Peripheral restricted lpar1 antagonists and uses thereof

Abstract

Described herein, inter alia, are peripheral-restricted LPAR1 antagonists and uses thereof.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 564,423, filed March 12, 2024, which is incorporated herein by reference in its entirety and for all purposes. Background Technology

[0003] Lysophosphatidic acid (LPA) is a family of bioactive phospholipids involved in various cellular functions. Although the long-chain fatty acid backbones of family members differ in length and saturation (Fujiwara et al., J. Biol. Chem., 2005), 280 (35038-35050), all of which are capped by glycerophosphate groups via ester bonds. LPA is produced in vivo from membrane phospholipids through a multi-step cascade reaction mediated by enzymes including lysophospholipase D (lysoPLD), autocrine motor factor (ATX), phospholipase A1 (PLA1), phospholipase A2 (PLA2), and acylglycerol kinase (AGK) (Mutoh et al., British J. Pharmacol., 2012). 165 (829-844). After formation, LPA can regulate multiple cellular signaling pathways by binding to a class of seven transmembrane domain G protein-coupled receptors (GPCRs). These receptors are collectively referred to as LPA receptors (LPARs), of which the following six have been characterized: LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 (Choi, JW, Annu. Rev. Pharmacol. Toxicol., 2010, 829-844). 50 , 157-186). The biological responses induced by the binding of LPA and LPAR are both broad and context-dependent (Yung et al., J. Lipid Res. 2014, ). 55 , 1192-1214; Yung et al., Neuron 2015, 85(669-682). These may include inducing cell proliferation, stimulating cell migration and contraction, promoting neurite retraction, inhibiting apoptosis, initiating chemotaxis, closing gap junctions, and other responses (Chun et al., eds., Lysophospholipid Receptors: Signaling and Biochemistry, 2013, Wiley, ISBN: 978-0-470-56905-4). Furthermore, aberrant upregulation of the LPA pathway has been identified as associated with a variety of diseases, including cancer, inflammatory diseases, infertility, neuropathic pain, psychotic disorders and neurodegenerative diseases, atherosclerosis, and fibrosis of the skin, kidneys, lungs, and liver (Choi, JW, Annu. Rev. Pharmacol. Toxicol., 2010). 50 ,157-186; Noguchi et al., Curr. Opin Pharmacol., 2009, 9 , 15-23; Yanagida et al., J. Biochem., 2011, 150 (223-232). Therefore, targeting LPA receptors has been, and continues to be, a highly focused area for identifying potential treatments for these conditions. This article discloses, in particular, solutions to these and other problems in the field. Summary of the Invention

[0004] In one respect, a compound, or a pharmaceutically acceptable salt or solvate thereof, is provided having the formula:

[0005] (I).

[0006] R 1 It is isopropyl or isobutyl.

[0007] R 2 is -C(O)OH, -CH2C(O)OH, -CH2CH2C(O)OH, -C(O)NHS(O)2R 2A -P(O)(OH)2, -P(O)(OH)R 2A , -SO3H, -SO2H, -NHC(O)NHS(O)2R 2A , , , , , , , ,or .

[0008] R2A It is an unsubstituted C1-C4 alkyl group.

[0009] R 3 R 4 R 5 and R 6 It is independently hydrogen or an unsubstituted C1-C4 alkyl group.

[0010] In one respect, a compound, or a pharmaceutically acceptable salt or solvate thereof, is provided having the formula:

[0011] (II). R 1 R 2 R 3 R 4 R 5 and R 6 As described herein, it is included in the embodiments.

[0012] In one aspect, a pharmaceutical composition is provided comprising the compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0013] In one aspect, a method is provided for treating peripherally restricted LPAR1-related disease in a subject with such need, the method comprising administering to the subject a therapeutically effective amount of the compound described herein, or a pharmaceutically acceptable salt of a solvation thereof.

[0014] In one respect, a method for modulating LPAR1 activity in a subject is provided, which involves administering to the subject the compound described herein, or a pharmaceutically acceptable salt or solvate thereof. Detailed Implementation

[0015] I. Definition

[0016] The abbreviations used in this article have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described in this article are constructed according to the standard rules of chemical valence known in the field of chemistry.

[0017] When substituent groups are specified by their conventional chemical formula (written from left to right), they equally cover chemically identical substituents that would result from writing the structure from right to left; for example, -CH2O- is equivalent to -OCH2-.

[0018] Unless otherwise stated, the term "alkyl" itself, or as part of another substituent, means a straight (i.e., unbranched) or branched carbon chain (or carbon) or combination thereof, which may be fully saturated, monounsaturated, or polyunsaturated and may include monovalent, divalent, and polyvalent groups. Alkyl groups may include a specified number of carbons (e.g., C1-C1).10 (Refers to one to ten carbons). In the examples, the alkyl group is fully saturated. In the examples, the alkyl group is monounsaturated. In the examples, the alkyl group is polyunsaturated. The alkyl group is an uncyclic chain. Examples of saturated hydrocarbon groups include, but are not limited to, groups such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, methyl, for example, homologues and isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. Unsaturated alkyl groups are alkyl groups having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotonyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl, and higher homologues and isomers. An alkoxy group is an alkyl group attached to the rest of the molecule via an oxygen linker (-O-). The alkyl portion may be an alkenyl portion. The alkyl moiety can be an alkynyl moiety. An alkenyl group includes one or more double bonds. An alkynyl group includes one or more triple bonds.

[0019] Unless otherwise stated, the term "alkylene" itself, or as part of another substituent, refers to a divalent radical derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-. Typically, the alkyl (or alkylene) group will have 1 to 24 carbon atoms, with those having 10 or fewer carbon atoms being preferred herein. "Lower alkyl" or "lower alkylene" is a shorter-chain alkyl or alkylene group typically having eight or fewer carbon atoms. Unless otherwise stated, the term "alkenyl" itself, or as part of another substituent, refers to a divalent group derived from an alkene. Unless otherwise stated, the term "alkynyl," itself, or as part of another substituent, refers to a divalent radical derived from an alkyne. In the examples, the alkylene is fully saturated. In the examples, the alkylene is monounsaturated. In the examples, the alkylene is polyunsaturated. Alkenyl comprises one or more double bonds. Alynyl comprises one or more triple bonds.

[0020] Unless otherwise stated, the term "heteroalkyl" on its own or in combination with another term means a stable straight or branched chain or combination thereof, comprising at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), wherein nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom (e.g., N, S, Si, or P) may be located at any internal position of the heteroalkyl group or at a position where the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclic chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S-CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. At most two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include up to eight optionally different heteroatoms (e.g., O, N, S, Si, or P). Unless otherwise stated, the term "heteroalkenyl" itself or in combination with another term means a heteroalkyl group comprising at least one double bond. In addition to one or more double bonds, a heteroalkenyl group may optionally include more than one double bond and / or one or more triple bonds. Unless otherwise stated, the term "heteroyynyl" itself or in combination with another term means a heteroalkyl group comprising at least one triple bond. In addition to one or more triple bonds, a heteroyynyl group may optionally include more than one triple bond and / or one or more double bonds. In embodiments, the heteroalkyl group is fully saturated. In embodiments, the heteroalkyl group is monounsaturated. In embodiments, the heteroalkyl group is polyunsaturated.

[0021] Similarly, unless otherwise stated, the term "heteroalkylene" itself, or as part of another substituent, refers to a divalent group derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatom may also occupy any one or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, the direction in which the formula of the linking group is written does not imply the orientation of the linking group. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As mentioned above, the heteroalkyl groups used herein include those groups attached to the rest of the molecule by a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SO2R'. Where the term "heteroalkyl" is used, followed by a specific heteroalkyl group (such as -NR'R'', etc.), it should be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is described for clarity. Therefore, the term "heteroalkyl" should not be construed herein as excluding a specific heteroalkyl group (such as -NR'R'', etc.). Unless otherwise stated, the term "heteroalkenyl," either itself or as part of another substituent, refers to a divalent radical derived from a heteroalkene. Unless otherwise stated, the term "heteroynyl," either itself or as part of another substituent, refers to a divalent radical derived from a heteroyne. In the examples, the heteroalkyl group is fully saturated. In the examples, the heteroalkyl group is monounsaturated. In the examples, the heteroalkyl group is polyunsaturated. The heteroalkenyl group comprises one or more double bonds. The heteroynyl group comprises one or more triple bonds.

[0022] Unless otherwise stated, the terms "cycloalkyl" and "heterocycloalkyl" on their own or in combination with other terms refer to the cyclic form of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, the heteroatom may occupy the position where the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, etc. "Cycloalkylene" and "heterocycloalkylene" refer, alone or as part of another substituent, to divalent groups derived from cycloalkyl and heterocycloalkyl groups, respectively. In the examples, the cycloalkyl group is fully saturated. In the examples, the cycloalkyl group is monounsaturated. In the examples, the cycloalkyl group is polyunsaturated. In the examples, the heterocycloalkyl group is fully saturated. In the examples, the heterocycloalkyl group is monounsaturated. In the examples, the heterocycloalkyl group is polyunsaturated.

[0023] In the embodiments, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In the embodiments, a monocyclic ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, wherein such a group may be saturated or unsaturated, but is not aromatic. In the embodiments, the cycloalkyl group is fully saturated. A bicyclic or polycyclic cycloalkyl ring system refers to a plurality of rings fused together, wherein at least one of the fused rings is a cycloalkyl ring and wherein the plurality of rings are attached to the parent molecule moiety through any carbon atom contained within the cycloalkyl ring of the plurality of rings.

[0024] In the embodiments, the cycloalkyl group is a cycloalkenyl group. The term "cycloalkenyl" is used according to its common meaning. In the embodiments, the cycloalkenyl group is a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. A bicyclic or polycyclic cycloalkenyl ring system refers to a plurality of rings fused together, wherein at least one of the fused rings is a cycloalkenyl ring and wherein the plurality of rings are attached to the parent molecule moiety through any carbon atom contained within the cycloalkenyl ring of the plurality of rings.

[0025] In the embodiments, the term "heterocyclic alkyl" refers to a monocyclic, bicyclic, or polycyclic heterocyclic alkyl ring system. In the embodiments, the heterocyclic alkyl groups are fully saturated. A bicyclic or polycyclic heterocyclic alkyl ring system refers to a plurality of rings fused together, wherein at least one of the fused rings is a heterocyclic alkyl ring and wherein the plurality of rings are attached to the parent molecule moiety by any atoms contained within the heterocyclic alkyl rings of the plurality of rings.

[0026] Unless otherwise stated, the terms "halogenated" or "halogen" mean, either alone or as part of another substituent, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "halogenated alkyl" are intended to include both monohalogenated and polyhalogenated alkyl groups. For example, the term "halogenated (C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0027] Unless otherwise stated, the term "acyl" means -C(O)R, where R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0028] Unless otherwise stated, the term "aryl" means a polyunsaturated aromatic hydrocarbon substituent, which may be a single ring or fused together (i.e., a fused-ring aryl) or a plurality of covalently bonded rings (preferably one to three rings). A fused-ring aryl refers to a plurality of fused rings, wherein at least one of the fused rings is an aryl ring and wherein the plurality of rings are attached to the parent molecule moiety by any carbon atom contained within the aryl ring of the plurality of rings. The term "heteroaryl" refers to an aryl (or ring) containing at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., a plurality of fused rings, wherein at least one of the fused rings is a heteroaromatic ring and wherein the plurality of rings are attached to the parent molecule moiety by any atom contained within the heteroaromatic ring of the plurality of rings). 5,6-Fused-ring heteroaryl refers to two fused rings, one with 5 members and the other with 6 members, and at least one of the rings is a heteroaryl ring. Similarly, 6,6-Fused-ring heteroaryl refers to two fused rings, one with 6 members and the other with 6 members, and at least one of the rings is a heteroaryl ring. And 6,5-Fused-ring heteroaryl refers to two fused rings, one with 6 members and the other with 5 members, and at least one of the rings is a heteroaryl ring. Heteroaryl groups can be attached to the rest of the molecule via carbon or heteroatoms. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thiopheneyl, pyridinyl, pyrimidinyl, benzothiazolyl, benzoxazolylbenzimidazolyl, benzofuran, isobenzofuranyl, indoleyl, isoindoleyl, benzothiapheneyl, isoquinolinyl, quinoxalinyl, quinolinyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl. Pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinel, 2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl, and 6-quinolinyl. The substituents in the above aryl and heteroaryl ring systems are selected from the following acceptable substituent groups. "Arylidene" and "heteroarylidene" refer, alone or as part of another substituent, to divalent groups derived from aryl and heteroaryl groups, respectively. Heteroaryl substituents can be -O- bonded to a nitrogen atom in a cyclic heteroatom.

[0029] A spirocyclic ring is two or more rings, wherein adjacent rings are attached by a single atom. Individual rings within a spirocyclic ring can be identical or different. Individual rings within a spirocyclic ring can be substituted or unsubstituted and can have substituents different from other individual rings within a group of spirocyclic rings. Possible substituents for individual rings within a spirocyclic ring are possible substituents used for the same ring when not part of the spirocyclic ring (e.g., substituents for cycloalkyl or heterocyclic alkyl rings). A spirocyclic ring can be a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heteroalkyl, or a substituted or unsubstituted heteroalkylene, and the individual rings within the spirocyclic group can be any of the immediately preceding list, including all rings of the same type (e.g., all rings are substituted heteroalkylene, wherein each ring can be the same or different substituted heteroalkylene). When referring to a spirocyclic system, heterocyclic spirocyclic means a spirocyclic ring in which at least one ring is heterocyclic and each ring can be a different ring. When referring to a spiroring system, a substituted spiroring means that at least one ring is substituted and each substituent may optionally be different.

