 1 hour until a clear solution is obtained. V. Pharmaceutical Compositions, Formulations and Combinations
[00282] [00282] In some embodiments, a pharmaceutical composition is provided which comprises a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition also contains at least one pharmaceutically acceptable inactive ingredient.
[00283] [00283] In some embodiments, a pharmaceutical composition is provided which comprises a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable inactive ingredient. In one aspect, the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, inhalation, nasal administration, topical administration, ophthalmic administration or optical administration. 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, ointment, lotion, eye drops or ear drops.
[00284] [00284] In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutically active agents selected from: corticosteroids (eg, dexamethasone or fluticasone), immunosuppressants (eg, tacrolimus and pimicrolimus), painkillers, anticancer agent , anti-inflammatory drugs, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists (eg, montelukast or zafirlucte), leukotriene formation inhibitors, monoacyl glycerol kinase inhibitors, phospholipase A1 inhibitors, phospholipase A2 inhibitors, lysophospholipase D inhibitors (lisaPLD), autotaxin inhibitors, decongestants, antihistamines (eg, loratidine), mucolytics, anticholinergics, antitussives, expectorants, anti-infectives (eg fusidic acid, especially for treating atopic dermatitis), antifungals (eg clotriazole, particularly for atopic dermatitis), te rapes with anti-IgE antibody (for example, omalizumab), β-2 adrenergic agonists (for example, albuterol or salmeterol), other PGD2 antagonists that act on other receptors, such as DP antagonists, PDE4 inhibitors (for example , cilomilast), drugs that modulate cytokine production, for example, TACE inhibitors, drugs that modulate Th2 cytokine activity IL-4 & IL-5 (eg, blocking monoclonal antibodies and soluble receptors), agonists of PPAR (eg, rosiglitazone and pyoglobitazone), 5-lipoxygenase inhibitors (eg, zileuton).
[00285] [00285] In some embodiments, the pharmaceutical composition further comprises one or more additional antifibrotic agents selected from pirfenidone, nintedanib, thalidomide, carlumab, FG-3019, fresolimumab, interferon alfa, lecithinized superoxide dismutase, simtuzumab, tanzisertib, tralokinuma , hu3G9, AM3 152, 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, obeticolic acid, aramchol, GFT-505, eicosapentaenoic acid ethyl ester, metformin, metrelepine, muromonab-CD3, oltipraz, IMM-124-E, MK-4074, PX -102, RO-
[00286] [00286] In some embodiments, one or more additional therapeutically active agents, except a compound of Formula (I), or a pharmaceutically acceptable salt thereof, are selected from: corticosteroids (for example, dexamethasone or fluticasone), immunosuppressants (eg, tacrolimus & pimecrolimus), analgesics, anticancer agent, anti-inflammatories, chemokine receptor antagonists, bronchodilators, leuko-triene receptor antagonists (eg, montelukast or zafirlukast), formation inhibitors leukotriene, monoacylglycerol kinase inhibitors, phospholipase A1 inhibitors, phospholipase A2 inhibitors, lysophospholipase inhibitors
[00287] [00287] In some embodiments, the one or more additional therapeutically active agents, except a compound of Formula (I), or a pharmaceutically acceptable salt thereof, are other antifibrotic agents selected from pirfenidone, nintedanib, thalidomide, carlumab , FG-3019, fresolimumab, interferon alfa, lecithinized superoxide dismutase, simtuzumab, tanzisertib, tralokinumab, hu3G9, AM-152, IFN-gamma-1b, IW-001, PRM-151, PXS-25, pentoxifylline / N- acetyl-cysteine, pentoxifylline / vitamin E, salbutamol sulphate, [Sar9, Met (O2) 11] - Substance P, pentoxifylline, mercaptamine bitartrate, obeticolic acid, aramchol, GFT-505, ethosapentyl ester, metformin, metrelep - tub, muromonab-CD3, oltipraz, IMM-124- E, MK-4074, PX-102, RO-
[00288] [00288] In some embodiments, one or more additional therapeutically active agents, except a compound of Formula (I), or a pharmaceutically acceptable salt thereof, are selected from ACE inhibitors, ramipril, AII antagonists, irbesartan , antiarrhythmic drugs,
[00289] [00289] In some embodiments, one or more additional therapeutically active agents, except a compound of Formula (I), or a pharmaceutically acceptable salt thereof, are selected from Gremlin-1 mAb, PA1-1 mAb, Promedior (PRM -151; Pentraxin-2 human recombinant); FGF21, TGFβ antagonists, -v6 & v pan-antagonists; FAK inhibitors, TG2 inhibitors, LOXL2 inhibitors, NOX4 inhibitors, MGAT2 inhibitors, GPR120 agonists.
[00290] [00290] The pharmaceutical formulations described in this document are administrable to an individual in several ways by various routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical or transdermal. The pharmaceutical formulations described in this document
[00291] [00291] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered orally.
[00292] [00292] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered topically. In such embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is formulated in a variety of topically administered compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, massagers , smears, medicated sticks, medicated dressings, medicated bandages, balms, creams or ointments. Such pharmaceutical compounds may contain solubilizers, stabilizers, tonicity-enhancing agents, buffers and preservatives. In one aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered topically to the skin.
[00293] [00293] In another aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered by inhalation. In one embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered by inhalation that targets the pulmonary system directly.
[00294] [00294] In another aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is formulated for administration
[00295] [00295] In another aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is formulated as eye drops.
[00296] [00296] In another aspect is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament to treat a disease, disorder or condition in which the activity of at least one LPA receptor contributes to the pathology and / or symptoms of the disease or condition. In such a modality, 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 in this document.
[00297] [00297] In any of the aspects mentioned above are modalities in which: (a) the effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is systemically administered to the mammal; and / or (b) the effective amount of the compound is administered orally to the mammal; and / or (c) the effective amount of the compound is administered intravenously to the mammal; and / or (d) the effective amount of the compound is administered by inhalation; and / or (e) the effective amount of the compound is administered by natural 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 apically 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.
[00298] [00298] In any of the aspects mentioned above are modalities comprising single administrations of an amount
[00299] [00299] In any of the aspects mentioned above are modalities comprising several administrations of an effective amount of the compound, including other modalities in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between several 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 other alternative modalities, the method comprises a range of drugs, in which the administration of the compound is temporarily suspended or the dose of the compound being administered temporarily reduced; at the end of the drug interval, compounding is resumed. In one embodiment, the duration of the drug interval varies from 2 days to 1 year.
[00300] [00300] A method of inhibiting the physiological activity of LPA in a mammal is also provided comprising administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the mammal in need thereof.
[00301] [00301] In one aspect, a medicament is provided to treat an LPA-dependent or LPA-mediated disease or condition in a mammal comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. .
[00302] [00302] In some cases disclosed in this document is the use of a compound of Formula (I), or a pharmaceutically acceptable salt
[00303] [00303] In some cases disclosed in this document is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the treatment or prevention of an LPA-dependent or LPA-mediated disease or condition.
[00304] [00304] In one aspect, there is a method for treating or preventing an LPA-dependent or LPA-mediated disease or condition in a mammal comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutical salt. acceptable level of it.
[00305] [00305] In one aspect, diseases or conditions dependent or mediated by LPA include, but are not limited to, fibrosis of organs or tissues, scarring, liver disease, dermatological conditions, cancer, cardiovascular diseases, diseases or conditions respiratory diseases, inflammatory diseases, diseases of the gastrointestinal tract, kidney diseases, disease associated with the urinary tract, inflammatory disease of the lower urinary tract, dysuria, frequent urination, pancreas disease, arterial obstruction, cerebral infarction, cerebral hemorrhage, pain, peripheral neuropathy and fibromyalgia.
[00306] [00306] In one aspect, the disease dependent or mediated by LPA or the condition is a respiratory disease or condition. In some modalities, the disease or respiratory condition is asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary arterial hypertension or acute respiratory distress syndrome.
[00307] [00307] In some modalities, the condition or condition dependent or LPA-mediated is selected from idiopathic pulmonary fibrosis; other diffuse parenchymal lung diseases of different etiologies, including drug-induced iatrogenic fibrosis, occupational and / or environmental fibrosis, granulomatous diseases (sarcoidosis,
[00308] [00308] In one aspect, the disease or condition dependent on LPA or mediated by LPA is described herein.
[00309] [00309] In one aspect, a method is provided for the treatment or prevention of organ fibrosis in a mammal comprising administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a mammal in need of treatment. same.
[00310] [00310] In one aspect, organ fibrosis comprises pulmonary fibrosis, renal fibrosis, or liver fibrosis.
[00311] [00311] In one aspect, a method of improving lung function in a mammal is provided 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 was diagnosed as having pulmonary fibrosis.
[00312] [00312] In one aspect, compounds disclosed in this document are used to treat idiopathic pulmonary fibrosis (usual interstitial pneumonia) in a mammal.
[00313] [00313] In some embodiments, the compounds disclosed in this document are used to treat diffuse interstitial lung diseases in mammals: induced by iatrogenic, occupational / environmental (farmer's lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonia) , collagen vascular disease (scleroderma and others), alveolar proteinosis, granulomatosis of langerhans cells, lymphangioleiomyomatosis, Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease.
[00314] [00314] In some embodiments, the compounds disclosed in this document are used to treat post-transplant fibrosis associated with chronic rejection in a mammal: Bronchiolitis obliterans for lung transplantation.
[00315] [00315] In some embodiments, the compounds disclosed in this document are used to treat cutaneous fibrosis in a mammal: cutaneous scleroderma, Dupuytren's disease, keloids.
[00316] [00316] In one aspect, the compounds disclosed in this document are used to treat liver fibrosis with or without cirrhosis in a mammal: drug / drug-induced (hemochromatosis), alcoholic liver disease, viral hepatitis (hepatitis B virus, virus hepatitis C, HCV), non-alcoholic liver disease (NAFLD, NASH), metabolic disease
[00317] [00317] In one aspect, the compounds disclosed in this document are used to treat renal fibrosis in a mammal: tubular interstitial fibrosis, glomerular sclerosis.
[00318] [00318] In any of the aspects mentioned above involving the treatment of diseases or conditions dependent on LPA are additional modalities comprising administering at least one additional agent in addition to administering a compound having the structure of Formula (I), or a salt pharmaceutically acceptable product. In various modalities, each agent is administered in any order, including simultaneously.
[00319] [00319] In any of the modalities disclosed in this document, the mammal is a human being.
[00320] [00320] In some embodiments, the compounds provided in this document are administered to a human.
[00321] [00321] In some embodiments, the compounds provided in this document are administered orally.
[00322] [00322] In some embodiments, the compounds provided in this document are used as antagonists of at least one LPA receptor. In some embodiments, the compounds provided in this document are used to inhibit the activity of at least one LPA receptor or to treat a disease or condition that would benefit from inhibiting the activity of at least one LPA receptor. In one aspect, the LPA receptor is LPA1.
[00323] [00323] In other embodiments, the compounds provided in this document are used for the formulation of a drug for inhibiting LPA1 activity.
[00324] [00324] Articles of manufacture, which include packaging material, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, within the packaging material, a label indicating which compound or composition, or pharmaceutically acceptable salt, tautomers, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvent thereof, is used to inhibit the activity of at least one LPA receptor, or for treatment, pre- preventing or ameliorating one or more symptoms of a disease or condition that would benefit from inhibiting the activity of at least one LPA receptor, are provided. SAW. General Overview Including Schemes
[00325] [00325] The compounds of the present invention can be prepared in various 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, together with synthetic methods known in the art of synthetic organic chemistry, or by variations appreciated therein by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are carried out in one or solvent or mixture of solvents suitable for the reagents and materials used and suitable for the transformations carried out. It will be understood by those skilled in the technique of organic synthesis that the functionality present in the molecule must be consistent with the proposed transformations. This sometimes requires judgment to modify the order of the synthetic steps or to select a specific process scheme over another in order to obtain a desired compound of the invention.
[00326] [00326] It will also be recognized that another important consideration in planning any synthetic route in this field is the careful choice of the protection group used to protect the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained professional is Greene et al., (Protective Groups in Organic Synthe-
[00327] [00327] The compounds of formula (I) can be prepared by the exemplary procedures described in the following schemes and working examples, as well as the relevant procedures of the published literature that are used by one skilled in the art. Examples of procedures and reagents for these reactions appear in this document after and in the working examples. Protection and deprotection in the processes below can be carried out by procedures generally known in the art (see, for example, Wuts, P.G.M., Greene's Protective Groups in Organic Synthesis, 5th Edition, Wiley (2014)). General methods of organic synthesis and transformations of functional groups are found in: Trost, BM 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); Larock, R.C., Comprehensive Organic Transformations, 2nd Edition, Wiley-VCH, New York, NY (1999), and references cited therein.
[00328] [00328] Scheme 1 describes the synthesis of N-carbamoyl-triazole-aryloxy cyclohexyl 16 and 17. A dihalo derivative (preferably dibromo) phenyl or azine (for example, pyridine) 1 is coupled with a propargyl alcohol 2 suitably protected (for example, as tetrahydropyranyl ether) under Sonogashira conditions (for example, Alper, P. et al., WO 2008097428) to obtain propargyl alcohol protected with bromo-aryl or bromo-heteroaryl 3. Thermal reaction of alkaline 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, BC, et al. , J. Am. Chem. Soc., 2008, 130, 8923-8930) provides the hydroxylmethyl-
[00329] [00329] For the specific example of analogs 20, where R2 = CH3 (Scheme 1A), instead of using an alkyl azide for cycloaddition to the protected hydroxyalkyl alkaline 3, trimethylsilyl azide is a viable replacement reagent (Qian, Y. et al., J. Med. Chem., 2012, 55, 7920-7939) that can be used under conditions catalyzed by thermal or transition metals (Boren, BC et al., J. Am. Chem. Soc. , 2008, 130, 8923-8930). Under these conditions, the desired 18-triazole regioisomer is obtained as the main product of the cycloaddition reaction 1,3-
[00330] [00330] Scheme 2 describes an alternative synthetic route to N-carbamoyl triazole-aryloxy cyclohexyl 16 or 17. A derivative of dihalo (preferably dibromo) phenyl or azine (for example, pyridine) 1 is coupled with alcohol propargyl under Sonogashira conditions (Alper, P. et al., WO 2008097428) for the corresponding bromo-aryl or bromoheteroaryl propargyl alcohol 21. Thermal reaction of alkaline 21 with an alkyl azide 4 (with or without an appropriate catalyst, Qian , Y. et al, J. Med. Chem., 2012, 55, 7920-7939; Boren, BC et al., J. Am. Chem. Soc., 2008, 130, 8923-8930) provides the hydroxymethyl triazoles corresponding regions from which the desired triazole regioisomer 22 can be isolated. Triazole alcohol 18 is reacted with a bromination agent (for example, PBr3 or CBr4 / Ph3P) to obtain the corresponding bromide 23. Displacement of bromide 23 with NaN3 (or other appropriate azide reagents) results in azide 24, which undergoes reduction (eg Staudinger reduction with Ph3P / H2O) to generate triazole amine 25. The protection of triazole amine 25 provides intermediate 26. Bromo-aryl / heteroaryl triazole 26 is then converted to hydroxy-aryl / heteroaryl triazole 27 corresponding through the corresponding boronate using the same 2-step sequence [borylation with B2 (pin) 2 / Pd catalyst followed by boronate-mediated H2O2 oxidation] as described in Scheme 1. Hydroxyaryl triazole 27 is then subjected to a Mitsunobu reaction with a 3-hydroxy 8-cycloalkyl ester 8 to provide the corresponding triazole cycloalkyl ether ester 28. Amine 28 is deprotected to give the key triazyl amine intermediate 13, which is then converted to N-carbamate acids 16 or 17 by the synthetic sequences described in Scheme
[00331] [00331] Scheme 3 describes an alternative synthetic route to triazole N-carbamate acids of cyclohexyl 16 and 17. The reaction of triazole amine 25 with an acylating reagent 14 in the presence of base provides triazole N-carbamate 29. Bromo-aryl / heteroaryl triazole 29 is converted
[00332] [00332] Scheme 4 describes an alternative synthetic route to cyclohexyl N-carbamate triazole acids 16 and 17. The reaction of an alkoxyphenyl or azine derivative (eg pyridine or pyrazine) 31 with trimethylsilyl acetylene under Sonogashira conditions (Alper, P. et al., WO 2008097428) provides the corresponding alkoxy-aryl or heteroaryl silyl acetylene, which is then desilylated under standard conditions (for example, Bu4NF) to give alkaline 32. The alkaline thermal reaction 32 with azide sodium provides the corresponding triazole (Roehrig, U. et al., WO 2009127669), which is then alkylated with an alkyl 25 iodide in the presence of the base to give a mixture of re- alkylated triazoles
[00333] [00333] Scheme 5 describes the synthesis of N-carbamoyl-triazole-aryloxy α-fluoro cyclohexyl 44 and 45 acids. Diels-Alder reaction of 1,3-butadiene and a suitably protected 2-fluoroacrylate ester (for example , procedure by Kotikyan et al., Bull.
