Inhibition of Human Integrin α4β7

Abstract

To provide small molecule antagonists of human α4β7 integrin, and methods of using the same to treat many diseases and conditions.SOLUTION: The invention provides a compound represented by formula (I) in the figure, which is, e.g., (S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 916,062, filed on October 16, 2019.

[0002] Novel compounds useful for the inhibition of α4β7 integrin, and related methods are disclosed. The compounds and methods disclosed herein are applicable for the development of pharmaceuticals for the treatment of α4β7 integrin-mediated pathologies such as, for example, inflammatory bowel disease (IBD), ulcerative colitis (UC), and Crohn's disease (CD).

Background Art

[0003] Integrins are cell surface receptors of non-covalently associated α / β heterodimers that are involved in many cell processes. Differential expression of integrins regulates the adhesive properties of cells and enables the recruitment of various leukocyte populations to specific organs in response to various inflammatory signals. α4 integrins, including α4β7, are involved in lymphocyte trafficking throughout the gastrointestinal tract. The integrin is expressed on most leukocytes, including B and T lymphocytes, and mediates cell adhesion through selective binding to its primary ligand, mucosal addressin cell adhesion molecule (MadCAM). Memory T lymphocytes expressing α4β7 integrin preferentially migrate into the gastrointestinal tract through stable adhesion to mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1).

[0004] Inhibitors of specific integrin-ligand interactions are being used in the treatment of various diseases. For example, monoclonal antibodies that exhibit high binding affinity for α4β7 have shown therapeutic effects against gastrointestinal autoinflammatory / autoimmune diseases such as Crohn's disease and ulcerative colitis. However, these treatments also have certain undesirable characteristics for patients. Monoclonal antibody α4β7 integrin inhibitors are administered parenterally, have a long half-life, cannot rapidly alter exposure, and their activity is reduced by the formation of anti-drug antibodies. Monoclonal antibody therapy can also be difficult to manufacture compared to small molecule therapeutics. In addition, some therapeutics that inhibit α4β7 also interfere with α4β1 integrin-ligand interactions, causing dangerous side effects in patients. In immunosuppressed patients, the activity of α4β1 integrin is involved in the development of progressive multifocal leukoencephalopathy (PML), a life-threatening progressive brain infection.

[0005] For example, as an important addition to pharmaceuticals for the treatment of α4β7 integrin-mediated conditions such as inflammatory bowel disease (IBD), ulcerative colitis (UC), and Crohn's disease (CD), there remains a medical need for effective and safe oral α4β7 integrin inhibitors.

Summary of the Invention

[0006] In certain embodiments, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Chemical formula

Chemical formula

[0007] In some embodiments of the present invention, in the compound of formula (I), only one of R a 、R b 、and R c is substituted or unsubstituted -(C1-C5)alkylene-N-(R x )(R y ); R1 is (C1-C6)alkyl (e.g., isobutyl); R 3a and R 3bis independently selected from the group consisting of H, (C1-C4)-alkyl (e.g., methyl), halide (e.g., F or Cl), CF3, C(H)F2, and C(F)H2, provided that R 3a and R 3b are not both H; and R4 may be a compound that is H.

[0008] In some examples, the compound of formula (I) has only one of R a , R b , and R c being a substituted or unsubstituted -(C1-C5)alkylene-N-(R x )(R y ); R x and R y are each independently an unsubstituted (C1-C6)-alkyl (e.g., methyl), or R x and R y form a substituted or unsubstituted 4- to 6-membered heterocyclyl ring together with the N to which they are attached; R1 is an unsubstituted (C1-C6)alkyl (e.g., isobutyl); R 3a and R 3b are independently selected from the group consisting of H, unsubstituted (C1-C4)-alkyl (e.g., methyl, ethyl, etc.), halide (e.g., F or Cl), CF3, C(H)F2, and C(F)H2, provided that R 3a and R 3b are not both H; R 3c is selected from the group consisting of H, F, Cl, hydroxyl, substituted or unsubstituted (C1-C4)-alkyl (e.g., methyl), substituted or unsubstituted (C3-C6)-cycloalkyl (e.g., cyclopropyl), (C1-C4)-alkoxy (e.g., methoxy); R 3d is selected from the group consisting of H, halide (e.g., F or Cl), substituted or unsubstituted (C1-C4)-alkyl (e.g., methyl) and hydroxyl; and R4 may be a compound that is H. In some examples, the compounds of formula (I), formula (Ia) and / or formula (Ib) have R a , R b, and R c Only one of them is a substituted or unsubstituted -(C1-C5) alkylene-N-(R x )(R y ); R x and R y are each independently unsubstituted methyl, or R x and R y together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclic ring; R1 is isobutyl; R 3a and R 3b are independently selected from the group consisting of unsubstituted (C1-C4)-alkyl (such as methyl, etc.), halides (such as F or Cl), CF3, C(H)F2, and C(F)H2, R 3c and R 3d are both H; and R4 may be H. For example, the compounds of formula (I), formula (Ia) and / or formula (Ib) are such that R1 is isobutyl; R 3a and R 3b are independently selected from the group consisting of unsubstituted (C1-C4)-alkyl (such as methyl), halides (such as F or Cl), CF3, C(H)F2, and C(F)H2; R 3c and R 3d are both H; R4 is H; and R 5a and R 5e may each be a substituted or unsubstituted (C1-C4)-alkyl (such as methyl). The compound of formula (I) is such that only one of R a , R b , and R c is a substituted or unsubstituted -(C1-C5) alkylene-N-(R x )(R y ); R x and R y are each independently unsubstituted methyl, or R x and R y together with the N to which they are attached form a 4- to 6-membered heterocyclic ring optionally substituted with a halide (such as F); R1 is isobutyl; R 3a and R3b is independently selected from the group consisting of unsubstituted (C1-C4)-alkyl (e.g., methyl), halide (e.g., F or Cl), CF3, C(H)F2, and C(F)H2; R 3c and R 3d are both H; R4 is H; R 5a and R 5e are each substituted or unsubstituted (C1-C4)-alkyl (e.g., methyl), and R 5b , R 5c , and R 5d are each independently selected from the group consisting of H, CN, halide (e.g., F, Cl), CF3, C(H)F2, C(F)H2, (C1-C5)-alkyl, hydroxyl, and (C1-C4)-alkoxy. In certain embodiments, the present invention relates to a method of treating an autoinflammatory / autoimmune disease such as, for example, Crohn's disease and ulcerative colitis, the method comprising administering to a subject in need thereof a therapeutically effective amount of any one of the compounds described herein.

[0009] In some embodiments, the compound of formula (I) is a compound of formula (Ia):

Chemical formula

[0010]

Chemical formula

[0011] Methods for preparing and isolating compounds of formula (I), formula (Ia) and / or formula (Ib) are also provided herein.

Brief Description of the Drawings

[0012]

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DETAILED DESCRIPTION OF THE INVENTION

[0013] In certain embodiments, the present invention relates to compounds that antagonize α4β7 integrin. The compounds are useful for the treatment of diseases treatable by inhibition of α4β7 integrin, such as Crohn's disease (CD) and ulcerative colitis (UC).

[0014] Definition For the sake of simplicity, before detailing the present invention, the specific terms employed in this specification, the examples and the appended claims are collected herein. These definitions should be read in light of the remainder of the present disclosure and the understanding of those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0015] To make the present invention more readily understood, specific terms and phrases are defined below and throughout this specification.

[0016] The articles "a" and "an" are used in the present disclosure to refer to one or more (i.e., at least one) of the grammatical objects of the article. By way of example, "an element" means one element or more than one element.

[0017] As used in this specification and the claims, the phrase "and / or" is to be understood to mean "either, or both" of the elements so conjoined. That is, the elements may exist connected in some instances and separately in other instances. Multiple elements listed in "and / or" are to be construed in the same fashion. That is, they are to be construed as "one or more" of the elements so conjoined. Optionally, whether or not specifically identified with another element, other elements may be present in addition to those specifically identified by the phrase "and / or". Thus, as a non-limiting example, when used in conjunction with open-ended language such as "comprising", a reference to "A and / or B" may, in one embodiment, refer to only A (optionally including elements other than B), in another embodiment, refer to only B (optionally including elements other than A), and in yet another embodiment, refer to both A and B (optionally including other elements).

[0018] As used in the specification and the claims, "or" is to be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive. That is, it includes at least one of the number of elements or items in the list, but also includes more than one, and optionally items not in the additional list. Only terms that are clearly indicated to be the contrary, such as, for example, "only one of" or "exactly one of", or "consisting of" when used in the claims, refer to the inclusion of exactly one of the number of elements or items in the list. Generally, as used in this specification, the term "or" is to be interpreted to indicate exclusive alternatives (i.e., "one or the other but not both") only when preceded by exclusive terms such as, for example, "either", "one of", "only one of", or "exactly one of". As used in the claims, "consisting essentially of" shall have its ordinary meaning as used in the field of patent law.

[0019] As used in the specification and claims, the phrase "at least one" in relation to a list of one or more elements is to be understood to mean at least one element selected from any one or more of the elements in the list of such elements. However, it is not necessarily intended to include at least one of each and every element specifically listed within the list of such elements, nor is it intended to exclude any combinations of elements in the list of such elements. This definition further allows for the possibility that elements other than those specifically identified within the list of elements referred to by the phrase "at least one" may optionally exist, whether or not they are related to the specifically identified elements. Thus, by way of non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B" or equivalently, "at least one of A and / or B") may, in one embodiment, refer to at least one, optionally including a plurality of A, and no B (and optionally including elements other than B). In another embodiment, it may refer to at least one, optionally including a plurality of B, and no A (and optionally including elements other than A). In yet another embodiment, it may refer to at least one, optionally including a plurality of A, and at least one, optionally including a plurality of B (and optionally including other elements).

[0020] It should be understood that, unless clearly indicated to the contrary, in any method claimed in this specification that includes a plurality of steps or acts, the order of the steps and acts of the method is not necessarily limited to the order in which the steps and acts of the method are recited.

[0021] In the claims and the above specification, all transitional phrases such as, for example, "comprising", "including", "having", "containing", "involving", "carrying", "consisting of", etc. are to be understood to be open-ended, i.e., to mean including but not limited to the following. Only the transitional phrases "consisting of" and "essentially consisting of" are respectively restrictive or semi-restrictive transitional phrases, and this is described in the United States Patent and Trademark Office's Manual of Patent Examining Procedure, Section 2111.03.

[0022] The specific compounds contained in the compositions of the present invention may exist in specific geometric forms or stereoisomeric forms. Further, the polymers of the present invention may be optically active. The present invention contemplates all such compounds, including cis and trans isomers, R - enantiomers and S - enantiomers, diastereomers, (D) - isomers, (L) - isomers, their racemic mixtures, and other mixtures thereof, as being within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as, for example, alkyl groups. All such isomers, and mixtures thereof, are intended to be included in the present invention.

[0023] For example, if a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis or by derivatization using a chiral auxiliary, and the resulting mixture of diastereomers is separated and the auxiliary is cleaved to produce the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as, for example, an amino group, or an acidic functional group such as, for example, a carboxyl group, diastereomeric salts are formed with an appropriate optically active acid or base, and then the diastereomers formed are resolved by fractional crystallization or chromatography methods known in the art, and thereafter the pure enantiomer is collected.

[0024] The structures shown in this specification are also intended to include compounds that differ only by the presence of one or more isotope-enriched atoms. For example, compounds produced by substituting hydrogen with deuterium or tritium, or compounds produced by substituting carbon with 13 C or 14 carbon enriched in

[0025] As used herein, terms such as "α4β7", "a4B7", "a4b7", "alpha-4 beta-7", and "alpha4 beta7" all refer to α4β7.

[0026] As used herein, the terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" mean pharmaceutically acceptable substances, compositions or vehicles such as, for example, liquid or solid fillers, diluents, excipients, solvents or encapsulating materials, which are involved in the transport or delivery of the subject compound from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, not being harmful to the patient, and being substantially free of pyrogenic activity. Some examples of substances that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free distilled water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic and compatible substances employed in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the invention are non-pyrogenic. That is, they do not induce a significant increase in temperature when administered to a patient.

[0027] The term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic base addition salts of the compounds. These salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free form with a suitable organic or inorganic acid and isolating the formed salt. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfonate, etc. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).

[0028] In other instances, compounds useful in the methods of the present invention may contain one or more acidic functional groups and, accordingly, are capable of forming pharmaceutically acceptable base addition salts with pharmaceutically acceptable bases. In these instances, the term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic base addition salts of the compounds. These salts may likewise be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid form with a suitable base such as, for example, a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include salts of lithium, sodium, potassium, calcium, magnesium and aluminum, etc. Representative organic amines useful in the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (See, for example, Berge et al. supra).

[0029] For use in therapy, a "therapeutically effective amount" (or "effective amount") of a compound, as part of a desired dosing regimen or for cosmetic purposes, when administered (to a mammal, preferably a human), is an amount of the compound in a preparation that, at a reasonable benefit / risk ratio applicable to any medical treatment, reduces symptoms, improves the condition, or delays the onset of a disease state, in accordance with clinically accepted standards for the disorder or condition being treated.

[0030] The term "preventive or therapeutic" treatment is recognized in the art and includes administration to one or more hosts of a composition of the subject. When administered prior to the clinical signs of an undesirable state (e.g., a disease or other undesirable state of the host animal), the treatment is preventive (i.e., protects the host from the manifestation of the undesirable state). On the other hand, when administered after the manifestation of an undesirable state, the treatment is therapeutic (i.e., is intended to reduce, improve, or stabilize an already existing undesirable state or its side effects).

[0031] The term "patient" refers to a mammal in need of a particular treatment. In certain embodiments, the patient is a primate, dog, cat, or horse. In certain embodiments, the patient is a human.

[0032] Aliphatic chains include the classes of alkyl, alkenyl, and alkynyl as defined below. Straight-chain aliphatic chains are limited to non-branched carbon chain moieties. As used herein, the term "aliphatic group" refers to straight-chain, branched-chain, or cyclic aliphatic hydrocarbon groups, including saturated aliphatic groups and unsaturated aliphatic groups such as alkyl groups, alkenyl groups, or alkynyl groups.

[0033] "Alkyl" refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having a specified number of carbon atoms, or having 1 to 30 carbon atoms if no specification is given. For example, alkyl having 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and moieties that are positional isomers of these moieties. Alkyl having 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. In certain embodiments, the straight-chain or branched-chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C 30 , C3-C 30 for branched chains), more preferably 20 or fewer. The alkyl group may be substituted or unsubstituted. As used herein, both "Me" and -CH3 refer to methyl.

[0034] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbons, such as 2 to 12 carbon atoms, and containing two attachment points for the remainder of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, and the like. The alkylene group may be cyclic or acyclic, branched or unbranched carbon chain moiety, and may optionally be substituted with one or more substituents.