[0030] A bridged ring is two or more rings sharing three or more atoms, with the two bridgehead atoms separated by a bridge containing at least one atom. Individual rings within a bridged ring can be substituted or unsubstituted and can have substituents different from those of other individual rings within a set of bridged rings. Possible substituents for individual rings within a bridged ring are possible substituents for that ring when the same ring is not part of the bridged ring (e.g., substituents for cycloalkyl or heteroalkyl rings). A bridged ring can be a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heteroalkyl, or a substituted or unsubstituted heteroalkylene, and the individual rings within the bridged ring group can be any of the immediately preceding list, including all rings of the same type (e.g., all rings are substituted heteroalkylene, where each ring can be the same or different substituted heteroalkylene). When referring to a bridged ring system, a heterocyclic bridged ring means a bridged ring in which at least one ring is heterocyclic and each ring can be a different ring. When referring to a bridged ring system, a substituted bridged ring means that at least one ring is substituted and each substituent can optionally be different.

[0031] symbol" "" indicates the attachment point between the chemical part and the rest of the molecule or chemical formula.

[0032] As used in this article, the term "oxo" refers to oxygen that is double-bonded to a carbon atom.

[0033] The term "alkylarylene" refers to an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In the examples, the alkylarylene group has the following formula:

[0034] or .

[0035] The alkylarylene moiety may be substituted (e.g., with substituents) at the alkylene moiety or the arylene junction (e.g., at carbons 2, 3, 4, or 6), said substituents being halogens, oxo-substituted, -N3, -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3, -SO3H, -OSO3H, -SO2NH2, –NHNH2, –ONH2, –NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl groups, or substituted or unsubstituted 2- to 5-membered heteroalkyl groups. In the examples, the alkylarylene group is unsubstituted.

[0036] Each of the above terms (e.g., "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "aryl", and "heteroaryl") includes both the substituted and unsubstituted forms of the indicated group. Preferred substituents for each type of group are provided below.

[0037] The substituents of alkyl and heteroalkyl radicals (including those commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR''C(O)NR''R''', -NR''C(O)2R', -NRC(N One or more of the following groups are selected: R'R'R''')=NR'''', -NRC(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)OR'' and -NR'OR'', with the number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in the group. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl (e.g., an aryl substituted with 1 to 3 halogens), a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl, an alkoxy or thioalkoxy, or an aralkyl. When the compounds described herein include more than one R group, for example, each R group is chosen independently, and when more than one of these groups is present, so too are each R', R'', R''', and R'''' groups. When R' and R'' are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 4, 5, 6, or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. As will be understood from the above discussion of substituents, those skilled in the art will appreciate that the term "alkyl" is intended to include groups containing a carbon atom bonded to a group other than hydrogen, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0038] Similar to the substituents described for alkyl radicals, substituents for aryl and heteroaryl groups are diverse and selected from, for example: -OR', -NR'R'', -SR', halogens, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR''C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R'' The number of substituents R', R'', R''', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy and fluoro(C1-C4)alkyl, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)OR'', -NR'OR'', ranging from zero to the total number of open valences on the aromatic ring system; and wherein the substituents R', R'', R''' and R'''' are preferably independently selected independently from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When the compounds described herein include more than one R group, for example, each R group is chosen independently, and when there are more than one of these groups, the same applies to each R', R'', R''' and R'''' group.

[0039] Substituents on the ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) can be described as substituents on the ring rather than on a specific atom of the ring (often referred to as floating substituents). In this case, the substituent can attach to any atom of the ring (following the valence rules), and in the case of fused or spirocyclic rings, the substituent described as being associated with a member of the fused or spirocyclic ring (floating substituents on a single ring) can be a substituent on any ring of the fused or spirocyclic ring (floating substituents on multiple rings). When a substituent attaches to the ring but not to a specific atom (floating substituent) and the substituent's subscript is an integer greater than one, multiple substituents can be on the same atom, the same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent can optionally be different. Where the attachment point of the ring to the rest of the molecule is not limited to a single atom (floating substituent), the attachment point can be any atom of the ring, and in the case of fused or spirocyclic rings, it can be any atom of any ring of the fused or spirocyclic ring, while following the valence rules. In the case where a ring, fused ring, or spirocyclic ring contains one or more cyclic heteroatoms and the ring, fused ring, or spirocyclic ring is shown to have one or more floating substituents (including, but not limited to, attachment sites to the rest of the molecule), the floating substituents may be bonded to the heteroatoms. When, in a structure or formula with floating substituents, the cyclic heteroatom is shown to be bonded to one or more hydrogen atoms (e.g., a cyclic nitrogen with two bonds to the ring atom and a third bond to the hydrogen), the substituents should be understood to substitute for the hydrogen atoms when the heteroatoms are bonded to the floating substituents, while following the rules of chemical valence.

[0040] Two or more substituents may optionally be linked to form aryl, heteroaryl, cycloalkyl, or heterocyclic alkyl groups. Such so-called cyclic substituents are typically (but not necessarily) attached to a cyclic base structure. In one embodiment, the cyclic substituent is attached to an adjacent member of the base structure. For example, two cyclic substituents attached to an adjacent member of the cyclic base structure produce a fused ring structure. In another embodiment, the cyclic substituent is attached to a single member of the base structure. For example, two cyclic substituents attached to a single member of the cyclic base structure produce a spirocyclic structure. In yet another embodiment, the cyclic substituent is attached to a non-adjacent member of the base structure.

[0041] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form the formula -TC(O)-(CRR'). q A -U- ring, wherein T and U are independently -NR-, -O-, -CRR'-, or single bonds, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -A-(CH2). rThe substituents -B- are substituted, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or single bonds, and r is an integer from 1 to 4. One of the single bonds in the newly formed ring may optionally be substituted with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with the formula -(CRR'). s -X'-(C''R''R''') d The substituents are substituted, wherein s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0042] As used herein, the term "heteroatom" or "cyclic heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In the embodiments, the term "heteroatom" or "cyclic heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0043] As used in this article, "substituent group" refers to a group selected from the following:

[0044] (A) Oxygenated, Halogenated, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, –NHNH2, –ONH2, –NHC (O)NHNH2, –NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C... 10 Aryl, C 10 Aryl or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0045] (B) Alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C6-C... 10 Aryl, C 10 The aryl or phenyl group (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl) is substituted by at least one substituent selected from the following:

[0046] (i) Oxygenated, halogenated, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, –NHNH2, –ONH2, –NHC (O)NHNH2, –NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C... 10 Aryl, C 10 Aryl or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0047] (ii) Alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C6-C... 10 Aryl, C 10 Aryl or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), which is substituted with at least one selected substituent selected from the following:

[0048] (a) Oxygenated, Halogenated, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, –NHNH2, –ONH2, –NHC (O)NHNH2, –NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C... 10 Aryl, C 10 Aryl or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0049] (b) Alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C6-C... 10 Aryl, C 10The aryl or phenyl group (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl) is substituted with at least one selected substituent selected from the group consisting of: oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –O SO3H, -SO2NH2, –NHNH2, –ONH2, –NHC(O)NHNH2, –NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C... 10 Aryl, C 10 (aryl or phenyl) or unsubstituted heteroaryl (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl or 5 to 6-membered heteroaryl).

[0050] As used herein, “size-restricted substituent” or “size-restricted substituent group” refers to a group selected from all substituents described above for “substituent group”, wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C2 alkyl group. 20 Alkyl groups, each substituted or unsubstituted heteroalkyl group being a substituted or unsubstituted 2- to 20-membered heteroalkyl group; each substituted or unsubstituted cycloalkyl group being a substituted or unsubstituted C3-C8 cycloalkyl group; each substituted or unsubstituted heterocycloalkyl group being a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group; and each substituted or unsubstituted aryl group being a substituted or unsubstituted C6-C8 cycloalkyl group. 10 Aryl group, and each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 10-membered heteroaryl group.

[0051] As used herein, “lower substituent” or “lower substituent group” means a group selected from all the substituents described above for “substituent group”, wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C8 alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 8-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3- to 7-membered cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl group, each substituted or unsubstituted aryl group is a substituted or unsubstituted phenyl group, and each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 6-membered heteroaryl group.

[0052] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein is substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-restricted substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

[0053] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl group may be a substituted or unsubstituted C1-C2. 20 Alkyl groups, each substituted or unsubstituted heteroalkyl group being a substituted or unsubstituted 2- to 20-membered heteroalkyl group; each substituted or unsubstituted cycloalkyl group being a substituted or unsubstituted C3-C8 cycloalkyl group; each substituted or unsubstituted heterocycloalkyl group being a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group; and each substituted or unsubstituted aryl group being a substituted or unsubstituted C6-C8 cycloalkyl group. 10 The aryl group, and / or each substituted or unsubstituted heteroaryl group, is a substituted or unsubstituted 5- to 10-membered heteroaryl group. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene group is a substituted or unsubstituted C1-C... 20 Alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene, and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C 10The aryl group, and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5 to 10-membered heteroaryl group.

[0054] In some embodiments, each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C8 alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 8-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3-C7 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl group, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 cycloalkyl group. 10 The aryl group, and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 9-membered heteroaryl group. In some embodiments, each substituted or unsubstituted alkylene group is a substituted or unsubstituted C1-C8 alkylene group, each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 2- to 8-membered heteroaryl group, each substituted or unsubstituted cycloalkylene group is a substituted or unsubstituted C3-C7 cycloalkylene group, each substituted or unsubstituted heterocycloalkylene group is a substituted or unsubstituted 3- to 7-membered heterocycloalkylene group, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 alkylene group. 10 The arylene group, and / or each substituted or unsubstituted heteroarylene group is a substituted or unsubstituted 5 to 9-membered heteroarylene group. In some embodiments, the compound is a chemical substance illustrated in the Examples section, figure, or table below.

[0055] In the embodiments, the substituted or unsubstituted portions (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene and / or substituted or unsubstituted heteroaryl) are unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene and / or unsubstituted heteroaryl). In the embodiments, the substituted or unsubstituted portions (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene and / or substituted or unsubstituted heteroaryl) are substituted (e.g., respectively substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene and / or substituted heteroaryl).

[0056] In the embodiments, the substituted portion (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted portion is substituted with multiple substituent groups, each substituent group may optionally be different. In the embodiments, if the substituted portion is substituted with multiple substituent groups, each substituent group is different.

[0057] In embodiments, the substituted portion (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-restricted substituent, wherein if the substituted portion is substituted with multiple size-restricted substituents, the size-restricted substituents may optionally be different. In embodiments, if the substituted portion is substituted with multiple size-restricted substituent groups, each size-restricted substituent group is different.

[0058] In embodiments, the substituted portion (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted portion is substituted with multiple lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted portion is substituted with multiple lower substituent groups, each lower substituent group is different.

[0059] In embodiments, the substituted portion (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent group, a size-restricted substituent group, or a lower substituent group; wherein if the substituted portion is substituted with a plurality of groups selected from substituent groups, size-restricted substituent groups, and lower substituent groups; each substituent group, size-restricted substituent group, and / or lower substituent group may optionally be different. In embodiments, if the substituted portion is substituted with a plurality of groups selected from substituent groups, size-restricted substituent groups, and lower substituent groups; each substituent group, size-restricted substituent group, and / or lower substituent group is different.

[0060] Certain compounds disclosed herein have asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, those that can be defined in absolute stereochemistry as (R)- or (S)- or (D)- or (L)- stereoisomers for amino acids, and independent isomers are all covered within the scope of this disclosure. The compounds disclosed herein do not include those known in the art to be too unstable to synthesize and / or isolate. This disclosure is intended to include compounds in both racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain an alkene bond or other geometrically asymmetric center, and unless otherwise stated, the compounds are intended to include both E and Z geometric isomers.

[0061] As used herein, the term "isomer" refers to a compound that has the same number and type of atoms and therefore the same molecular weight, but differs in the arrangement or configuration of the atoms.

[0062] As used in this article, "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomer form to another.

[0063] It will be apparent to those skilled in the art that certain compounds of this disclosure may exist in tautomer forms, all of which are within the scope of this disclosure.

[0064] Unless otherwise stated, the structures described herein are also intended to include all stereochemical forms of the structure; that is, the R and S configurations of each asymmetric center. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers and diastereomers, are within the scope of this disclosure.

[0065] Unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, those having structures other than those where hydrogen is replaced by deuterium or tritium, or those with... 13 C- or 14 Compounds of the present invention with C-enriched carbon replacing carbon other than carbon are within the scope of this disclosure.

[0066] The compounds disclosed herein may also contain atomic isotopes in non-natural proportions at one or more of the atoms constituting such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as, for example, tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14C). All isotopic variants of the compounds disclosed herein, whether radioactive or not, are covered within the scope of this disclosure.

[0067] It should be noted that throughout this application, alternatives are written in the form of Markush groups, for example, each containing more than one possible amino acid position. In particular, it is taken into account that each member of a Markush group should be considered individually to constitute another embodiment, and that a Markush group is not to be understood as a single unit.

[0068] The terms "analog," "analogue," or "derivative" are used in their usual sense within the fields of chemistry and biology and refer to compounds that are structurally similar to another compound (i.e., the so-called "reference" compound) but have a different composition. For example, one atom may be replaced by an atom of a different element, or a specific functional group may be present, or one functional group may be replaced by another, or the reference compound may have one or more chiral centers with absolute stereochemistry. Therefore, an analog is a compound that is functionally or physically similar to or equivalent to a reference compound but not structurally or geographically similar to or equivalent to it.