[00334] [00334] Scheme 6 describes the synthesis of N-carbamoyl methyltriazol-aryloxy cyclohexyl 44 and 45. The addition of an alkyl-organic reagent (eg R7aLi or R7aMgX) for aldehyde 35 provides triazole alcohol 46, which is then protected as 47. Deprotection of hydroxyarene / hydroxyheteroarene, followed by Mitsububu reaction with 8, provides cyclohexyl ether triazole 48. Deprotection 48 provides alcohol 49, which can be transported to cyclohexyl N-carbamate-triazole acids 50 and 51, following the general synthetic procedure described in Scheme 1.
[00335] [00335] Scheme 7 describes the synthesis of directly linked N-carbamoyl triazole acids 54 and 55. Oxidation of cyclohexyl ether triazol-alcohol 10 in carboxylic acid 52 (for example, directly in the acid with pyridinium dichromate or through a two-step procedure using aldehyde [Swern oxidation or Dess-Martin periodinane followed by oxidation of NaClO2 to acid, eg Lindgren, BO, Acta Chem. Scand. 1973, 27, 888]). Curtius rearrangement of 52 in the presence of an R4-OH alcohol provides the triazole NH-carbamate 53. Deprotection of the triazole NH-carbamate ester 53 provides the triazole acids NH-carbamate 54. Alternatively, NH-carbamate cyclohexyl ester 53 is deprotonated with a suitable base and alkylated (as in Scheme 1) with an alkyl R3-halide to give the triazole acids N-alkyl carbamate 55.
[00336] [00336] Scheme 8 describes the synthesis of N-carbamoyl triazole-aryloxy cyclohexyl 59 and 60. Triazole 10 alcohol is oxidized to the corresponding aldehyde (eg Dess-Martin periodinane or Swern oxidation ), which is then subjected to an olefin reaction (eg Wittig or Peterson olefin reaction) that provides terminal olefin 56. The hydroboration of olefin 56 on the terminal carbon (for example, with 9-BBN), followed by oxidative processing, provides the corresponding triazole ethyl alcohol 57. Triazole ethyl alcohol 57 is subjected to the 3-step sequence described in Scheme 1 (bromination, azide displacement, azide reduction) to give the main triazole-ethylamine intermediate 58. Triazole-ethylamine 58 is then transported to cyclohexyl-triazole-ethyl-N-carbamate acids 59 and 60 using the same synthetic sequence described for converting amine 13 to triazole carbamate acids 16 and 17 in Scheme 1 .
[00337] [00337] Scheme 9 describes the synthesis of N-ureido-triazole-aryloxy cyclohexyl 63 and 65 acids. Triazole-amine cyclohexyl ester 13 undergoes reaction with a carbamoyl chloride 62 (prepared, for example , from the reaction of a secondary amine 61 with triphosgene) to give the corresponding cyclohexyl ester ureido-triazole, which is then deprotected to provide the cyclohexyl N, N'-dialkyl-ureido-triazole-aryloxy acids 63. In a complementary synthetic route, the triazole amine cyclohexyl ester 13 undergoes a reaction directly with triphosgen to give carbamoyl chloride 64 (CDI for the corresponding intermediate), which reacts with a primary amine R3-NH2 (or with a secondary amine 61) to give (after deprotection of the ester) the corresponding N-alkyl-ureido-triazole aryloxy cyclohexyl 65 acids (with secondary amines, the products are N, N'-dialkyl ureido-triazole acids 63) .
[00338] [00338] Scheme 10 describes the synthesis of urea acids cyclohexyl N-linked to triazole 67 and 68. Cyclohexyl ether triazole-alcohol 10 undergoes oxidation to triazole carboxylic acid 66 (for example, directly to acid with, for example, pyridinium dichromide or by a two-step procedure via aldehyde [Swern oxidation or Dess-Martin periodinane followed by oxidation of NaClO2 to acid, for example, Lindgren, BO, Acta Chem. Scand. 1973 , 27, 888]). The Curtius rearrangement (for example, with (PhO) 2PON3) of triazole acid 66 provides the corresponding intermediate triazole isocyanate, which is then reacted with a primary amine R3NH2 or with a secondary amine R3R4NH to supply, after ester deprotection, triazole-ureido-NH-alkyl-cyclohexyl-67 acids or triazole-ureido-N, N-dialkyl-cyclohexyl acids 68.
[00339] [00339] Scheme 11 describes the synthesis of triazole sulfonylureide cyclohexyl 70 acids. Triazole amine cyclohexyl ester 13 undergoes reaction with a dialkyl sulfamoyl chloride 69 (prepared from the reaction of a secondary amine 61 with chloride of sulfuryl) to give the corresponding sulfonylureido-triazole cyclohexyl ester, which is then deprotected to provide the sulfonylureido-triazole-aryloxy cyclohexyl 70 acids. Scheme 11 VII. EXAMPLES
[00340] [00340] The following examples are offered as illustrative, as a partial scope and specific modalities of the invention and are not intended to limit the scope of the invention. Abbreviations and chemical symbols have their usual and usual meanings, unless otherwise indicated. Unless otherwise indicated, the compounds used in this document have been prepared, isolated and characterized using the schemes and other methods disclosed in this document or can be prepared using the same.
[00341] [00341] As appropriate, the reactions were conducted under an atmosphere of dry nitrogen (or argon). For anhydrous reactions, EM DRISOLV® solvents were used. For other reactions, reagent grade or HPLC grade solvents were used. Unless otherwise indicated, all commercially obtained reagents were used as received.
[00342] [00342] Microwave reactions were performed using a 400W Biotage Initiator instrument in microwave reaction vessels under microwave irradiation (2.5 GHz). HPLC / MS and preparatory / analytical HPLC methods used in the characterization or purification of examples
[00343] [00343] 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 resonance of the solvent as an internal standard. The spectral data of 1HRMN are normally reported as follows: chemical displacement, multiplicity (s = singlet, br s = broad singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, sep = septet , m = multiple-to, app = apparent), coupling constants (Hz) and integration.
[00344] [00344] In the examples where 1H NMR spectra were collected
[00345] [00345] The term HPLC refers to a Shimadzu high performance liquid chromatography instrument with one of the following methods: HPLC-1: Sunfire C18 column (4.6 × 150 mm) 3.5 m, gradient from 10 to 100% B: A for 12 min, then wait 3 min to 100% B. Mobile Phase A: 0.05% TFA in water: CH3CN (95: 5) Mobile Phase B: 0.05% TFA in CH3CN: water (95: 5) pH of TFA Buffer = 2.5; Flow rate: 1 ml / min; Wavelength: 254 nm, 220 nm.
[00346] [00346] A mixture of 20% buta-1,3-diene in toluene (13.8 ml, 41.1 mmoles) and ethyl 2-fluoroacrylate (3.07 ml, 27.4 mmoles) was heated to 120ºC in a tube sealed for 7 days, then it was cooled to RT and concentrated in vacuo. The residue was chromatographed (80 g SiO2; continuous gradient from 0% to 10% EtOAc in hexane for 20 min) to give Intermediate 1A (3.80 g, 22.1 mmoles, 80% yield) as an oil clear. 1H NMR (500 MHz, CDCl3) δ 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) δ -162.69 (s, 1F).
[00347] [00347] A mixture of Intermediate 1A (3.80 g, 22.1 mmoles) and aqueous LiOH. (55.2 ml of a 2.0 M solution, 110 mmoles) in THF (50 ml) was stirred at RT for 18 h. The reaction was acidified to pH = 2 with conc. (9.19 ml, 110 mmoles), 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 mmoles, 94% yield) as a light yellowish oil. 1H NMR (500 MHz, CDCl3) δ 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) δ -163.02 (s, 1F). Intermediate 1C. () -1-fluoro-4-iodo-6-oxabicyclo [3,2,1] octan-7-one
[00348] [00348] To a mixture of Intermediate 1B (3.0 g, 20.8 mmoles) in water (20 ml), NaHCO3 (5.25 g, 62.4 mmoles) was added in portions and the mixture was stirred until it becomes homogeneous. A solution of aqueous I2 (prepared by dissolving I2 (5.81 g, 22.0 mmoles) and KI (20.7 g, 125 mmoles) in 20 ml of water) was added and the reaction was stirred overnight at RT at 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; continuous gradient from 0% to 50% EtOAc in hexane for 20 min) to give Intermediate 1C (3.53 g, 13.1 mmoles, 62.8% yield ) as a white solid. 1H NMR (500 MHz, CDCl3) δ 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,
[00349] [00349] To a solution of intermediate 1C (350 mg, 1.30 mmol) and AIBN (21 mg, 0.130 mmol) in benzene (5 ml), tris (trimethylsilyl) silane (0.60 ml, 1.94) was added mmol) in portions for 10 min at 60ºC. The reaction was stirred at 70ºC for 2 h, cooled to RT and then concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated aqueous NH4Cl, dried (MgSO4) and concentrated in vacuo. The crude oil was chromatographed (12 g SiO2; continuous gradient from 0% to 30% EtOAc in hexane for 10 min) to give Intermediate 1D (124 mg, 0.860 mmol, 66.4% yield) as a white solid 19. F NMR (471 MHz, CDCl3) δ -167.01 (s, 1F); 1H NMR (500 MHz, CDCl3) δ 4.98 - 4.81 (m, 1H), 2.75 (dtdd, J = 15.9, 6.8, 3.3, 1.7 Hz, 13 1H) , 2.24 - 1.89 (m, 5H), 1.82 - 1.65 (m, 1H), 1.60 - 1.46 (m, 1H); C NMR (126 MHz, CDCl3) δ 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
[00350] [00350] Acetyl chloride (0.061 ml, 0.860 mmol) was added in portions to isopropanol (3 ml) at 0ºC 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 it was concentrated in vacuo. The residual crude oil was chromatographed (4 g SiO2; continuous gradient from 0% to 50% EtOAc in hexane for 10 min) to give Intermediate 1 (140 mg, 0.685 mmol, 80% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 5.08 (spt, J = 6.3 Hz, 1H), 3.91
[00351] [00351] To a solution of 2,5-dibromo-6-methyl-pyridine (5 g, 21.11 mmol) and 2- (prop-2-in-1-yloxy) tetrahydro-2H-pyran (4 , 44 g, 31.7 mmoles) in MeCN (42.2 ml), Et3N (8.83 ml, 63.3 mmoles) was added. The solution was degassed under N2, then (Ph3P) 2PdCl2 (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 plug of Celite® and the buffer was washed with EtOAc (2 X 10 ml). The combined filtrates were 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 mmoles, 96% yield). 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 2.0 Hz, 1H), 7.80 (dd, J = 8.3, 2.3 Hz, 1H),
[00352] [00352] A solution of Example 1A (6.0 g, 20.3 mmoles) in toluene (20 ml) and TMSCH2N3 (7.85 g, 60.8 mmoles) was heated to 90 ° C under Air for 15 h, then it was cooled to TA. The volatiles were removed in vacuo and the residue was dissolved in THF (20 ml). To the mixture, TBAF (20.3 ml of a 1M solution in THF, 20.3 mmoles) was added at 0ºC. After stirring for 10 min, the reaction was completed as determined by analytical HPLC. The volatiles were removed 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 (2.1 g, 29% yield) as a solid White. 1H NMR (400 MHz, CDCl3) δ 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). 1C. 2-Methyl-6- (1-methyl-5 - ((((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1H-1,2,3-triazol-4-yl) pyridin-3 -ol
[00353] [00353] To a degassed solution (sprayed with 3X Ar) of Example 1B (213 mg, 0.60 mmol), bis (pinacolate) diboro (230 mg, 0.91 mmol) and KOAc (178 mg, 1.81 mmol ) in THF, Pd (dppf) Cl2 (22 mg, 0.03 mmol) was added. The reaction mixture was heated in a sealed tube at 80ºC for 16 h, then it was cooled to RT and divided between water and EtOAc.
[00354] [00354] To a solution of Example 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 mmoles) in toluene (81 ml), Bu3P (3.17 ml, 12.2 mmoles) was added. To this stirred mixture, (E) -diazene-1,2-diylbis (piperidin-1-yl-methanone) (3.08 g, 12.2 mmoles) was added in portions, and the reaction mixture was heated to 50 ° C for 120 min, then it was cooled to RT.