[0035] "Cycloalkyl" means a monocyclic or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic ring, each having 3 to 12 carbon atoms. Similarly, preferred cycloalkyl has 3 to 10 carbon atoms in its cyclic structure, more preferably 3 to 6 carbons in the cyclic structure. The cycloalkyl group may be substituted or unsubstituted.

[0036] Unless otherwise specified, as used herein, "lower alkyl" means an alkyl group as defined above, having from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms, in its backbone structure, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" also have similar chain lengths. Throughout this application, the preferred alkyl group is lower alkyl. In certain embodiments, the substituent designated as alkyl herein is lower alkyl.

[0037] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups of 3 to 12 members, where each atom of the ring is carbon (i.e., carbocyclic aryl) or one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, the aryl group includes a ring of 5 to 12 members, more preferably a ring of 6 to 10 members. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings, where two or more carbons are shared by two adjacent rings and at least one of the rings is aromatic. For example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc. Heteroaryl groups include substituted or unsubstituted aromatic ring structures of 3 to 12 members, more preferably 5 to 12 members, more preferably 5 to 10 members, and the ring structure contains 1 to 4 heteroatoms. Examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl and heteroaryl may be monocyclic, bicyclic, or polycyclic.

[0038] As used herein, the terms "halo", "halide", or "halogen" mean halogen and include, for example, but not limited to, fluoro, chloro, bromo, iodo, etc. in both radioactive and non-radioactive forms. In preferred embodiments, halo is selected from the group consisting of fluoro, chloro, and bromo.

[0039] The term "heterocyclyl" or "heterocyclic group" refers to a ring structure having 3 to 12 members, more preferably 5 to 12 members, and even more preferably 5 to 10 members, and the ring structure contains 1 to 4 heteroatoms. The heterocycle may be monocyclic, bicyclic, spirocyclic, or polycyclic. Examples of heterocyclyl groups include thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactone, lactam, such as azetidinone and pyrrolidinone, sultam, sultone, and the like. The heterocyclic ring may be substituted at one or more positions with substituents such as those described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphate, phosphonate, phosphinate, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic moiety or heteroaromatic moiety, -CF3, -CN, etc.

[0040] The term "carbonyl" is recognized in the art and includes moieties that can be represented by the following formula:

Chem.

[0041] As used herein, the term "substituted" is expected to include all acceptable substituents of an organic compound. In a broad aspect, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Exemplary substituents include, for example, those described above, and those substituted with one or more substituents selected from, for example, alkyl, cycloalkyl, heterocyclyl acyl, halogen, OH, OMe, C(H)F2, C(F)H2, CF3, C(H)2CF3, SF5, CHFCH2 amine, CH2 amine, and CN. The acceptable substituents may be one or more and may be the same or different for a suitable organic compound. For the purposes of the present invention, a heteroatom such as nitrogen, for example, may have a hydrogen substituent satisfying the valence of the heteroatom and / or any acceptable substituent of the organic compounds described herein. The present invention is not intended to be limited in any way by the acceptable substituents of the organic compounds. "Substituted" or "substituted with" implies the implicit conditions that such substitution is in accordance with the acceptable valences of the atoms being substituted and the substituents, and that the substitution results in a stable compound, i.e., a compound that does not undergo spontaneous transformation such as rearrangement, cyclization, elimination, etc.

[0042] As used herein, the term "nitro" means -NO2. The term "halogen" refers to -F, -Cl, -Br, or -I. The term "hydroxyl" means -OH. The term "cyano" means -CN.

[0043] As used herein, the definition of each expression, for example, alkyl, m, n, etc., is intended to be independent of its definition at another location within the same structure when it occurs multiple times in any structure.

[0044] As used herein, the term "prodrug" encompasses a compound that is converted to a therapeutically active agent under physiological conditions. A common method for making a prodrug is to include a select moiety that is hydrolyzed under physiological conditions to expose the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal.

[0045] For the purposes of the present invention, it is specified according to the inside of the cover of the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986 - 87.

[0046] Exemplary compounds In some embodiments, the present invention relates to a compound of formula (I), formula (Ia), or formula (Ib), or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

[0047] In some embodiments, the compound of formula (Ia) may be a compound as follows, or a pharmaceutically acceptable salt thereof: R a is Me; R b is substituted or unsubstituted -(C 1- C5)alkylene-N-(R x )(R y ); R x and R y are independently selected from the group consisting of H and substituted or unsubstituted (C1-C6)-alkyl; or R x and R y form a 4- to 6-membered ring together with the N to which they are attached; R c is H; R1 is (C1-C6)-alkyl; R 3a is halide; R 3b is (C1-C5)-alkyl; R 3c is H; R 3d is H; R4 is H; R 5a and R 5e are (C1-C5)-alkyl; and R 5b 、R 5c 、and R 5dIndependently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, -CH2CF3, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, hydroxyl, and (C1-C4)-alkoxy.

[0048] In some embodiments, the compound of formula (Ia) may be a compound as follows, or a pharmaceutically acceptable salt thereof: R a is Me; R b is substituted or unsubstituted -(C 1- C5)alkylene-N-(R x )(R y ) and; R x and R y are independently selected from the group consisting of H and substituted or unsubstituted (C1-C6)-alkyl; or R x and R y together with the N to which they are attached form a 4- to 6-membered ring; R c is H; R1 is (C1-C6)-alkyl; R 3a is a halide; R 3b is a halide; R 3c is H; R 3d is H; R4 is H; R 5a and R 5e are (C1-C5)-alkyl; and R 5b R 5c and R 5d are independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, -CH2CF3, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, hydroxyl, and (C1-C4)-alkoxy.

[0049] In some embodiments, the compound of formula (Ia) may be a compound as follows, or a pharmaceutically acceptable salt thereof: R ais H; R b is a substituted or unsubstituted -(C 1- C5)alkylene-N-(R x )(R y ); R x and R y are independently selected from the group consisting of H and substituted or unsubstituted (C1-C6)-alkyl; or R x and R y together with the N to which they are attached form a 4- to 6-membered ring; R c is CH(F)2; R1 is (C1-C6)-alkyl; R 3a is a halide; R 3b is (C1-C5)-alkyl; R 3c is H; R 3d is H; R4 is H; R 5a and R 5e are (C1-C5)-alkyl; and R 5b , R 5c , and R 5d are independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, -CH2CF3, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, hydroxyl, and (C1-C4)-alkoxy.

[0050] In some embodiments, the compound of formula (Ia) may be a compound as follows, or a pharmaceutically acceptable salt thereof: R a is H; R b is a substituted or unsubstituted -(C 1- C5)alkylene-N-(R x )(R y ); R x and R y are independently selected from the group consisting of H and substituted or unsubstituted (C1-C6)-alkyl; or R x and R y together with the N to which they are attached form a 4- to 6-membered ring; R cis a halide; R1 is (C1-C6)-alkyl; R 3a is a halide; R 3b is (C1-C5)-alkyl; R 3c is H; R 3d is H; R4 is H; R 5a and R 5e is (C1-C5)-alkyl; and R 5b 、R 5c 、and R 5d are independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, -CH2CF3, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, hydroxyl, and (C1-C4)-alkoxy.

[0051] In some embodiments, the compound of formula (Ia) may be a compound as follows, or a pharmaceutically acceptable salt thereof: R a is CF3; R b is substituted or unsubstituted -(C 1- C5)alkylene-N-(R x )(R y ); R x and R y are independently selected from the group consisting of H and substituted or unsubstituted (C1-C6)-alkyl; or R x and R y form a 4- to 6-membered ring together with the N to which they are attached; R c is H; R1 is (C1-C6)-alkyl; R 3a is a halide; R 3b is (C1-C5)-alkyl; R 3c is H; R 3d is H; R4 is H; R 5a and R 5e are (C1-C5)-alkyl; and R 5b 、R 5c 、and R 5dis independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, -CH2CF3, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, hydroxyl, and (C1-C4)-alkoxy.

[0052] In some embodiments, the compound of formula (Ia) may be a compound as follows, or a pharmaceutically acceptable salt thereof: R a is CF3; R b is substituted or unsubstituted -(C 1- C5)alkylene-N-(R x )(R y )wherein; R x and R y are independently selected from the group consisting of H and substituted or unsubstituted (C1-C6)-alkyl; or R x and R y together with the N to which they are attached form a 4- to 6-membered ring; R c is H; R1 is (C1-C6)-alkyl; R 3a is halide; R 3b is CF3; R 3c is H; R 3d is H; R4 is H; R 5a and R 5e are (C1-C5)-alkyl; and R 5b , R 5c , and R 5d are independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, -CH2CF3, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, hydroxyl, and (C1-C4)-alkoxy.

[0053] In some embodiments, the compound of formula (Ia) may be a compound as follows, or a pharmaceutically acceptable salt thereof: R ais CF3; R b is a substituted or unsubstituted -(C 1- C5)alkylene-N-(R x )(R y )wherein; R x and R y are independently selected from the group consisting of H and substituted or unsubstituted (C1-C6)-alkyl; or R x and R y together with the N to which they are attached form a 4- to 6-membered ring; R c is H; R1 is (C1-C6)-alkyl; R 3a is a halide; R 3b is a halide; R 3c is H; R 3d is H; R4 is H; R 5a and R 5e are (C1-C5)-alkyl; and R 5b , R 5c , and R 5d are independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, -CH2CF3, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, hydroxyl, and (C1-C4)-alkoxy.

[0054] In some embodiments, the compound of formula (Ia) may be a compound as follows, or a pharmaceutically acceptable salt thereof: R a is CF3; R b is a substituted or unsubstituted -(C 1- C5)alkylene-N-(R x )(R y )wherein; R x and R y are independently selected from the group consisting of H and substituted or unsubstituted (C1-C6)-alkyl; or R x and R y together with the N to which they are attached form a 4- to 6-membered ring; R cis H; R1 is (C1-C6)-alkyl; R 3a is a halide; R 3b is (C3-C6)-cycloalkyl; R 3c is H; R 3d is a halide; R4 is H; R 5a and R 5e are (C1-C5)-alkyl; and R 5b , R 5c , and R 5d are independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, -CH2CF3, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, hydroxyl, and (C1-C4)-alkoxy.

[0055] In some embodiments, the compound of formula (Ia) may be a compound as follows, or a pharmaceutically acceptable salt thereof: R a is CF3; R b is substituted or unsubstituted -(C 1- C5)alkylene-N-(R x )(R y ); R x and R y are independently selected from the group consisting of H and substituted or unsubstituted (C1-C6)-alkyl; or R x and R y form a 4- to 6-membered ring together with the N to which they are attached; R c is H; R1 is (C1-C6)-alkyl; R 3a is a halide; R 3b is CF3; R 3c is H; R 3d is a halide; R4 is H; R 5a and R 5e are (C1-C5)-alkyl; and R 5b , R 5c , and R 5dis independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, -CH2CF3, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, hydroxyl, and (C1-C4)-alkoxy.

[0056] In some embodiments, the compound of formula (Ia) may be a compound as follows, or a pharmaceutically acceptable salt thereof: R a is CF3; R b is substituted or unsubstituted -(C 1- C5)alkylene-N-(R x )(R y ) and; R x and R y are independently selected from the group consisting of H and substituted or unsubstituted (C1-C6)-alkyl; or R x and R y together with the N to which they are attached form a 4- to 6-membered ring; R c is H; R1 is (C1-C6)-alkyl; R 3a is halide; R 3b is (C1-C5)-alkyl; R 3c is H; R 3d is halide; R4 is H; R 5a and R 5e are (C1-C5)-alkyl; and R 5b R 5c and R 5d are independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, -CH2CF3, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, hydroxyl, and (C1-C4)-alkoxy.

[0057] In some embodiments, the compound of formula (Ia) is R 5ais a halide or (C1-C5)-alkyl; R 5b is H, a halide, or a substituted or unsubstituted (C1-C5)-alkyl; R 5c is H, a halide, a substituted or unsubstituted (C1-C5)-alkyl, or a substituted or unsubstituted (C3-C6)-cycloalkyl; and R 5d is selected from the group consisting of H, a halide, CF3, C(H)F2, C(F)H2, -CH2CF3, a substituted or unsubstituted (C1-C5)-alkyl, a substituted or unsubstituted (C3-C6)-cycloalkyl, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, hydroxyl, and (C1-C4)-alkoxy; and R5e may be a halide or (C1-C5)-alkyl, a compound.

[0058] In some embodiments, the compound of formula (I) may be a compound of formula (Ia), a compound of formula (Ib), a compound of formula (Ic), and / or a compound of formula (Id):

Chemical formula

[0059] In some embodiments, the compound of formula (I) may be a compound of formula (II) comprising a compound of formula (IIa), a compound of formula (IIb), or a compound of formula (IIc).

Chemical formula

[0060] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is unsubstituted (C1-C6) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is substituted (C1-C6) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is substituted or unsubstituted (C1-C4) alkyl. In certain embodiments, R1 is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, sec-butyl, or t-butyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is [Chemical formula] selected from the group consisting of. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is substituted (C1-C4)-alkylene-(C3-C6)-cycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is unsubstituted (C1-C4)-alkylene-(C3-C6)-cycloalkyl. In certain embodiments, R1 is [Chemical formula] . In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, R1 is [Chemical formula] . In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is [Chemical formula] That is. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is

Chemical formula

[0061] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3a is H; provided that both R 3a and R 3b are not both H. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3a is unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3a is substituted (C1-C4) alkyl. In certain embodiments, the substituted (C1-C5) alkyl is substituted with a halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 3a is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3a is substituted (C3-C6) cycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3a is substituted or unsubstituted (C3-C6) cycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3a is cyclopropyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3a is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3ais CF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3a is C(H)F2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3a is C(F)H2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3a is a substituted (C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3a is an unsubstituted (C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3a is -OCF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3a is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3a is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3a is F.

[0062] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is H; provided that both R 3a and R 3b are not both H. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is an unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3bis a substituted (C1-C4) alkyl. In certain embodiments, the substituted (C1-C5) alkyl is substituted with a halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 3b is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is a substituted (C3-C6) cycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is a substituted or unsubstituted (C3-C6) cycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is cyclopropyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is CF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is C(H)F2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is C(F)H2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is a substituted (C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is an unsubstituted (C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is -OCF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3bis a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is selected from the group consisting of (C1-C4)-alkylene optionally substituted with one or more halides, and (C3-C6)-cycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is selected from the group consisting of methyl, cyclopropyl, and CF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is methyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is selected from the group consisting of halides, (C1-C4)-alkylene optionally substituted with one or more halides, and (C3-C6)-cycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is selected from the group consisting of F, Cl, methyl, and CF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is methyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is F. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is Cl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3b is CF3.