[0069] As used herein, the terms “a” or “an” mean one or more. Furthermore, as used herein, the phrase “substituted with a[n]” means that the specified group can be substituted with one or more of any or all of the named substituents. For example, when a group, such as an alkyl or heteroaryl group, is “unsubstituted with an unsubstituted C1-C…” 20 When "alkyl or unsubstituted 2- to 20-membered heteroalkyl" is used, the group may contain one or more unsubstituted C1-C groups. 20 Alkyl and / or one or more unsubstituted 2- to 20-membered heteroalkyl groups.

[0070] Furthermore, when a portion is substituted by an R substituent, the group can be referred to as "R-substituted". In the case of partial R substitution, the portion is substituted by at least one R substituent, and each R substituent is optionally different. When a particular R group is present in the description of a chemical genus (such as formula (I)), Roman numeral symbols can be used to distinguish each occurrence of that particular R group. For example, when multiple R groups are present... 13 When substituents are used, each R 13 Substituents can be classified as R 13.A R 13.B R 13.C R 13.D etc., where R 13.A R 13.B R 13.C R 13.D Each of them is in R 13Defined within the scope of the definition and optionally different. When the R moiety, group or substituent as disclosed herein is linked by a single bond and the R moiety, group or substituent is oxo, those skilled in the art will immediately recognize that, according to the normal rules of chemical valence, oxo is linked by a double bond.

[0071] The description of the compounds disclosed herein is limited by the principles of chemical bonding known to those skilled in the art. Therefore, when a group can be substituted by one or more of a plurality of substituents, these substitutions are chosen to conform to the principles of chemical bonding, resulting in compounds that are inherently unstable and / or known to those skilled in the art to be unstable under environmental conditions such as aqueous, neutral, and several known physiological conditions. For example, according to the principles of chemical bonding known to those skilled in the art, heterocyclic alkyl or heteroaryl groups avoid inherently unstable compounds by attaching cyclic heteroatoms to the remainder of the molecule.

[0072] The term "pharmaceutically acceptable salt" refers to a salt comprising an active compound prepared with a relatively non-toxic acid or base, depending on the specific substituents present on the compound described herein. When the compounds of this disclosure contain relatively acidic functional groups, a base addition salt can be obtained by contacting such a compound in its neutral form with a sufficient amount of the desired base (pure or in a suitable inert solvent). Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this disclosure contain relatively basic functional groups, an acid addition salt can be obtained by contacting such a compound in its neutral form with a sufficient amount of the desired acid (pure or in a suitable inert solvent). Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, oxalic acid, and methanesulfonic acid. Also included are salts of amino acids, such as arginine salts, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of this disclosure contain both basic and acidic functional groups, allowing the compounds to be converted into base or acid addition salts.

[0073] Therefore, the compounds of this disclosure can exist as salts, such as salts formed with pharmaceutically acceptable acids. This disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrates, (-)-tartrates or mixtures thereof, including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, as well as quaternary ammonium salts (e.g., iodomethane, iodoethane, etc.). These salts can be prepared by methods known to those skilled in the art.

[0074] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0075] In addition to salt forms, this disclosure provides compounds in prodrug form. The prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of this disclosure. The prodrugs of the compounds described herein can be converted in vivo after administration. Additionally, the prodrugs can be converted into the compounds of this disclosure in an in vitro environment by chemical or biochemical methods, such as, for example, when contacted with suitable enzymes or chemical reagents.

[0076] Some compounds of this disclosure may exist in both unsolvable and solvable forms (including hydrated forms). Generally, solvable forms are equivalent to unsolvable forms and are covered within the scope of this disclosure. Some compounds of this disclosure may exist in a variety of crystalline or amorphous forms. Generally, all physical forms are equivalent to the intended use of this disclosure and are intended to be within the scope of this disclosure.

[0077] A polypeptide or cell is “recombinant” when it is artificial or engineered, or derived from or contains artificial or engineered proteins or nucleic acids (e.g., non-natural or non-wild-type). For example, a polynucleotide inserted into a vector or any other heterologous location (e.g., in the genome of a recombinant organism) such that it is not associated with a nucleotide sequence typically side-joined to that polynucleotide as found in nature is a recombinant polynucleotide. Proteins expressed in vitro or in vivo by recombinant polynucleotides are examples of recombinant polypeptides. Similarly, polynucleotide sequences not found in nature, such as variants of naturally occurring genes, are recombinant.

[0078] As used herein, “cell” means a cell that performs metabolic or other functions sufficient to preserve or replicate its genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining by a specific dye, the ability to produce offspring, or, in the case of gametes, the ability to combine with a second gamete to produce viable offspring. Cells can include prokaryotic and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells derived from plants and animals, such as mammalian cells, insect cells (e.g., fall armyworm cells), and human cells. Cells may be useful when they are naturally non-adhesive or are treated to be non-adhesive to surfaces, for example, by trypsin digestion.

[0079] The term "treating" or "treatment" refers to any sign of success in treating or improving an injury, disease, pathology, or symptom, including any objective or subjective parameters such as relief; regression; reduction of symptoms or making the injury, pathology, or symptom more tolerable for the patient; slowing the rate of deterioration or decline; making the final degree of deterioration less disabling; or improving the patient's physical or mental health. Treatment or improvement of symptoms can be based on objective or subjective parameters, including the results of physical examination, neuropsychiatric examination, and / or psychiatric evaluation. For example, some methods proposed herein have successfully treated cancer by reducing the incidence of cancer and / or inducing cancer regression. In some embodiments of the compositions or methods described herein, treating cancer includes slowing the rate of growth or spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors. The term "treatment" and variations thereof include prevention of injury, pathology, symptom, or disease. In embodiments, treatment is prevention. In embodiments, treatment does not include prevention. In embodiments, treatment is not preventative treatment.

[0080] "Effective amount" is the amount of a compound sufficient to achieve its intended purpose (e.g., to achieve the effect of its administration, treat a disease, reduce enzyme activity, increase enzyme activity, reduce signal transduction pathways, or reduce one or more symptoms of a disease or condition) in the absence of the compound. An example of an "effective amount" is an amount sufficient to help treat, prevent, or alleviate one or more symptoms of a disease; when used in this context, it may also be referred to as a "therapeutic effective amount." "Amelioration" (and its grammatical equivalents) of one or more symptoms means a reduction in the severity or frequency of those symptoms, or the elimination of those symptoms. A "preventive effective amount" of a drug is the amount of drug that has the intended preventive effect when administered to a subject, such preventive effect being, for example, preventing or delaying the onset (or recurrence) of an injury, disease, pathology, or condition, or reducing the incidence of an injury, disease, pathology, condition, or its symptoms. The possibility of relapse (or recurrence). Complete preventative effect does not necessarily occur with the administration of a single dose, but may only occur after a series of doses. Therefore, an effective preventative dose may be administered in one or more administrations. As used herein, “activity-reducing dose” refers to the amount of antagonist required to reduce enzyme activity relative to the absence of an antagonist. As used herein, “functional-damaging dose” refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of an antagonist. As used herein, “activity-increasing dose” refers to the amount of agonist required to increase enzyme activity relative to the absence of an agonist. As used herein, “functional-increasing dose” refers to the amount of agonist required to increase the function of an enzyme or protein relative to the absence of an agonist. The exact amount will depend on the purpose of treatment and will be determined by someone skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Volume 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th ed., 2003, Gennaro, eds. Lippincott, Williams & Wilkins).

[0081] "Control" or "controlled experiment" is used in its usual sense and refers to a parallel experiment in which subjects or reagents are treated the same, but a certain procedure, reagent, or variable is omitted. In some cases, controls are used as comparative criteria for evaluating experimental effects. In some embodiments, a control is a measurement of protein activity (e.g., signal transduction pathway) in the absence of compounds as described herein (including examples, instances, figures, or tables).

[0082] "Contact" is used in its simple, ordinary sense and refers to a process that allows at least two different substances (e.g., compounds, including biomolecules or cells) to come into sufficient proximity to react, interact, or physically contact. It should be understood that, however, the resulting reaction product can be produced directly from the reaction between the added reagents or from an intermediate that can be produced in the reaction mixture by one or more of the added reagents.

[0083] The term "contact" can include allowing two species to react, interact, or physically contact, where the two species can be compounds and cellular components (e.g., proteins, ions, lipids, nucleic acids, nucleotides, amino acids, proteins, particles, organelles, cellular compartments, microorganisms, viruses, lipid droplets, vesicles, small molecules, protein complexes, protein aggregates, or macromolecules) as described herein. In some embodiments, contact includes allowing the compounds described herein to interact with cellular components (e.g., proteins, ions, lipids, nucleic acids, nucleotides, amino acids, proteins, particles, viruses, lipid droplets, organelles, cellular compartments, microorganisms, vesicles, small molecules, protein complexes, protein aggregates, or macromolecules) involved in signal transduction pathways.

[0084] As defined herein, the terms “activation,” “activate,” “activating,” and similar expressions relating to proteins refer to the transformation of a protein from an initially inactive or inactive state into a biologically active derivative. These terms refer to activation, or the activation, sensitization, or upregulation of signal transduction or enzyme activity or the amount of protein that is reduced in a disease.

[0085] The terms "agonist," "activator," and "upregulator" refer to substances that can detectably increase the expression or activity of a given gene or protein. Compared to a control without an agonist, an agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99%. In some cases, expression or activity is 1.5, 2, 3, 4, 5, 10, or higher than that without an agonist.

[0086] As defined herein, the terms “inhibition,” “inhibit,” “inhibiting,” and similar expressions relating to cell component-inhibitor interactions mean an adverse effect (e.g., reduction) on the activity or function of a cell component relative to the absence of an inhibitor (e.g., a reduction in signaling pathways stimulated by the cell component (e.g., proteins, ions, lipids, viruses, lipid droplets, nucleic acids, nucleotides, amino acids, proteins, particles, organelles, cell compartments, microorganisms, vesicles, small molecules, protein complexes, protein aggregates, or macromolecules)). In embodiments, inhibition means an adverse effect (e.g., reduction) on the concentration or level of a cell component relative to the absence of an inhibitor. In some embodiments, inhibition refers to the reduction of a disease or disease symptom. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway (e.g., a reduction in pathways involving cell components). Thus, inhibition includes at least partially or completely blocking, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signaling pathways or enzyme activity or the amount of a cell component.

[0087] The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” are used interchangeably to refer to a substance that can detectably reduce the expression or activity of a given gene or protein. Antagonists can reduce expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% compared to a control without an antagonist. In some cases, expression or activity is 1.5, 2, 3, 4, 5, 10, or less of the expression or activity without an antagonist.

[0088] The term "lysophosphatidyl receptor 1 antagonist" or "LPAR1 antagonist" refers to any exogenously administered compound or agent capable of partially or completely inhibiting or reversing the effect of an agonist (e.g., lysophosphatidyl) on the LPAR1 receptor. This term includes compounds or agents characterized or described as antagonists, partial antagonists, and negative allosteric modulators.

[0089] The term "modifier" refers to a composition that, relative to the absence of a composition, increases or decreases the level or function of a target molecule or the physical state of a target molecule (e.g., the target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cell compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)).

[0090] The term "expression" encompasses any step involved in the production of a polypeptide, including but not limited to transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for protein detection, such as ELISA, Western blotting, flow cytometry, immunofluorescence, and immunohistochemistry.

[0091] The term "regulation" is used in its usual sense and refers to the act of changing or altering one or more properties. "Regulation" refers to the process of changing or adjusting one or more properties. For example, when applied to the effect of a regulator on a target protein, regulation means altering the property or function of the target molecule or the amount of the target molecule by increasing or decreasing it.

[0092] "Patient," "patient in need," "subject," or "subject in need" means a living organism that suffers from or is susceptible to a disease or condition that can be treated by administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, bovine animals, rats, mice, dogs, monkeys, goats, sheep, dairy cows, deer, and other non-mammals. In this embodiment, the patient is a human. In this embodiment, the patient in need is a human. In this embodiment, the subject is a human. In this embodiment, the subject in need is a human.

[0093] "Disease" or "symptom" refers to the state or health condition of a patient or subject that can be treated with the compounds or methods provided herein. In some embodiments, a disease is a condition related to (e.g., caused by) cellular components (e.g., proteins, ions, lipids, nucleic acids, nucleotides, amino acids, proteins, particles, organelles, cell compartments, microorganisms, vesicles, small molecules, protein complexes, protein aggregates, or macromolecules). In an embodiment, the disease is a fibrotic disease. In an embodiment, the disease is idiopathic pulmonary fibrosis. In an embodiment, the disease is renal fibrosis. In an embodiment, the disease is non-alcoholic steatohepatitis. In an embodiment, the disease is scleroderma. In an embodiment, the disease is cancer. In an embodiment, the disease is ovarian cancer. In an embodiment, the disease is breast cancer. In an embodiment, the disease is liver cancer. In an embodiment, the disease is stomach cancer. In an embodiment, the disease is pancreatic cancer. In an embodiment, the disease is lung cancer. In an embodiment, the disease is osteosarcoma.

[0094] As used herein, the terms “fibrotic disease” and “fibrosis” refer to any disease or condition characterized by the formation of an excess of fibrous connective tissue. The formation of an excess of fibrous connective tissue may be a response to a repair or reactive process. Fibrotic diseases include, but are not limited to, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF)), liver fibrosis (e.g., nonalcoholic steatohepatitis (NASH)), myelofibrosis, skin fibrosis (e.g., scleroderma), ocular fibrosis, mediastinal fibrosis, cardiac fibrosis, renal fibrosis, stromal fibrosis, epidural fibrosis, epithelial fibrosis, or idiopathic fibrosis.