[00355] [00355] To a solution of Example 1D (1.7 g, 3.71 mmoles) in MeOH (37 ml), PPTS (0.932 g, 3.71 mmoles) was added. The reaction mixture was heated to 60ºC for 2 h, then it was cooled to RT, diluted with water and saturated aqueous NaHCO3, then extracted with EtOAc (3 X 10 ml). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and chromatographed (SiO2; continuous gradient from 0% to 100% EtOAc in hexanes for 20 min) to give the title compound as a white foam (1.36 g, 3.63 mmoles, 98% yield). 1H NMR (400 MHz, CDCl3) δ 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. (1S, 3S (((6- (5- (bromomethyl) -1-methyl-1H-1,2,3-triazol-4-yl) -2-methylpyridin-3-yl) oxy) cyclohexanecarboxylate ) -isopropyl
[00356] [00356] To a solution of Example 1E (0.28 g, 0.721 mmol) in DME (7 ml), PBr3 (0.17 ml, 1.80 mmol) was added at 0 ° C. The reaction was stirred overnight at RT, then cooled to 0 ° C and neutralized with saturated aqueous NaHCO3 to pH = ~ 7. The mixture was partitioned between EtOAc (50 ml) and water (5 ml), and the aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (12 g SiO2; continuous gradient from 0% to 50% EtO-Ac / hexanes for 25 min) to give the title compound (300 mg, 0.665 mmol, 92% yield) as a white solid. LCMS, [M + H] + =
[00357] [00357] To a solution of Example 1F (100 mg, 0.222 mmol) in DMF (1.5 ml), NaN3 (36 mg, 0.554 mmol) was added and the reaction was stirred at 80 ° C for 1 h, then cooled to TA. LCMS analysis indicated that the reaction was complete. The reaction mixture was partitioned between EtOAc and water, and the mixture was stirred at RT for 15 min. The organic layer was dried (Na2SO4) and found in vacuo to give the crude title compound, which was used in the next step without further purification. LCMS, [M + H] + = 414.3. 1H. 3 ((1S, 3S) ((6- (5- (aminomethyl) -1-methyl-1H-1,2,3-triazol-4-yl) -2-methylpyridin-3-yl) oxy) cyclohexanecarboxylate ) -isopropyl
[00358] [00358] To a solution of Example 1G (92 mg, 0.22 mmol) in THF (1 ml) and H2O (0.3 ml), Ph3P (58 mg, 0.22 mmol) was added and the reaction it was stirred at RT overnight. The reaction mixture was partitioned between EtOAc and water, and the resulting mixture was stirred at RT for 15 min. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed (12 g SiO2; 100% EtOAc for 10 min and then a gradient of 0% to 10% MeOH in CH2Cl2 for 20 min; flow rate = 30 ml / min) to give the title compound (81 mg, 0.21 mmol, 94% yield) as a beige oil. LCMS, [M + H] + = 388.3. Example 1
[00359] [00359] To a solution of Example 1H (8 mg, 0.021 mmol) and (S) -2-methylbutyl (4-nitrophenyl) carbonate (7 mg, 0.027 mmol) in THF (0.4 ml), was added N- ethyl-N-isopropylpropan-2-amine (11 µL, 0.062 mmol). The mixture was stirred at RT for 1 h, after which THF (0.8 ml) / H2O (0.4 ml) / MeOH (0.4 ml) and LiOH.H2O (5 mg, 0.105 mmol) were added. The reaction mixture was stirred at RT overnight, then it was concentrated in vacuo and diluted with H2O (5 ml). The pH of the mixture was adjusted with 1N aqueous HCl to ~ 5 and extracted with EtOAc (3 x 5 ml). The combined organic extracts were washed with brine (2 ml), dried (MgSO4) and concentrated in vacuo. The residual crude product was purified by preparative LC / MS. Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5 μm particles; Mobile Phase A: 5:95 MeCN: H2O with 0.1% TFA; Mobile Phase B: 95: 5 MeCN: H2O with 0.1% TFA; Gradient: 50-90% B for 20 min, then a 5 min wait at 100% B; Flow: 20 ml / min. Fractions containing the desired product were concentrated in vacuo by centrifugal evaporation to provide the title compound (6.6 mg, 0.014 mmol, 68% yield). LCMS, [M + H] + = 460.3. 1H NMR (500 MHz, DMSO-d6) δ 7.80 (d, J = 8.2 Hz, 1H), 7.55 (br., 1H), 7.46 (d, J = 8.7 Hz, 1H), 4.80 - 4.62 (m, 3H), 4.02 (s, 3H), 3.76 - 3.67 (m, 2H), 2.62 - 2.55 (m, 1H), 2.42 (s, 3H), 2.04 - 0.93 (m, 11H), 0.83 - 0.72 (m, 6H). hLPA1 IC50 = 18 nM.
[00360] [00360] To a 0 ° C mixture of the compound of Example 1 (1.7 mg, 3.70 µmoles) in DMF (0.2 ml) under N2, NaH (0.5 mg of a 60% dispersion in mineral oil; 0.011 mmol) and the reaction was stirred for 30 min at 0C. MeI (0.7 µL, 0.011 mmol) was then added and the reaction was stirred at RT for 1 h, then it was concentrated in vacuo. The residue was dissolved in THF (0.8 ml) / MeOH (0.4 ml) / water (0.4 ml) and LiOH.H2O (1 mg, 18.5 µmoles) was added to RT. The reaction mixture was stirred at RT overnight, then it was concentrated in vacuo and diluted with H2O (5 ml). The pH of the mixture was adjusted with 1N aqueous HCl to ~ 5 and the mixture was extracted with EtOAc (3 x 5 ml). The combined organic extracts were washed with brine (2 ml), dried (MgSO4) and concentrated in vacuo. This crude product was purified by preparative LC / MS: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5 μm particles; Mobile Phase A: 5:95 MeCN: H2O with 0.1% TFA; Mobile Phase B: 95: 5 MeCN: H2O with 0.1% TFA; Gradient: 50-90% B for 20 min, then a 5 min wait at 100% B; Flow: 20 ml / min. Fractions containing the desired product were concentrated in vacuo by centrifugal evaporation to provide the title compound (1 mg, 2.1 µmoles, 56.5% yield). LCMS, [M + H] + = 474.0. 1H NMR (500 MHz, DMSO-
[00361] [00361] To a solution of Example 1H (10 mg, 0.026 mmol) in EtOAc (0.3 ml) and saturated aqueous NaHCO3 (0.3 ml), n-butyl chloroformate (0.017 ml, 0.129 mmol) was added to RT . The reaction mixture was stirred overnight, then it was concentrated in vacuo. This crude product was used in the next step without further purification. LCMS, [M + H] + = 488.3. Example 3
[00362] [00362] To a solution of crude Example 3A (12.7 mg, 0.026 mmol) in THF (0.8 ml) / H2O (0.400 ml) / MeOH (0.400 ml), Li
[00363] [00363] To a solution of 1-bromo-4-iodobenzene (10.0 g, 35.3 mmoles) in DMF (50 ml), TEA (25 ml, 177 molecules), CuI (0.40) were added g, 2.12 mmol), Pd (Ph3P) 4 (0.82 g, 0.71 mmol) and 2- (prop-2-in-1-yloxy) tetrahydro-2H-pyran (6.44 g , 46.0 mmoles). The reaction mixture was stirred at RT under N2 for 16 h, then it was concentrated in vacuo. The residue was chromatographed (120 g SiO2; isocratic hexanes / EtOAc = 95: 5) to generate the title compound (10.0 g, 33.9 mmoles, 96% yield) as a colorless oil. LCMS, [M + Na] + = 319.0. 1H NMR (500 MHz, CDCl3) δ 7.46 - 7.42 (m, 2H), 7.33 - 7.29 (m, 2H), 4.89 (t, J = 3.4 Hz, 1H) , 4.54 - 4.40 (m, 2H), 3.89 (ddd, J = 11.5, 9.0, 2.9 Hz, 1H), 3.61 - 3.54 (m, 1H) , 1.92 - 1.51 (m, 6H). 4B. 4- (4-Bromophenyl) -5 - ((((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1- ((trimethylsilyl) methyl) -1H-1,2,3-triazole
[00364] [00364] To a solution of 4A (3.0 g, 10.2 mmoles) in toluene (10 ml), TMSCH2N3 (1.8 ml, 12.2 mmoles) was added. The mixture was refluxed under Ar for 15 h, then it was cooled to RT and concentrated in vacuo. The crude residue was chromatographed (120 SiO2; continuous gradient from 0 to 20% EtOAc in hexane for 25 min, then maintained at 20% EtOAc for 20 min) to give the title compound (667 mg, 1 , 57 mmol, 15% yield) as a beige solid. LCMS, [M + H] + = 424.1. 1H NMR (500 MHz, CDCl3) δ 7.73 - 7.69 (m, 2H), 7.60 - 7.56 (m, 2H), 4.84 (d, J = 12.9 Hz, 1H) , 4.70 - 4.64 (m, 2H), 3.87 - 3.79 (m, 3H), 3.58 - 3.49 (m, 1H), 1.88 - 1.51 (m, 6H), 0.23 (s, 9H). 4C. 4- (4-Bromophenyl) -1-methyl-5 - ((((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1H-
[00365] [00365] To a solution of Example 4B (660 mg, 1.56 mmol) in THF (10 ml), H2O (0.06 ml, 3.1 mmol) was added and the reaction was cooled to 0 ° C. TBAF (1.87 ml of a 1.0 M THF solution; 1.87 mmol) was added and the reaction was stirred at 0 ° C for 10 min. The volatiles were removed in vacuo and the crude product was chromatographed (40 g SiO2; continuous gradient from 100% hexane to 50:50 hexane: EtOAc for 30 min, maintained at 50% hexane: EtOAc for 10 min) to give the title compound (510 mg, 1.49 mmol, 93% yield) as a beige oil. LCMS, [M + H] + = 352.0. 1H NMR (500 MHz, CDCl3) δ 7.70 - 7.66 (m, 2H), 7.61 - 7.57 (m, 2H), 4.87 (d, J = 12.9 Hz, 1H) , 4.74 - 4.65 (m, 2H), 4.15 (s, 3H), 3.82 (ddd, J = 11.3, 8.1, 3.2 Hz, 1H), 3.58 - 3.49 (m, 1H), 1.88 - 1.50 (m, 6H). 4D. 4- (1-Methyl-5 - ((((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1H-1,2,3-triazol-4-yl) phenol
[00366] [00366] A mixture of Pd2 (dba) 3 (44 mg, 0.048 mmol), di-tert-butyl (2 ', 4', 6'-triisopropyl- [1,1'-biphenyl] -2-yl ) phosphine (81 mg, 0.191 mmol), KOH (268 mg, 4.77 mmol), and Example 4C (281 mg, 0.80 mmol) in 1,4-dioxane (3 ml) and water (3 ml) was rapidly evacuated under vacuum and filled with Ar (repeated 3X). The mixture was stirred at 85ºC for 16 h, then it was cooled to RT and carefully acidified with
[00367] [00367] To a mixture of 0ºC of 4D (0.19 g, 0.64 mmol), cis-3-hydroxy cyclohexane-1-carboxylate of () -isopropyl (0.21 g, 1.15 mmol ), Et3N (0.16 ml, 1.15 mmol) and Ph3P (0.30 g, 1.15 mmol) in THF (4 ml), DIAD (0.22 ml, 1.15 mmol) was added in drops . The reaction was stirred overnight at RT. Water (4 ml) was added and the reaction mixture was acidified with 1 N aqueous HCl and extracted with EtOAc (3 X 10 ml). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed (40 g SiO2; continuous gradient from 0% to 80% EtOAc in hexanes for 30 min and 80% EtOAc / hexanes for 20 min) to give the title compound (0.12 g, 0.257 mmol, 40% yield) as a beige oil. LCMS, [M + H] + = 458.1. 4F. () -Trans-1,3-Isopropyl 3- (4- (5- (hydroxymethyl) -1-methyl-1H-1,2,3-triazol-4-yl) phenoxy) cyclohexanecarboxylate
[00368] [00368] To a solution of Example 4E (115 mg, 0.251 mmol) in MeOH (2.5 ml), PPTS (6 mg, 0.025 mmol) was added. The reaction was stirred overnight at RT. LCMS showed that the reaction was still incomplete, so the mixture was heated to 60ºC for another 6 h, then it was cooled to RT. The mixture was concentrated in vacuo and the residue was chromatographed (12 g SiO2; continuous gradient of 80-100% EtOAc in hexanes for 10 min) to give the title compound (84 mg, 90% yield) as a brown oil. LCMS, [M + H] + = 374.2. 4G. () -Trans-1,3-Isopropyl 3- (4- (5- (bromomethyl) -1-methyl-1H-1,2,3-triazol-4-yl) phenoxy) cyclohexanecarboxylate
[00369] [00369] To a mixture of 0ºC of Example 4F (84 mg, 0.225 mmol) and CBr4 (82 mg, 0.247 mmol) in DCM (1.2 ml), Ph3P (65 mg, 0.247 mmol) was added in portions . The reaction was allowed to warm slowly to RT overnight, then it was concentrated in vacuo. The residue was chromatographed (12 g SiO2; 25 min continuous gradient from 0% to 70% EtOAc in hexane; flow rate = 30 ml / min). The pure fractions were concentrated in vacuo to give the title compound (66 mg, 0.151 mmol, 67% yield) as a colorless oil.
[00370] [00370] To a solution of Example 4G (65 mg, 0.149 mmol) in DMF (1 ml), NaN3 (24 mg, 0.37 mmol) was added and the reaction was stirred at 80 ° C for 1 h, then , was cooled to TA. LCMS analysis indicated that the reaction was complete. The reaction mixture was partitioned between EtOAc and water (5 ml each) and the resulting mixture was stirred at RT. After 15 min, the organic layer was dried (Na2SO4) and concentrated in vacuo. The crude azide product was used in the next step without further purification. 4I. () -Trans-1,3-Isopropyl 3- (4- (5- (aminomethyl) -1-methyl-1H-1,2,3-triazol-4-yl) phenoxy) cyclohexanecarboxylate
[00371] [00371] To a solution of Example 4H (59 mg, 0.149 mmol) in THF (0.6 ml) and H2O (0.2 ml), Ph3P (39 mg, 0.149 mmol) was added and the reaction was stirred at RT during the night. The reaction mixture was partitioned between EtOAc and water (5 ml each), and the resulting mixture was stirred at RT. After 15 min, the organic layer was dried (Na2SO4), and found in vacuo. The residue was chromatographed (8 g SiO2; 100%
[00372] [00372] A solution of 3-methylbutan-1-ol (6 mg, 0.064 mmol), CDI (11 mg, 0.064 mmol) and LiOH.H2O (3 mg, 0.11 mmol) in toluene (0.5 ml) it was stirred at 60ºC for 2 h. To this mixture, Example 4I (8 mg, 0.021 mmol) was added and the reaction was stirred at 60 ° C overnight, then cooled to RT. The mixture was partitioned between EtO-Ac and water; the aqueous phase was extracted with EtOAc (3X), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. To a solution of this crude product in THF (0.8 ml) and H2O (0.40 ml) and MeOH (0.40 ml), was added LiOH.H2O (7 mg, 0.168 mmol) to RT. The reaction was stirred at RT overnight, then it was concentrated in vacuo and diluted with H2O (5 ml). The mixture was adjusted with 1N aqueous HCl to pH ~ 3 and extracted with EtOAc (3 x 5 ml). The combined organic extracts were washed with brine (2 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by preparative LC / MS: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5 μm particles; Mobile Phase A: 5:95 MeCN: H2O with 0.1% TFA; Mobile Phase B: 95: 5 MeCN: H2O with 0.1% TFA; Gradient: 50-90% B for 20 min, then a 5 min wait at 100% B; Flow rate: 20 ml / min) to give the title compound (1.4 mg, 3.15 µmoles, 15% yield). LCMS, [M + H] + = 445.1. 1H NMR (500 MHz, DMSO-d6) δ 7.77 (br. S., 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.02 (d, J = 8.5 Hz, 2H), 4.72 - 4.64 (m, 1H), 4.41 (d, J = 5.2 Hz, 2H), 4.06 - 3.94 (m, 5H), 2.70 - 2.59 (m, 1H), 1.98 - 1.34 (m, 11H), 0.86 (d, J = 6.1 Hz, 6H). hLPA1 IC50 = 148 nM.