[0063] In certain embodiments, R 3aand R 3b are each independently selected from the group consisting of H, (C1-C5)-alkyl, halide, CF3, C(H)F2, and C(F)H2; provided that R 3a and R 3b are not both H. For example, R 3a and R 3b may each independently be selected from the group consisting of H, methyl, Cl, F, CF3, C(H)F2, and C(F)H2; provided that R 3a and R 3b are not both H. In certain embodiments, R 3a is a halide, and R 3b is selected from the group consisting of (C1-C4)-alkylene optionally substituted with one or more halides, and (C3-C6)-cycloalkyl. In certain embodiments, R 3a is F, and R 3b is selected from the group consisting of (C1-C4)-alkylene optionally substituted with one or more halides, and (C3-C6)-cycloalkyl. In certain embodiments, R 3a is F, and R 3b is selected from the group consisting of methyl, cyclopropyl, and CF3. In certain embodiments, R 3a is F, and R 3b is selected from the group consisting of F, Cl, methyl, and CF3. In certain embodiments, R 3a is F, and R 3b is selected from the group consisting of F, Cl, methyl, cyclopropyl, and CF3.

[0064] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3c is selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted cyclopropyl, hydroxyl, methoxy, halide, CF3, C(H)F2, C(F)H2, and -CN. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3cis H. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3c is unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3c is substituted (C1-C4) alkyl. In certain embodiments, the substituted (C1-C5) alkyl is substituted with halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 3c is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3c is substituted (C3-C6) cycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3c is substituted or unsubstituted (C3-C6) cycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3c is cyclopropyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3c is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3c is CF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3c is C(H)F2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3c is C(F)H2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3c is substituted (C1-C4) -alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3cis an unsubstituted (C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3c is -OCF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3c is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3c is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe.

[0065] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3c is H, and R 3a is a halide; R 3b is selected from the group consisting of (C1-C4)-alkylene optionally substituted with one or more halides, and (C3-C6)-cycloalkyl. In certain embodiments, R 3c is H, and R 3a is F; and R 3b is selected from the group consisting of (C1-C4)-alkylene optionally substituted with one or more halides, and (C3-C6)-cycloalkyl. In certain embodiments, R 3c is H; R 3a is F; R 3b is selected from the group consisting of methyl, cyclopropyl, and CF3. In certain embodiments, R 3c is H; R 3a is F; R 3b is selected from the group consisting of F, Cl, methyl, and CF3. In certain embodiments, R 3c is H; R 3a is F; R 3bis selected from the group consisting of F, Cl, methyl, cyclopropyl, and CF3. In certain embodiments, the invention relates to any one of the foregoing compounds, wherein R 3d is selected from the group consisting of H, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl, halide, methoxy, halide, CF3, C(H)F2, and C(F)H2. In certain embodiments, the invention relates to any one of the foregoing compounds, wherein R 3d is H. In certain embodiments, the invention relates to any one of the foregoing compounds, wherein R 3d is unsubstituted (C1-C4) alkyl. In certain embodiments, the invention relates to any one of the foregoing compounds, wherein R 3d is substituted (C1-C4) alkyl. In certain embodiments, the substituted (C1-C5) alkyl is substituted with a halogen. In certain embodiments, the halogen is F. In certain embodiments, R 3d is methyl. In certain embodiments, the invention relates to any one of the foregoing compounds, wherein R 3d is substituted (C3-C6) cycloalkyl. In certain embodiments, the invention relates to any one of the foregoing compounds, wherein R 3c is substituted or unsubstituted (C3-C6) cycloalkyl. In certain embodiments, the invention relates to any one of the foregoing compounds, wherein R 3d is cyclopropyl. In certain embodiments, the invention relates to any one of the foregoing compounds, wherein R 3d is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, the invention relates to any one of the foregoing compounds, wherein R 3d is CF3. In certain embodiments, the invention relates to any one of the foregoing compounds, wherein R 3dis C(H)F2. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 3d is C(F)H2. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 3d is a substituted (C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 3d is an unsubstituted (C1-C4)-alkoxy. In certain embodiments, -(C1-C4)-alkoxy is methoxy. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 3d is -OCF3. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 3d is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 3d is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe.

[0066] In some embodiments, R 3c and R 3d are the same. In some embodiments, R 3c and R 3d are both H. In some embodiments, R 3c and R 3d are different. In some embodiments, R 3c is H and R 3d is H or a halide. In some embodiments, R 3c is H and R 3d is F.

[0067] In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 3c and R3d Both are H; R 3a is a halide; and R 3b is selected from the group consisting of (C1-C4)-alkylene optionally substituted with one or more halides, and (C3-C6)-cycloalkyl. In certain embodiments, R 3c and R 3d both are H; R 3a is F; and R 3b is selected from the group consisting of (C1-C4)-alkylene optionally substituted with one or more halides, and (C3-C6)-cycloalkyl. In certain embodiments, R 3c and R 3d both are H; R 3a is F; and R 3b is selected from the group consisting of methyl, cyclopropyl, and CF3. In certain embodiments, R 3c and R 3d both are H; R 3a is F; R 3b is selected from the group consisting of F, Cl, methyl, and CF3. In certain embodiments, R 3c and R 3d both are H; R 3a is F; R 3b is selected from the group consisting of F, Cl, methyl, cyclopropyl, and CF3.

[0068] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 3c is H; R 3d is F; R 3a is a halide; and R 3b is selected from the group consisting of (C1-C4)-alkylene optionally substituted with one or more halides, and (C3-C6)-cycloalkyl. In certain embodiments, R 3c is H; R 3d is F; R 3a is F; and R 3bis selected from the group consisting of (C1-C4)-alkylene optionally substituted with one or more halides, and (C3-C6)-cycloalkyl. In certain embodiments, R 3c is H; R 3d is F; R 3a is F; and R 3b is selected from the group consisting of methyl, cyclopropyl, and CF3. In certain embodiments, R 3c is H; R 3d is F; R 3a is F; R 3b is selected from the group consisting of F, Cl, methyl, and CF3. In certain embodiments, R 3c is H; R 3d is F; R 3a is F; R 3b is selected from the group consisting of F, Cl, methyl, cyclopropyl, and CF3.

[0069] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is H. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is substituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is methyl, ethyl, n-propyl, or i-propyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is methyl or ethyl.

[0070] In certain embodiments, R5 is H. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5a is substituted or unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5ais unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5a is substituted (C1-C4) alkyl. In certain embodiments, the substituted (C1-C5) alkyl is substituted with one or more halogens. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5a is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, R 5a is methyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5a is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, R 5a is substituted (C 3- C6)-cycloalkyl. In certain embodiments, R 5a is unsubstituted (C 3- C6) cycloalkyl. In some embodiments, the (C3-C6)-cycloalkyl is cyclopropyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5a is CF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5a is C(H)F2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5a is C(F)H2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5a is (C1-C4)-alkoxy. In some embodiments, the (C1-C4)-alkoxy is methoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5a is methoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5ais hydroxyl. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5a is -OCF3. In certain embodiments, R 5a is CN. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5a is substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5a is unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe. In certain embodiments, R 5a is CH2OH.

[0071] In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5b is CN. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5b is unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5b is substituted (C1-C4) alkyl. In certain embodiments, the substituted (C1-C5) alkyl is substituted with a halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5b is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, R 5a is methyl. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5b is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, R 5b is substituted (C 3- C6)-cycloalkyl. In certain embodiments, R5b is an unsubstituted (C 3- C6) cycloalkyl. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5b is CF3. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5b is C(H)F2. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5b is C(F)H2. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5b is (C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5b is methoxy. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5b is hydroxyl. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5b is -OCF3. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5b is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5b is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5b is hydrogen.

[0072] In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5c is CN. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R5c is unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5c is substituted (C1-C4) alkyl. In certain embodiments, the substituted (C1-C5) alkyl is substituted with halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5c is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, R 5c is methyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5c is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, R 5c is substituted (C 3- C6)-cycloalkyl. In certain embodiments, R 5c is cyclopropyl. In certain embodiments, R 5c is unsubstituted (C 3- C6) cycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5c is CF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5c is C(H)F2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5c is C(F)H2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5c is (C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5c is methoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5cis hydroxyl. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5c is -OCF3. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5c is substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5c is unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5c is hydrogen.

[0073] In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5d is CN. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5d is unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5d is substituted (C1-C4) alkyl. In certain embodiments, the substituted (C1-C5) alkyl is substituted with halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5d is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, R 5d is methyl. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5d is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, R 5d is substituted (C 3- C6)-cycloalkyl. In certain embodiments, R5d is an unsubstituted (C 3- C6) cycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is CF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is C(H)F2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is C(F)H2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is (C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is methoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is hydroxyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is -OCF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is hydrogen.

[0074] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5e is CN. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R5e is an unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5e is a substituted (C1-C4) alkyl. In certain embodiments, the substituted (C1-C5) alkyl is substituted with a halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5e is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, R 5e is methyl. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5e is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, R 5e is a substituted (C 3- C6)-cycloalkyl. In certain embodiments, R 5e is an unsubstituted (C 3- C6) cycloalkyl. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5e is CF3. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5e is C(H)F2. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5e is C(F)H2. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5e is a (C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5e is methoxy. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5e is hydroxyl. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5eis -OCF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5e is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5e is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5e is hydrogen.

[0075] In certain embodiments, R 5b is H. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5b is a substituted or unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5b is an unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5b is a substituted (C1-C4) alkyl. In certain embodiments, the substituted (C1-C5) alkyl is substituted with one or more halogens. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5b is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5b is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, R 5b is a substituted (C 3- C6)-cycloalkyl. In certain embodiments, R 5b is an unsubstituted (C 3-C6) is a cycloalkyl. In some embodiments, (C3-C6)-cycloalkyl is cyclopropyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5b is CF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5b is C(H)F2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5b is C(F)H2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5a is (C1-C4)-alkoxy. In some embodiments, (C1-C4)-alkoxy is methoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5b is methoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5b is hydroxyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5b is -OCF3. In certain embodiments, R 5b is CN. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5b is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5b is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe. In certain embodiments, R 5b is CH2OH.

[0076] In certain embodiments, R 5c is H. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R5c is a substituted or unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5a is an unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5c is a substituted (C1-C4) alkyl. In certain embodiments, the substituted (C1-C5) alkyl is substituted with one or more halogens. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5c is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5c is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, R 5c is a substituted (C 3- C6)-cycloalkyl. In certain embodiments, R 5c is an unsubstituted (C 3- C6) cycloalkyl. In some embodiments, the (C3-C6)-cycloalkyl is cyclopropyl. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5c is CF3. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5c is C(H)F2. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5c is C(F)H2. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5c is a (C1-C4)-alkoxy. In some embodiments, the (C1-C4)-alkoxy is methoxy. In certain embodiments, the present invention relates to any one of the foregoing compounds, wherein R 5cis methoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5c is hydroxyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5c is -OCF3. In certain embodiments, R 5c is CN. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5a is substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5c is unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe. In certain embodiments, R 5c is CH2OH.

[0077] In certain embodiments, R 5d is H. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is substituted or unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is substituted (C1-C4) alkyl. In certain embodiments, the substituted (C1-C5) alkyl is substituted with one or more halogens. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5d is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5dis a halide. In some embodiments, the halide is Cl or F. In certain embodiments, R 5d is a substituted (C 3- C6)-cycloalkyl. In certain embodiments, R 5d is an unsubstituted (C 3- C6) cycloalkyl. In some embodiments, the (C3-C6)-cycloalkyl is cyclopropyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is CF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is C(H)F2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is C(F)H2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is a (C1-C4)-alkoxy. In some embodiments, the (C1-C4)-alkoxy is methoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is methoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is hydroxyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is -OCF3. In certain embodiments, R 5d is CN. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5d is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5dis unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe. In certain embodiments, R 5d is CH2OH.

[0078] In certain embodiments, R 5e is H. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5e is substituted or unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5e is unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5e is substituted (C1-C4) alkyl. In certain embodiments, the substituted (C1-C5) alkyl is substituted with one or more halogens. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5e is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5e is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, R 5e is substituted (C 3- C6)-cycloalkyl. In certain embodiments, R 5e is unsubstituted (C 3- C6) cycloalkyl. In some embodiments, (C3-C6)-cycloalkyl is cyclopropyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5e is CF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R 5eis C(H)F2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5e is C(F)H2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5e is (C1-C4)-alkoxy. In some embodiments, the (C1-C4)-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5e is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5e is hydroxyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5e is -OCF3. In certain embodiments, R 5e is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5e is substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5e is unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe. In certain embodiments, R 5e is CH2OH.

[0079] In some embodiments, R 5a and R 5e are the same. For example, R 5a and R 5e may both be substituted or unsubstituted (C1-C4)-alkyl. In some examples, R 5a and R 5e are both unsubstituted (C1-C4)-alkyl (e.g., methyl). In some examples, R 5a and R 5e are both unsubstituted methyl.

[0080] In some embodiments, R 5b and R 5d are the same. For example, both R 5a and R 5e may be hydrogen.

[0081] In some embodiments, both R 5a and R 5e are substituted, and both R 5b and R 5d are hydrogen. For example, both R 5a and R 5e may both be (the same or different) substituted or unsubstituted (C1-C4)-alkyl. In some examples, both R 5a and R 5e may both be unsubstituted (C1-C4)-alkyl (e.g., methyl), and both R 5b and R 5d are hydrogen. In some embodiments, both R 5a and R 5e are both unsubstituted methyl, and both R 5b and R 5d are hydrogen. In some embodiments, R 5a and R 5e are independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, (C1-C5)-alkyl, hydroxyl, and (C1-C4)-alkoxy.

[0082] In some embodiments, R 5c is hydrogen, halide (e.g., F), substituted or unsubstituted (C1-C4)-alkoxy (e.g., methoxy), or substituted or unsubstituted (C1-C4)alkyl (e.g., methyl).

[0083] In some embodiments, both R 5a and R 5e are both substituted or unsubstituted (C1-C5)alkyl, and R 5b and R 5dare both hydrogen, and R 5c is hydrogen, a halide (e.g., F), a substituted or unsubstituted (C1-C4) alkoxy (e.g., methoxy), or a substituted or unsubstituted (C1-C4) alkyl (e.g., methyl). For example, R 5a and R 5e may both be methyl; R 5b and R 5d may both be hydrogen; and R 5c is selected from the group consisting of hydrogen, a halide (e.g., F), a substituted or unsubstituted (C1-C4)-alkoxy (e.g., methoxy), and a substituted or unsubstituted (C1-C4) alkyl (e.g., methyl). In some examples, R 5a and R 5e may both be methyl; R 5b and R 5d may both be hydrogen; and R 5c is selected from the group consisting of hydrogen, F, Cl, methoxy, and methyl. In some examples, R 5a , R 5c , and R 5e are each methyl; and R 5b and R 5d may both be hydrogen. In some embodiments, R 5b , R 5c , and R 5d are independently selected from the group consisting of H, CN, a halide, CF3, C(H)F2, C(F)H2, (C1-C5)-alkyl, hydroxyl, and (C1-C4)-alkoxy.