[0095] As used herein, the term "cancer" refers to all types of cancer, growths, or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that can be treated with the compounds or methods provided herein include thyroid cancer, endocrine system cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer, colorectal cancer, or pancreatic cancer. Other examples include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, rhabdomyosarcoma, essential thrombocytosis, essential macroglobulinemia, malignant pancreatic islet tumors, malignant carcinoid tumors, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, tumors of the endocrine or exocrine pancreas, medullary thyroid carcinoma, melanoma, papillary thyroid carcinoma, hepatocellular carcinoma, or prostate cancer.

[0096] The term “leukemia” broadly refers to a progressive malignant disease of the blood-forming organs and is generally characterized by the abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia is usually classified clinically based on the following: (1) the duration and characteristics of acute or chronic disease; (2) the cell type involved; myeloid (myeloid-derived), lymphoid (lymphoid-derived), or monocytic cell lineage; and (3) the increase or absence of an abnormal number of cells in the blood—leukemic or non-leukemic (subleukemic). Exemplary leukemias that can be treated with the compounds or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocythemic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myeloid leukemia, cutaneous leukemia, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, and hemocytoblastic leukemia. Leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloid leukemia, myeloid leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia. Leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0097] As used in this article, the term "lymphoma" refers to a group of cancers that affect hematopoietic and lymphatic tissues. It begins with lymphocytes, blood cells primarily found in lymph nodes, spleen, thymus, and bone marrow. The two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin's disease. Hodgkin's disease accounts for approximately 15% of all diagnosed lymphomas. It is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphoma (NHL) can be classified based on the rate of cancer growth and the cell types involved. There are aggressive (high-grade) and indolent (low-grade) types of NHL. Based on the cell types involved, there are B-cell and T-cell NHL. Exemplary B-cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodular (monocyte-like B-cell) lymphoma, splenic lymphoma, diffuse large cell B-cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-cell lymphoma. Exemplary T-cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-cell lymphoma.

[0098] The term "sarcoma" generally refers to a tumor composed of a substance similar to embryonic connective tissue and typically consists of tightly packed cells embedded in fibrous or homogeneous material. Sarcomas that can be treated with the compounds or methods provided in this article include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, and Kupffer cell sarcoma. Cell sarcoma, angiosarcoma, leukemic sarcoma, malignant stromal sarcoma, extraperiosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or capillary hemangiosarcoma.

[0099] The term "melanoma" refers to a tumor caused by the melanocyte system of the skin and other organs. Melanomas that can be treated with the compounds or methods provided herein include, for example, acral lentigines melanoma, amelanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, malignant lentigines melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial diffuse melanoma.

[0100] The term "cancer" refers to malignant new growth composed of epithelial cells that tend to infiltrate surrounding tissues and cause metastasis. Exemplary cancers that can be treated with the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinar carcinoma, adenocarcinoma, adenoid cystic carcinoma, adenocarcinoma-like carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell tumor, basal cell-like carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, brain carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine endometrial cancer, cribriform carcinoma, armored carcinoma, skin cancer (carcinoma cutaneum), columnar carcinoma, columnar cell carcinoma, tubular carcinoma, sclerosing carcinoma, embryonal carcinoma, brain-like carcinoma, epidermoid carcinoma, adenoid epithelial cell carcinoma, explant carcinoma, ulcerative carcinoma, fibrocarcinoma, colloid carcinoma, and gelatinous carcinoma. Carcinoma, giant cell carcinoma, adenocarcinoma, granular cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, adrenal carcinoma, naive embryonal carcinoma, carcinoma in situ, intraepithelial carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, molluscum carcinoma, mucinous carcinoma, mucinous cell carcinoma Mucocellular carcinoma, mucoepidermoid carcinoma, mucosular carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossificans carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthosis pilaris, pultaceous carcinomaRenal cell carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scleroderma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato-shaped carcinoma, spherical cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, cord carcinoma, telangiectatic carcinoma, telangiectodes carcinoma, transitional cell carcinoma, tuberosum carcinoma, tuberous carcinoma, verrucous carcinoma, or villous carcinoma.

[0101] As used herein, the term “peripherally restricted LPAR1-related disease” refers to any disease or condition caused by abnormal activity or signal transduction of LPAR1 outside the central nervous system. For example, the following diseases would be considered to be caused by abnormal activity or signal transduction within the central nervous system and are therefore not included in the term "peripherally restrictive LPAR1-related diseases": Alexander disease, Alpert disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia-telangiectasia, Barton's disease (also known as Spearmeyer-Walter-Sjögren-Barton's disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scharink syndrome, Huntington's disease, HIV-related dementia, Kennedy's disease, Crabb's disease, Kuru disease, Lewy body dementia, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neurospirochete disease, Parkinson's disease, Perize- Metzbach disease, Pick's disease, primary lateral sclerosis, prions, Refsum disease, Sandhof disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (various types with different characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, tabes dorsalis, brain cancer, medulloblastoma, neuroblastoma, glioma, glioblastoma multiforme, primary brain tumor, astrocytoma, atypical teratoma / rhabdoid tumor, craniopharyngioma, ependymoblastoma, ependymoma, retinoblastoma, medullary epithelioma, intermediately differentiated pineal parenchymal tumors, pinealoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumors and primary central nervous system lymphomas. In the examples, peripherally restricted LPAR1-related diseases are fibrotic diseases. In one embodiment, the peripherally restricted LPAR1-related disease is idiopathic pulmonary fibrosis. In another embodiment, the peripherally restricted LPAR1-related disease is renal fibrosis. In another embodiment, the peripherally restricted LPAR1-related disease is non-alcoholic steatohepatitis. In another embodiment, the peripherally restricted LPAR1-related disease is scleroderma. In another embodiment, the peripherally restricted LPAR1-related disease is cancer. In another embodiment, the peripherally restricted LPAR1-related disease is ovarian cancer. In another embodiment, the peripherally restricted LPAR1-related disease is breast cancer. In another embodiment, the peripherally restricted LPAR1-related disease is liver cancer. In another embodiment, the peripherally restricted LPAR1-related disease is gastric cancer. In another embodiment, the peripherally restricted LPAR1-related disease is pancreatic cancer. In another embodiment, the peripherally restricted LPAR1-related disease is lung cancer. In another embodiment, the peripherally restricted LPAR1-related disease is osteosarcoma.

[0102] The term "drug" is used in its usual sense and refers to a substance that has a physiological effect (e.g., a beneficial effect, used to treat the subject) when introduced into or onto a subject (e.g., in or on the subject or patient). A drug component is a group of the drug.

[0103] "Detectable reagent," "detectable compound," "detectable label," or "detectable moiety" is a substance (e.g., an element), molecule, or composition that can be detected by spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. For example, detectable reagents include... 18 F, 32 P, 33 P, 45 Ti、 47 Sc、 52 Fe、 59 Fe、 62 Cu、 64 Cu、 67 Cu、 67 Ga、 68 Ga、 77 As、 86 Y、 90 Y、 89 Sr、 89 Zr、 94 Tc, 94 Tc, 99m Tc, 99 Mo、 105 Pd, 105 Rh、 111 Ag、 111 In、 123 I, 124 I, 125 I, 131 I, 142 Pr, 143 Pr、 149 Pm, 153 Sm、 154-1581 Gd, 161 Tb, 166 Dy、 166 Ho、 169 Er、 175 Lu、 177 Lu、 186 Re、 188 Re、 189 Re、 194 Ir、 198 Au、 199 Au、 211 At、 211 Pb, 212 Bi、212 Pb, 213 Bi、 223 Ra、 225 Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, 32 P, fluorophores (e.g., fluorescent dyes), modified oligonucleotides (e.g., portions described in PCT / US2015 / 022063, which are incorporated herein by reference), electron-dense reagents, enzymes (e.g., enzymes commonly used in ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultra-small superparamagnetic iron oxide (“USPIO”) nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide (“SPIO”) nanoparticles, SPIO nanoparticle aggregates, single-crystal iron oxide nanoparticles, single-crystal iron oxide, nanoparticle contrast agents, liposomes or other delivery carriers containing gadolinium chelate (“Gd-chelate”) molecules, gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium-82), fluoride deoxygenated fluoride Glucose (e.g., fluorine-18 labeled), any gamma-ray emitting radionuclide, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g., including microbubble shells containing albumin, galactose, lipids and / or polymers; microbubble gas cores, including air, heavy gases, perfluorocarbons, nitrogen, octafluoropropane, perfluoroalkane lipid microspheres, perfluoropropane, etc.), iodinated contrast agents (e.g., iohexol, iodixanol, iodofol, iophanate-methyl, iodoxanol, iopromide, diatrizoic acid, methatrizoic acid, iodixanol), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or may be formulated into detectable haptens and proteins or other entities, for example, by incorporating radiolabels into peptides or antibodies that specifically react with target peptides.

[0104] According to embodiments of this disclosure, radioactive materials (e.g., radioactive isotopes) that can be used as imaging and / or labeling agents include, but are not limited to, those that can be used as imaging and / or labeling agents. 18 F, 32 P, 33 P, 45 Ti、 47 Sc、 52 Fe、 59 Fe、 62 Cu、 64 Cu、 67 Cu、 67 Ga、 68 Ga、 77 As、 86 Y、 90Y、 89 Sr、 89 Zr、 94 Tc, 94 Tc, 99m Tc, 99 Mo、 105 Pd, 105 Rh、 111 Ag、 111 In、 123 I, 124 I, 125 I, 131 I, 142 Pr、 143 Pr、 149 Pm, 153 Sm、 154-1581 Gd, 161 Tb, 166 Dy、 166 Ho、 169 Er、 175 Lu、 177 Lu、 186 Re、 188 Re、 189 Re、 194 Ir、 198 Au、 199 Au、 211 At、 211 Pb, 212 Bi、 212 Pb, 213 Bi、 223 Ra and 225 Ac. Paramagnetic ions that can be used as additional imaging agents according to embodiments of this disclosure include, but are not limited to, ions of transition and lanthanide metals (e.g., metals with atomic numbers 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.

[0105] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate the administration and absorption of an active agent by a subject, and that can be included in the compositions of the present invention without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, aqueous saline solutions, lactated Ringer's solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethyl cellulose, polyvinylpyrrolidone, and pigments. Such formulations can be sterilized and, if desired, can be mixed with adjuvants that do not adversely react with the compounds of the present invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring substances, and / or aromatic substances. Those skilled in the art will recognize that other pharmaceutical excipients can be used in the present invention.

[0106] The term "formulation" is intended to include a formulation comprising an active compound and an encapsulating material as a carrier, the carrier providing a capsule in which the active component (with or without another carrier) is surrounded by the carrier, and the carrier is thus bound to the active component. Similarly, this includes capsules and tablets. Tablets, powders, capsules, pills, capsules, and tablets can be used as solid dosage forms suitable for oral administration.

[0107] As used herein, the term "about" means a range of values ​​that include a specified value and that will be reasonably considered by those skilled in the art to be reasonably similar to the specified value. In embodiments, "about" means within the standard deviation using a measurement generally acceptable in the art. In embodiments, "about" means a range extending to + / - 10% of the specified value. In embodiments, "about" includes the specified value.

[0108] As used herein, the term "administration" is used in its usual and common sense and includes oral administration, administration as a suppository, local contact, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intrathecal administration, intranasal administration, or subcutaneous administration, or implantation of a sustained-release device (e.g., a micro-osmotic pump) into the subject. Administration is by any route, including parenteral and transmucosal administration (e.g., via the mouth, sublingual, palate, gingiva, nose, vagina, rectum, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other delivery modalities include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. "Co-administration" means administering the composition described herein simultaneously, immediately before, or immediately after administering one or more adjunctive therapies (e.g., cancer therapies such as chemotherapy, hormone therapy, radiotherapy, or immunotherapy). The compounds of the present invention can be administered alone or co-administered to a patient. Co-administration is intended to include the simultaneous or sequential administration of single or combined compounds (more than one compound). Therefore, the formulations can also be combined with other active substances when needed (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered transdermally via a local route and formulated into applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, gels, lotions, powders, and aerosols.

[0109] The compounds described herein can be used in combination with each other, in combination with other active agents known to be effective in treating cell-related diseases that express disease-related cellular components, or in combination with adjuvants that may be ineffective on their own but may contribute to the efficacy of the active agents.

[0110] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the second active agent. Co-administration includes administering the two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition comprising the two active agents. In other embodiments, the active agents may be formulated individually. In another embodiment, the active agents and / or adjuvants may be linked or conjugated to each other.

[0111] In therapeutic use for treating diseases, the compounds in the pharmaceutical compositions of the present invention may be administered at an initial dose of about 0.001 mg / kg to about 1000 mg / kg per day. Daily dose ranges may be used, including about 0.01 mg / kg to about 500 mg / kg, or about 0.1 mg / kg to about 200 mg / kg, or about 1 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 50 mg / kg. However, the dose may vary depending on the patient's needs, the severity of the condition being treated, and the compound or drug used. For example, the dose may be determined empirically considering the type and stage of the disease diagnosed in a particular patient (e.g., fibrotic disease or cancer). In the context of the present invention, the dose administered to the patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The magnitude of the dose will also be determined by the presence, nature, and extent of any adverse side effects accompanying the administration of the compound in a particular patient. The determination of the appropriate dose in a specific situation is within the skill of a practicing physician. Generally, treatment begins with a smaller dose than the optimal dose of the compound. Subsequently, the dosage is increased slightly until the optimal effect is achieved in various situations. For convenience, the total daily dose can be divided into several portions and administered in batches throughout the day, if necessary.