[00373] [00373] To a solution of 3,6-dibromopyridine (25.0 g, 100 mmoles) and prop-2-in-1-ol (8.70 ml, 149 mmoles) in MeCN (141 ml), was added Et3N (33.2 ml, 240 mmoles). The solution was degassed under Ar (sprinkled with 3X Ar), after which (Ph3P) 2PdCl2 (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, after which the mixture was filtered through a plug of Celite (R), which was washed with EtOAc (3 X 50 ml). The combined filtrates were concentrated in vacuo. 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 (16.6 g, 74% yield). 1H NMR (400 MHz, CD3OD) δ 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). 5B. (4- (5-bromopyridin-2-yl) -1-methyl-1H-1,2,3-triazol-5-yl) methanol
[00374] [00374] To a degassed solution (sprayed with Ar 3X) of 5A (1.9 g, 8.40 mmoles) in dioxane (42.0 ml), chlorine (pentamethylcyclopentadienyl) bis (triphenylphosphine) ruthenium was added (II) (0.402 g, 0.504 mmol). The mixture was degassed under Ar (3X), after which TMSCH2N3 (1.87 ml, 12.6 mmoles) was added. The reaction was stirred at 50ºC for 15 h under Ar, then it was cooled to RT and concentrated in vacuo. The crude oily product was dissolved in THF (90 ml) and cooled to 0 ° C. TBAF (5.40 ml of 1.0 M THF solution; 5.40 mmoles) 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. 1 H NMR (500 MHz, CDCl3) δ 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). 5C. 5-Bromo-2- (5- (bromomethyl) -1-methyl-1H-1,2,3-triazol-4-yl) pyridine
[00375] [00375] To a stirred solution of Example 5B (300 mg, 1.15 mmol) in dry CH2Cl2 (8 ml), PBr3 (0.21 ml, 2.23 mm) was added and the resulting solution was stirred at 0 ° C for 45 min. The reaction mixture was then quenched with water (20 ml), extracted with EtOAc (2 x 20 ml) and the combined organic extracts were washed with brine (25 ml), dried (Na2SO4) and concentrated in vacuo to generate the title compound (250 mg, 67%) as a yellow oily liquid. LCMS, [M + H] + = 329.9. 1H NMR (300 MHz, CDCl3) δ
[00376] [00376] To a solution of Example 5C (220 mg, 0.66 mmol) in dry DMF (2.5 ml), NaN3 (86 mg, 1.33 mmol) was added and the resulting solution was stirred at 70 ° C for 16 h, then it was cooled to RT and poured into water (25 ml). The precipitated solid product was filtered, washed with water (5 ml) and dried in vacuo to generate the title compound (162 mg, 82%) as a white solid. LCMS, [M + H] + = 296.0. 1H NMR (400 MHz, DMSO-d6) δ 8.76 (dd, J = 0.8, 2.4 Hz, 1H), 8.18 (dd, J = 2.4, 8.4 Hz, 1H) , 8.06 (dd, J = 0.8, 8.6 Hz, 1H), 5.10 (s, 2H), 4.11 (s, 3H). 5E. Tert-Butyl carbamate ((4- (5-bromopyridin-2-yl) -1-methyl-1H-1,2,3-triazol-5-yl) methyl) carbamate
[00377] [00377] To a solution of Example 5D (100 mg, 0.34 mmol) in THF (3 ml) under N2, Ph3P (178 mg, 0.680 mmol) and water (1 ml) were added and the resulting solution was stirred at TA for 16 h. To this reaction mixture, NaOH (34 mg, 0.85 mmol) was added followed by (Boc) 2O (0.10 ml, 0.48 mmol) and the reaction was stirred at RT for another 16 h. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (2 x 20 ml). The combined organic extracts were washed with brine (25 ml), dried (Na2SO4), and concentrated in vacuo to generate the title compound (100 mg, 80%) as a white solid. LCMS, [M + H] + = 368.2. 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J = 2.1 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.92 (dd, J = 2 , 4, 8.4 Hz, 1H), 5.98 - 5.99 (m, 1H), 4.60 (d, J = 6.0 Hz, 2H), 4.21 (s, 3H), 1 , 41 (s, 9H). 5F. ((1-methyl-4- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) - 1H-1,2,3-triazole -5-yl) methyl) tert-Butyl carbamate
[00378] [00378] To a solution of Example 5E (50 mg, 0.136 mmol) in dioxane (5 ml), bis (pinacolate) diboro (51.7 mg, 0.204 mmol) and KOAc (27 mg, 0.27 mmol) were added . The reaction mixture was purged with N2 for 5 min, after which 1,1'-bis (diphenylphosphine) ferrocenopalladium (II) dichloride complex (6 mg, 0.006 mmol) was added. The reaction mixture was stirred at 90ºC for 16 h, then it was cooled to RT. The mixture was filtered and the filtrate was concentrated in vacuo to generate the crude title compound (70 mg) as a brown liquid. LCMS: [M + H] + = 416.0. This crude product was used for the next reaction without further purification. 5G. ((4- (5-hydroxypyridin-2-yl) -1-methyl-1H-1,2,3-triazol-5-yl) methyl) tert-Butyl carbamate
[00379] [00379] To a stirred solution of Example 5F (70 mg, 0.722 mmol), in THF (5 ml) and water (1.5 ml), sodium perborate monohydrate (41 mg, 0.407 mmol) was added. The reaction mixture was stirred at RT for 1 h, then it was diluted with water (20 ml). This mixture was extracted 1. with 10% MeOH in CHCl3 (2 x 10 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was chromatographed (Redisep® SiO2 12 g column, eluting with 3% MeOH in CHCl3) to generate the title compound (40 mg, 96%) as a light yellow liquid. LCMS, [M + H] + = 306.2. This crude material was used without further purification in the following reaction. 5H. 3 - ((6- (5 - ((((tert-butoxycarbonyl) amino) methyl) -1-methyl-1H-1,2,3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexanecarboxylate (1S, 3S) -Etila
[00380] [00380] To a solution of Example 5G (1.80 g, 5.90 mmoles) in THF (35 ml), di-tert-butyl azodicarboxylate (4.07 g, 17.7 mmoles) were successively added, Ph3P (4.64 g, 17.7 mmoles) and (1S, 3R) -ethyl 3-hydroxy cyclohexanecarboxylate (synthesized according to the analogous procedure described in US2007 / 0197788A1, 1.52 g, 8.84 mmoles ) under N2. The reaction solution was stirred at 60ºC for 16 h, then it was cooled to RT and concentrated in vacuo. The crude product was chromatographed (24 g SiO2, 40% EtOAc in hexanes) to generate the title compound (1.9 g, 70%) as a light yellow solid. LCMS, [M + H] + = 460.1. 1H NMR (300 MHz, CDCl3) δ 8.30 (d, J = 2.1 Hz, 1H), 8.15 (d, J = 5.4 Hz, 1H), 7.34 (dd, J = 2 , 4, 6.5 Hz, 1H), 6.13 (s, 1H), 4.71 (s, 1H), 4.58 (d, J = 1.5 Hz, 2H), 4.20 (s , 3H), 4.12 (q, J = 3.0 Hz, 2H), 2.80-2.82 (m, 1H), 2.02-2.05 (m, 1H), 1.84- 1.99 (m, 3H), 1.56-
[00381] [00381] To a stirred solution of Example 5H (1.90 g, 4.13 mm) in CH2Cl2 (50 ml), HCl in dioxane (10.3 ml of 4 M solution, 41.3 mmoles) was added ) and the resulting solution was stirred at RT for 12 h. The reaction mixture was concentrated in vacuo to generate the title compound (1.25 g, 84%) as a light yellow solid. LCMS, [M + H] + = 360.0. This crude product was used without further purification for the next reaction. 5J. (1S, 3S) -3 - ((6- (5 - ((((butoxycarbonyl) amino) methyl) -1-methyl-1H-1,2,3-triazol-4-yl) pyridin-3-yl) oxide ) ethyl cyclohexane-1-carboxylate
[00382] [00382] To a stirred solution of Example 5I (30 mg, 0.083 mmol) in CH2Cl2 (5 ml) under N2, n-butyl chloroformate (78 µL, 0.83 mmol) was added, and the resulting solution was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and the crude product was chromatographed (12 g SiO2, isocratic 27% EtOAc in hexanes) to generate the title compound (30 mg, 82%) as a light yellow liquid. LCMS, [M + H] + = 432.2.
[00383] [00383] To a stirred solution of Example 5J (30 mg, 0.046 mmol) in THF (4 ml) and MeOH (1 ml), a solution of Li-OH.H2O (2 mg, 0.093 mmol) in water ( 1.5 ml) and the resulting solution was stirred at RT for 16 h. The reaction mixture was diluted with water (20 ml) and washed with Et2O (20 ml). The aqueous layer was neutralized with 1.5 N aqueous HCl (2 ml) and extracted with 5% MeOH in CHCl3 (25 ml). The organic layer was washed with brine (25 ml), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by preparative reverse phase HPLC (Sunfire C18 (150 x19) mm; 5 m; Mobile Phase A: 10 mM aqueous NH4OAc (pH: 4.5); Mobile Phase B: MeCN, flow rate : 15 ml / min; time (min) /% B: 0/20, 25/60; retention time: 15.19 min) to generate the title compound (6 mg, 32%) as a white solid. LCMS, [M + H] + = 432.0. 1H NMR (400 MHz, CD3OD) δ 8.40 (br. S, 1 H) 8.00 (d, J = 8.8 Hz, 1 H) 7.53 (dd, J = 8.8, 2 , 7 Hz, 1 H), 4.70-4.80 (m, 1 H) 4.58 (s, 3 H) 4.20 (s, 3 H) 4.03 (t, J = 6.6 Hz, 2 H) 2.77 - 2.88 (m, 1 H) 1.87 - 2.15 (m, 3 H) 1.45 - 1.86 (m, 6 H) 1.23 - 1, 44 (m, 2 H) 0.92 (t, J = 7.3 Hz, 3 H). hLPA1 IC50 = 96 nM.
[00384] [00384] Table 1 below lists additional Examples that were made using the same synthetic method described in this document.
[00385] [00385] Table 2 below lists additional Examples that were synthesized through the intermediates described as follows. Intermediate 2 (4-nitrophenyl (1-propylcyclopropyl) methyl) carbonate Intermediate 2A. Tert-butyl 1-propylcyclopropane-1-carboxylate
[00386] [00386] To a solution of LDA in THF (40 ml of 0.8 M solution; 33.2 mmoles) at -78 ° C, tert-butyl cyclopropane carboxylate (3.78 g, 26, 6 mmoles) in drops for 10 min. The solution was stirred at -78 ° C for 2 h, after which 1-bromopropane (4.84 ml, 53.2 mmoles) was added in drops for 20 min at -78 °. The reaction was allowed to warm slowly to RT and stirred overnight at RT, then it was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was distilled under reduced pressure (20 torr, BP = 95 ° C) to give the title compound (2.99 g, 61% yield) as an oil. 1H NMR (500 MHz, CDCl3) δ 1.48 (m, 4H), 1.45 (s, 9H), 1.12 (m, 2H), 0.92 (m, 3H), 0.61 (m , 2H). Intermediate 2B. (1-propylcyclopropyl) methanol
[00387] [00387] To a solution of Intermediate 2A (250 mg, 1.36 mmol) in Et2O (5 ml), LiAlH4 (103 mg, 2.71 mmoles) was added in portions at RT; the reaction was stirred overnight at RT. The mixture was sequentially treated with water (0.1 ml), 15% aqueous NaOH (0.1 ml), and water (0.3 ml), then it was stirred at RT for 1 h, dried ( MgSO 4) and concentrated in vacuo. The residue was distilled under reduced pressure to give the slightly impure title compound (186 mg) as an oil. 1H NMR (500 MHz, CDCl3) δ 3.44 (br s, 2H), 1.48 - 1.36 (m, 4H), 0.93 (t, J = 7.0 Hz, 3H), 0, 44 - 0.27 (m, 4H). Intermediate 2
[00388] [00388] To a solution at the TA of Intermediate 2B (155 mg, 1.36 mmol) in CH2Cl2 (10 ml), was added pyridine (0.44 ml, 5.43 moles) and 4-nitrophenyl chloroform (410 mg, 2.04 mmol). After stirring for 2 h at RT, the reaction mixture was concentrated in vacuo and the residue was chromatographed (SiO2; continuous gradient of 0-25% EtOAc in hexanes) to give the title compound Intermediate 2 (226 mg, 60% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 9.1 Hz, 2H), 7.42 (d, J = 9.1 Hz, 2H), 4.15 (s, 2H), 1.45 (m,
[00389] [00389] The following intermediates were prepared using the same synthetic sequence as for Intermediate 2 starting from tert-butyl cyclopropanecarboxylate or tert-butyl cyclobutanecarboxylate and then alkylating with the required alkyl iodide or bromide. Intermediate 3. (1-methylcyclopropyl) methyl (4-nitrophenyl) carbonate 1 H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 9.2 Hz, 2H), 7.40 (d, J = 9.2 Hz, 2H), 4.10 (s, 2H), 1.22 (s, 3H), 0.60 (m, 2H), 0.47 (m, 2H). Intermediate 4. (1-ethylcyclopropyl) methyl (4-nitrophenyl) carbonate 1 H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 9.2 Hz, 2H), 7.39 (d, J = 9.2 Hz, 2H), 4.14 (s, 2H), 1.48 (q, J = 7.3 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H), 0 , 54 (m, 4H). Intermediate 5. (1-ethylcyclobutyl) methyl (4-nitrophenyl) carbonate 1 H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 9.4 Hz, 2H), 7.42 (d, J = 9.4 Hz, 2H), 4.27 (s, 2H), 1.99 - 1.83 (m, 6H), 1.63 (q, J = 7.4 Hz, 2H), 0.90 ( t, J = 7.4 Hz, 3H). Intermediate 6. 4-nitrophenyl ((1-propylcyclobutyl) methyl) 1 H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 9.4 Hz, 2H), 7.42 (d, J = 9.4 Hz, 2H), 4.26 (s, 2H), 1.99 - 1.85 (m, 6H), 1.56 (m, 2H), 1.32 (m, 2H), 0, 97
[00390] [00390] To a stirred solution of (1S, 3S) -3 - ((6- (5- (hydroxymethyl) -1- methyl-1H-1,2,3-triazol-4-yl) -2-methylpyridin- 3-yl) oxy) cyclohexane-1-methyl carboxylate (synthesized analogously to the isopropyl ester corresponding to Example 1E; 3.28 g, 9.10 mmol) in CH2Cl2 (45.5 ml), NaHCO3 was added (3.82 g, 45.5 mmoles) and Dess-Martin periodinane (4.63 g, 10.9 mmoles) and the reaction mixture was stirred at RT for 1 h. The white solid was filtered through Celite® and rinsed with EtOAc. The combined filtrates were washed with saturated aqueous NaHCO3, water, brine, dried (Na2SO4), and concentrated in vacuo. The crude product was chromatographed (Redisep® SiO2 120 g column; 60% EtOAc in Hex isocratic) to generate the title compound as a clear, colorless oil (3.10 g, 95%). LC-MS, [M + H] + = 359.1. 1 H NMR (500 MHz, CDCl3) 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). 64B. 4- (5 - (((1S, 3S) -3- (methoxycarbonyl) cyclohexyl) oxide) -6-methylpyridin-2-yl) -1-methyl-1H-1,2,3-triazole-5 acid -carboxylic