[0084] In certain embodiments, the invention relates to any one of the foregoing compounds, wherein R a , R b and R c comprise a charged amine. R a , R b and R c at least one of which may be a substituted or unsubstituted (C1-C5) alkylene-N-(R x )(R y ); wherein Rx and R y is independently selected from the group consisting of H, substituted or unsubstituted (C1-C6)-alkyl, or substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; or R x and R y together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclyl ring.

[0085] In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R a , R b and R c only one of is substituted or unsubstituted -(C1-C5) alkylene-N-(R x )(R y ); wherein R x and R y are independently selected from the group consisting of H, substituted or unsubstituted (C1-C6)-alkyl, or substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R a , R b and R c only one of is substituted or unsubstituted -(C1-C5) alkylene-N-(R x )(R y ); wherein R x and R y are independently selected from the group consisting of substituted or unsubstituted (C1-C6)-alkyl, or substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R a , R b and R c only one of is substituted or unsubstituted -(C1-C5) alkylene-N-(R x )(R y ); wherein R x and R yis independently selected from the group consisting of substituted or unsubstituted (C1-C6)-alkyl.

[0086] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R a , R b and R c only one of which is substituted or unsubstituted -(C1-C5) alkylene-N-(R x )(R y ); wherein R x and R y together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclyl ring. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R a , R b and R c only one of which is substituted or unsubstituted -(C1-C5) alkylene-N-(R x )(R y ); wherein R x and R y together with the N to which they are attached form a 4- to 6-membered heterocyclyl ring optionally substituted with one or more halides (e.g., F, Cl).

[0087] In some embodiments, R a , R b and R c are independently selected from the group consisting of H, substituted or unsubstituted (C1-C5)-alkyl, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C4)-alkoxy, -OCF3, and at least one of R a , R b and R c is --(C1-C3) alkylene-N-(R x )(R y ), wherein R x and R y are independently selected from the group consisting of H and (C1-C6)-alkyl; or R x and R yForm a 4- to 6-membered heterocyclic ring optionally substituted with one or more halides (e.g., F or Cl), together with the N to which they are attached.

[0088] In some embodiments, R a , R b and R c are independently selected from the group consisting of H, substituted or unsubstituted (C1-C5)-alkyl, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C4)-alkoxy, -OCF3, and R a , R b and R c at least one of which is --(C1-C3)alkylene-N-(R x )(R y ), wherein R x and R y are independently selected from the group consisting of (C1-C6)-alkyl (e.g., methyl); or R x and R y form a 4- to 6-membered heterocyclic ring optionally substituted with one or more halides (e.g., F or Cl), together with the N to which they are attached.

[0089] In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein only one of R a , R b and R c is selected from the group consisting of

Chemical formula

Chemical formula

Chemical formula

[0090] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R a is selected from the group consisting of H, substituted or unsubstituted (C1-C5)-alkyl, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C4)-alkoxy, and -OCF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R a is selected from the group consisting of H, substituted or unsubstituted (C1-C5)-alkyl, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C4)-alkoxy, and -OCF3; and one of b R c is substituted or unsubstituted -(C1-C5)alkylene-N-(R x )(R y ); wherein R x R y are independently selected from the group consisting of H, substituted or unsubstituted (C1-C6)-alkyl, or substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; or R x R y together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclyl ring.

[0091] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R a is H. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R a is Me. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R ais a halide. In some embodiments, the halide is Cl or F. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R a is CF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R a is C(H)F2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R a is C(F)H2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R a is a substituted (C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R a is an unsubstituted (C1-C4) alkoxy. In some embodiments, the (C1-C4)-alkoxy is methoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R a is -OCF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R a is a substituted -(C1-C5) alkylene-N-(R x )(R y ). In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R a is an unsubstituted -(C1-C5) alkylene-N-(R x )(R y ). In some embodiments, the -(C1-C5) alkylene of -(C1-C5) alkylene-N-(R x )(R y ) is substituted with one or more halides, or -(C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein --(C1-C5) alkylene-N-(R x )(R y ) is --(C1-C4) alkylene-N-(R x )(R y ).

[0092] In some embodiments, R a is a substituted (C1-C5)-alkyl, a substituted (C1-C4)-alkoxy, or a substituted -(C1-C5)alkylene-N-(R x )(R y ), where in this case, substituted means substituted with a halide or a (C1-C4)-alkoxy. In some embodiments, R a is a substituted (C1-C5)-alkyl, a substituted (C1-C4)-alkoxy, or a substituted -(C1-C5)alkylene-N-(R x )(R y ), where in this case, substituted means substituted with F or methoxy. In some embodiments, R a is

Chemical formula

Chemical formula

Chemical formula

[0093] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R a is selected from the group consisting of H, a substituted or unsubstituted (C1-C5)-alkyl, a halide, CF3, C(H)F2, C(F)H2, a substituted or unsubstituted (C1-C4)-alkoxy, and -OCF3; and R b is a substituted or unsubstituted -(C1-C5)alkylene-N-(R x )(R y ); wherein R xand R y is independently selected from the group consisting of H, substituted or unsubstituted (C1-C6)-alkyl, or substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; or R x and R y together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclic ring.

[0094] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R b is H. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R b is Me. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R b is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R b is CF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R b is C(H)F2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R b is C(F)H2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R b is a substituted (C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R b is an unsubstituted (C1-C4) alkoxy. In some embodiments, the (C1-C4)-alkoxy is methoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R b is -OCF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R b is a substituted -(C1-C5) alkylene-N-(Rx )(R y ) is. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R b is unsubstituted -(C1-C5) alkylene - N-(R x )(R y ). In some embodiments, the -(C1-C5) alkylene of -(C1-C5) alkylene - N-(R x )(R y ) is substituted with one or more halides or -(C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein --(C1-C5) alkylene - N-(R x )(R y ) is --(C1-C4) alkylene - N-(R x )(R y ).

[0095] In some embodiments, R b is substituted (C1-C5)-alkyl, substituted (C1-C4)-alkoxy, or substituted -(C1-C5) alkylene - N-(R x )(R y ), where substituted means substituted with a halide or (C1-C4)-alkoxy. In some embodiments, R b is substituted (C1-C5)-alkyl, substituted (C1-C4)-alkoxy, or substituted -(C1-C5) alkylene - N-(R x )(R y ), where substituted means substituted with F or methoxy. In some embodiments, R b is -(C1-C5) alkylene - N-(R x )(R y ), wherein R x and R y are each methyl, or R x and R yforms, together with the N to which they are attached, a 4- to 6-membered heterocyclic ring optionally substituted with one or more halides (e.g., F or Cl). In some embodiments, R b is -(C2-C3)alkylene-N-(R x )(R y ), wherein R x and R y are each methyl, or R x and R y form, together with the N to which they are attached, a 4- to 6-membered heterocyclic ring optionally substituted with one or more halides (e.g., F or Cl). In some embodiments, R b is -(C2-C3)alkylene-N-(R x )(R y ), wherein R x and R y are each methyl, or R x and R y form, together with the N to which they are attached, a 4-membered heterocyclic ring optionally substituted with one or more halides (e.g., F or Cl). In some embodiments, R b is -(C2-C3)alkylene-N-(R x )(R y ), wherein R x and R y are each methyl, or R x and R y form, together with the N to which they are attached, a 4- to 6-membered heterocyclic ring optionally substituted with one or more halides (e.g., F or Cl). In some embodiments, R b is -(C2-C3)alkylene-N-(R x )(R y ), wherein R x and R y are each methyl, or R x and R y form, together with the N to which they are attached, a 4-membered heterocyclic ring optionally substituted with one or more halides (e.g., F or Cl).

[0096] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R b is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0097] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R c is H. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R c is Me. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R c is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R c is CF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R c is C(H)F2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R c is C(F)H2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R c is a substituted (C1-C4)-alkoxy. In some embodiments, the (C1-C4)-alkoxy is methoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R c is an unsubstituted (C1-C4) alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R cIn certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R c is a substituted -(C1-C5)alkylene-N-(R x )(R y In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R c is an unsubstituted -(C1-C5)alkylene-N-(R x )(R y In some embodiments, -(C1-C5)alkylene-N-(R x )(R y In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein the -(C1-C5)alkylene-N-(R x )(R y ) is --(C1-C4)alkylene-N-(R x )(R y ).

[0098] In some embodiments, R c is a substituted (C1-C5)-alkyl, a substituted (C1-C4)-alkoxy, or a substituted -(C1-C5)alkylene-N-(R x )(R y ), where substituted means substituted with halide or (C-C)-alkoxy. In some embodiments, R c is a substituted (C1-C5)-alkyl, a substituted (C1-C4)-alkoxy, or a substituted -(C1-C5)alkylene-N-(R x )(R y ), in which case substituted means substituted with F or methoxy.

[0099] In some embodiments, R c teeth, [ka] is selected from the group consisting of. In some embodiments, R c is

Chemical formula

[0100] In some embodiments, at least one of R a , R b and R c is H.

[0101] In some embodiments, at least one of R a , R b and R c is a charged amine, and at least one of R a , R b and R c is H.

[0102] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R x is H. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R x is a substituted (C1-C6) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R x is an unsubstituted (C1-C6) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R x is a substituted (C1-C4) alkyl. In some embodiments, the (C1-C6)-alkyl is substituted with OMe, CN or a halide. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R x is an unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R xis (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -(CH2)2OMe. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R x is Me.

[0103] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R y is H. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R y is substituted (C1-C6) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R y is unsubstituted (C1-C6) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R y is substituted (C1-C4) alkyl. In some embodiments, (C1-C6)-alkyl is substituted with OMe, CN or halide. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R y is unsubstituted (C1-C4) alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R y is (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -(CH2)2OMe. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R y is Me.

[0104] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R x is Me; R y is Me.

[0105] In certain embodiments, the present invention relates to any one of the aforementioned compounds, where R x and R y together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered ring. In some embodiments, the 4- to 6-membered ring is a substituted or unsubstituted heterocycloalkyl. In some embodiments, the substituted 4- to 6-membered heterocycloalkyl is substituted with a (C1-C6) alkyl halide. In some embodiments, the 4- to 6-membered ring is a substituted or unsubstituted heteroaryl. In some embodiments, the substituted 4- to 6-membered heteroaryl is substituted with a (C1-C6) alkyl halide. In some embodiments, the 4- to 6-membered ring is selected from

Chemical formula

Chemical formula

Chemical formula

[0106] In some embodiments, R a is (C1-C5) alkyl optionally substituted with halide; R b is -(C1-C5) alkylene-N-(R x )(R y ), wherein R x and R y are each methyl, or R x and R yforms, together with the N to which they are attached, a 4- to 5-membered heterocyclyl ring optionally substituted with one or more halides or alkoxy (e.g., methoxy); and R c is hydrogen, a halide, or (C1-C5)-alkyl optionally substituted with a halide. In some embodiments, R a is methyl optionally substituted with a halide; R b is -(C2-C3)alkylene-N-(R x )(R y ), wherein R x and R y are each methyl, or R x and R y form, together with the N to which they are attached, a 4- to 5-membered heterocyclyl ring optionally substituted with one or more halides (e.g., F); and R c is hydrogen, a halide, or methyl optionally substituted with a halide. In some embodiments, R a is methyl or CF3; R b is -(C2-C3)alkylene-N-(R x )(R y ), wherein R x and R y are each methyl, or R x and R y form, together with the N to which they are attached, a 4- to 5-membered heterocyclyl ring optionally substituted with one or more F or methoxy; and R c is hydrogen, F, CH2F, CHF2, CF3.

[0107] In certain embodiments, the invention relates to a compound of formula (Ia) or (Ib):

Chemical formula

[0108] In certain embodiments, the present invention relates to any one of the compounds depicted in FIG. 1. In certain embodiments, the present invention relates to any one of the compounds depicted in FIG. 2. In certain embodiments, the present invention relates to any one of the compounds depicted in FIG. 3. In certain embodiments, the present invention relates to any one of the compounds depicted in FIG. 4.

[0109] In certain embodiments, the compound is a compound of formula (I) that is not the compound illustrated in FIG. 1. In certain embodiments, the compound is a compound of formula (I) that is not the compound illustrated in FIG. 2. In certain embodiments, the compound is a compound of formula (I) that is not the compound illustrated in FIG. 3. In certain embodiments, the compound is a compound of formula (I) that is not the compound illustrated in FIG. 4. In certain embodiments, the compound is a compound of formula (I) that is not the compound illustrated in FIGS. 2, 3 or 4.

[0110] In certain embodiments, the present invention relates to a compound of formula (IIIa): [Chemical formula] wherein, R1, R a , R x , R y , R 3b , R 5b , R 5c , R 5d are as defined above with respect to formula (I).

[0111] In certain embodiments, the present invention relates to a compound of formula (IVa): [Chemical formula] wherein, R1, R a , R x , R y , R 3b , R 5b , R 5c , R 5d are as defined above with respect to formula (I).

[0112] In certain embodiments, the present invention relates to a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof: (3S)-3-(4,5-difluoro-2’,6’-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2’,6’-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid; (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3’,4-difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid; (3S)-3-(2-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid; (3S)-3-(4,4'-Difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (3S)-3-(5-Chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoic acid; (3S)-3-(4,4'-Difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propanoic acid; (3S)-3-(4-Fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; and (3S)-3-(4-Fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid.

[0113] In certain embodiments, the present invention relates to a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:

Chemical Structure

[0114] In certain embodiments, the present invention relates to a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:

Chemical Structure

[0115] In certain embodiments, the present invention relates to a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof: (S)-3-(4,5-Difluoro-2’,6’-dimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2’,6’-dimethyl-5-(trifluoromethyl)-[1,1’-biphenyl]-3-yl)propanoic acid; (S)-3-((S)-2-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3’,4-difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid; (S)-3-((S)-2-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-3’-methoxy-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid; (S)-3-(4,4’-Difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; (S)-3-(5-Chloro-4-fluoro-2’,6’-dimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2’,4’,5,6’-tetramethyl-[1,1’-biphenyl]-3-yl)propanoic acid; (S)-3-(4,4’-Difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; (S)-3-((S)-2-(5-(2-(Dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamide)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid; (S)-3-(4-Fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; and (S)-3-(4-Fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid.