[0112] In the context of a substance or its activity or function related to a disease (e.g., a protein-related disease, a disease related to cellular components), the term "related" or "associated with" means that the disease (e.g., a fibrotic disease or cancer) is caused by (all or part) a substance or its activity or function, or that the symptoms of the disease are caused by (all or part) a substance or its activity or function, or that the disease or its symptoms can be treated by modulating (e.g., inhibiting or activating) a substance (e.g., a cellular component). As used herein, a substance described as being related to a disease, if it is a pathogenic factor, can be a target for treating the disease.

[0113] As used herein, the term “abnormal” refers to a state different from the normal state. When used to describe enzymatic activity, abnormality refers to an activity that is greater than or less than the average activity of a normal control or a normal, non-disease-related control sample. Abnormal activity can refer to an amount of activity that causes disease, wherein restoring abnormal activity to a normal or non-disease-related amount (e.g., by administering a compound or using methods as described herein) results in the reduction of disease or symptoms of one or more diseases.

[0114] When applied to nucleic acids or proteins, the term "isolated" means that the nucleic acid or protein is substantially free of other cellular components associated with it in its native state. For example, it may be in a homogeneous state and may be in a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high-performance liquid chromatography. Proteins, as the main species present in the formulation, are substantially purified.

[0115] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimics that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those that have been modified, such as hydroxyproline, γ-carboxyglutamic acid, and O-phosphoserine. Amino acid analogs are compounds with the same basic chemical structure as naturally occurring amino acids (i.e., the α-carbon is bonded to hydrogen, a carboxyl group, an amino group, and an R group), such as homoserine, ortholeucine, methionine sulfoxide, and methionine methylsulfonium. These analogs have modified R groups (e.g., ortholeucine) or modified peptide backbones, but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimics are chemical compounds with a structure different from the general chemical structure of amino acids, but that function in a manner similar to naturally occurring amino acids. The terms "non-naturally occurring amino acids" and "non-natural amino acids" refer to amino acid analogs, synthetic amino acids, and amino acid mimics that are not found in nature.

[0116] Amino acids may be represented in this article using their commonly known three-letter symbols or the single-letter symbols recommended by the IUPAC-IUB Biochemistry Nomenclature Committee. Similarly, nucleotides may be referred to by their generally accepted single-letter codes.

[0117] In this document, the terms “polypeptide,” “peptide,” and “protein” are used interchangeably to refer to polymers of amino acid residues, wherein, in the examples, the polymer may be conjugated with portions not composed of amino acids. The terminology applies to amino acid polymers in which one or more amino acid residues are artificial chemical mimics of naturally occurring amino acids, as well as to both naturally occurring and non-naturally occurring amino acid polymers.

[0118] The "position" of an amino acid or nucleotide base is indicated by a number, which sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5' end). Because deletions, insertions, truncations, fusions, etc., must be considered when determining optimal alignment, the number of amino acid residues in the test sequence, determined by counting only from the N-terminus, may not necessarily be the same as their corresponding position number in the reference sequence. For example, in the case of a variant with deletions relative to the aligned reference sequence, the variant will not contain an amino acid corresponding to the position at the deletion site in the reference sequence. In the case of insertions in the aligned reference sequence, the insertions will not correspond to the numbered amino acid positions in the reference sequence. In the case of truncation or fusion, the reference sequence or the aligned sequence may contain amino acid segments that do not correspond to any amino acid in the corresponding sequence.

[0119] When used in the context of numbering a given amino acid or polynucleotide sequence, the terms “reference…number” or “corresponding to” refer to the number of residues in a reference sequence when comparing a given amino acid or polynucleotide sequence to a reference sequence.

[0120] The term "protein complex" is used in its usual sense and refers to a protein associated with an additional substance (e.g., another protein, a protein subunit, or a compound). Protein complexes typically have a defined quaternary structure. The association between the protein and the additional substance can be covalent. In embodiments, the association between the protein and the additional substance (e.g., a compound) is through non-covalent interactions. In embodiments, a protein complex refers to a combination of two or more polypeptide chains. The proteins in a protein complex are linked by non-covalent protein-protein interactions. A non-limiting example of a protein complex is the proteasome.

[0121] The term "lysophosphatidyl receptor" or "LPAR" refers to one or more receptors in the G protein-coupled receptor family of lysophosphatidyl acid (LPA). In the examples, LPARs include LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6.

[0122] The term "lysophosphatidic acid receptor 1" or "LPAR1" refers to a G protein-coupled receptor (including its homologs, isotypes, and functional fragments) that binds the lipid signaling molecule lysophosphatidic acid (LPA). This term includes any recombinant or naturally occurring form of LPAR1 or its variants that maintains LPAR1 activity (e.g., activity within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% compared to wild-type LPAR1). In examples, the LPAR1 protein encoded by the LPAR1 gene has an amino acid sequence contained in or corresponding to Entrez 1902, UniProt Q92633, RefSeq (protein) NP_001392.2, or RefSeq (protein) NP_476500.1. In examples, the LPAR1 gene has a nucleic acid sequence listed in RefSeq (mRNA) NM_001401.3 or RefSeq (mRNA) NM_057159.2. In the embodiments, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing this application.

[0123] The terms "selective" or "selectivity" in relation to compounds or agents refer to the ability of a compound or agent to preferentially increase or decrease the activity of a specific molecular target (e.g., a protein, enzyme, etc.) over one or more different molecular targets (e.g., a compound selective for lysophosphatidyl receptor 1 (LPAR1) will preferentially inhibit LPAR1 over other lysophosphatidyl receptors). In the examples, "lysophosphatidyl receptor 1 selective compound" or "LPAR1 selective compound" refers to a compound selective for lysophosphatidyl receptor 1 (LPAR1) (e.g., the compound described herein). In the examples, the compound (e.g., the compound described herein) has a selectivity for lysophosphatidyl receptor 1 (LPAR1) that is about 5, 10, 20, 30, 40, 50, or about 100 times higher than the selectivity for one or more of LPAR2, LPAR3, LPAR4, LPAR5, or LPAR6. In the examples, the compounds (e.g., those described herein) exhibit selectivity for lysophosphatidylcholine receptor 1 (LPAR1) that is at least 5, 10, 20, 30, 40, 50, or at least 100 times higher than that for one or more of LPAR2, LPAR3, LPAR4, LPAR5, or LPAR6.

[0124] II. Compounds

[0125] In one respect, a compound, or a pharmaceutically acceptable salt or solvate thereof, is provided having the formula:

[0126] (I).

[0127] R 1 It is isopropyl or isobutyl.

[0128] R 2 is -C(O)OH, -CH2C(O)OH, -CH2CH2C(O)OH, -C(O)NHS(O)2R 2A -P(O)(OH)2, -P(O)(OH)R 2A , -SO3H, -SO2H, -NHC(O)NHS(O)2R 2A , , , , , , , ,or .

[0129] R 2A It is an unsubstituted C1-C4 alkyl group.

[0130] R 3 R 4 R 5 and R 6 It is independently hydrogen or an unsubstituted C1-C4 alkyl group.

[0131] In the embodiments, the compound has the following formula:

[0132] (Ia). R 1 R 2 R 3 R 4 R 5 and R 6 As described herein, it is included in the embodiments.

[0133] In the embodiments, the compound has the following formula:

[0134] (Ib). R 2 As described herein, it is included in the embodiments.

[0135] In one respect, a compound, or a pharmaceutically acceptable salt or solvate thereof, is provided having the formula:

[0136] (II). R 1 R 2 R 3 R 4 R 5 and R 6As described herein, it is included in the embodiments.

[0137] In the embodiments, the compound has the following formula:

[0138] (IIa). R 1 R 2 R 3 R 4 R 5 and R 6 As described herein, it is included in the embodiments.

[0139] In the embodiments, the compound has the following formula:

[0140] (IIb). R 2 As described herein, it is included in the embodiments.

[0141] In the embodiment, R 1 It is isopropyl (i.e., unsubstituted isopropyl). In the examples, R 1 It is isobutyl (i.e., unsubstituted isobutyl).

[0142] In the embodiment, R 2 It is -C(O)OH. In the examples, R 2 It is -CH2C(O)OH. In the examples, R 2 It is -CH2CH2C(O)OH. In the examples, R... 2 -C(O)NHS(O)2R 2A , where R 2A As described herein, it is included in the embodiments. In the embodiments, R 2 It is -C(O)NHS(O)2CH3. In the embodiment, R 2 It is -P(O)(OH)2. In the examples, R 2 -P(O)(OH)R 2A , where R 2A As described herein, it is included in the embodiments. In the embodiments, R 2 It is -P(O)(OH)CH3. In the examples, R 2 It is -SO3H. In the embodiment, R 2 It is -SO2H. In the embodiment, R 2 -NHC(O)NHS(O)2R 2A , where R 2A As described herein, it is included in the embodiments. In the embodiments, R 2 It is -NHC(O)NHS(O)2CH3. In the examples, R 2 for In the embodiment, R 2 for In the embodiment, R 2 for In the embodiment, R 2 for In the embodiment, R 2 for In the embodiment, R 2 for In the embodiment, R 2 for In the embodiment, R 2 for .

[0143] In the embodiment, R 2A R is an unsubstituted methyl group. In the examples, R 2A It is an unsubstituted ethyl group. In the examples, R... 2A It is an unsubstituted propyl group. In the examples, R 2A It is an unsubstituted n-propyl group. In the examples, R 2A It is an unsubstituted isopropyl group. In the examples, R 2A It is unsubstituted butyl. In the embodiment, R... 2A It is an unsubstituted n-butyl. In the examples, R 2A It is an unsubstituted isobutyl group. In the embodiments, R 2A It is unreplaced tert-butyl.

[0144] In the embodiment, R 3 It is hydrogen or an unsubstituted C1-C4 alkyl group. In the examples, R 3 It is hydrogen. In the examples, R is... 3 R is an unsubstituted methyl group. In the examples, R 3 It is an unsubstituted ethyl group. In the examples, R... 3 It is an unsubstituted propyl group. In the examples, R 3 It is an unsubstituted n-propyl group. In the examples, R 3 It is an unsubstituted isopropyl group. In the examples, R 3 It is unsubstituted butyl. In the embodiment, R... 3 It is an unsubstituted n-butyl. In the examples, R 3 It is an unsubstituted isobutyl group. In the embodiments, R 3 It is unreplaced tert-butyl.

[0145] In the embodiment, R 4 It is hydrogen or an unsubstituted C1-C4 alkyl group. In the examples, R 4 It is hydrogen. In the examples, R is...4 R is an unsubstituted methyl group. In the examples, R 4 It is an unsubstituted ethyl group. In the examples, R... 4 It is an unsubstituted propyl group. In the examples, R 4 It is an unsubstituted n-propyl group. In the examples, R 4 It is an unsubstituted isopropyl group. In the examples, R 4 It is unsubstituted butyl. In the embodiment, R... 4 It is an unsubstituted n-butyl. In the examples, R 4 It is an unsubstituted isobutyl group. In the embodiments, R 4 It is unreplaced tert-butyl.

[0146] In the embodiment, R 5 It is hydrogen or an unsubstituted C1-C4 alkyl group. In the examples, R 5 It is hydrogen. In the examples, R is... 5 R is an unsubstituted methyl group. In the examples, R 5 It is an unsubstituted ethyl group. In the examples, R... 5 It is an unsubstituted propyl group. In the examples, R 5 It is an unsubstituted n-propyl group. In the examples, R 5 It is an unsubstituted isopropyl group. In the examples, R 5 It is unsubstituted butyl. In the embodiment, R... 5 It is an unsubstituted n-butyl. In the examples, R 5 It is an unsubstituted isobutyl group. In the embodiments, R 5 It is unreplaced tert-butyl.

[0147] In the embodiment, R 6 It is hydrogen or an unsubstituted C1-C4 alkyl group. In the examples, R 6 It is hydrogen. In the examples, R is... 6 R is an unsubstituted methyl group. In the examples, R 6 It is an unsubstituted ethyl group. In the examples, R... 6 It is an unsubstituted propyl group. In the examples, R 6 It is an unsubstituted n-propyl group. In the examples, R 6 It is an unsubstituted isopropyl group. In the examples, R 6 It is unsubstituted butyl. In the embodiment, R... 6 It is an unsubstituted n-butyl. In the examples, R 6 It is an unsubstituted isobutyl group. In the embodiments, R 6 It is unreplaced tert-butyl.

[0148] In the embodiment, R3 R 4 R 5 and R 6 It can be hydrogen or an unsubstituted methyl group.

[0149] In the embodiments, the compound has the following formula:

[0150] .

[0151] In the embodiments, the compound has the following formula:

[0152] .

[0153] In the embodiments, the compound may be used as a comparative compound. In the embodiments, the comparative compound may be used to evaluate the activity of the test compound, as described herein in the assays (e.g., as shown in the Examples section, figures, or tables).

[0154] In the embodiments, the compounds are those described herein (including the compounds in the embodiments). In the embodiments, the compounds are those described herein (e.g., in the Examples section, figures, tables, or claims).

[0155] In the embodiments, the compound does not significantly cross the blood-brain barrier. In the embodiments, the compound crosses the blood-brain barrier undetectably. In the embodiments, the compound does not cross the blood-brain barrier. In the embodiments, the compound has a K0.2. p,uu K p,uu It is the unbound brain-plasma partition coefficient and describes the unbound concentration of the compound in the brain relative to plasma. In the examples, the compound has a K0.18. p,uu In the examples, the compound has a K0.16. p,uu In the examples, the compound has a K0.14. p,uu In the examples, the compound has a K0.12. p,uu In the examples, the compound has a K0.1. p,uu In the examples, the compound has a K0.08. p,uu In the examples, the compound has a K0.06. p,uu In the examples, the compound has a K0.04. p,uu In the examples, the compound has a K0.02. p,uu In the examples, the compound has a K0.2. p,uu In the examples, the compound has a K0.18. p,uu In the examples, the compound has a K0.16. p,uuIn the examples, the compound has a K0.14. p,uu In the examples, the compound has a K0.12. p,uu In the examples, the compound has a K0.1. p,uu In the examples, the compound has a K0.08. p,uu In the examples, the compound has a K0.06. p,uu In the examples, the compound has a K0.04. p,uu In the examples, the compound has a K0.02. p,uu .