[00391] [00391] To a mixture of 64A (260 mg, 0.725 mmol), NaH2PO4
[00392] [00392] A mixture of 64B (60 mg, 0.160 mmol), diphenyl phosphoryl azide (63 µL, 0.288 mmol), 2-methylpropan-2-ol (36 mg, 0.240 mmol), TEA (89 µL, 0.641 mmol) in toluene (1 ml) was stirred at 80 ° C for 1 h, then cooled to RT and concentrated in vacuo. LC / MS indicated the formation of the desired product. The crude product was chromatographed (12 g SiO2; continuous gradient of 0% to 80% EtOAc in hexanes for 30 min and 80% EtOAc / hexanes for 20 min) to generate the title compound (60 mg , 0.135 mmol, 84% yield). 1H NMR (400 MHz, CDCl3) δ 8.00 - 7.81 (m, 1H), 7.28 - 7.15 (m, 1H), 4.84 - 4.62 (m, 1H), 4, 14 - 4.06 (m, 3H), 3.76 - 3.67 (m, 3H), 2.92 - 2.77 (m, 1H), 2.57 - 2.49 (m, 3H), 2.25 - 2.09 (m, 1H), 2.05 - 1.60 (m, 8H), 1.58 - 1.48 (m, 9H). Example 64
[00393] [00393] To a stirred solution of 64C (30 mg, 0.067 mmol) in THF (1.5 ml), MeOH (0.100 ml) and water (0.15 ml) at RT, was added
[00394] [00394] Table 3 below lists additional Examples. Some of these Examples (103 to 107) were synthesized using the triazole-ethanol intermediate 7 (shown below). Specifically, intermediate alcohol 7 was converted into the following examples using the same method and procedure shown in Scheme 1 and exemplified by the 5-step conversion from intermediate 1E to Example 1. Intermediate 7. (1S, 3S) -3 - (((6- (5- (2-hydroxyethyl) -1-methyl-1H-1,2,3-triazol-4-yl) -2-methylpyridin-3-yl) oxy) cyclohexane-1-carboxylate of methyl 7A. (1S, 3S) -3 - ((2-methyl-6- (1-methyl-5-vinyl-1H-1,2,3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane Methyl -1-carboxylate
[00395] [00395] To a 0 ° C suspension of Ph3PCH3Br (3.77 g, 10.6 mm) in THF (70 ml), KOtBu (0.947 g, 8.44 mmoles) was added, and the reaction mixture was stirred at 0 ° C for 30 min. A solution of Example 241A (2.52 g, 7.03 mmoles) in THF (10 ml) was added to the reaction, which was stirred at 0 ° C for 30 min, then it was allowed to warm to RT. The reaction was stirred for 1 h at RT, then was quenched with saturated aqueous NH4Cl and 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 product was chromatographed (220 g Redisep® SiO2 column; 0-60% continuous gradient of EtOAc in hexane) to give 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). Intermediate 7
[00396] [00396] To a 0ºC solution of Intermediate 7A (1.45 g, 4.07 mmoles) in THF (13.6 ml), 9-BBN drops (17.9 ml of at 0.5 M THF solution; 8.95 mmoles). The ice bath was removed and the reaction was heated to 65ºC for 4 h, then it was cooled to 0ºC. A solution of sodium perborate tetrahydrate (2.50 g, 16.3 mmol) in water (10 ml) was added. The reaction was heated to
[00397] [00397] To a 0ºC solution of triphosgene (269 mg, 0.91 mmol) in CH2Cl2 (5 ml), a solution of 1-cyclobutyl-N-methylmethanamine (150 mg, 1.51 mmol) was added in drops and pyridine (183 µL, 2.27 moles) in CH2Cl2 (3 ml). The reaction mixture was allowed to warm to RT for 30 min, then it was quenched by the caustic addition of 0.1N aqueous HCl (5 ml). The aqueous phase was extracted with
[00398] [00398] 108A (18 mg, 0.11 mmol) was added to a solution of Example 1H (28 mg, 0.072 mmol) and TEA (12 µL, 0.087 mmol) in CH2Cl2 (1 ml) at 0 ° C, followed by DMAP ( 1 mg, 7 µmoles). After 10 min at 0 ° C, the reaction mixture was allowed to warm to RT and stirred at RT for 2 h, then it was concentrated in vacuo. The crude product was chromatographed (4 g SiO2; continuous gradient from 0% to 100% EtOAc / Hexane for 10 min) to give the title compound (35 mg, 0.068 mmol, 94% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 8.5 Hz, 1H), 7.32 - 7.27 (m, 1H), 6.92 (br t, J = 6.1 Hz, 1H), 5.05 (quin, J = 6.3 Hz, 1H), 4.75 - 4.69 (m, 1H), 4.60 (d, J = 6.3 Hz, 2H), 4.28 (s, 3H), 3.24 (d, J = 7.2 Hz, 2H), 2.87 - 2.74 (m, 4H), 2.55 (s, 3H), 2.48 (dt, J = 15.5, 7.9 Hz, 1H), 2.14 - 2.07 (m, 1H), 2.03 - 1.58 (m, 13H), 1.29 - 1.24 (m, 6H) Example 108
[00399] [00399] A mixture of 108B (32 mg, 0.062 mmol) and 1.0 M aqueous Na-OH (0.31 ml, 0.31 mmol) in THF (1 ml), was stirred at 45 ° C for
[00400] [00400] The examples in Table 4 below were synthesized according to the procedures described for the preparation of Example 108. Table 4 Ex # Structure & Name Analytical & Biological Data 109 LCMS, [M + H] + = 493.1 ; 1 H NMR (500MHz, CDCl3) ӧ 8.21 (d, J = 9.1 Hz, 1H), 8.00 (d, J = 9.1 Hz, 1H), 7.44 - 7.11 (m , 5H), 4.89 (br. S, 1H), 4.68 - 4.47 (m, 4H), 4.15 (br., 3H), 2.98 (s, 3H), 2.88 (br. S., 1H), 2.73 (s, 3H), 2.26 - 2.12 (m, 1H), 2.03 - 1.58 (m, 7H); (1S, 3S) -3 - ((6- (5 - ((3-benzyl-3-methyl - hLPA1 IC50 = 85 nM. Ureido) methyl) -1-methyl-1H-1,2,3-triazole -4-yl) - 2-methylpyridin-3-yl) oxy) cyclohexanecarboxylic
[00401] [00401] To a solution of (1S, 3S) -3 - ((6- (5- (aminomethyl) -1-methyl-1H- 1,2,3-triazol-4-yl) -2-methylpyridin-3 -yl) oxy) methyl cyclohexane-1-carboxylate (synthesized analogously to the corresponding isopropyl ester of Example 1H, 30 mg, 0.083 mmol) in DCE (1.7 ml), Et3N (29 µL, 0.21 was added) mmol) followed by CDI (27.1 mg, 0.17 mmol). The reaction was stirred at RT for 1 h, after which benzylamine (23 µL, 0.21 mmol) was added. The reaction was stirred at RT for 30 min and then heated to 80ºC for 30 min, then cooled to RT. Water was added to the reaction mixture, which was neutralized to pH 7 with 1 M aqueous HCl, then it was extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (41 mg, 100%) as a colorless, clear residue. The material was used in the next step without further purification. LCMS, [M + H] + = 493.4. Example 112
[00402] [00402] To a solution of 112A (41 mg, 0.083 mmol) in THF (0.56 ml), 1.0 M of aqueous LiOH was added. (0.42 ml, 0.42 mmol). The reaction was stirred at RT for 23 h, then it was concentrated in vacuo. The residue was dissolved in 1: 1 MeCN: H2O (1.5 ml) and TFA was added to adjust the pH to 3. This material was purified by preparative HPLC (Column: Sunfire Prep C18 OBD, 30 x 100 mm, 5 μm particles; Mobile Phase A: 10:90 MeCN: H2O with 0.1% TFA; Mobile Phase B: 90:10 MeCN: H2O with 0.1% TFA; Gradient: 10-100% B per 10 min, then a 2 min wait at 100% B; Flow: 40 ml / min) to give the title compound (10 mg, 20%) as a white solid.
[00403] [00403] To a solution at the aldehyde RT of Example 64A (325 mg, 0.91 mmol) in MeOH (3.6 ml), MeNH2.HCl (92 mg, 1.36 mmol) was added. The reaction was stirred at RT for 20 min, then NaBH3CN (85 mg, 1.36 mmol) was added. The reaction was stirred at RT for 2 h, then it was partitioned between EtOAc and 1.0 M aqueous K2HPO4. The aqueous layer was extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to give a viscous yellow oil. The residue was chromatographed (SiO2; 0-10% continuous gradient MeOH / CH2Cl2)
[00404] [00404] To a solution at 0ºC of 113A (20 mg, 0.054 mmol) in DCE (1.1 ml), Et3N (52 µL, 0.38 mmol) was added followed by triphosgene (24 mg, 0.080 mmol) . The reaction was stirred at 0ºC for 30 min; benzylamine (35 µL, 0.32 mmol) was then added. The reaction was allowed to warm to RT (a white precipitate formed over time) and stirred at RT for 1 h. The reaction mixture was divided between EtOAc and 0.5 M aqueous HCl. The aqueous layer was extracted with EtOAc (2x). The combined organic extracts were washed with 1.0 M aqueous K2HPO4 and brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (27 mg, 100%) as a light, pale yellow oil. This material was used in the next step without additional purification. LCMS, [M + H] + = 507.4. Example 113
[00405] [00405] To a solution of 113B (27 mg, 0.053 mmol) in THF (0.36 ml), 1.0 M of aqueous LiOH was added. (0.27 ml, 0.27 mmol). The reaction was stirred at RT for 18.5 h, then it was divided between water and EtOAc. The aqueous layer was extracted with EtOAc (2x) and these combined organic extracts were discarded. The aqueous layer was acidified
[00406] [00406] The examples in Table 5 below have been synthesized according to the procedures described for the preparation of Examples 112 and 113. Table 5 Ex # Structure & Name Analytical & Biological Data- Method cos LCMS, [M + H] + = 471.3; 1 114 H NMR (500 MHz, DMSO-d6 and D2O) δ 7.96 (d, J = 8.8 Hz, 1H), 7.75 (br d, J = 7.4 Example Hz, 1H), 4 , 87 (br s, 1H), 4.55 112 (s, 2H), 4.11 (s, 3H), 3.25 - 3.17 (m, 2H), 2.77 (s, 3H), 2.68 - 2.59 (m, 1H), 2.54 (s, Acid (1S, 3S) -3 - ((6- (5 - ((3- (2- 3H), 2.09 - 1 , 99 (m, 1H), cyclopropyl-ethyl) -3-methylureido) methyl) - 1.92 - 1.75 (m, 3H), 1.70 - 1-methyl-1H-1,2,3-triazole -4-yl) -2- 1.44 (m, 4H), 1.25 (q, J = 7.2 methylpyridin-3-yl) oxy) cyclohexane-1 Hz, 2H), 0.56 - 0.45 (m, 1H), carboxylic, TFA salt 0.31 - 0.24 (m, 2H), -0.05 - - 0.13 (m, 2H); hLPA1 IC50 = 112 nM.
[00407] [00407] To a microwave flask containing a suspension of Example 64B (30 mg, 0.080 mmol) in toluene (0.80 ml), Et3N (67 µL, 0.48 mmol) and (PhO) were added 2PON3 (43 µL, 0.20 mmol). The reaction was heated in a microwave reactor at 100ºC for 1 h, then it was cooled to RT. Benzylamine (22 µL, 0.20 mmol) was added and the reaction was heated in a microwave reactor at 100ºC for 10 min, then it was cooled to RT. The reaction mixture was partitioned between EtOAc and 1.0 M aqueous K2HPO4. The aqueous layer was extracted with EtOAc (2x). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The clear, colorless residue was purified by preparative HPLC (Column: Sunfire Prep C18 OBD, 30 x 100 mm, 5 μm particles; Mobile Phase A: 10:90 MeOH: H2O with 0.1% TFA; Mobile Phase B: 90:10 MeOH: H2O with 0.1% TFA; Gradient: 25-100% B for 10 min, then a 2 min wait at 100% B; Flow: 40 ml / min) to give the title compound (22 mg, 46%) as a clear, colorless oil. LCMS, [M + H] + = 479.3. Example 135
[00408] [00408] To a solution of 135A (22 mg, 0.037 mmol) in THF (0.24 ml), 1.0 M aqueous LiOH (0.22 ml, 0.22 mmol) was added. The reaction was stirred at RT for 20 h, then it was concentrated in vacuo. The residue was dissolved in 1: 1 MeCN: H2O (1.5 ml); TFA was added to adjust the pH to 3. This material was purified by preparative HPLC (Column: Sunfire Prep C18 OBD, 30 x 100 mm, 5 μm particles; Mobile Phase A: 10:90 MeCN: H2O with 0, 1% TFA; Mobile Phase B: 90:10 MeCN: H2O with 0.1% TFA; Gradient: 10-100% B for 10 min, then a 2 min wait at 100% B; Flow : 40 ml / min) to give the title compound (13 mg, 61%) as a white solid. LCMS, [M + H] + = 465.3. 1H NMR (500 MHz, CDCl3) δ 11.59 - 11.45 (m, 1H), 9.76 - 9.66 (m, 1H), 8.16 (d, J = 8.8 Hz, 1H) , 7.92 (d, J = 9.1 Hz, 1H), 7.42 - 7.38 (m, 2H), 7.38 - 7.32 (m, 2H), 7.31 - 7.26 (m, 1H), 4.76 - 4.67 (m, 1H), 4.53 (br d, J = 5.0 Hz, 2H), 4.11 (s, 3H), 2.89 - 2 , 82 (m, 1H), 2.26 (s, 3H), 2.23 - 2.15 (m, 1H), 2.06 - 1.93 (m, 2H), 1.86 - 1.63 (m, 4H), 1.63 - 1.52 (m, 1H). 27 of 28 protons found, missing the acid proton. hLPA1 IC50 = 329 nM. Example 136. (1S, 3S) -3 - ((2-methyl-6- (1-methyl-5- (3 - ((R) -1- phenylethyl) ureido) -1H-1,2,3- triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylic, 1TFA
[00409] [00409] Example 136 was synthesized according to the procedures described for the preparation of Example 135. LCMS, [M + H] + = 479.1; 1H NMR (500 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.80 (br d, J = 7.9 Hz, 1H), 7.73 (br d, J = 8.5 Hz , 1H), 7.51 (br d, J = 8.5 Hz, 1H), 7.39 - 7.26 (m, 4H), 7.25 - 7.19 (m, 1H), 4.86 - 4.73 (m, 2H), 3.84 (s, 3H), 2.69 - 2.59 (m, 1H), 2.54 (s, 3H), 2.11 - 1.95 (m , 1H), 1.92 - 1.72 (m, 3H), 1.70 - 1.44 (m, 4H), 1.39 (br d, J = 7.0 Hz, 3H); proton of carboxylic acid not observed. hLPA1 IC50 = 103 nM. Example 137. (1S, 3S) -3 - ((6- (5 - ((((N- (cyclopentylmethyl) -N-methylsulfamoyl) amino) methyl) -1-methyl-1H-1,2,3-triazole acid -4-yl) -2-methylpyridin-3-yl) oxy) cyclohexane-1-carboxylic
[00410] [00410] To a 0 M solution of 1.0 M sulfuryl chloride in CH2Cl2 (514 µL, 0.51 mmol) in CH2Cl2 (1 ml), a salt mixture of 1-cyclopentyl-N- methylmethanamine-HCl (77 mg, 0.51 mmol) and TEA (179 µL, 1.29 mmol) in CH2Cl2 (1 ml). The reaction mixture was allowed to warm to RT and stirred at RT for 2 h to give the crude title compound, which was used in the next reaction without further purification. 137B. (1S, 3S) -3 - ((6- (5- (hydroxymethyl) -1-methyl-1H-1,2,3-triazol-4-yl) -2-methyl-pyridin-3-yl) oxy) tert-butyl cyclohexane-1-carboxylate
[00411] [00411] A mixture of (1S, 3S) -3 - ((6- (5- (hydroxymethyl) -1- methyl-1H-1,2,3-triazol-4-yl) -2-methyl-pyridin -3-yl) oxy) cyclohexane-1-carboxylic (from 1E LiOH-mediated hydrolysis; 500 mg, 1.44 mmol) and tert-butyl (N) -N, N'-diisopropylcarbamimidate (867 mg, 4.33 mm) in tert-butyl alcohol (1 ml) / THF (1 ml) was stirred at RT for 18 h.