[0116] In certain embodiments, the present invention relates to a compound selected from the group consisting of: [Chemical formula] TIFF0007702004000043.tif51161

[0117] In certain embodiments, the present invention relates to any one of the above compounds, which is in the form of a pharmaceutically acceptable salt.

[0118] In certain embodiments, the present invention relates to a compound selected from the group consisting of: [Table 1] TIFF0007702004000045.tif214163TIFF0007702004000046.tif214165TIFF0007702004000047.tif219166 Exemplary pharmaceutical compositions The compounds of formula (I) can be formulated in various pharmaceutical compositions. The compounds of formula (I) (including the compounds of formula (Ia) and formula (Ib) provided herein), as well as pharmaceutically acceptable salts thereof, may be combined with one or more other ingredients to form an active pharmaceutical ingredient (API) for a pharmaceutical composition of a formulation raw material. The pharmaceutical composition of the formulation raw material (DS) can include the API (i.e., the compound of formula (I) or a pharmaceutically acceptable salt thereof), as well as one or more pharmaceutically acceptable carriers, diluents, and / or excipients. The carrier, diluent, or excipient can be compatible with the other ingredients of the formulation and can be selected to be appropriately safe and effective for the intended therapy. The desired weight concentration of the compound of formula (I) as an active pharmaceutical ingredient (API) can be combined with other inert ingredients that form the formulation raw material (DS) in a formulation batch. Pharmaceutically acceptable compositions can be formulated for administration by an appropriate route, such as by oral delivery (including as capsules or tablets) in unit dosage form. Such compositions may be prepared by associating the active pharmaceutical ingredient (API) comprising the compound of formula (I) with a carrier or excipient.

[0119] In certain embodiments, the present invention provides a pharmaceutical composition formulated for oral delivery of an α4β7 integrin inhibitor, the composition comprising an α4β7 integrin inhibitor compound of formula (I) as an API and a pharmaceutically acceptable carrier, which is formulated for oral therapeutic administration of the α4β7 integrin inhibitor compound.

[0120] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0121] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), a compound of formula (Ia) or a pharmaceutically acceptable salt thereof.

[0122] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), a compound of formula (Ib), or a pharmaceutically acceptable salt thereof.

[0123] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (3S)-3-(4,5-difluoro-2’,6’-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0124] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2’,6’-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0125] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3’,4-difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0126] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-3’-methoxy-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0127] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0128] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0129] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0130] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0131] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamide)-3-(4-fluoro-2’,5,6’-trimethylbiphenyl-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0132] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (3S)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0133] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (3S)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0134] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (S)-3-(4,5-difluoro-2’,6’-dimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0135] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2’,6’-dimethyl-5-(trifluoromethyl)-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0136] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3’,4-difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0137] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-3’-methoxy-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0138] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (S)-3-(4,4’-difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0139] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2’,4’,5,6’-tetramethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0140] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (S)-3-(4,4’-difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0141] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamide)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0142] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (S)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0143] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), the compound (S)-3-(4-fluoro-2′,5,6′-trimethyl-[1,1′-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0144] In certain embodiments, the present invention relates to a pharmaceutical composition comprising a compound selected from the group consisting of:

Chemical formula

[0145] In certain embodiments, the present invention relates to a pharmaceutical composition comprising, as an active pharmaceutical ingredient (API), a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof:

Table 2

[0146] The pharmaceutical composition can be provided in a unit dosage form containing a predetermined amount of API, including the compound of formula (I) per unit dose. Such units may contain a desirable amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient. Thus, such unit doses may be administered at desirable dosing intervals. The concentration of the active compound in the pharmaceutical composition depends on various application parameters and considerations such as, for example, the rate of absorption, inactivation, and excretion of the drug, as well as other factors known to those skilled in the art. It should be noted that the dosage values also vary depending on the severity of the condition being alleviated. For any particular subject, the specific dosing regimen should be adjusted over time according to the individual needs and the professional judgment of the person implementing or supervising the administration of the composition, and it is further understood that the concentration ranges described herein are merely illustrative and do not limit the scope or practice of the claimed composition. The active ingredient may be administered once or divided into a number of smaller doses and administered at various intervals.

[0147] In certain embodiments, the mode of administration of the active compound is oral. Oral compositions generally include an inert diluent or an edible carrier. The oral composition may be enclosed in a gelatin capsule or compressed into a tablet. For the purpose of oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents and / or adjuvant substances may be included as part of the composition. A pharmaceutical composition containing a compound of formula (I) formulated for oral delivery may be prepared in unit dosage form, such as a capsule of the desired dosage strength of the compound of formula (I). For oral administration in liquid form, the oral pharmaceutical ingredient may be combined with any non-toxic, pharmaceutically acceptable inert carrier for oral use, such as ethanol, glycerol, water, etc. For oral administration in the form of tablets or capsules, the compound of formula (I) may be combined with a non-toxic, pharmaceutically acceptable inert carrier for oral use. Other examples of excipients, diluents, and carriers suitable for such formulations include fillers and extenders such as starches and sugars; and binding agents such as cellulose derivatives. Further, if desired or necessary, suitable binding agents, lubricants, disintegrants, and coloring agents may be incorporated into the mixture. Suitable binding agents include starches, natural sugars, natural and synthetic rubbers, etc. Lubricants and / or glidants may be used in these dosage forms. Tablets, pills, capsules, troches, and the like may contain any of the following ingredients, or compounds of a similar nature: for example, binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to the substances of the above types, a liquid carrier such as a fatty oil. Further, the unit dosage form may contain various other substances that modify the physical form of the dosage unit, such as, for example, sugar coating, or other enteric solvents.

[0148] The compounds may be administered as components of elixirs, suspensions, syrups, wafers. Syrups may contain, in addition to the active compounds, sucrose or a sweetening agent as a sweetening agent, as well as certain preservatives, dyes, as well as coloring and flavoring agents.

[0149] The compounds may be formulated as solutions suitable for parenteral administration, for example, by intramuscular, subcutaneous, or intravenous routes. For example, the compounds of formula (I) may be dissolved in a suitable buffer. A pharmaceutical composition containing the desired concentration of the compound of formula (I) may be formulated as an injectable solution (useful, for example, in preclinical animal studies).

[0150] Exemplary methods Compounds that inhibit α4β7 are useful in the development of agents for treating patients with ulcerative colitis and Crohn's disease. Patients with ulcerative colitis (UC) and Crohn's disease (CD) suffer from autoimmune inflammation in the gastrointestinal tract, and many of these patients have CD4 +Memory T cells secrete pro-inflammatory effector cytokines that affect peripheral immune cells and peripheral tissues in the intestine, thereby inducing disease progression and exacerbation. The progression and exacerbation of these disease states are thought to involve extravasation of T cells from the blood into intestinal tissue, leading to the inflammatory states found in UC and CD, via integrin-related mechanisms. Inhibition of α4β7 disrupts this mechanism, thereby preventing T cells from localizing to tissues and effectively treating and preventing diseases such as UC and CD. Homing of T cells to the intestine requires surface expression of integrin α4β7 and chemokine receptor CCR9. CCR9 is utilized for cell migration along the gradient of CCL25 expressed in the small intestine. On the other hand, α4β7 is a tethering molecule that binds to the ligand mucosal addressin cell adhesion molecule 1 (MAdCAM-1). Integrin α4β7 binds to MAdCAM-1 with high affinity, promoting cell rolling and stable adhesion, and then causing extravasation into the tissue.

[0151] The pharmaceutical composition may comprise a compound that inhibits α4β7 integrin on inflammatory cells, enabling the inflammatory cells to adhere to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), and inhibits or prevents the inflammatory cells from entering the intestinal lamina propria and intestinal-associated lymphoid tissue.

[0152] The compounds of formula (I) were evaluated using a fluorescence polarization (FP) assay as described in Example 5. The FP assay was used to evaluate the potency of the compounds against purified proteins. The FP assay consists of measuring the binding of purified integrin αβ heterodimer extracellular domain or headpiece to a surrogate ligand or truncated ligand. The results of the FP assay for exemplary compounds of formula (I) are provided herein.

[0153] The compounds of formula (I) were further evaluated using a ligand binding assay (LBA) as described in Example 6, and the potency of the compounds with respect to free ligand binding to receptors expressed on cells was verified. The MAdCAM ligand binding assay measures the binding of fluorescently labeled MAdCAM-1-Fc to RPMI8866 cells in the presence of Mn++ using flow cytometry. This assay evaluates the binding of the compound to the native full-length receptor on the cell surface. One advantage of the MAdCAM ligand binding assay is its ability to quantify and discriminate the activity of potent compounds that exceed the functional sensitivity limit of the FP assay (about 10 nM in Mn). A ligand binding assay (LBA) is used to verify the potency and selectivity of the compounds with respect to free ligand binding to receptors expressed on cells.

[0154] In some embodiments, the compounds of the invention may be selected from one or more of the following numbered embodiments: 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

Chemical formula

Chemical formula

[0155] 2. The compound according to Embodiment 1, wherein R1 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl.

[0156] 3. The compound according to Embodiment 2, wherein R1 is iso-butyl.

[0157] 4. R1 is

Chemical formula

[0158] 5. R1 is

Chemical formula

[0159] 6. R 3a and R 3e are independently selected from the group consisting of halide, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted (C1-C4)-alkoxy, CF3, C(H)F2 and C(F)H2, and the compound according to any one of Embodiments 1 to 5.

[0160] 7. R 3a and R 3bThe compound according to embodiment 6, independently selected from the group consisting of a halide and (C1-C4) alkyl.

[0161] 8. The compound according to embodiment 7, wherein the halide is Cl or F.

[0162] 9. The compound according to embodiment 7 or 8, wherein (C1-C4)-alkyl is methyl.

[0163] 10. R 3a is methyl; and R 3b is F, the compound according to any one of embodiments 1 to 7.

[0164] 11. R 3a is F; and R 3b is methyl, the compound according to any one of embodiments 1 to 7.

[0165] 12. The compound according to any one of embodiments 1 to 11, wherein R4 is H.

[0166] 13. The compound according to any one of embodiments 1 to 11, wherein R4 is methyl, ethyl, n-propyl, or iso-propyl.

[0167] 14. R 5a and R 5e are independently selected from the group consisting of a halide, CF3, C(H)F2, C(F)H2, and substituted or unsubstituted (C1-C4)-alkyl, the compound according to any one of embodiments 1 to 13.

[0168] 15. R 5a is a halide, the compound according to any one of embodiments 1 to 14.

[0169] 16. R 5a is the compound according to Embodiment 15, which is F or Cl.

[0170] 17. R 5a is the compound according to any one of Embodiments 1 to 14, which is CF3.

[0171] 18. R 5a is the compound according to any one of Embodiments 1 to 14, which is C(H)F2.

[0172] 19. R 5a is the compound according to any one of Embodiments 1 to 14, which is C(F)H2.

[0173] 20. R 5a is the compound according to any one of Embodiments 1 to 14, which is unsubstituted (C1-C4)-alkyl.

[0174] 21. R 5a is the compound according to Embodiment 20, which is methyl.

[0175] 22. R 5a is the compound according to any one of Embodiments 1 to 14, which is (C1-C5)-alkyl substituted with at least one halide.

[0176] 23. R 5a is the compound according to any one of Embodiments 1 to 14, which is unsubstituted (C1-C4)-alkoxy.

[0177] 24. R 5a is the compound according to Embodiment 23, which is OMe.

[0178] 25. R 5eThe compound according to any one of Embodiments 1 to 24, which is a halide.

[0179] 26. R 5e The compound according to Embodiment 25, wherein R is F or Cl.

[0180] 27. R 5e The compound according to any one of Embodiments 1 to 24, wherein R is CF3.

[0181] 28. R 5e The compound according to any one of Embodiments 1 to 24, wherein R is C(H)F2.

[0182] 29. R 5e The compound according to any one of Embodiments 1 to 24, wherein R is C(F)H2.

[0183] 30. R 5e The compound according to any one of Embodiments 1 to 24, wherein R is unsubstituted (C1-C4)-alkyl.

[0184] 31. R 5e The compound according to Embodiment 30, wherein R is methyl.

[0185] 32. R 5e The compound according to any one of Embodiments 1 to 24, wherein R is (C1-C5)-alkyl substituted with at least one halide.

[0186] 33. R 5e The compound according to any one of Embodiments 1 to 24, wherein R is unsubstituted (C1-C4)-alkoxy.

[0187] 34. R 5e The compound according to Embodiment 33, wherein R is OMe.

[0188] 35. R 5b 、R 5c and R 5d is independently selected from the group consisting of H, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, and substituted or unsubstituted (C1-C4)-alkoxy, the compound according to any one of Embodiments 1 to 34.

[0189] 36. R 5b is H, the compound according to any one of Embodiments 1 to 35.

[0190] 37. R 5b is a halide, the compound according to any one of Embodiments 1 to 35.

[0191] 38. R 5b is Cl or F, the compound according to Embodiment 37.

[0192] 39. R 5b is CF3, the compound according to any one of Embodiments 1 to 35.

[0193] 40. R 5b is C(H)F2, the compound according to any one of Embodiments 1 to 35.

[0194] 41. R 5b is C(F)H2, the compound according to any one of Embodiments 1 to 35.

[0195] 42. R 5b is unsubstituted (C1-C4)-alkyl, the compound according to any one of Embodiments 1 to 35.

[0196] 43. R 5bThe compound according to Embodiment 37, wherein R is methyl.

[0197] 44. R 5b The compound according to any one of Embodiments 1 to 35, wherein R is unsubstituted (C1-C4)-alkoxy.

[0198] 45. R 5b The compound according to Embodiment 44, wherein R is OMe.

[0199] 46. R 5b The compound according to any one of Embodiments 1 to 35, wherein R is unsubstituted (C3-C6)-cycloalkyl.

[0200] 47. R 5b The compound according to Embodiment 46, wherein R is cyclopropyl.

[0201] 48. R 5c The compound according to any one of Embodiments 1 to 47, wherein R is H.

[0202] 49. R 5c The compound according to any one of Embodiments 1 to 47, wherein R is a halide.

[0203] 50. R 5c The compound according to Embodiment 49, wherein R is Cl or F.

[0204] 51. R 5c The compound according to any one of Embodiments 1 to 47, wherein R is CF3.

[0205] 52. R 5c The compound according to any one of Embodiments 1 to 47, wherein R is C(H)F2.

[0206] 53. R 5c is the compound according to any one of Embodiments 1 to 47, which is C(F)H2.

[0207] 54. R 5c is the compound according to any one of Embodiments 1 to 47, which is unsubstituted (C1-C4)-alkyl.

[0208] 55. R 5c is the compound according to Embodiment 54, which is methyl.

[0209] 56. R 5c is the compound according to any one of Embodiments 1 to 47, which is unsubstituted (C1-C4)-alkoxy.