[0156] III. Pharmaceutical Compositions

[0157] In one aspect, a pharmaceutical composition is provided comprising the compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0158] In the embodiments, the compound is a compound of formula (I), (Ia), (Ib), (II), (IIa) or (IIb), including its embodiments.

[0159] In some embodiments, the pharmaceutical composition comprises an effective amount of the compound. In others, the pharmaceutical composition comprises a therapeutically effective amount of the compound.

[0160] IV. Usage Method

[0161] In one aspect, a method is provided for treating peripherally restricted LPAR1-related disease in a subject with such need, the method comprising administering to the subject a therapeutically effective amount of the compound described herein, or a pharmaceutically acceptable salt of a solvation thereof.

[0162] In the embodiments, the compound is a compound of formula (I), (Ia), (Ib), (II), (IIa) or (IIb), including its embodiments.

[0163] In the embodiments, peripherally restricted LPAR1-related diseases are fibrotic diseases. In the embodiments, fibrotic diseases are pulmonary fibrosis. In the embodiments, fibrotic diseases are idiopathic pulmonary fibrosis. In the embodiments, fibrotic diseases are renal fibrosis. In the embodiments, fibrotic diseases are skin fibrosis. In the embodiments, fibrotic diseases are ocular fibrosis. In the embodiments, fibrotic diseases are non-alcoholic steatohepatitis. In the embodiments, fibrotic diseases are scleroderma. In the embodiments, fibrotic diseases are hypertrophic scars or keloids (e.g., burn-induced or surgically induced, sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease, or Peroni's disease). In the embodiments, fibrotic diseases are iatrogenic pulmonary fibrosis. In the embodiments, fibrotic diseases are radiation-induced fibrosis. In the embodiments, fibrotic diseases are silicosis-induced pulmonary fibrosis. In the embodiments, fibrotic diseases are asbestos-induced pulmonary fibrosis. In this embodiment, the fibrotic disease is pleural fibrosis. In this embodiment, the fibrotic disease is pulmonary fibrosis associated with SARS-CoV-2 infection and / or COVID-19. In this embodiment, the fibrotic disease is pulmonary fibrosis secondary to systemic inflammatory disease. In this embodiment, the fibrotic disease is pulmonary fibrosis secondary to sarcoidosis. In this embodiment, the fibrotic disease is intestinal fibrosis. In this embodiment, the fibrotic disease is head and neck fibrosis. In this embodiment, the fibrotic disease is cirrhosis. In this embodiment, the fibrotic disease is alcohol-induced liver fibrosis. In this embodiment, the fibrotic disease is endometriosis. In this embodiment, the fibrotic disease is spinal cord fibrosis. In this embodiment, the fibrotic disease is myelofibrosis. In this embodiment, the fibrotic disease is cardiac fibrosis. In this embodiment, the fibrotic disease is perivascular fibrosis. In this embodiment, the fibrotic disease is Peroni's disease. In this embodiment, the fibrotic disease is abdominal or intestinal adhesions. In this embodiment, the fibrotic disease is bladder fibrosis. In this embodiment, the fibrotic disease is nasal passage fibrosis. In this embodiment, the fibrotic disease is fibroblast-mediated fibrosis. In one embodiment, the fibrotic disease is renal fibrosis associated with chronic kidney disease (CKD). In another embodiment, the fibrotic disease is intestinal fibrosis. In yet another embodiment, the fibrotic disease is gastrointestinal fibrosis.

[0164] In one embodiment, peripherally restricted LPAR1-related disease is cancer. In another embodiment, the cancer is ovarian cancer. In yet another embodiment, the cancer is breast cancer. In a third embodiment, the cancer is liver cancer. In a fourth embodiment, the cancer is stomach cancer. In a fifth embodiment, the cancer is pancreatic cancer. In a sixth embodiment, the cancer is lung cancer. In a seventh embodiment, the cancer is osteosarcoma.

[0165] In this embodiment, peripherally restrictive LPAR1-related disease is inflammatory bowel disease. In this embodiment, inflammatory bowel disease is chronic inflammatory bowel disease. In this embodiment, inflammatory bowel disease is ulcerative colitis. In this embodiment, inflammatory bowel disease is Crohn's disease. In this embodiment, inflammatory bowel disease is intestinal fibrosis. In this embodiment, inflammatory bowel disease is gastrointestinal fibrosis.

[0166] In one respect, a method for modulating LPAR1 activity in a subject is provided, which involves administering to the subject the compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0167] V. Example

[0168] Example P1. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the formula:

[0169] (I); among which

[0170] R 1 It is isopropyl or isobutyl;

[0171] R 2 is -C(O)OH, -CH2C(O)OH, -CH2CH2C(O)OH, -C(O)NHS(O)2R 2A -P(O)(OH)2, -P(O)(OH)R 2A , -SO3H, -SO2H, -NHC(O)NHS(O)2R 2A , , , , , , , ,or ;

[0172] R 2A It is an unsubstituted C1-C4 alkyl group; and

[0173] R 3 R 4 R 5 and R 6 It is independently hydrogen or an unsubstituted C1-C4 alkyl group.

[0174] Example P2. The compound according to Example P1, wherein R... 3 R 4 R 5 and R 6 It can be hydrogen or an unsubstituted methyl group.

[0175] Example P3. The compound according to Example P1 has the formula: (Ia).

[0176] Example P4. The compound according to Example P1 has the formula: (Ib).

[0177] Example P5. The compound according to any one of Examples P1 to P4, wherein R 2 It is -C(O)OH, -CH2C(O)OH, -CH2CH2C(O)OH, -C(O)NHS(O)2CH3, -P(O)(OH)2, -P(O)(OH)CH3, -SO3H, -SO2H, -NHC(O)NHS(O)2CH3, , , , , , , ,or .

[0178] Example P6. The compound according to any one of Examples P1 to P4, wherein R 2 It is -C(O)OH.

[0179] Example P7. The compound according to Example P1 has the formula: .

[0180] Example P8. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the formula:

[0181] (II); among which

[0182] R 1 It is isopropyl or isobutyl;

[0183] R 2 is -C(O)OH, -CH2C(O)OH, -CH2CH2C(O)OH, -C(O)NHS(O)2R 2A -P(O)(OH)2, -P(O)(OH)R 2A , -SO3H, -SO2H, -NHC(O)NHS(O)2R 2A , , , , , , , ,or ;

[0184] R 2A It is an unsubstituted C1-C4 alkyl group; and

[0185] R 3 R 4 R 5 and R 6 It is independently hydrogen or an unsubstituted C1-C4 alkyl group.

[0186] Example P9. The compound according to Example P8, wherein R... 3 R 4 R 5 and R 6 It can be hydrogen or an unsubstituted methyl group.

[0187] Example P10. The compound according to Example P8 has the formula: (IIa).

[0188] Example P11. The compound according to Example P8 has the formula: (IIb).

[0189] Example P12. The compound according to one of Examples P8 to P11, wherein R 2 It is -C(O)OH, -CH2C(O)OH, -CH2CH2C(O)OH, -C(O)NHS(O)2CH3, -P(O)(OH)2, -P(O)(OH)CH3, -SO3H, -SO2H, -NHC(O)NHS(O)2CH3, , , , , , , ,or .

[0190] Example P13. The compound according to one of Examples P8 to P11, wherein R 2 It is -C(O)OH.

[0191] Example P14. The compound according to any one of Examples P1 to P13 has the formula: .

[0192] Example P15. A pharmaceutical composition comprising a compound according to any one of Examples P1 to P14, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0193] Example P16. A method of treating peripherally restricted LPAR1-related disease in a subject with this need, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Examples P1 to P14, or a pharmaceutically acceptable salt or solvate thereof.

[0194] Example P17. The method according to Example P16, wherein the peripherally restrictive LPAR1-related disease is a fibrotic disease.

[0195] Example P18. The method described in Example P17, wherein the fibrotic disease is idiopathic pulmonary fibrosis, renal fibrosis, non-alcoholic steatohepatitis, or scleroderma.

[0196] Example P19. The method according to Example P16, wherein the peripherally restricted LPAR1-related disease is cancer.

[0197] Example P20. The method described in Example P19, wherein the cancer is ovarian cancer, breast cancer, liver cancer, stomach cancer, pancreatic cancer, lung cancer, or osteosarcoma.

[0198] Example P21. A method for modulating LPAR1 activity in a subject, the method comprising administering to the subject a compound according to any one of Examples P1 to P14, or a pharmaceutically acceptable salt or solvate thereof.

[0199] It should be understood that the examples and embodiments described herein are for illustrative purposes only and various modifications or variations suggested by those skilled in the art are intended to be included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated in their entirety for all purposes.

[0200] Example

[0201] 1. Preparation of compounds

[0202] The compounds used in the reactions described herein were prepared using known organic synthesis techniques, and their starting materials were commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" were purchased from standard commercial sources, including AcrosOrganics (Gil, Belgium), Aldrich Chemical (Milwaukee, Wisconsin, USA, including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, Illinois, USA), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, Pennsylvania, USA), Combi-blocks (San Diego, California, USA), Crescent Chemical Co. (Happap, NY, USA), eMolecules (San Diego, California, USA), Fisher Scientific Co. (Pittsburgh, Pennsylvania, USA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah, USA), ICN Biomedicals, Inc. (Costa Mesa, California, USA), Key Organics (Cornwall, UK), Lancaster Synthesis (Wyndham, New Hampshire, USA), Matrix Scientific (Columbia, South Carolina, USA), and Maybridge Chemical Co. Ltd. (Cormwick, UK), Parish Chemical Co. (Olem, Utah, USA), Pfaltz & Bauer, Inc. (Waterbury, Connecticut, USA), Polyorganix (Houston, Texas, USA), Pierce Chemical Co. (Rockford, Illinois, USA), Riedel de Haen AG (Hanover, Germany), Ryan Scientific, Inc. (Mount Pleasant, South Carolina, USA), Spectrum Chemicals (Gardina, California, USA), Sundia Meditech (Shanghai, China), TCI America (Portland, Oregon, USA), TransWorld Chemicals, Inc. (Rockville, Maryland, USA), and WuXi (Shanghai, China).

[0203] Suitable reference books and monographs that detail the reactant synthesis that can be used to prepare the compounds described herein, or provide articles introducing the preparation methods, include, for example, "Synthetic Organic Chemistry," New York: John Wiley & Sons, Inc., 1982; Sandler SR et al., "Organic Functional Group Preparations," 2nd ed., New York: Academic Press, 1983; House, HO, "Modern Synthetic Reactions," 2nd ed., Menlo Park: WA Benjamin, Inc., 1972; Gilchrist, TL, "Heterocyclic Chemistry," 2nd ed., New York: Wiley, 1992; March, J., "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th ed., New York: Wiley, 1992.Other suitable reference books and monographs that detail the reactant synthesis that can be used to prepare the compounds described herein, or that provide an article introducing the preparation method, include, for example, Fuhrhop, J., Penzlin, G., "Organic Synthesis: Concepts, Methods, Starting Materials," 2nd ed., New York: Wiley, 1994; Hoffman, RV, "Organic Chemistry, An Intermediate Text," Oxford: Oxford University Press, 1996; Larock, RC, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations," 2nd ed., New York: Wiley, 1999; Otera, J., "Modern Carbonyl Chemistry," New York: Wiley, 2000; Solomons, TWG, "Organic Chemistry," 7th ed., New York: Wiley, 2000; Stowell, JC, "Intermediate Organic Chemistry," 2nd ed., New York: Wiley, 1993; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia," New York: Wiley, Vol. 8; "Organic Reactions," New York: Wiley, Vol. 55; and "Chemistry of Functional Groups," New York: Wiley, Vol. 73.

[0204] Specific and similar reactants are also identified by an index of known chemical substances compiled by the American Chemical Society's Chemical Abstracts Service, which is available in most public and university libraries, as well as online databases (for more details, contact the American Chemical Society in Washington, D.C.). Chemicals known but not commercially available in the catalogue are optionally prepared by custom chemical synthesis companies, many of which are standard chemical suppliers (e.g., those listed above) that offer custom synthesis services. For information on the preparation and selection of pharmaceutical salts of the compounds described herein, see Stahl, PH, Wermuth, CG, "Handbook of Pharmaceutical Salts," Zurich: Verlag Helvetica Chimica Acta, 2002.

[0205] List of abbreviations

[0206] As used above and throughout this application specification, unless otherwise stated, the following abbreviations should be understood to have the following meanings:

[0207]

[0208] General synthesis scheme

[0209] The compounds of formula (I) or (II) of this disclosure can be prepared by the combination of an amine (1) with a secondary aryl amine (2a) or (2b) in the presence of a suitable C=O source (such as CDI, phosgene, triphosgene, etc.) and a suitable base (such as pyridine, TEA, DIEA, sodium hydride, etc.) (Scheme 1). Depending on the reactivity of the two amine coupling partners, it may be advantageous to first react the amine (1) with the aforementioned C=O source and base to obtain the desired carbamoyl chloride, carbamoyl imidazole, or isocyanate intermediate, or vice versa, before adding the other amine coupling partner. In some cases, the formation of the final urea bond can be promoted by adding an activator (such as DMAP, freshly activated molecular sieves, heat, etc.).