[00412] [00412] A mixture of 137B (300 mg, 0.75 mmol), DBU (0.23 ml, 1.49 mmol) and (PhO) 2PON3 (0.24 ml, 1.12 mmol) in THF (5 ml ) was stirred at RT overnight. Ph3P (391 mg, 1.49 mmol) and H2O (1 ml) were added, and the reaction mixture was stirred at RT for 2 h, then it was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na 2 SO 4) and concentrated in vacuo. The crude oil was chromatographed (24 g of SiO2; continuous gradient of 0-10% EtO-Ac / Hexane for 10 min) to give the title compound (280 mg, 0.697 mmol, 94% yield) as a clear oil . [M + H] + = 402.2. Example 137
[00413] [00413] 137A (21 mg, 0.10 mmol) was added to a solution of 137C (20 mg, 0.050 mmol) and iPr2NEt (0.026 ml, 0.149 mmol) in DCM (1 ml) at 0 ° C for 5 min. The reaction was stirred at RT for 20 h, after which TFA (0.5 ml) was added. The reaction was stirred at RT for 2 h, then it was concentrated in vacuo. The crude product was purified by preparative HPLC (Sunfire C18 regenerated column 30 x 100 mm;
[00414] [00414] The following examples in Table 6 were synthesized according to the procedures described for the preparation of Example 136. Table 6 Ex # Structure & Name Analytical & Biological Data 138 LCMS, [M + H] + = 495, two; 1 H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 8.8 Hz, 1H), 7.80 (br d, J = 8.8 Hz, 1H), 4.85 (br s, 1H), 4.48 (s, 2H), 4.18 (s, 3H), 3.15 - 3.08 (m, 2H), 2.91 (br d, J = 3.9 Hz, 1H) , 2.78 (s, 3H), 2.73 (s, 3H), 2.20 - 1.64 (m, 9H), 1.58 - 1.49 (m, 2H), 1.32 (dq , J = 14.9, 7.4 Hz, 2H), 0.93 (t, J = 7.3 Acid (1S, 3S) -3 - ((6- (5 - (((N-butyl-N - Hz, 3H); methylsulfamoyl) amino) methyl) -1-methyl-1H-hLPA1 IC50 = 449 nM. 1,2,3-triazol-4-yl) -2-methylpyridin-3-yl) oxy) cyclo- hexane-1-carboxylic
[00415] [00415] The following examples in Table 7 below were synthesized according to the procedures described for the preparation of Example 64. Table 7 Ex # Structure & Name Analytical & Biological Data 140 LCMS, [M + H] + = 446 ,two; 1 O H NMR (500 MHz, DMSO-d6) δ
[00416] [00416] The following examples were synthesized according to the procedures described above.
[00417] [00417] To a solution at RT of 5-hydroxypentan-2-one (400 mg, 3.92 mmoles) and 4-nitrophenyl chloroformate (947 mg, 4.70 mmoles) in THF (8 ml), was added pyridine (0.95 ml, 11.8 mmoles). The reaction mixture was stirred at RT for 48 h; the solids were filtered and the filtrate was concentrated in vacuo to give the crude product. This material was chromatographed (40 g SiO2; continuous gradient of 0% to 50% EtOAc in hexanes in 12 min, then maintained at 50% EtOAc in hexane for 10 min) to give the title compound ( 500 mg,
[00418] [00418] The 4-nitrophenyl carbonate intermediates required for the preparation of the following examples were synthesized from the corresponding alcohols according to the procedure described for the preparation of intermediate 2. Intermediate- Structure & Name Analytical Data rio # 1 9 H NMR (400 MHz, CDCl3) δ 8.32 - 8.24 (m, 2H), 7.42 - 7.34 (m, 2H), 4.29 - 4.14 (m, 2H), 2, 45 - 2.26 (m, 2H), 2.17 - 1.99 (m, 1H), 1.17 (d, J = 6.2 Hz, 3H). 4-nitrophenyl carbonate (4,4,4-trifluoro-2-methylbutyl) 10 LCMS, [M + H] + = 276.0; 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 9.1 Hz, 2H), 7.38 (d, J = 9.0 Hz, 2H), 4.50 (t, J = 6 , 6 Hz, 2H), 2.36 (tt, J = 3,3-difluorobutyl carbonate (4- 15.6, 6.6 Hz, 2H), 1.70 (t, J = 18.6 nitrophenyl) Hz, 3H). 11 LCMS, [M + H] + = 264.1; 1H NMR (500 MHz, CDCl3) δ 8.28 (dd, J = 9.0, 1.7 Hz, 2H), 7.40 (d, J = 9.2 Hz, 2H), 5.29 (p , J = 7.0 Hz, 1H), 2.60 - 2.49 4-nitrophenyl esp- (m, 2H), 2.49 - 2.35 (m, 2H), 0.52 (br ro [2.3] hexan-5-yl s, 4H). 12 LCMS, [M + H] + = 274.0; 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 9.1 Hz, 2H), 7.41 (d, J = 9.2 Hz, 2H), 5.07 (qty, J = 7 , 6, 5.5, 3.4 Hz, 1H), 3,3-difluorocyclobutyl carbonate 3.15 (ddt, J = 15.6, 11.5, 7.1 Hz, 2H), (4-nitrophenyl ) 2.96 - 2.78 (m, 2H).
[00419] [00419] The examples in the following table were synthesized according to the procedures described for the preparation of Examples 1 and 2 using the above 4-nitrophenyl carbonate intermediates. Ex # Structure & Name Analytical & Biological Data Method 154 LCMS, [M + H] + = 501.4; Example 1 H NMR (500 MHz, DMSO-d6) 1 δ 8.64 (s, 2H), 7.59 (s, 1H), 4.88 (s, 1H), 4.75 (d, J = 5 , 5 Hz, 2H), 4.08 (s, 3H), 3.83 (d, J = 6.1 Hz, 2H), 2.72 - 2.63 (m, 1H), 2.37 - 1 , 48 (m, 10H), 0.94 (d, J = 6.6 Hz, 3H); hLPA1 IC50 = 2905 nM. (1S, 3S) -3 - ((2- (1-methyl-5- ((((((4,4,4-trifluoro-2-methylbutoxy) carbonyl) amine) methyl) -1H-1,2 , 3-triazol-4-yl) pyrimidin-5-yl) oxy) cyclohexane-1-carboxylic 155 LCMS, [M + H] + = 515.3; Example 1 H NMR (500 MHz, DMSO-d6) 1 δ 8.59 (s, 1H), 7.60 (s, 1H), 5.38 (s, 1H), 4.72 (d, J = 5 , 3 Hz, 2H), 4.05 (s, 3H), 3.82 (d, J = 6.2 Hz, 2H). 2.69 - 2.58 (m, 1H), 2.33 - 1.41 (m, 10H), 0.93 (d, J = 6.6 Hz, 3H); hLPA1 IC50 = 85 nM. (1S, 3S) -3 - (((3-methyl-5- (1-methyl-5 - (((((4,4,4-trifluoro-2-methylbutoxy) carbonyl) amino) methyl) -1H) -1,2,3-triazol-4-yl) pyrazin-2-yl) oxy) cyclohexane-1-carboxylic
[00420] [00420] To a solution of 1S, 3S) -3 - ((6- (5- (aminomethyl) -1-methyl-1H- 1,2,3-triazol-4-yl) -2-methylpyridin-3- il) oxy) methyl cyclohexane-1-carboxylate (synthesized as in Example 1H, except using (1S, 3R) -methyl 3-hydroxy cyclohexanecarboxylate instead of isopropyl ester; 25 mg, 0.070 mmol) and 4- nitrophenyl (4-oxopentyl) carbonate (22 mg, 0.083 mmol) in THF (0.2 ml), iPr2NEt (0.036 ml, 0.209 mmol) was added. The mixture was stirred at RT for 52 h, then it was concentrated in vacuo. The residue was chromatographed (12 g of SiO2; continuous gradient from 0% to 100% EtOAc in hexanes in 19 min, waiting for 5 min) to give the title compound (31 mg, 0.064 mmol, 91% yield) like a colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 8.6 Hz, 1H), 7.27 (s, 1H), 7.07 (br s, 1H), 4.75 (dq, J = 5.0, 2.6 Hz, 1H), 4.63 (d, J = 5.4 Hz, 2H), 4.23 (s, 3H), 4.07 (t, J = 6.3 Hz, 2H), 3.73 (s, 3H), 2.86 (tt, J = 10.3, 3.9 Hz, 1H), 2.57 (s, 3H), 2.50 (t, J = 7.2 Hz, 2H), 2.19 - 1.61 (m, 13H). LCMS, [M + H] + = 488.1.
[00421] [00421] To a solution of Example 206A (25 mg, 0.051 mmol) in DCM (0.5 ml), DAST (0.027 ml, 0.205 mmol) was added at 0 ° C. The reaction mixture was stirred at RT for 2 h, then it was quenched with water (0.5 ml) and concentrated in vacuo. The residue was dissolved in THF (1 ml) and water (0.5 ml) and LiOH.H2O (22 mg, 0.51 mmol) was added. The reaction was stirred at RT overnight, then adjusted to pH ~ 5 with 1N aqueous HCl and extracted with EtOAc (3 x 2 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude material was purified by preparative LC / MS (Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile Phase A: 5:95 MeCN: H2O with 0.1% TFA; Mobile Phase B: 95: 5 MeCN: H2O with 0.1% TFA; Gradient: 10-55% B for 19 min, then a 5 min wait at 100% B; Flow: 20 ml / min). Fractions containing the desired product were combined and dried by centrifugal evaporation to generate the title compound (17.2 mg, 0.027 mmol, 53% yield; LCMS purity = 97%). LCMS [M + H] + = 496.3; 1H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 4.77 (d, J = 5.5 Hz, 3H ), 4.07 (s, 3H), 3.99 (t, J = 6.5 Hz, 2H), 2.70 - 2.61 (m, 1H), 2.42 (s, 3H), 2 , 06 - 1.47 (m, 15H). hLPA1 IC50 = 71 nM. Example 207. (1S, 3S) -3 - ((6- (5 - (((((((R) -2,2-difluorocyclopropyl) methoxy) carbonyl) amino) methyl) -1-methyl-1H diethylammonium salt -1,2,3-triazol-4-yl) -2-methylpyridin-3-yl) oxy) cyclohexane-1-carboxylate (first elution isomer; the stereochemistry of the cyclopropyl chiral center is arbitrarily attributed)
[00422] [00422] The individual diastereomers of Example 180 were separated by SFC (Column: Chiralpak AD-H, 21 x 250 mm, 5 m; Flow rate: 45 ml / min; Oven temperature: 40ºC; BPR configuration: 150 bar; UV wavelength: 255 nm; Mobile Phase: 90% CO2 / 10% MeOH -0.1% DEA (isocratic); Injection: 0.5 ml ~ 14 mg / ml in MeOH: MeCN) to give two diastereomers. The chiral purity of both compounds was determined to be> 93% ee under these analytical conditions: Column: Chiralpak AD-H, 4.6 x 250 mm, 5 µm (analytical); Flow rate: 2 ml / min; Oven temperature: 40ºC; BPR configuration: 150 bar; UV wavelength: 254 nm; Mobile Phase: 10% MeOH - 0.1% DEA / 85% CO2 (isocratic).
[00423] [00423] Example 207. First eluting enantiomer: LCMS, [M + H] + = 480.2. hLPA1 IC50 = 44 nM.
[00424] [00424] Example 208. Second eluting enantiomer: LCMS, [M
[00425] [00425] To a solution of Example 1C (0.193 g, 0.634 mmol)) and Intermediate 1 (0.194 g, 0.951 mmol) in toluene (18 ml), Ph3P (0.317 ml, 1.268 mmol) and (E) were added -diazene-1,2-diylbis (piperidin-1-ylmethanone) (0.320 g, 1.268 mmol). The reaction was stirred at 50ºC for 5 h, then it was cooled to RT and filtered. The filtrate was concentrated in vacuo. The crude oil was chromatographed (24 g SiO2; continuous gradient from 0% to 50% EtOAc in hexane for 10 min) to give the title compound (0.06 g, 0.122 mmol, 19.29% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 5.31 - 5.17 (m , 2H), 5.04 (dt, J = 12.4, 6.3 Hz, 1H), 4.72 - 4.66 (m, 1H), 4.64 - 4.57 (m, 1H), 4.07 (s, 3H), 3.82 (tt,
[00426] [00426] A mixture of Example 209A (0.18 g, 0.367 mmol) and p-TsOH (0.021 g, 0.110 mmol) in MeOH (10 ml) was stirred at 60 ° C for 3 h, then cooled to RT and NaHCO3 (0.031 g, 0.367 mmol) was added. The mixture was stirred at RT for 1 h, then DCM (10 ml) was added. The mixture was filtered; the filtrate was concentrated in vacuo. The crude oil was chromatographed (12 g SiO2; continuous gradient from 0% to 100% EtOAc in hexane for 14 min) to give the title compound (0.133 g, 0.327 mmol, 89% yield) as an oil clear. 1H NMR (500 MHz, CDCl3) δ 7.22 - 7.18 (m, 1H), 5.03 (spt, J = 6.3 Hz, 1H), 4.74 (d, J = 1.1 Hz , 2H), 4.65 (quin, J = 5.0 Hz, 1H), 3.99 (s, 3H), 2.44 (s, 3H), 2.40 - 2.28 (m, 1H) , 2.12 - 1.76 (m, 6H), 1.52 19 - 1.41 (m, 1H), 1.23 (dd, J = 6.3, 2.8 Hz, 6H); F NMR (471 MHz, CDCl3) δ -153.01 (s, 1F). 209C. 3 - ((6- (5 - (((((benzyloxy) carbonyl) amino) methyl) -1-methyl-1H-1,2,3-triazol-4-yl) -2-methylpyridin-3-yl) oxide (-1) -Cis-isopropyl -1-fluorocyclohexanecarboxylate
[00427] [00427] A solution of Example 209B (33 mg, 0.081 mmol), benzyl N- [(tert-butoxy) carbonyl] carbamate (30.6 mg, 0.122 mmol), n-Bu3P (0.030 ml, 0.122 mmol), and 1.1 '- (azodicarbonyl) dipiperidine (31 mg, 0.122 mmol) in toluene (2 ml) was stirred at 50 ° C for 3 h, then cooled to RT. TFA (1 ml) was added and the reaction was stirred at RT for 1 h, then it was concentrated in vacuo. The crude oil was purified by preparative HPLC (Sunfire C18 column 30 x 100 mm; detection at 220 nm; flow rate = 40 ml / min; continuous gradient of 20% B to 100% B for 10 min waiting time + 2 min 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 (40 mg , 0.074 mmol, 91% yield) as a clear oil. [M + H] + = 540.3. Example 209
[00428] [00428] A mixture of Example 209C (40 mg, 0.074 mmol) and 2.0 M aqueous LiOH. (1.86 ml, 3.71 mmoles) in THF (3 ml) was stirred at RT for 3 h. The product was purified by preparative HPLC (Sun-fire C18 column 30 x 100 mm; detection at 220 nm; flow rate = 40 ml / min; continuous gradient of 20% B to 100% B for a waiting time of 10 min + 2 min 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 (37 , 1 mg, 0.058 mmol, 79% yield) as a clear oil. [M + H] + = 498.2; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.39 - 7.28 (m , 5H), 5.10 (s, 2H), 4.93 (br. S, 1H), 4.59 (s, 2H), 4.16 (s, 3H), 2.68 (s, 3H ), 2.45 - 2.29 (m, 1H), 2.25 - 1.87 (m, 197H), 1.68 (br. S., 1H); F NMR (377MHz, CDCl3) δ -154.52 (s, 1F).