[0210] 57. R 5c is the compound according to Embodiment 56, which is OMe.

[0211] 58. R 5c is the compound according to any one of Embodiments 1 to 47, which is unsubstituted (C3-C6)-cycloalkyl.

[0212] 59. R 5b is the compound according to Embodiment 58, which is cyclopropyl.

[0213] 60. R 5d is the compound according to any one of Embodiments 1 to 59, which is H.

[0214] 61. R 5d is the compound according to any one of Embodiments 1 to 59, which is a halide.

[0215] 62. R 5d is the compound according to Embodiment 61, which is Cl or F.

[0216] 63. R 5d is a compound according to any one of Embodiments 1 to 59, wherein R is CF3.

[0217] 64. R 5d is a compound according to any one of Embodiments 1 to 59, wherein R is C(H)F2.

[0218] 65. R 5d is a compound according to any one of Embodiments 1 to 59, wherein R is C(F)H2.

[0219] 66. R 5d is a compound according to any one of Embodiments 1 to 59, wherein R is unsubstituted (C1-C4)-alkyl.

[0220] 67. R 5d is a compound according to Embodiment 66, wherein R is methyl.

[0221] 68. R 5d is a compound according to any one of Embodiments 1 to 67, wherein R is unsubstituted (C1-C4)-alkoxy.

[0222] 69. R 5d is a compound according to Embodiment 68, wherein R is OMe.

[0223] 70. R 5d is a compound according to any one of Embodiments 1 to 67, wherein R is unsubstituted (C3-C6)-cycloalkyl.

[0224] 71. R 5d is a compound according to Embodiment 70, wherein R is cyclopropyl.

[0225] 72. R 5b and R 5dThe compound according to any one of Embodiments 1 to 35, wherein each is H.

[0226] 73. R a The compound according to any one of Embodiments 1 to 72, wherein R is H.

[0227] 74. R a The compound according to any one of Embodiments 1 to 72, wherein R is Me.

[0228] 75. R a The compound according to any one of Embodiments 1 to 72, wherein R is a halide.

[0229] 76. R a The compound according to Embodiment 75, wherein R is Cl or F.

[0230] 77. R a The compound according to any one of Embodiments 1 to 72, wherein R is CF3.

[0231] 78. R a The compound according to any one of Embodiments 1 to 72, wherein R is C(H)F2.

[0232] 79. R a The compound according to any one of Embodiments 1 to 72, wherein R is C(F)H2.

[0233] 80. R a The compound according to any one of Embodiments 1 to 72, wherein R is unsubstituted -(C1-C3)alkylene-N-(R x )(R y ).

[0234] 81. R a The compound according to any one of Embodiments 1 to 72, wherein R is substituted -(C1-C3)alkylene-N-(R substituted with F or OMex )(R y ) which is the compound according to any one of Embodiments 1 to 72.

[0235] 82. R b is H, the compound according to any one of Embodiments 1 to 81.

[0236] 83. R b is Me, the compound according to any one of Embodiments 1 to 81.

[0237] 84. R b is a halide, the compound according to any one of Embodiments 1 to 81.

[0238] 85. R b is Cl or F, the compound according to Embodiment 84.

[0239] 86. R b is CF3, the compound according to any one of Embodiments 1 to 81.

[0240] 87. R b is C(H)F2, the compound according to any one of Embodiments 1 to 81.

[0241] 88. R b is C(F)H2, the compound according to any one of Embodiments 1 to 81.

[0242] 89. R b is unsubstituted -(C1-C3) alkylene - N-(R x )(R y ) which is the compound according to any one of Embodiments 1 to 81.

[0243] 90. R bis a substituted-(C1-C3)alkylene-N-(R x )(R y ) and is a compound according to any one of Embodiments 1 to 81.

[0244] 91. R c is H and is a compound according to any one of Embodiments 1 to 90.

[0245] 92. R c is Me and is a compound according to any one of Embodiments 1 to 90.

[0246] 93. R c is a halide and is a compound according to any one of Embodiments 1 to 90.

[0247] 94. R c is Cl or F and is a compound according to Embodiment 93.

[0248] 95. R c is CF3 and is a compound according to any one of Embodiments 1 to 90.

[0249] 96. R c is C(H)F2 and is a compound according to any one of Embodiments 1 to 90.

[0250] 97. R c is C(F)H2 and is a compound according to any one of Embodiments 1 to 90.

[0251] 98. R c is an unsubstituted-(C1-C3)alkylene-N-(R x )(R y ) and is a compound according to any one of Embodiments 1 to 90.

[0252] 99. R c is a substituted-(C1-C3) alkylene-N-(R x )(R y ) and is a compound according to any one of Embodiments 1 to 90.

[0253] 100. R c is H and is a compound according to any one of Embodiments 1 to 99.

[0254] 101. R x is unsubstituted (C1-C6)-alkyl and is a compound according to any one of Embodiments 1 to 99.

[0255] 102. R y is H and is a compound according to any one of Embodiments 1 to 100.

[0256] 103. R y is unsubstituted (C1-C6)-alkyl and is a compound according to any one of Embodiments 1 to 100.

[0257] 104. R x and R y together with the N to which they are attached form an unsubstituted 4- to 6-membered ring and is a compound according to any one of Embodiments 1 to 72, 80 to 81, 89 to 90, and 98 to 99.

[0258] 105. R x and R y together with the N to which they are attached form a substituted 4- to 6-membered ring substituted with at least one halide, substituted or unsubstituted (C1-C4) alkyl, or OMe and is a compound according to any one of Embodiments 1 to 72, 80 to 81, 89 to 90, and 98 to 99.

[0259] 106. The compound according to embodiment 104 or 105, wherein the 4- to 6-membered ring is a 3- to 6-membered heterocycloalkyl.

[0260] 107. The compound according to embodiment 104 or 105, wherein the 4- to 6-membered ring is a 4- to 5-membered heterocycloalkyl.

[0261] 108. The compound according to embodiment 1, wherein the compound is a compound of the following formula (Ia):

Chemical formula

[0262] 109. R 5a and R 5e Are independently unsubstituted (C1-C4) alkyl, the compound according to embodiment 108.

[0263] 110. R b is unsubstituted -(C1-C3) alkylene-N(R x )(R y ), the compound according to embodiment 108 or 109.

[0264] 111. R aThe compound according to Embodiment 1 or 108, which is selected from the group consisting of H, C(H)F2, CF3 and Me.

[0265] 112. R b is

Chemical formula

[0266] 113. R b is

Chemical formula

[0267] 114. R c is H or F, the compound according to Embodiment 1 or 108.

[0268] 115. R1 is

Chemical formula

[0269] 116. R 5a is CF3, the compound according to any one of Embodiments 108 to 115.

[0270] 117. R 5a is C(H)F2, the compound according to any one of Embodiments 108 to 115.

[0271] 118. R 5a is C(F)H2, the compound according to any one of Embodiments 108 to 115.

[0272] 119. R 5a is a compound according to any one of Embodiments 108 to 115, where R is methyl.

[0273] 120. R 5a is a compound according to any one of Embodiments 108 to 115, where R is OMe.

[0274] 121. R 5a is a compound according to any one of Embodiments 108 to 115, where R is F or Cl.

[0275] 122. R 5b is a compound according to any one of Embodiments 108 to 121, where R is H.

[0276] 123. R 5b is a compound according to any one of Embodiments 108 to 121, where R is CF3.

[0277] 124. R 5b is a compound according to any one of Embodiments 108 to 121, where R is C(H)F2.

[0278] 125. R 5b is a compound according to any one of Embodiments 108 to 121, where R is C(F)H2.

[0279] 126. R 5b is a compound according to any one of Embodiments 108 to 121, where R is methyl.

[0280] 127. R 5b is a compound according to any one of Embodiments 108 to 121, where R is OMe.

[0281] 128. R5b The compound according to any one of Embodiments 108 to 121, wherein R is F or Cl.

[0282] 129. R 5c The compound according to any one of Embodiments 108 to 128, wherein R is H.

[0283] 130. R 5c The compound according to any one of Embodiments 108 to 128, wherein R is CF3.

[0284] 131. R 5c The compound according to any one of Embodiments 108 to 128, wherein R is C(H)F2.

[0285] 132. R 5c The compound according to any one of Embodiments 108 to 128, wherein R is C(F)H2.

[0286] 133. R 5c The compound according to any one of Embodiments 108 to 128, wherein R is methyl.

[0287] 134. R 5c The compound according to any one of Embodiments 108 to 128, wherein R is OMe.

[0288] 135. R 5c The compound according to any one of Embodiments 108 to 128, wherein R is F or Cl.

[0289] 136. R 5d The compound according to any one of Embodiments 108 to 135, wherein R is H.

[0290] 137. R 5d The compound according to any one of Embodiments 108 to 135, wherein R is CF3.

[0291] 138. R 5d is the compound according to any one of Embodiments 108 to 135, which is C(H)F2.

[0292] 139. R 5d is the compound according to any one of Embodiments 108 to 135, which is C(F)H2.

[0293] 140. R 5d is the compound according to any one of Embodiments 108 to 135, which is methyl.

[0294] 141. R 5d is the compound according to any one of Embodiments 108 to 135, which is OMe.

[0295] 142. R 5d is the compound according to any one of Embodiments 108 to 135, which is F or Cl.

[0296] 143. R 5e is the compound according to any one of Embodiments 108 to 142, which is CF3.

[0297] 144. R 5e is the compound according to any one of Embodiments 108 to 142, which is C(H)F2.

[0298] 145. R 5e is the compound according to any one of Embodiments 108 to 142, which is C(F)H2.

[0299] 146. R 5e is the compound according to any one of Embodiments 108 to 142, which is methyl.

[0300] 147. R 5e is the compound according to any one of Embodiments 108 to 142, which is OMe.

[0301] 148. R 5e is the compound according to any one of Embodiments 108 to 142, which is F or Cl.

[0302] 149. R 5b R 5c and R 5d at least one of which is H, is the compound according to Embodiment 1 and any one of Embodiments 108 to 121.

[0303] 150. R 5b R 5c and R 5d at least two of which are H, is the compound according to Embodiment 1 and any one of Embodiments 108 to 121.

[0304] 151. R 5b R 5c and R 5d are H, is the compound according to Embodiment 1 and any one of Embodiments 108 to 121.

[0305] 152. R 3a is H, is the compound according to Embodiment 1 and any one of Embodiments 108 to 151.

[0306] 153. R 3a is methyl, is the compound according to Embodiment 1 and any one of Embodiments 108 to 151.

[0307] 154. R 3a is a halide, is the compound according to Embodiment 1 and any one of Embodiments 108 to 151.

[0308] 155. R3a The compound according to any one of Embodiments 1 and 108 to 151, wherein R is CF3.

[0309] 156. R 3a The compound according to any one of Embodiments 1 and 108 to 151, wherein R is C(H)F2.

[0310] 157. R 3a The compound according to any one of Embodiments 1 and 108 to 151, wherein R is C(F)H2.

[0311] 158. R 3a The compound according to any one of Embodiments 1 and 108 to 151, wherein R is OMe.

[0312] 159. R 3b The compound according to any one of Embodiments 1 and 108 to 158, wherein R is H.

[0313] 160. R 3b The compound according to any one of Embodiments 1 and 108 to 158, wherein R is methyl.

[0314] 161. R 3b The compound according to any one of Embodiments 1 and 108 to 158, wherein R is a halide.

[0315] 162. R 3b The compound according to any one of Embodiments 1 and 108 to 158, wherein R is CF3.

[0316] 163. R 3b The compound according to any one of Embodiments 1 and 108 to 158, wherein R is C(H)F2.

[0317] 164. R3b The compound according to any one of Embodiments 1 and 108 to 158, which is C(F)H2.

[0318] 165. R 3b The compound according to any one of Embodiments 1 and 108 to 158, which is OMe.

[0319] 166. R 3b The compound according to any one of Embodiments 1 and 108 to 158, which is OCF3.

[0320] 167. R 3b The compound according to any one of Embodiments 1 and 108 to 158, which is cyclopropyl.

[0321] 168. R 3a is methyl, and R 3b is F, the compound according to any one of Embodiments 108 to 151.

[0322] 169. R 3a is F, and R 3b is methyl, the compound according to any one of Embodiments 108 to 151.

[0323] 170. The compound according to Embodiment 1, wherein the compound is selected from any one of the compounds in Figure 1 or its enantiomer.

[0324] 171. The compound according to Embodiment 1, wherein the compound is a compound of the following formula (Ic) or a pharmaceutically acceptable salt thereof:

Chemical formula

[0325] 172. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof: (3S)-3-(4,5-Difluoro-2’,6’-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2’,6’-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid; (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3’,4-difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid; (3S)-3-(2-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid; (3S)-3-(4,4'-Difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (3S)-3-(5-Chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoic acid; (3S)-3-(4,4'-Difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propanoic acid; (3S)-3-(4-Fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (3S)-3-(4-Fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; and (3S)-3-(5-Chloro-4-fluoro-2’,6’-dimethyl-[1,1’-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid.

[0326] 173. The compound according to embodiment 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof:

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0327] 186. The compound according to embodiment 1, wherein the compound is (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2’,6’-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0328] 187. The compound according to embodiment 1, wherein the compound is (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3’,4-difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0329] 188. The compound according to embodiment 1, wherein the compound is (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-3’-methoxy-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0330] 189. The compound according to embodiment 1, wherein the compound is (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0331] 190. The compound according to embodiment 1, wherein the compound is (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0332] 191. The compound according to embodiment 1, wherein the compound is (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0333] 192. The compound according to embodiment 1, wherein the compound is (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0334] 193. The compound according to embodiment 1, wherein the compound is (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamide)-3-(4-fluoro-2’,5,6’-trimethylbiphenyl-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0335] 194. The compound according to embodiment 1, wherein the compound is (3S)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0336] 195. The compound according to embodiment 1, wherein the compound is (3S)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0337] 196. The compound according to embodiment 1, wherein the compound is (3S)-3-(5-chloro-4-fluoro-2’,6’-dimethyl-[1,1’-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0338] 197. The compound according to embodiment 1, wherein the compound is (S)-3-(4,5-difluoro-2’,6’-dimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0339] 198. The compound according to embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2’,6’-dimethyl-5-(trifluoromethyl)-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0340] 199. The compound according to embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3’,4-difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0341] 200. The compound according to embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-3’-methoxy-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0342] 201. The compound according to embodiment 1, wherein the compound is (S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0343] 202. The compound according to embodiment 1, wherein the compound is (S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0344] 203. The compound according to embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0345] 204. The compound according to embodiment 1, wherein the compound is (S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0346] 205. The compound according to embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamide)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0347] 206. The compound according to embodiment 1, wherein the compound is (S)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0348] 207. The compound according to embodiment 1, wherein the compound is (S)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0349] 208. The compound according to embodiment 1, wherein the compound is (S)-3-(5-chloro-4-fluoro-2’,6’-dimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0350] 209. A pharmaceutical composition comprising the compound according to any one of embodiments 1 to 208 and a pharmaceutically acceptable excipient.