[0210] Option 1

[0211]

[0212] The product urea (3a) or (3b) itself can be a compound of formula (I) or formula (II), and can be further functionalized using synthetic methods known to those skilled in the art to obtain another compound of formula (I) or formula (II). Examples of such transformations include, but are not limited to:

[0213] (a) Hydrolyze the ester present in (3a) or (3b) using a suitable reagent (such as lithium hydroxide, sodium hydroxide or potassium hydroxide).

[0214] (b) Hydrolyze the nitriles present in (3a) or (3b) using a suitable reagent (such as wet sulfuric acid, wet hydrochloric acid, lithium hydroxide, sodium hydroxide, etc.).

[0215] (c) In the presence of a suitable promoter (such as dibutyltin(IV), protic acid, heat, etc.), a suitable azide (such as trimethylsilyl azide, sodium azide, tetrabutylammonium azide, etc.) is used to cause the nitrile present in (3a) or (3b) to undergo cycloaddition.

[0216] (d) In the presence of a suitable base (such as TEA, pyridine, sodium hydride, cesium carbonate, etc.), use a suitable N-sulfonyl isocyanate, N-sulfonyl carbamate, etc., to cap the unmasked amine exposed in (3a) or (3b) after the masking group is removed using conditions known to those skilled in the art.

[0217] (e) In the presence of a suitable coupling agent (such as HATU, CDI, T3P, EDC, etc.) and a suitable base (such as TEA, DIEA, NMI, etc.), the carboxylic acid present in (3a) or (3b) is coupled with a suitably functionalized sulfonamide.

[0218] (f) Using conditions known to those skilled in the art, the carboxylic acid present in (3a) or (3b) is first initially activated to an acyl chloride or anhydride, and then quenched with a suitably functionalized sulfonamide in the presence of a suitable base (such as TEA, DIEA, NMI, etc.).

[0219] (g) Using suitable reagents such as aqueous HCl solution, aqueous sodium hydroxide solution, etc., or using the two-step McKenna method, hydrolyze the dialkylphosphonate or alkylphosphonate present in (3a) or (3b), wherein the dialkylphosphonate or alkylphosphonate is first treated with trimethylbromosilane and then treated with wet methanol, etc.

[0220] (h) The thioacetic acid ester or thioether present in (3a) or (3b) is initially oxidized with tert-butyl hypochlorite, N-chlorosuccinimide, etc., and then quenched with water.

[0221] (i) The thioacetic acid ester or thioether present in (3a) or (3b) is initially oxidized with tert-butyl hypochlorite, N-chlorosuccinimide, etc., and then reduced with an aqueous solution of sodium sulfite, etc.

[0222] (j) Using conditions known to those skilled in the art, the alcohol present in (3a) or (3b) is first initially activated to an alkyl halide or alkyl trifluoromethanesulfonate, and then quenched with lithium-ionized thiazoline-2,4-dione, oxazolidine-2,4-dione, etc.

[0223] (k) Using conditions known to those skilled in the art, the nitrile present in (3a) or (3b) is first initially converted to the corresponding N-hydroxyimine amide, and then quenched with a suitable acylating agent (such as isobutyl chloroformate, 1,1′-thiocarbonyldiimidazole, thionyl chloride, etc.) in the presence of a suitable promoter (such as heat, boron trifluoride ether, DBU, etc.).

[0224] (l) The unmasked amine, which is exposed after the masking group is removed using conditions known to those skilled in the art, and which is present in (3a) or (3b), is heated together with squaric acid.

[0225] (m) Using appropriate chiral columns (such as ChiralPAK IF, CHIRAL ART Amylose SA, CHIRAL ART Cellulose SB, etc.), mixtures of stereoisomers are separated into their stereochemically enriched components.

[0226] For some embodiments, those skilled in the art can obtain the secondary heteroaryl amine (2a) or (2b) for coupling as described in Scheme 1 (Scheme 2) by combining a suitably functionalized amine (4) with a suitably functionalized heteroaryl halide (5a) or (5b) in the presence of a promoter (such as a palladium catalyst, a copper catalyst, heat, etc.) and a base (such as potassium phosphate, TEA, bis(trimethylsilyl)aminopotassium, etc.).

[0227] Option 2

[0228]

[0229] In some embodiments, the secondary heteroarylamine (2a) or (2b) used for coupling as described in Scheme 1 may instead be obtained by reductive amination of a suitably functionalized ketone (6) with a suitably functionalized heteroarylamine (7a) or (7b) in the presence of a suitable reducing agent (such as sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) and a suitable additive (such as acetic acid, titanium isopropoxide (IV), etc.) (Scheme 3).

[0230] Option 3

[0231]

[0232] In some embodiments, the introduction of R is delayed because, for example, the desired starting material is more readily available or the desired bonding is more readily achieved. 1Groups may be advantageous. In these cases, secondary haloarylamines (9a) or (9b) synthesized from the corresponding haloarylamines (8a) or (8b) themselves according to previously disclosed strategies can be converted to secondary haloarylamines (2a) or (2b) by metal-catalyzed cross-coupling with a suitably functionalized organometallic reagent (10) under conditions known to those skilled in the art (Scheme 4). In some cases, the conversion of (9a) to (2a) or (9b) to (2b) may require a two-step sequence, including first metal-catalyzed cross-coupling with (10) followed by hydrogenation of the intermediate olefin or alkyne.

[0233] Option 4

[0234]

[0235] The general synthetic schemes described above have been presented in an illustrative manner and are intended to be suggestive rather than limiting. It should also be understood that many of the reagents provided in the examples below can be substituted with other suitable reagents (see, for example, Fieser, L. et al., "Encyclopedia of Reagents for Organic Synthesis," 2nd ed., New York: Wiley, 2009). Furthermore, it should be understood that conditions such as the choice of solvent, reaction temperature, volume, and reaction time can be varied while still yielding the desired compound. Such changes and modifications can be made without departing from the spirit and scope of this work, including but not limited to those relating to the chemical structures, substituents, derivatives, intermediates, and / or synthesis provided herein.

[0236] Example

[0237] Unless otherwise specified, reagents and solvents were used in the condition received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and / or oxygen. Yields were not optimized. Reaction times were approximate and not optimized. Unless otherwise specified, column chromatography was performed on silica gel.

[0238] Preparation of intermediate amine 1: ethyl trans-4-((4-isopropylpyridin-3-yl)amino)cyclohexane-1-carboxylate

[0239]

[0240] Step 1In a thick-walled glass reaction vessel equipped with a magnetic stirrer and a PTFE screw cap, ethyl trans-4-aminocyclohexanecarbamate (1 equivalent), 4-chloro-3-iodopyridine (1.5 equivalent), tris(dibenzylacetone)dipalladium (0) (0.1 equivalent), 2-dicyclohexylphosphine-2′,6′-bis(N,N-dimethylamino)biphenyl (0.2 equivalent), and cesium carbonate (3 equivalent) were mixed in 1,4-dioxane (0.73 M). The resulting purple suspension was then deoxygenated by purging the liquid surface with nitrogen for 10 min, and the reaction vessel was then sealed and heated at 100 °C for 60 h. The resulting dark brown suspension was cooled to RT, diluted with EtOAc, and washed successively with water and brine. The resulting organic extract was then dried with Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The crude product obtained therefrom was purified by column chromatography (SiO2, gradient elution: 9:1 (v / v) Hex: EtOAc → EtOAc) to give trans-4-((4-chloropyridin-3-yl)amino)cyclohexane-1-carboxylic acid ethyl ester, as a yellow oil (74% yield).

[0241] Step 2 In a thick-walled glass reaction vessel equipped with a magnetic stirrer and a PTFE screw cap, ethyl trans-4-((4-chloropyridin-3-yl)amino)cyclohexane-1-carboxylate (1 equivalent), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxoborhexacyclopentane (2 equivalents), tetra(triphenylphosphine)palladium (0) (0.2 equivalents), and potassium carbonate (3 equivalents) from the previous step were mixed in a 5:1 (v / v) solution (0.15 M) of 1,4-dioxane and water. The resulting mixture was deoxygenated by purging the liquid surface with nitrogen for 10 min, and then the reaction vessel was sealed and heated at 90 °C for 72 h. The now dark brown suspension was cooled to RT, quenched with water, and extracted with EtOAc. The combined organic extracts were further washed with water and brine, dried with Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude product obtained therefrom was purified by column chromatography (SiO2, gradient elution: 9:1 (v / v)Hex: EtOAc → EtOAc) to give trans-4-((4-(prop-1-en-2-yl)pyridin-3-yl)amino)cyclohexane-1-carboxylic acid ethyl ester, which was a yellow oil (96% yield).

[0242] Step 3In a dry round-bottom flask equipped with a magnetic stirrer, ethyl trans-4-((4-(prop-1-en-2-yl)pyridin-3-yl)amino)cyclohexane-1-carboxylate (1 equivalent) from the previous step was dissolved in methanol (0.11 M). The resulting solution was then deoxygenated by purging under nitrogen for 10 min, followed by a rapid addition of palladium (10% w / w, dried on activated carbon, 0.1 equivalent). The resulting black suspension was then purged under hydrogen for 10 min, and stirred at RT for 24 h under a static hydrogen atmosphere (maintained by a balloon). The reaction was then quenched with dichloromethane and filtered through a layer of diatomaceous earth moistened with dichloromethane. The filtrate was concentrated under vacuum to give the title compound as a yellow oil (83% yield).

[0243] Preparation of intermediate amine 2: Ethyl trans-4-((3-isopropylpyridin-2-yl)amino)cyclohexane-1-carboxylate

[0244]

[0245] Step 1 In a dry round-bottom flask equipped with a magnetic stirrer, ethyl trans-4-aminocyclohexanecarboxylate (1 equivalent), 3-bromo-2-fluoropyridine (1.5 equivalent), and N,N-diisopropylethylamine (3 equivalent) were mixed in dimethyl sulfoxide (0.78 M). The resulting solution was then heated at 120 °C for 16 h. After cooling to RT, the reaction was quenched with water and extracted with EtOAc. The combined organic extracts were then washed further with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude product thus obtained was purified by column chromatography (SiO2, gradient elution: 9:1 (v / v) Hex: EtOAc → EtOAc) to give ethyl trans-4-((3-bromopyridin-2-yl)amino)cyclohexane-1-carboxylate as a white solid (83% yield).

[0246] Step 2In a thick-walled glass reaction vessel equipped with a magnetic stirrer and a PTFE screw cap, ethyl trans-4-((3-bromopyridin-2-yl)amino)cyclohexane-1-carboxylate (1 equivalent), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxoborane (2 equivalents), tetra(triphenylphosphine)palladium (0) (0.2 equivalents), and potassium carbonate (3 equivalents) from the previous step were mixed in a 5:1 (v / v) solution (0.08 M) of 1,4-dioxane and water. The resulting mixture was deoxygenated by purging the liquid surface with nitrogen for 10 min, and then the reaction vessel was sealed and heated at 90 °C for 16 h. The now dark brown suspension was cooled to RT, quenched with water, and extracted with EtOAc. The combined organic extracts were further washed with water and brine, dried with Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude product obtained therefrom was purified by column chromatography (SiO2, gradient elution: 9:1 (v / v)Hex:EtOAc→EtOAc) to give trans-4-((3-(prop-1-en-2-yl)pyridin-2-yl)amino)cyclohexane-1-carboxylic acid ethyl ester, which was a yellow oil (68% yield).

[0247] Step 3 In a dry round-bottom flask equipped with a magnetic stirrer, ethyl trans-4-((3-(prop-1-en-2-yl)pyridin-2-yl)amino)cyclohexane-1-carboxylate (1 equivalent) from the previous step was dissolved in methanol (0.19 M). The resulting solution was then deoxygenated by purging under nitrogen for 10 min, followed by a rapid addition of palladium (10% w / w, dried on activated carbon, 0.1 equivalent). The resulting black suspension was then purged under hydrogen for 10 min, followed by stirring at RT for 1 h under a static hydrogen atmosphere (maintained by a balloon). The reaction was then quenched with dichloromethane and filtered through a layer of diatomaceous earth moistened with dichloromethane. The filtrate was concentrated under vacuum to give the title compound as a yellow oil (92% yield).

[0248] Preparation of intermediate amine 3: 2-(difluoromethoxy)-6-methoxypyridine-3-amine

[0249]

[0250] Step 1In a dry round-bottom flask equipped with a magnetic stirrer, 6-methoxy-3-nitropyridine-2-ol (1 equivalent) was suspended in acetonitrile (0.10 M). Sodium hydride (60% w / w dispersion in paraffin oil, 2.8 equivalent) was then rapidly added in one addition, and the resulting mixture was stirred at RT for 10 min to obtain a brownish-yellow suspension. Subsequently, 2,2-difluoro-2-(fluorosulfonyl)acetic acid (1.8 equivalent) was added dropwise over 5 min in pure form, during which a slight exothermic reaction was observed. After stirring for 16 h, another aliquot of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (1.8 equivalent) was added dropwise over 5 min in pure form. After stirring at RT for another 48 h, the crude reaction mixture was carefully quenched with water and subsequently diluted with a 1:1 (v / v) solution of ethyl acetate and hexane. The organic layer was then separated and washed sequentially with saturated NaHCO3 aqueous solution, water, and brine. The solution was dried over MgSO4, filtered, and the filtrate was concentrated under vacuum. The crude product obtained was purified by column chromatography (SiO2, gradient elution: Hex → 1:1 (v / v) Hex: EtOAc) to give 2-(difluoromethoxy)-6-methoxy-3-nitropyridine as a yellow solid (75% yield).