[00429] [00429] The absolute stereochemistry of Examples 210 and 211 has not been determined - the stereochemistry in the structures shown are arbitrarily drawn. The two individual enantiomers of Example 209 (32 mg, 0.064 mmol) were obtained by chiral SFC separation: Instrument: Berger MGII-SFC, Column: Chiralpak IC, 21 x 250 mm, 5 m, Mobile Phase: 20% MeOH / 80% CO2, Flow conditions: 45 ml / min, 150 Bar, 40 ° C; Detector Wavelength: 254 nm, Injections: 0.5 ml of 8 mg / ml solution in MeOH: MeCN (1: 1).
[00430] [00430] Example 210 - first eluting enantiomer (8.4 mg, 0.017 mmol, 25.7% yield); [M + H] + = 498.1; 1H NMR (400 MHz, CDCl3) δ 8.06 (br. S, 1H), 7.32 (br. S., 6H), 5.08 (br. S., 2H), 4.92
[00431] [00431] Example 211 - second eluting enantiomer (11 mg, 0.022 mmol, 33.7% yield); [M + H] + = 498.1; 1H NMR (400 MHz, CDCl3) δ 8.06 (br. S., 1H), 7.32 (br. S., 6H), 5.08 (br. S., 2H), 4.92 - 4 , 50 (m, 3H), 4.21 (br. S., 2H), 2.52 (br. S., 4H), 2.32 - 1.27 (m, 8H); 19 F NMR (377 MHz, CDCl3) δ -150.17 (s, 1F); hLPA1 IC50 = 192 nM. Intermediate 40. 2,5-dibromo-3-fluoro-6-methylpyridine Intermediate 40A. 3-fluoro-6-methylpyridin-2-amine
[00432] [00432] To a solution of 2-bromo-3-fluoro-6-methylpyridine (5.0 g, 26.3 mmoles) in ethylene glycol (50 ml) and 28% aqueous NH4OH (63 ml; 450 mmoles), Cu2O (0.19 g, 1.32 mmol), K2CO3 (0.73 g, 5.26 mmoles) and N1, N1-dimethylethane-1,2-diamine (0.29 ml, 2.63 mmoles) were added . The reaction mixture was purged with N2, then heated to 80 ° C overnight in a sealed tube, after which it was cooled to RT and extracted with CH2Cl2 (3x). The combined organic extracts were dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed (SiO2; continuous gradient of 0-100% EtOAc in hexanes) to give the title compound (2.81 g, 85% yield). 1H NMR (500 MHz, CDCl3) δ 7.11 (dd, J = 10.6, 8.1 Hz, 1H), 6.47 (dd, J = 8.0, 3.0 Hz, 1H), 4 , 55 (br s, 2H), 2.38 (s, 3H). Intermediate 40B. 5-bromo-3-fluoro-6-methylpyridin-2-amine
[00433] [00433] To a 0ºC solution of Intermediate 34A (3.91 g, 31.0 mmoles) in CH3CN (100 ml), was added in NBS portions (5.52 g, 31.0 mmoles) while maintaining the reaction temperature at ≤5 ° C. The reaction mixture was stirred at RT for 30 min, then it was concentrated in vacuo. The residue was chromatographed (SiO2; isocratic 30% EtOAc in hexanes) to give the title compound (6.14 g, 97% yield). 1H NMR (500 MHz, CDCl3) δ 7.37 (d, J = 9.6 Hz, 1H), 4.59 (br s, 2H), 2.48 (d, J = 1.1 Hz, 3H) . Intermediate 40
[00434] [00434] To a solution at 0ºC of 48% aqueous HBr (23.7 ml, 210 mmoles, 48%), Intermediate 34B (6.14 g, 29.9 mmoles) was added slowly in portions. Br2 (3.09 ml, 59.9 mmoles) was added in drops while maintaining the reaction temperature at ≤5 ° C. The reaction mixture was stirred at 0 ° C for 30 min, after which a solution of NaNO2 (5.17 g, 74.9 mmoles) in water (10 ml) was added in drops while maintaining the temperature reaction at ≤5 ° C. The reaction mixture was stirred for 30 min at 0 ° C, then poured into ice water, basified with 50% aqueous NaOH and extracted with EtOAc (2x). The combined organic extracts were washed with 10% aqueous Na2S2O3, brine, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed (SiO2; continuous gradient of 0-25% EtOAc in hexanes) to give the title compound (3.90 g, 48% yield). 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 6.6 Hz, 1H), 2.64 (d, J = 1.4 Hz, 3H). Intermediate 41. (1S, 3S) -3 - ((6- (5- (aminomethyl) -1-methyl-1H-1,2,3-triazol-4-yl) -5-fluoro-2-methylpyridin-3 -yl) oxy) isopropyl cyclohexane-1-carboxylate
[00435] [00435] Intermediate 41 was prepared using the same synthetic sequence that was used to prepare Example 1E, except that Intermediate 40 was used instead of 2,5-dibromo-6-methyl-pyridine that was used for synthesis of Example 1A. LCMS, [M + H] + = 407. 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 11.9 Hz, 1H), 5.05 (quin, J = 12.5 Hz, 1H ), 4.76 (s, 2H), 4.66 (m, 1H), 4.13 (s, 3H), 2.77 (m, 1H), 2.50 (d, J = 1.1 Hz , 3H), 2.07 - 2.02 (m, 2H), 1.97 - 1.86 (m, 2H), 1.81 - 1.62 (m, 4H), 1.27 (dd, J = 6.2, 3.7 Hz, 6H). Intermediate 42. 4- (3-Fluoro-5 - ((((1S, 3S) -3- (isopropoxycarbonyl) cyclohexyl) oxide) -6-methylpyridin-2-yl) -1-methyl-1H-1, 2,3-triazole-5-carboxylic
[00436] [00436] Intermediate 42 was prepared using the same synthetic sequence that was used to prepare Example 64B. Intermediate 40 was used instead of 2,5-dibromo-6-methyl-pyridine in the synthetic sequence.
[00437] [00437] The examples in the following table were synthesized using the general procedures described for the preparation of Examples 1 and 64 and using intermediates 41 and 42; or Example 137. Ex # Structure & Name Biological & Analytical Data Method
[00438] [00438] To a solution of 2-methyl-2-phenoxypropanoic acid (4.2 mg, 0.023 mmol) in DCM (0.3 ml) was added 1-chloro-N, N, 2-trimethylprop-1-en- 1-amine (3 µL, 0.023 mmol). The mixture was stirred at RT for 10 min, then it was concentrated in vacuo. To the residue, THF (0.3 ml), Example 1H (6 mg, 0.015 mmol) and iPr2NEt (5 µL, 0.03 mmol) were added. The reaction was stirred at RT for 1 h, after which MeOH (0.2 ml), THF / water (0.5 ml each) and LiOH.H2O (4 mg, 0.1 mmol) were added. The reaction mixture was stirred at RT overnight; the pH was adjusted to ~ 5 with 1N aqueous HCl. The mixture was extracted with EtOAc (3 x 2 ml). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The crude product was purified by preparative LC / MS (Column: XBridge C18, 19 x 200 mm, particles of
[00439] [00439] The material was further purified using preparative LC / MS (Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile Phase A: 5:95 MeCN: H2O with 10 mM aqueous NH4OAc; Mobile Phase B: 95: 5 MeCN: H2O with 10 mM aqueous NH4OAc; Gradient: 16-56% B for 25 min, then a 5 min wait at 100% B; Flow: 20 ml / min). Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (3.9 mg; 47% yield; LCMS purity = 95%). LCMS, [M + H] + = 508.2; 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H ), 7.02 (t, J = 7.8 Hz, 2H), 6.86 (t, J = 7.3 Hz, 1H), 6.60 (d, J = 8.0 Hz, 2H), 4.73 - 4.66 (m, 3H), 4.10 (s, 3H), 2.49 - 2.43 (m, 1H), 2.31 (s, 3H), 1.91 - 1, 46 (m, 8H), 1.36 (s, 3H), 1.35 (s, 3H). hLPA1 IC50 = 392 nM. Example 235. (1S, 3S) -3 - ((6- (5 - (((2-cyclopentylacetamido) methyl) -1- methyl-1H-1,2,3-triazol-4-yl) -2-methylpyridin -3-yl) oxy) cyclohexanecarboxylic 235A. 3 - ((6- (5- (aminomethyl) -1-methyl-1H-1,2,3-triazol-4-yl) -2-methylpyridin-3-yl) oxy) cyclohexanecarboxylate (1S, 3S ) -ethyl
[00440] [00440] To a solution at 3 - ((6- (5- (aminomethyl) -1-methyl-1H-1,2,3-triazol-4-yl) -2-methyl-pyridin-3-yl ) oxy) (1S, 3S) -ethyl cyclohexane (20 mg, 0.054 mmol; prepared in the same way as Intermediate 1H) and Et3N (7.5 µL, 0.054 mmol) in DCM (3 ml) under N2 , 2-cyclopentylacetyl chloride (9.4 mg, 0.064 mmol) was added. The reaction was stirred at RT for 2 h, then it was concentrated in vacuo. The crude title compound was used for the next reaction without further purification. Example 235
[00441] [00441] To a solution of 235A (20 mg, 0.041 mmol) in THF / MeOH (1.5 ml each), LiOH.H2O (3 mg, 0.124 mmol) in water (1.5 ml) was added. The reaction was stirred for 14 h at RT, then it was diluted with water (20 ml), washed with Et2O (10 ml) and neutralized with 1.5 N aqueous HCl (1.5 ml). The mixture was stirred with 5% MeOH in CHCl3 (20 ml) for 2 min. The organic phase was washed with brine, dried (Na 2 SO 4) and concentrated in vacuo. The crude product was purified by preparative HPLC (Column: Ascentis Express C18 (50 x 2.1 mm), 2.7 μm; Mobile Phase A: 5:95 MeCN: water with 10 mM aqueous NH4OAc; Mobile Phase B: 95 : 5 MeCN: water with 10 mM aqueous NH4OAc; Temperature: 50ºC; Gradient: 0-100% B for 3 min; Flow: 1.1 ml / min) to give the title compound (8.7 mg, 0.019 mmol, 46.2% yield) as a clear oil. [M + H] + = 456.2; 1H NMR (400 MHz, CD3OD): δ 7.84 (d, J = 8.40 Hz, 1H), 7.47 (d, J = 8.80 Hz, 1H), 4.89 (s, 2H) , 4.74-4.78 (m, 1H), 4.16 (s, 3H), 2.71-2.79 (m, 1H), 2.56 (s, 3H), 2.10-2 , 21 (m, 3H), 1.91-1.97 (m, 3H), 1.49-1.78 (m, 11H), 1.07-
[00442] [00442] The examples in the following table were synthesized according to the procedures described for the synthesis of Example 235. Ex # Structure & Name Analytical & Biological Data 236 LCMS, [M + H] + = 442.2; 1 H NMR (400 MHz, CD3OD): δ 8.42 (s, 1H), 8.00 (d, J = 9.20 Hz, 1H), 7.53 (dd, J = 2.40, 8, 80 Hz, 1H), 4.74-4.79 (m, 1H), 4.52 (s, 2H), 4.20 (s, 3H), 2.78-2.84 (m, 1H), 2.06-2.20 (m, 3H), 1.90-2.02 (m, 3H), 1.49-1.84 (m, 11H), 1.03-1.10 (m, 2H ); (1S, 3S) -3 - ((6- (5 - ((2- hLPA1 IC50 = 569 nM. Cyclopentyl acetamido) methyl) -1- methyl-1H-1,2,3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexanecarboxylic 237 LCMS, [M + H] + = 430.2; 1 H NMR (400 MHz, CD3OD): δ 7.84 (d, J = 8.40 Hz, 1H), 7.47 (d, J = 8.80 Hz, 1H), 4.89 (s, 2H ), 4.74-4.78 (m, 1H), 4.16 (s, 3H), 2.71-2.79 (m, 1H), 2.56 (s, 3H), 2.21 ( t, J = 7.60 Hz, 2H), 2.09-2.12 (m, 1H), 1.92-1.98 (m, 3H), 1.61 1.78 (m, 4H) , 1.55 (p, 2H), 1.25-1.28 Acid (1S, 3S) -3 - ((2-methyl-6- (1- (m, 2H), 0.87 (t, J = 7.20 Hz, 3H); methyl-5- (pentanamidomethyl) -1H-hLPA1 IC50 = 783 nM. 1,2,3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexanecarboxylic Example 238 (1S, 3S) -3 - ((2-methyl-6- (1-methyl-5- (2- (2-phenylacetamido) ethyl) -1H-1,2,3-triazol-4-yl acid) pyridin-3-yl) oxy) cyclohexane-1-carboxylic OH O O N H N N N N O
[00443] [00443] The title compound was synthesized using the same procedure as for the preparation of Intermediate 1E, except that (1S, 3R) -methyl 3-hydroxycyclohexane carboxylate was used. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.7 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 4.81 (s, 2H), 4.72 (sd, J = 5.1, 2.7 Hz, 1H), 4.07 (s, 3H), 3.69 (s, 3H), 2.82 (tt, J = 10.2, 3.9 Hz, 1H), 2.53 (s, 3H), 2.19 - 1.54 (m, 8H). LC-MS, [M + H] + = 361.2. 238B. (1S, 3S) -3 - ((6- (5- (bromomethyl) -1-methyl-1H-1,2,3-triazol-4-yl) -2-methylpyridin-3-yl) oxy) cyclo- methyl hexane-1-carboxylate
[00444] [00444] To a 0ºC solution of 238A (1.0 g, 2.77 mmol) in DCM (25 ml), PBr3 (0.26 ml, 2.8 mmoles) was added. The reaction mixture was stirred at 0ºC for 1h, then it was neutralized by the slow addition of saturated aqueous NaHCO3; the mixture was extracted with EtOAc (3 x 25 ml). The combined organic extracts were washed with water and brine (15 ml each), dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed (SiO2; continuous gradient from 0% to 100% EtOAc in hexanes for 20 min) to give the title compound as a white foam (1.10 g, 2.6 mmol, 92% yield) , MS (ESI) m / z: 425.1 (M + 2 + H) +. 238C. (1S, 3S) -3 - ((6- (5- (cyanomethyl) -1-methyl-1H-1,2,3-triazol-4-yl) -2-methylpyridin-3-yl) oxy) cyclo- methyl hexane-1-carboxylate
[00445] [00445] To a solution of 238B (1.10 g, 2.60 mmoles) in MeCN (10 ml), NaCN (0.127 g, 2.60 mmoles) in DMSO (10 ml) was added in portions. The reaction mixture was stirred at 00C for 30 min, then it was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (3 X 20 ml). The combined organic extracts were concentrated in vacuo. The crude product was chromatographed (SiO2; continuous gradient from 0% to 100% EtOAc in hexanes for 20 min) to give the title compound as a white solid (0.864g, 2.34 mmoles, 90% yield). MS (+) MS = 370.2 1H NMR (400 MHz, CDCl3) δ 8.28 - 7.77 (m, 1H), 7.23 (d, J = 8.8 Hz, 1H), 4.79 - 4.55 (m, 3H), 4.20 (s, 3H), 3.72 (s, 3H), 3.06 - 2.72 (m, 1H), 2.53 (s, 3H), 2.25 - 2.08 (m, 1H), 2.03 - 1.59 (m, 7H) 238D. (1S, 3S) -3 - ((6- (5- (2-aminoethyl) -1-methyl-1H-1,2,3-triazol-4-yl) -2-methylpyridin-3-yl) ox) methyl cyclohexane-1-carboxylate
[00446] [00446] To a solution at 0ºC of 238C (155 mg, 0.42 mmol) in
[00447] [00447] To a solution of 238D (8 mg, 0.021 mmol) in THF / saturated aqueous NaHCO3 (1 ml each) was added acetyl 2-phenyl chloride (3.3 mg, 0.021 mmol). The reaction mixture was stirred at RT for 1 h, then EtOAc (2 ml) was added. The aqueous layer was extracted with EtOAc (2 x 1 ml). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to give the crude 2-phenyl acetamide ester (LCMS [M + H] + = 492.3), which was used in the next step without further purification. The crude product was dissolved in THF (1 ml) and 2M aqueous LiOH. (60 L, 0.12 mmol) was added. A reaction mixture was stirred at RT for 18 h, then it was concentrated in vacuo. The residue was dissolved in H2O (1 ml); the pH was adjusted with 1N aqueous HCl to ~ 3 and the mixture was extracted with EtOAc (2 x 1 ml). The combined organic extracts were washed with brine (1 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by preparative LC / MS: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5 μm particles; Mobile Phase A: 5:95 MeCN: H2O with 0.1% TFA; Mobile Phase B: 95: 5 MeCN: H2O with 0.1% TFA; Gradient: 50-90% B for 20 min, then a 5 min wait at 100% B; Flow: 20 ml / min. Fractions containing the desired product were combined and concentrated in vacuo by centrifugal evaporation to give the title compound as a colorless oil. (6.9 mg, 0.012 mmol, 54.1% yield). LCMS, [M + H] + = 478.1; 1H NMR (DMSO-d6) δ: 8.10 (br s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.46 (br d, J = 8.6 Hz, 1H ), 7.22-7.29 (m, 2H), 7.13-7.22 (m, 3H), 4.74 (br s, 1H), 3.89 (s, 3H), 3.21 -3.65 (m, 2H), 2.60 (br s, 1H), 2.55 (s, 3H), 2.44 (s, 3H), 1.97 (br d, J = 13.5 Hz, 1H), 1.75-1.92 (m, 4H), 1.60-1.71 (m, 2H), 1.49-1.60 (m, 2H); hLPA1 IC50 = 138 nM.