[0351] 210. A method of inhibiting α4β7 integrin in a cell, comprising contacting a cell with a compound according to any one of Embodiments 1 to 208 under conditions effective to reduce the adhesion of the cell to MAdCAM-1.

[0352] 211. A method of reducing the adhesion of a cell comprising α4β7 integrin to MAdCAM-1, comprising contacting the cell with a compound according to any one of Embodiments 1 to 208 under conditions effective to reduce the adhesion of the cell to MAdCAM-1.

[0353] 212. A method of treating inflammatory bowel disease, ulcerative colitis, or Crohn's disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of Embodiments 1 to 208.

[0354] In some embodiments, the compound of the present invention may be a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Chemical Formula

[0355] In some embodiments, the compounds of the invention may be compounds of formula (Ia) below or pharmaceutically acceptable salts thereof: [Chemical formula] Wherein, R a 、R b 、and R c are independently selected from the group consisting of H, Me, halide, CF3, C(H)F2, C(F)H2, and -(C 1- C5) alkylene - N-(R x )(R y ); provided that at least one of R a , R b , and R c is -(C 1- C5) alkylene - N-(R x )(R y ); R a , R b and R c at least one of which is -(C1 - C3) alkylene - N(R x )(R y ); R x and R y are independently selected from the group consisting of H and methyl; or R x and R y form a substituted or unsubstituted 4 - to 6 - membered ring together with the N to which they are attached; R1 is substituted or unsubstituted (C1 - C6) - alkyl, substituted or unsubstituted (C1 - C4) - alkylene - (C3 - C6) - cycloalkyl, or substituted or unsubstituted (C1 - C4) - alkylene - (C1 - C4) - alkoxy; R2 is

Chemical formula

[0356] In some embodiments, the compound of the invention may be a compound of formula (Ic) below or a pharmaceutically acceptable salt thereof:

Chemical formula

[0357] In one embodiment, the compound of the present invention may be the compound (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2-fluoro-3-methyl-5-((S)-2-methylpiperidin-1-yl)phenyl)propanoic acid, or a pharmaceutically acceptable salt thereof. [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0358] In certain embodiments, the present invention relates to any one of the foregoing methods, and the subject is a mammal. In certain embodiments, the present invention relates to any one of the foregoing methods, and the subject is a human. [Examples]

[0359] The present invention is generally described herein and is included merely as an illustration of specific aspects and embodiments of the present invention and is not intended to limit the present invention. It will be more readily understood by reference to the following examples.

[0360] Examples 1-4 describe the synthesis of specific compounds presented in Figure 1, including compounds of formula (Ia) and formula (Ib). The compounds of Figure 1 may be prepared as a mixture of diastereomeric compounds having a (3S) structure (i.e., at the stereocenter beta of the carboxylic acid moiety), such as those disclosed in Examples 1-4, and as a mixture of diastereomers (e.g., as shown in formula (Ib)) at the chiral center covalently bonded to the pyridone ring nitrogen atom of formula (I).

[0361] In Figure 1, compounds having higher activity in the fluorescence polarization (FP) assay of Example 5 are shown together with the stereochemistry diagram of formula (Ia). Example 5 describes the fluorescence polarization (FP) assay. Example 6 describes the ligand binding (LB) assay. Example 7 describes the cell adhesion (CA) assay.

[0362] Additional embodiments In some embodiments, the compound may be selected from one or more of the recited embodiments presented below: 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

Chemical formula

[0363] 2. The compound according to Embodiment 1, wherein R1 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl.

[0364] 3. The compound according to Embodiment 2, wherein R1 is iso-butyl.

[0365] 4. R1 is

Chemical formula

[0366] 5. R1 is

Chemical formula

[0367] 6. R 3a and R 3e are independently selected from the group consisting of halides, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted (C1-C4)-alkoxy, CF3, C(H)F2, and C(F)H2, the compound according to any one of Embodiments 1 to 5.

[0368] 7. R 3a and R 3b are independently selected from the group consisting of halides and (C1-C4) alkyl, the compound according to Embodiment 6.

[0369] 8. The halide is Cl or F, the compound according to Embodiment 7.

[0370] 9. (C1-C4)-alkyl is methyl, the compound according to Embodiment 7 or 8.

[0371] 10. R 3a is methyl; and R 3b is F, the compound according to any one of Embodiments 1 to 7.

[0372] 11. R 3a is F; and R 3b is methyl, a compound according to any one of Embodiments 1 to 7.

[0373] 12. R4 is H, a compound according to any one of Embodiments 1 to 11.

[0374] 13. R4 is methyl, ethyl, n-propyl, isopropyl, a compound according to any one of Embodiments 1 to 11.

[0375] 14. R 5a and R 5e are independently selected from the group consisting of halides, CF3, C(H)F2, C(F)H2, and substituted or unsubstituted (C1-C4)-alkyl, a compound according to any one of Embodiments 1 to 13.

[0376] 15. R 5a is a halide, a compound according to any one of Embodiments 1 to 14.

[0377] 16. R 5a is F or Cl, a compound according to Embodiment 15.

[0378] 17. R 5a is CF3, a compound according to any one of Embodiments 1 to 14.

[0379] 18. R 5a is C(H)F2, a compound according to any one of Embodiments 1 to 14.

[0380] 19. R 5a is C(F)H2, a compound according to any one of Embodiments 1 to 14.

[0381] 20. R 5a is a compound according to any one of Embodiments 1 to 14, which is unsubstituted (C1-C4)-alkyl.

[0382] 21. R 5a is methyl, the compound according to Embodiment 20.

[0383] 22. R 5a is (C1-C5)-alkyl substituted with at least one halide, the compound according to any one of Embodiments 1 to 14.

[0384] 23. R 5a is unsubstituted (C1-C4)-alkoxy, the compound according to any one of Embodiments 1 to 14.

[0385] 24. R 5a is OMe, the compound according to Embodiment 23.

[0386] 25. R 5e is a halide, the compound according to any one of Embodiments 1 to 24.

[0387] 26. R 5e is F or Cl, the compound according to Embodiment 25.

[0388] 27. R 5e is CF3, the compound according to any one of Embodiments 1 to 24.

[0389] 28. R 5e is C(H)F2, the compound according to any one of Embodiments 1 to 24.

[0390] 29. R 5eThe compound according to any one of Embodiments 1 to 24, wherein it is C(F)H2.

[0391] 30. R 5e The compound according to any one of Embodiments 1 to 24, wherein it is unsubstituted (C1-C4)-alkyl.

[0392] 31. R 5e The compound according to Embodiment 30, wherein it is methyl.

[0393] 32. R 5e The compound according to any one of Embodiments 1 to 24, wherein it is (C1-C5)-alkyl substituted with at least one halide.

[0394] 33. R 5e The compound according to any one of Embodiments 1 to 24, wherein it is unsubstituted (C1-C4)-alkoxy.

[0395] 34. R 5e The compound according to Embodiment 33, wherein it is OMe.

[0396] 35. R 5b R 5c and R 5d are independently selected from the group consisting of H, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, and substituted or unsubstituted (C1-C4)-alkoxy, the compound according to any one of Embodiments 1 to 34.

[0397] 36. R 5b The compound according to any one of Embodiments 1 to 35, wherein it is H.

[0398] 37. R 5b The compound according to any one of Embodiments 1 to 35, wherein it is halide.

[0399] 38. R 5b is the compound according to embodiment 37, wherein R is Cl or F.

[0400] 39. R 5b is the compound according to any one of embodiments 1 to 35, wherein R is CF3.

[0401] 40. R 5b is the compound according to any one of embodiments 1 to 35, wherein R is C(H)F2.

[0402] 41. R 5b is the compound according to any one of embodiments 1 to 35, wherein R is C(F)H2.

[0403] 42. R 5b is the compound according to any one of embodiments 1 to 35, wherein R is unsubstituted (C1-C4)-alkyl.

[0404] 43. R 5b is the compound according to embodiment 37, wherein R is methyl.

[0405] 44. R 5b is the compound according to any one of embodiments 1 to 35, wherein R is unsubstituted (C1-C4)-alkoxy.

[0406] 45. R 5b is the compound according to embodiment 44, wherein R is OMe.

[0407] 46. R 5b is the compound according to any one of embodiments 1 to 35, wherein R is unsubstituted (C3-C6)-cycloalkyl.

[0408] 47. R 5bThe compound according to embodiment 46, which is cyclopropyl.

[0409] 48. R 5c The compound according to any one of embodiments 1 to 47, wherein R is H.

[0410] 49. R 5c The compound according to any one of embodiments 1 to 47, wherein R is a halide.

[0411] 50. R 5c The compound according to embodiment 49, wherein R is Cl or F.

[0412] 51. R 5c The compound according to any one of embodiments 1 to 47, wherein R is CF3.

[0413] 52. R 5c The compound according to any one of embodiments 1 to 47, wherein R is C(H)F2.

[0414] 53. R 5c The compound according to any one of embodiments 1 to 47, wherein R is C(F)H2.

[0415] 54. R 5c The compound according to any one of embodiments 1 to 47, wherein R is unsubstituted (C1-C4)-alkyl.

[0416] 55. R 5c The compound according to embodiment 54, wherein R is methyl.

[0417] 56. R 5c The compound according to any one of embodiments 1 to 47, wherein R is unsubstituted (C1-C4)-alkoxy.

[0418] 57. R 5c is the compound according to Embodiment 56, which is OMe.

[0419] 58. R 5c is the compound according to any one of Embodiments 1 to 47, which is unsubstituted (C3-C6)-cycloalkyl.

[0420] 59. R 5b is the compound according to Embodiment 58, which is cyclopropyl.

[0421] 60. R 5d is the compound according to any one of Embodiments 1 to 59, which is H.

[0422] 61. R 5d is the compound according to any one of Embodiments 1 to 59, which is a halide.

[0423] 62. R 5d is the compound according to Embodiment 61, which is Cl or F.

[0424] 63. R 5d is the compound according to any one of Embodiments 1 to 59, which is CF3.

[0425] 64. R 5d is the compound according to any one of Embodiments 1 to 59, which is C(H)F2.

[0426] 65. R 5d is the compound according to any one of Embodiments 1 to 59, which is C(F)H2.

[0427] 66. R 5d is the compound according to any one of Embodiments 1 to 59, which is unsubstituted (C1-C4)-alkyl.

[0428] 67. R 5d is the compound according to embodiment 66, wherein R is methyl.

[0429] 68. R 5d is the compound according to any one of embodiments 1 to 67, wherein R is unsubstituted (C1-C4)-alkoxy.

[0430] 69. R 5d is the compound according to embodiment 68, wherein R is OMe.

[0431] 70. R 5d is the compound according to any one of embodiments 1 to 67, wherein R is unsubstituted (C3-C6)-cycloalkyl.

[0432] 71. R 5d is the compound according to embodiment 70, wherein R is cyclopropyl.

[0433] 72. R 5b and R 5d are each H, and is the compound according to any one of embodiments 1 to 35.

[0434] 73. R a is H, and is the compound according to any one of embodiments 1 to 72.

[0435] 74. R a is Me, and is the compound according to any one of embodiments 1 to 72.

[0436] 75. R a is a halide, and is the compound according to any one of embodiments 1 to 72.

[0437] 76. R aThe compound according to embodiment 75, wherein it is Cl or F.

[0438] 77. R a The compound according to any one of embodiments 1 to 72, wherein R is CF3.

[0439] 78. R a The compound according to any one of embodiments 1 to 72, wherein R is C(H)F2.

[0440] 79. R a The compound according to any one of embodiments 1 to 72, wherein R is C(F)H2.

[0441] 80. R a R is unsubstituted -(C1-C3) alkylene - N-(R x )(R y ) and is the compound according to any one of embodiments 1 to 72.

[0442] 81. R a R is substituted -(C1-C3) alkylene - N-(R x )(R y ) substituted with F or OMe and is the compound according to any one of embodiments 1 to 72.

[0443] 82. R b R is H and is the compound according to any one of embodiments 1 to 81.

[0444] 83. R b R is Me and is the compound according to any one of embodiments 1 to 81.

[0445] 84. R b R is a halide and is the compound according to any one of embodiments 1 to 81.

[0446] 85. R b is the compound according to Embodiment 84, which is Cl or F.

[0447] 86. R b is the compound according to any one of Embodiments 1 to 81, which is CF3.

[0448] 87. R b is the compound according to any one of Embodiments 1 to 81, which is C(H)F2.

[0449] 88. R b is the compound according to any one of Embodiments 1 to 81, which is C(F)H2.

[0450] 89. R b is unsubstituted -(C1-C3) alkylene-N-(R x )(R y ) and is the compound according to any one of Embodiments 1 to 81.

[0451] 90. R b is substituted -(C1-C3) alkylene-N-(R x )(R y ) substituted with F or OMe and is the compound according to any one of Embodiments 1 to 81.

[0452] 91. R c is H and is the compound according to any one of Embodiments 1 to 90.

[0453] 92. R c is Me and is the compound according to any one of Embodiments 1 to 90.

[0454] 93. R c is a halide and is the compound according to any one of Embodiments 1 to 90.

[0455] 94. R c is the compound according to Embodiment 93, which is Cl or F.

[0456] 95. R c is the compound according to any one of Embodiments 1 to 90, which is CF3.

[0457] 96. R c is the compound according to any one of Embodiments 1 to 90, which is C(H)F2.

[0458] 97. R c is the compound according to any one of Embodiments 1 to 90, which is C(F)H2.

[0459] 98. R c is the compound according to any one of Embodiments 1 to 90, which is unsubstituted -(C1-C3)alkylene-N-(R x )(R y ).

[0460] 99. R c is the compound according to any one of Embodiments 1 to 90, which is substituted -(C1-C3)alkylene-N-(R x )(R y ) substituted with F or OMe.

[0461] 100. R c is the compound according to any one of Embodiments 1 to 99, which is H.

[0462] 101. R x is the compound according to any one of Embodiments 1 to 99, which is unsubstituted (C1-C6)-alkyl.

[0463] 102. R yThe compound according to any one of Embodiments 1 to 100, which is H.

[0464] 103. R y The compound according to any one of Embodiments 1 to 100, which is unsubstituted (C1-C6)-alkyl.

[0465] 104. R x and R y The compound according to any one of Embodiments 1 to 72, 80 to 81, 89 to 90, and 98 to 99, which together with the N to which they are attached form an unsubstituted 4- to 6-membered ring.