[0251] Step 2 In a dry round-bottom flask equipped with a magnetic stirrer, 2-(difluoromethoxy)-6-methoxy-3-nitropyridine (1 equivalent) from the previous step was dissolved in methanol (0.17 M). The resulting yellow solution was then deoxygenated by purging under nitrogen for 10 min, followed by a rapid addition of palladium (10% w / w, dried on activated carbon, 0.08 equivalent). The resulting black suspension was then purged under hydrogen for 10 min, followed by stirring at RT for 90 min under a static hydrogen atmosphere (maintained by a balloon). The reaction was then diluted with EtOAc and filtered through a layer of diatomaceous earth moistened with dichloromethane. The insoluble matter was further washed with EtOAc. The resulting filtrate was concentrated under vacuum to give the title compound as a reddish-brown solid (>99% yield).

[0252] Example 1: Preparation of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(4-isopropylpyridin-3-yl)ureo)cyclohexane-1-carboxylic acid

[0253]

[0254] Step 1In a thick-walled glass reaction vessel equipped with a magnetic stirrer and a PTFE screw cap, intermediate amine 1 (1 equivalent) and pyridine (3 equivalents) were mixed in anhydrous dichloromethane (0.45 M). Triphosgene (1 equivalent) was then added to the mixture in batches over 15 minutes at RT. After the addition was complete, the vessel was sealed and heated at 60 °C for 1 h. The mixture was then cooled to 0 °C and carefully quenched by dropwise addition of methanol. Volatile substances were then removed under vacuum, and the crude product obtained was purified directly by column chromatography (SiO2, gradient elution: DCM → 10:1 (v / v) DCM:MeOH) to give trans-4-((chlorocarbonyl)(4-isopropylpyridin-3-yl)amino)cyclohexane-1-carboxylate as a yellow oil (71% yield).

[0255] Step 2 In a thick-walled glass reaction vessel equipped with a magnetic stirrer and a PTFE screw cap, ethyl trans-4-((chlorocarbonyl)(4-isopropylpyridin-3-yl)amino)cyclohexane-1-carboxylate (1 equivalent), intermediate amine 3 (2.5 equivalents), and DMAP (0.2 equivalents) from the previous step were mixed in anhydrous dichloroethane (0.28 M). N,N-diisopropylethylamine (3 equivalents) was then added dropwise to this mixture over 5 minutes at RT. After the addition was complete, the vessel was sealed and heated at 110 °C for 16 h. The mixture was then cooled to RT, quenched with water, and extracted with EtOAc. The combined organic extracts were further washed with water and brine, dried with Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The crude product obtained was purified by column chromatography (SiO2, gradient elution: 9:1 (v / v) Hex: EtOAc → EtOAc) to give trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(4-isopropylpyridin-3-yl)ureido)cyclohexane-1-carboxylic acid ethyl ester, which was a yellow oil (28% yield).

[0256] Step 3 In a round-bottom flask equipped with a magnetic stirrer, ethyl trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(4-isopropylpyridin-3-yl)ureido)cyclohexane-1-carboxylate (1 equivalent) from the previous step was dissolved in a 1:1 (v / v) solution (0.2 M) of THF and methanol. Lithium hydroxide (1 M aqueous solution, 5 equivalents) was then added to this solution, and the resulting mixture was stirred at RT for 3 h. The reaction mixture was then carefully quenched with HCl (1 M aqueous solution, 5 equivalents), and volatiles were removed under vacuum. The crude product obtained was then subjected to reversed-phase column chromatography (C2000). 18The solution was purified by gradient elution: 95:5 (v / v) H2O: MeCN + 10 mM NH4HCO3 → 5:95 (v / v) H2O: MeCN + 10 mM NH4HCO3, yielding the title compound as a grayish-white solid (81% yield). LCMS: m / z = 479.6 [M+H] + ; 1 HNMR (DMSO-d6): d = 10.23 (s, 1H), 8.54 (d, J = 5.0 Hz, 1H), 8.37 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.60 (t, J = 73.0 Hz, 1H), 7.52 (d, J = 5.0 Hz,1H), 6.91 (s, 1H), 6.61 (d, J = 8.5 Hz, 1H), 4.21 ~ 4.16 (m, 1H), 3.81 (s,3H), 3.14 (sept, J = 6.5 Hz, 1H), 2.06 ~ 1.89 (m, 4H), 1.81 ~ 1.76 (m, 1H), 1.45 ~ 1.34 (m, 2H), 1.33 ~ 1.26 (m, 1H), 1.23 (d, J = 6.5 Hz, 3H), 1.16 (d,J = 6.5 Hz, 3H), 0.98 ~ 0.95 (m, 1H).

[0257] Example 2: Preparation of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(3-isopropylpyridin-2-yl)ureo)cyclohexane-1-carboxylic acid

[0258]

[0259] Step 1In a thick-walled glass reaction vessel equipped with a magnetic stirrer and a PTFE screw cap, intermediate amine 2 (1 equivalent) and pyridine (3 equivalents) were mixed in anhydrous dichloromethane (0.43 M). Triphosgene (2 equivalents) was then added to the mixture in portions over 15 minutes at RT. After the addition was complete, the resulting mixture was stirred at RT for an additional 1 h. The mixture was then quenched with water and extracted with DCM. The combined organic extracts were further washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude product obtained was purified by column chromatography (SiO2, gradient elution: 9:1 (v / v) Hex: EtOAc → EtOAc) to give ethyl trans-4-((chlorocarbonyl)(3-isopropylpyridin-2-yl)amino)cyclohexane-1-carboxylate as a yellow oil (79% yield).

[0260] Step 2 In a thick-walled glass reaction vessel equipped with a magnetic stirrer and a PTFE screw cap, ethyl trans-4-((chlorocarbonyl)(3-isopropylpyridin-2-yl)amino)cyclohexane-1-carboxylate (1 equivalent), intermediate amine 3 (2.5 equivalents), and DMAP (0.2 equivalents) from the previous step were mixed in anhydrous dichloroethane (0.24 M). Pyridine (3 equivalents) was then added dropwise to this mixture over 5 minutes at RT. After the addition was complete, the vessel was sealed and heated at 110 °C for 2 h. The mixture was then cooled to RT, quenched with water, and extracted with DCM. The combined organic extracts were further washed with water and brine, dried with Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The crude product obtained was purified by column chromatography (SiO2, gradient elution: 9:1 (v / v) Hex: EtOAc → EtOAc) to give trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(3-isopropylpyridin-2-yl)ureido)cyclohexane-1-carboxylic acid ethyl ester, a white solid (68% yield).

[0261] Step 3 In a round-bottom flask equipped with a magnetic stirrer, ethyl trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(3-isopropylpyridin-2-yl)ureido)cyclohexane-1-carboxylate (1 equivalent) from the previous step was dissolved in a 1:1 (v / v) solution (0.13 M) of THF and methanol. Lithium hydroxide (1 M aqueous solution, 3 equivalents) was then added to this solution, and the resulting mixture was stirred at RT for 2 h. The reaction mixture was then carefully quenched with HCl (1 M aqueous solution, 3 equivalents), and volatiles were removed under vacuum. The crude product obtained was then subjected to reversed-phase column chromatography (C2000). 18The solution was purified by gradient elution: 95:5 (v / v) H2O: MeCN + 10 mM NH4HCO3 → 5:95 (v / v) H2O: MeCN + 10 mM NH4HCO3, yielding the title compound as a white solid (63% yield). LCMS: m / z = 479.4 [M+H] + ; 1 H NMR(DMSO-d6): d = 11.87 (s, 1H), 8.42 (dd, J = 4.8, 1.8 Hz, 1H), 7.94 (dd, J =7.8, 1.8 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.60 (t, J = 72.6 Hz, 1H), 7.44(dd, J = 7.8, 4.8 Hz, 1H), 6.86 (s, 1H), 6.61 (d, J = 8.4 Hz, 1H), 4.13 ~4.07 (m, 1H), 3.80 (s, 3H), 3.15 (sept, J = 6.0 Hz, 1H), 1.99 ~ 1.88 (m, 5H),1.37 ~ 1.33 (m, 4H), 1.17 (d, J = 6.8 Hz, 6H).

[0262] 2. Biological evaluation

[0263] Example 3: In vitro functional assay of lysophosphatidylcholine receptor 1 activity

[0264] Primary compound plates were prepared in 100% DMSO (Sigma-Aldrich), and secondary compound plates were prepared at 10-fold concentration in DMEM (Invitrogen), and then in the presence of HBSS (Ca-free) +2 / Mg -2Tertiary compound plates were prepared at 3-fold concentrations in assay buffers containing 0.1% BSA (Sigma-Aldrich) and Invitrogen (Invitrogen). Fluo-4 NW calcium assay dye (Invitrogen) was prepared in assay buffer according to the manufacturer's instructions. Stable B103 cells expressing human LPA1 (J. Chun's laboratory, UCSD) were cultured to confluence in DMEM medium (Invitrogen) containing 10% FBS (ATCC), 10% penicillin-streptomycin (Sigma-Aldrich), and 50 µg of genistein (Sigma-Aldrich), and detached from the cells with Accutase (Sigma-Aldrich) prior to assay. Freshly detached cells were resuspended in growth medium and cultured at 5 × 10⁻⁶ g / mL. 4 Cells were seeded at a density of 10 cells / well in black clear-bottomed 96-well plates (Costar) containing the compound (i.e., secondary compound plate). After seeding, cells were incubated at room temperature for 30 minutes and then transferred to a 37°C, 5% CO2 incubator for 24 hours. After 24 hours, the growth medium was removed and freshly prepared Fluo-4 NW calcium assay dye was added to the cells. The compound (i.e., tertiary compound plate) was then added back to the dye / cells, and the cells were returned to the incubator for 30 minutes, followed by an additional 30 minutes at room temperature. Finally, EC was added. 80 Calcium flux was measured using a FlexStation 3 (Molecular Devices) at a concentration of lysophosphatidic acid (18:1). An S-shaped dose-response curve was generated by measuring fluorescence over 45 seconds and calculating the area under the curve. Dose-response curves and IC50 were generated using Prism (GraphPad). 50 The compounds were tested in 0.1% DMSO at final concentrations ranging from 100 pM to 10 μM. The results are shown in Table 1.

[0265] Table 1

[0266]

[0267] A = IC 50 Less than 10 nM; B = IC 50 Less than 100 nM but greater than or equal to 10 nM; C = IC 50 Less than 1,000 nM but greater than or equal to 100 nM; D = IC 50 Greater than or equal to 1,000 nM

[0268] Table 2. Additional biological data

[0269]

[0270]

Claims

1. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the formula: (I)； in R 1 It is isopropyl or isobutyl; R 2 is -C(O)OH, -CH2C(O)OH, -CH2CH2C(O)OH, -C(O)NHS(O)2R 2A -P(O)(OH)2, -P(O)(OH)R 2A , -SO3H, -SO2H, -NHC(O)NHS(O)2R 2A , , , , , , , ,or ; R 2A It is an unsubstituted C1-C4 alkyl group; and R 3 R 4 R 5 and R 6 It is independently hydrogen or an unsubstituted C1-C4 alkyl group.

2. The compound according to claim 1, wherein R 3 R 4 R 5 and R 6 It can be hydrogen or an unsubstituted methyl group.

3. The compound according to claim 1, having the formula: (It)。 4. The compound according to claim 1, having the formula: (Ib).

5. The compound according to claim 1, wherein R 2 It is -C(O)OH, -CH2C(O)OH, -CH2CH2C(O)OH, -C(O)NHS(O)2CH3, -P(O)(OH)2, -P(O)(OH)CH3, -SO3H, -SO2H, -NHC(O)NHS(O)2CH3, , , , , , , ,or .

6. The compound according to claim 1, wherein R 2 It is -C(O)OH.

7. The compound according to claim 1, having the formula:

8. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the formula: (II); in R 1 It is isopropyl or isobutyl; R 2 is -C(O)OH, -CH2C(O)OH, -CH2CH2C(O)OH, -C(O)NHS(O)2R 2A -P(O)(OH)2, -P(O)(OH)R 2A , -SO3H, -SO2H, -NHC(O)NHS(O)2R 2A , , , , , , , ,or ; R 2A It is an unsubstituted C1-C4 alkyl group; and R 3 R 4 R 5 and R 6 It is independently hydrogen or an unsubstituted C1-C4 alkyl group.

9. The compound according to claim 8, wherein R 3 R 4 R 5 and R 6 It can be hydrogen or an unsubstituted methyl group.

10. The compound according to claim 8, having the formula: (IIa)。 11. The compound according to claim 8, having the formula: (IIb)。 12. The compound according to claim 8, wherein R 2 It is -C(O)OH, -CH2C(O)OH, -CH2CH2C(O)OH, -C(O)NHS(O)2CH3, -P(O)(OH)2, -P(O)(OH)CH3, -SO3H, -SO2H, -NHC(O)NHS(O)2CH3, , , , , , , ,or .

13. The compound according to claim 8, wherein R 2 It is -C(O)OH.

14. The compound according to claim 1, having the formula:

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

16. A method of treating peripherally restricted LPAR1-related disease in a subject with such need, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof.

17. The method of claim 16, wherein the peripherally restricted LPAR1-related disease is a fibrotic disease.

18. The method of claim 17, wherein the fibrotic disease is idiopathic pulmonary fibrosis, renal fibrosis, non-alcoholic steatohepatitis, or scleroderma.

19. The method of claim 16, wherein the peripherally restricted LPAR1-related disease is cancer.

20. The method of claim 19, wherein the cancer is ovarian cancer, breast cancer, liver cancer, stomach cancer, pancreatic cancer, lung cancer, or osteosarcoma.

21. A method for modulating LPAR1 activity in a subject, the method comprising administering to the subject a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof.

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