[00448] [00448] The examples in the following table were synthesized according to the procedures described for the preparation of the Example
[00449] [00449] Other features of the invention should become apparent in the course of the above descriptions of exemplary modalities that are provided for illustration of the invention and are not intended to be limiting thereof. The present invention can be incorporated in other specific forms without departing from the spirit or its essential attributes. This invention encompasses all combinations of preferred aspects of the invention observed here. It is understood that any and all modalities of the present invention can be taken in conjunction with any other modality or modalities to describe additional modalities. It is also understood that each individual element of the modalities is its own independent modality. In addition, any element of a modality is intended to be combined with any and all other elements of any modality to describe an additional modality.

权利要求:
Claims (33)
[1]
1. Compound according to Formula (I): (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, characterized by the fact that: X1, X2, X3 and X4 are each independently, CR6 or N; provided that no more than two of X1, X2, X3 or X4 are N; one from Q1, Q2 and Q3 is NR5, and the other two are N; and the dashed circle represents optional bonds that form an aromatic ring; Y1 is O or NR3; Y2 is either; Y3 is O or NR4a; provided that (1) Y1 and Y3 are not both O, and (2) when Y2 is C (O), Y1 is not O; L is a covalent bond or C1-4 alkylene substituted by 0 to 4 R7; R1 is (-CH2) to R9; a is an integer of 0 or 1; R2 is each independently halo, cyano, hydroxyl, amino, C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, or haloalkoxy ;
n is an integer of 0, 1 or 2; R3 and R4a are each independently hydrogen, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R4 is C1-10 alkyl, C1-10 deuterated alkyl, C1-10 haloalkyl, C1-10 alkenyl, C3-8 cycloalkyl, 6 to 10 membered aryl, 3 to 8 membered heterocyclyl, - (C1-6 alkylene) - (C3-8 cycloalkyl), - (C1-6 alkylene) - (6 to 10 membered aryl), - (C1-6 alkylene) - (3-8 membered heterocyclyl), or - (C1-6 alkylene) - (5- to 6-membered heteroaryl); wherein each of alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, alone or as part of another portion, is independently replaced by 0 to 3 R8; or, alternatively, R3 and R4 taken together with the atoms to which they are attached, form a 4- to 9-membered heterocyclic ring portion which is replaced by 0 to 3 R8; R5 is hydrogen, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; R6 is hydrogen, halo, cyano, hydroxyl, amino, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; R7 is halo, oxo, cyano, hydroxyl, amino, C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R8 are each independently deuterium, halo, hydroxyl, amino, cyano, C1-6 alkyl, C1-6 deuterated alkyl, C2-6 alkenyl, C2-6 alkynyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkyl- coxialkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, -CHO, phenyl, or 5- to 6-membered heteroaryl; or, alternatively, two R8s, taken together with the atoms to which they are attached, form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring
bros, each of which is independently replaced by 0 to 3 R12; R9 is selected from –CN, –C (O) OR10, –C (O) NR11aR11b,; Re is C1-6 alkyl, C3-6 cycloalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl; R10 is hydrogen or C1-10 alkyl; R11a and R11b are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; and R12 is halo, cyano, hydroxyl, amino, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl, or 5- to 6-membered heteroaryl.
[2]
2. Compound, according to claim 1, characterized by the fact that the portion is
,, or.
[3]
3. A compound according to claim 1 or 2, characterized by the fact that the portion is selected from, and Y4 is O or NH.
[4]
Compound according to any one of claims 1 to 3, characterized by the fact that n is 0 or 1.
[5]
Compound according to any one of claims 1 to 4, characterized by the fact that R5 is C1-4 alkyl.
[6]
6. Compound according to any one of claims 1 to 5, characterized by the fact that R1 is CO2H.
[7]
7. A compound according to any one of claims 1 to 6, characterized by the fact that R3 and R4, taken together with the N and O to which they are attached, form a heterocyclic ring portion 5 to 7 members which is replaced by 1 R8; and R8 is benzyl or phenyl.
[8]
A compound according to any one of claims 1 to 7, characterized by the fact that R4 is C1-10 alkyl, C1-10 haloalkyl, C3-6 cycloalkyl, - (C1-4 alkylene) - (C3- 6 cycloalkyl), - (C1-4 alkylene) - (C1-6 alkoxy), or - (C1-4 alkylene) -phenyl; wherein each of alkyl, alkylene, cycloalkyl and phenyl, alone or as part of another group, is independently replaced by 0 to 3 R8; and R8 is each independently halo, hydroxyl, amino, cyano, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; or, alternatively, two R8s, taken together with the atom (s) to which they are attached, form a 3- to 6-membered carbocyclic ring.
[9]
9. Compound according to any one of claims 1 to 8, characterized by the fact that it is represented by Formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf ): (IIa), (IIb), (IIc), (IId),
(IIe), (IIf), or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein: each R7a is independently hydrogen, halo, oxo, cyano, hydroxyl, amino, C1-6 alkyl, C3 -6 cycloalkyl, C4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; f is an integer of 0, 1 or 2; R3 and R4a are each independently hydrogen or C1-4 alkyl; R4 is C1-10 alkyl, C3-8 cycloalkyl, 6 to 10 membered aryl, - (C1-6 alkylene) - (C3-8 cycloalkyl), or - (C1-6 alkylene) - (6 to 10 membered aryl ); where each of alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, alone or as part of another portion, is independently replaced by 0 to 3 R8; or, alternatively, R3 and R4, taken together with the N and O to which they are attached, form a 4- to 6-membered heterocyclic ring portion that is replaced by 0 to 3 R8; n is 0 or 1; and R1, R2, R5, R5a, R8; X1, X2, X3, X4 and Z are the same as defined in any one of claims 1 to 7.
[10]
10. Compound according to claim 9, characterized by the fact that X1 is CR6, where R6 is hydrogen, C1-4 alkyl,
C1-4 haloalkyl or C1-4 alkoxyalkyl.
[11]
11. Compound according to claim 9 or 10, characterized by the fact that X3 is N.
[12]
12. A compound according to claim 9 or 10, characterized by the fact that the portion is selected from, and; R6a is each independently halo, cyano, hydroxyl, amino, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; and d is an integer of 0, 1 or 2.
[13]
13. Compound according to claim 12, characterized by the fact that the portion is selected from
, and; and R6 is each independently hydrogen, halo, cyano, hydroxyl, amino, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy.
[14]
14. A compound according to any one of claims 9 to 13, characterized by the fact that f is 0 or 1.
[15]
15. A compound according to any one of claims 1 to 14, characterized by the fact that it is represented by Formula (IIIa) or (IIIb): (IIIa) or (IIIb), or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein: R2a is hydrogen, chlorine, fluorine, or C1-4 alkyl; R3 is hydrogen or C1-6 alkyl; and R1, R4, X1, X2, X3, and X4 are the same as defined in any one of claims 1 to 14.
[16]
16. Compound according to claim 15, characterized by the fact that the portion is selected from
,and .
[17]
17. A compound according to claim 15 or 16, characterized by the fact that R1 is CO2H.
[18]
18. A compound according to any one of claims 15 to 17, characterized in that the portion is selected from, and; R6 is each independently hydrogen, CH3, CH2CH3, CH2OCH3, CHF2, or CF3.
[19]
19. A compound according to any one of claims 15 to 18, characterized in that R4 is C3-10 alkyl, C3-10 haloalkyl, C3-6 cycloalkyl, phenyl, - (C1-4 alkylene) - ( C1-3 alkoxy), - (C1-4 alkylene) - (C3-6 cycloalkyl), or benzyl; wherein alkyl, alkylene, cycloalkyl and benzyl are each independently replaced by 0 to 3 R8; and R8 is each independently halo, C1-6 alkyl, alkyl
lamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; or alternatively, two R8s, taken together with the atoms to which they are attached, form a 3- to 6-membered carbocyclic ring.
[20]
20. A compound according to any one of claims 15 to 19, characterized in that R4 is C3-10 alkyl, C3-10 haloalkyl, cyclobutyl, cyclopentyl, - (CH2) 1-2- (C1-3alkoxy ), - (CHR8a) 1-2-cyclopropyl, - (CHR8a) 1-2-cyclobutyl, or - (CHR8a) 1-2-phenyl; where cyclopropyl, cyclobutyl, cyclopentyl and phenyl are each independently replaced by 0 to 3 R8; or, alternatively, two R8, taken together with the atom to which they are attached, form cyclopropyl; R8a is each independently hydrogen or methyl; and R8 is each independently halo or C1-4 alkyl.
[21]
21. A compound according to claim 15, characterized by the fact that it is represented by Formula (VI): (IV), or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, in which: R2a is hydrogen, chlorine, fluorine or C1-4 alkyl; R3 is hydrogen or C1-6 alkyl; R4 is C1-10 alkyl, - (C1-6 alkylene) 0-1-phenyl, or - (C1-6 alkylene) 0-1- (C3-8 cycloalkyl);
and R6 is hydrogen, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy.
[22]
22. A compound according to claim 21, characterized by the fact that: R4 is C1-6 alkyl, - (CH2) 0-2- (C3-6 cycloalkyl), - (CHCH3) - (C3-6 cycloalkyl), - (CH2) 1-2-phenyl, or - (CHCH3) -phenyl and R6 is methyl or ethyl.
[23]
23. A compound according to claim 1, characterized by the fact that it is selected from any of the Examples described in the specification, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof.
[24]
24. Pharmaceutical composition, characterized by the fact that it comprises one or more compounds, as defined in any one of claims 1 to 23, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
[25]
25. A compound according to any one of claims 1 to 23, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, characterized in that it is for use in therapy.
[26]
26. A compound or stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 23, or a pharmaceutical composition, according to claim 24, characterized in that it is for use in the treatment of a disease, disorder or condition associated with dysregulation of lysophosphatidic acid receptor 1 (LPA1).
[27]
27. Compound or stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof or composition for use,
according to claim 26, characterized by the fact that the disease, disorder or condition is pathological fibrosis, transplant rejection, cancer, osteoporosis or inflammatory disorders.
[28]
28. Compound or stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof or composition for use, according to claim 26, characterized by the fact that pathological fibrosis is pulmonary, hepatic, renal, cardiac, dermal fibrosis ocular or pancreatic.
[29]
29. Compound or stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof or composition for use, according to claim 26, characterized by the fact that the disease, disorder or condition is idiopathic pulmonary fibrosis (IPF), es - non-alcoholic teato-hepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease and systemic sclerosis.
[30]
30. Compound or stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof or composition for use, according to claim 27, characterized by the fact that the cancer is of the bladder, blood, bone, brain, breast, system central nervous system, cervix, colon, endometrium, esophagus, gallbladder, genitalia, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin , spleen, small intestine, large intestine, stomach, testis or thyroid.
[31]
A compound according to any one of claims 1 to 23, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition, as defined in claim 24, characterized by fact that it is for use in the treatment of fibrosis in a mammal in need of it.
[32]
32. Compound or stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof or composition for use, according to claim 31, characterized by the fact that fibrosis is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis - lychee (NASH), chronic kidney disease, diabetic kidney disease and systemic sclerosis.
[33]
33. A compound according to any one of claims 1 to 23, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition, as defined in claim 24, characterized by fact that it is for use in the treatment of pulmonary fibrosis (idiopathic pulmonary fibrosis), asthma, chronic obstructive pulmonary disease (COPD), kidney fibrosis, acute kidney injury, chronic kidney disease, liver fibrosis (non-alcoholic steato hepatitis), fibrosis skin, bowel fibrosis, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, bowel cancer, head and neck cancer, melanoma, multiple myeloma, lymphoid leukemia - chronic cytitis, cancer pain, tumor metastasis, transplant organ rejection, scleroderma, ocular fibrosis, age-related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atherosclerosis, Ra phenomenon ynaud or neuropathic pain in a mammal in need of it.

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US201762607399P| true| 2017-12-19|2017-12-19|

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