[0466] 105. R x and R y The compound according to any one of Embodiments 1 to 72, 80 to 81, 89 to 90, and 98 to 99, which together with the N to which they are attached form a substituted 4- to 6-membered ring substituted with at least one halide, substituted or unsubstituted (C1-C4)alkyl, or OMe.

[0467] 106. The compound according to Embodiment 104 or 105, wherein the 4- to 6-membered ring is 3- to 6-membered heterocycloalkyl.

[0468] 107. The compound according to Embodiment 104 or 105, wherein the 4- to 6-membered ring is 4- to 5-membered heterocycloalkyl.

[0469] 108. The compound according to Embodiment 1, wherein the compound is a compound of the following formula (Ia):

Chemical formula

[0470] 109. R 5a and R 5e are each independently unsubstituted (C1-C4) alkyl, the compound according to embodiment 108.

[0471] 110. R b is unsubstituted -(C1-C3) alkylene-N(R x )(R y ), the compound according to embodiment 108 or 109.

[0472] 111. R a is selected from the group consisting of H, C(H)F2, CF3 and Me, the compound according to embodiment 1 or 108.

[0473] 112. R b is

Chemical formula

[0474] 113. R b is

Chemical formula

[0475] 114. R c is a compound according to Embodiment 1 or 108, which is H or F.

[0476] 115. R1 is

Chemical formula

[0477] 116. R 5a is CF3, a compound according to any one of Embodiments 108 - 115.

[0478] 117. R 5a is C(H)F2, a compound according to any one of Embodiments 108 - 115.

[0479] 118. R 5a is C(F)H2, a compound according to any one of Embodiments 108 - 115.

[0480] 119. R 5a is methyl, a compound according to any one of Embodiments 108 - 115.

[0481] 120. R 5a is OMe, a compound according to any one of Embodiments 108 - 115.

[0482] 121. R 5a is F or Cl, a compound according to any one of Embodiments 108 - 115.

[0483] 122. R 5b is H, a compound according to any one of Embodiments 108 - 121.

[0484] 123. R 5b is the compound according to any one of Embodiments 108 to 121, which is CF3.

[0485] 124. R 5b is the compound according to any one of Embodiments 108 to 121, which is C(H)F2.

[0486] 125. R 5b is the compound according to any one of Embodiments 108 to 121, which is C(F)H2.

[0487] 126. R 5b is the compound according to any one of Embodiments 108 to 121, which is methyl.

[0488] 127. R 5b is the compound according to any one of Embodiments 108 to 121, which is OMe.

[0489] 128. R 5b is the compound according to any one of Embodiments 108 to 121, which is F or Cl.

[0490] 129. R 5c is the compound according to any one of Embodiments 108 to 128, which is H.

[0491] 130. R 5c is the compound according to any one of Embodiments 108 to 128, which is CF3.

[0492] 131. R 5c is the compound according to any one of Embodiments 108 to 128, which is C(H)F2.

[0493] 132. R5c The compound according to any one of Embodiments 108 to 128, wherein R is C(F)H2.

[0494] 133. R 5c The compound according to any one of Embodiments 108 to 128, wherein R is methyl.

[0495] 134. R 5c The compound according to any one of Embodiments 108 to 128, wherein R is OMe.

[0496] 135. R 5c The compound according to any one of Embodiments 108 to 128, wherein R is F or Cl.

[0497] 136. R 5d The compound according to any one of Embodiments 108 to 135, wherein R is H.

[0498] 137. R 5d The compound according to any one of Embodiments 108 to 135, wherein R is CF3.

[0499] 138. R 5d The compound according to any one of Embodiments 108 to 135, wherein R is C(H)F2.

[0500] 139. R 5d The compound according to any one of Embodiments 108 to 135, wherein R is C(F)H2.

[0501] 140. R 5d The compound according to any one of Embodiments 108 to 135, wherein R is methyl.

[0502] 141. R 5d The compound according to any one of Embodiments 108 to 135, wherein R is OMe.

[0503] 142. R 5d is a compound according to any one of Embodiments 108 to 135, which is F or Cl.

[0504] 143. R 5e is a compound according to any one of Embodiments 108 to 142, which is CF3.

[0505] 144. R 5e is a compound according to any one of Embodiments 108 to 142, which is C(H)F2.

[0506] 145. R 5e is a compound according to any one of Embodiments 108 to 142, which is C(F)H2.

[0507] 146. R 5e is a compound according to any one of Embodiments 108 to 142, which is methyl.

[0508] 147. R 5e is a compound according to any one of Embodiments 108 to 142, which is OMe.

[0509] 148. R 5e is a compound according to any one of Embodiments 108 to 142, which is F or Cl.

[0510] 149. R 5b R 5c and R 5d at least one of which is H, is a compound according to Embodiment 1 and any one of Embodiments 108 to 121.

[0511] 150. R 5b R 5c and R 5dThe compound according to any one of Embodiment 1 and Embodiments 108 to 121, wherein at least two of them are H.

[0512] 151. R 5b , R 5c and R 5d are H, the compound according to any one of Embodiment 1 and Embodiments 108 to 121.

[0513] 152. R 3a is H, the compound according to any one of Embodiment 1 and Embodiments 108 to 151.

[0514] 153. R 3a is methyl, the compound according to any one of Embodiment 1 and Embodiments 108 to 151.

[0515] 154. R 3a is a halide, the compound according to any one of Embodiment 1 and Embodiments 108 to 151.

[0516] 155. R 3a is CF3, the compound according to any one of Embodiment 1 and Embodiments 108 to 151.

[0517] 156. R 3a is C(H)F2, the compound according to any one of Embodiment 1 and Embodiments 108 to 151.

[0518] 157. R 3a is C(F)H2, the compound according to any one of Embodiment 1 and Embodiments 108 to 151.

[0519] 158. R 3a is OMe, the compound according to any one of Embodiment 1 and Embodiments 108 to 151.

[0520] 159. R 3b is the compound according to Embodiment 1 and any one of Embodiments 108 to 158, which is H.

[0521] 160. R 3b is the compound according to Embodiment 1 and any one of Embodiments 108 to 158, which is methyl.

[0522] 161. R 3b is the compound according to Embodiment 1 and any one of Embodiments 108 to 158, which is a halide.

[0523] 162. R 3b is the compound according to Embodiment 1 and any one of Embodiments 108 to 158, which is CF3.

[0524] 163. R 3b is the compound according to Embodiment 1 and any one of Embodiments 108 to 158, which is C(H)F2.

[0525] 164. R 3b is the compound according to Embodiment 1 and any one of Embodiments 108 to 158, which is C(F)H2.

[0526] 165. R 3b is the compound according to Embodiment 1 and any one of Embodiments 108 to 158, which is OMe.

[0527] 166. R 3b is the compound according to Embodiment 1 and any one of Embodiments 108 to 158, which is OCF3.

[0528] 167. R 3b is the compound according to Embodiment 1 and any one of Embodiments 108 to 158, which is cyclopropyl.

[0529] 168. R 3a is methyl, and R 3b is F, the compound according to any one of Embodiments 108 to 151.

[0530] 169. R 3a is F, and R 3b is methyl, the compound according to any one of Embodiments 108 to 151.

[0531] 170. The compound according to Embodiment 1, wherein the compound is selected from any one of the compounds in Figure 1, or an enantiomer thereof.

[0532] 171. The compound according to Embodiment 1, wherein the compound is a compound of the following formula (Ic), or a pharmaceutically acceptable salt thereof:

Chemical formula

[0533] 172. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof: (3S)-3-(4,5-Difluoro-2’,6’-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; (3S)-3-(2-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2’,6’-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid; (3S)-3-(2-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3’,4-difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid; (3S)-3-(2-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-3’-methoxy-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid; (3S)-3-(4,4’-Difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; (3S)-3-(5-Chloro-4-fluoro-2’,6’-dimethyl-[1,1’-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; (3S)-3-(2-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2’,4’,5,6’-tetramethylbiphenyl-3-yl)propanoic acid; (3S)-3-(4,4’-Difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-(2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (3S)-3-(2-(5-(2-(Dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamido)-3-(4-fluoro-2’,5,6’-trimethylbiphenyl-3-yl)propanoic acid; (3S)-3-(4-Fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (3S)-3-(4-Fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; and (3S)-3-(5-Chloro-4-fluoro-2’,6’-dimethyl-[1,1’-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid.

[0534] 173. The compound according to embodiment 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof: TIFF0007702004000091.tif43145174. The compound according to embodiment 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof: TIFF0007702004000092.tif51145175. The compound according to embodiment 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof: TIFF0007702004000093.tif51145176. The compound according to embodiment 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof: TIFF0007702004000094.tif51145177. The compound according to embodiment 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof: TIFF0007702004000095.tif54145178. The compound according to embodiment 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof: TIFF0007702004000096.tif55145179. The compound according to embodiment 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof: TIFF0007702004000097.tif53145180. The compound according to embodiment 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof: TIFF0007702004000098.tif46145181. The compound according to embodiment 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof: TIFF0007702004000099.tif47145182. The compound according to embodiment 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof: TIFF0007702004000100.tif44145183. The compound according to embodiment 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof: TIFF0007702004000101.tif65145184. The compound according to embodiment 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof: TIFF0007702004000102.tif52145185. The compound according to embodiment 1, wherein the compound is (3S)-3-(4,5-difluoro-2’,6’-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0535] 186. The compound according to embodiment 1, wherein the compound is (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2’,6’-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0536] 187. The compound according to embodiment 1, wherein the compound is (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3’,4-difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0537] 188. The compound according to embodiment 1, wherein the compound is (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-3’-methoxy-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0538] 189. The compound according to embodiment 1, wherein the compound is (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0539] 190. The compound according to embodiment 1, wherein the compound is (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0540] 191. The compound according to embodiment 1, wherein the compound is (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0541] 192. The compound according to embodiment 1, wherein the compound is (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0542] 193. The compound according to embodiment 1, wherein the compound is (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamide)-3-(4-fluoro-2’,5,6’-trimethylbiphenyl-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0543] 194. The compound according to embodiment 1, wherein the compound is (3S)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0544] 195. The compound according to embodiment 1, wherein the compound is (3S)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0545] 196. The compound according to embodiment 1, wherein the compound is (3S)-3-(5-chloro-4-fluoro-2’,6’-dimethyl-[1,1’-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0546] 197. The compound according to embodiment 1, wherein the compound is (S)-3-(4,5-difluoro-2’,6’-dimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0547] 198. The compound according to embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2’,6’-dimethyl-5-(trifluoromethyl)-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0548] 199. The compound according to embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3’,4-difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0549] 200. The compound according to embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-3’-methoxy-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0550] 201. The compound according to embodiment 1, wherein the compound is (S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0551] 202. The compound according to embodiment 1, wherein the compound is (S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0552] 203. The compound according to embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0553] 204. The compound according to embodiment 1, wherein the compound is (S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0554] 205. The compound according to embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamide)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0555] 206. The compound according to embodiment 1, wherein the compound is (S)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0556] 207. The compound according to embodiment 1, wherein the compound is (S)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0557] 208. The compound according to embodiment 1, wherein the compound is (S)-3-(5-chloro-4-fluoro-2’,6’-dimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0558] 209. A pharmaceutical composition comprising the compound according to any one of embodiments 1 to 208 and a pharmaceutically acceptable excipient.

[0559] 210. A method for inhibiting α4β7 integrin in a cell, comprising contacting the cell with a compound according to any one of Embodiments 1 to 208 under conditions effective to reduce the adhesion of the cell to MAdCAM-1.

[0560] 211. A method for reducing the adhesion of a cell containing α4β7 integrin to MAdCAM-1, comprising contacting the cell with a compound according to any one of Embodiments 1 to 208 under conditions effective to reduce the adhesion of the cell to MAdCAM-1.

[0561] 212. A method for treating inflammatory bowel disease, ulcerative colitis, or Crohn's disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of Embodiments 1 to 208.

[0562] In some embodiments, a compound of formula (I):

Chemical formula

Chemical formula

[0563] In some embodiments, the compound is (S)-3-(4,5-difluoro-2’,6’-dimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0564] In some embodiments, the compound is (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2’,6’-dimethyl-5-(trifluoromethyl)-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0565] In some embodiments, the compound is (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3’,4-difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0566] In some embodiments, the compound is (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-3’-methoxy-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0567] In some embodiments, the compound is (S)-3-(4,4’-difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0568] In some embodiments, the compound is (S)-3-(5-chloro-4-fluoro-2’,6’-dimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0569] In some embodiments, the compound is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2’,4’,5,6’-tetramethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0570] In some embodiments, the compound is (S)-3-(4,4’-difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0571] In some embodiments, the compound is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamide)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0572] In some embodiments, the compound is (S)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0573] In some embodiments, the compound is (S)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0574] In some embodiments, a pharmaceutical composition comprising a compound of formula (I) as an active pharmaceutical ingredient:

Chemical formula

Chemical formula

Chemical formula

[0575] In some embodiments, the compound is

Chemical formula

[0576] In some embodiments, the compound is

Chemical formula

[0577] In some embodiments, the compound is

Chemical formula

[0578] In some embodiments, the compound is

Chemical formula

[0579] In some embodiments, the compound is

Chemical formula

[0580] In some embodiments, the compound is

Chemical formula

[0581] In some embodiments, the compound is

Chemical formula

[0582] In some embodiments, the compound is

Chemical formula

[0583] In some embodiments, the compound is

Chemical formula

[0584] In some embodiments, the compound is

Chemical formula

[0585] In some embodiments, the compound is

Chemical formula

[0586] In some embodiments, a compound of formula (Ia):

Chemical formula

Chemical formula

Chemical formula

[0587] In some embodiments, the compound is

Chemical formula

[0588] In some embodiments, the compound is

Chem.

[0589] In some embodiments, the compound is

Chem.

[0590] In some embodiments, the compound is

Chem.

[0591] In some embodiments, the compound is

Chem.

[0592] In some embodiments, the compound is

Chem.

[0593] In some embodiments, the compound is

Chem.

[0594] The compound, wherein

Chem.

[0595] When the compound is

Chemical formula

[0596] In some embodiments, the compound is

Chemical formula

[0597] In some embodiments, the compound is

Chemical formula

[0598] In some embodiments, the pharmaceutical composition comprises, as an active pharmaceutical ingredient, the compound of the present application or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention relates to a compound of formula (I), formula (Ia), or formula (Ib), or a pharmaceutically acceptable salt thereof:

Chemical formula

Chemical formula

[0599] In one embodiment of the above formula (Ib), the compound is not the compound listed in FIG. 1.

[0600] In one embodiment of the above formula (Ib), the compound is the compound listed in FIG. 2 and / or FIG. 3.

[0601] In some embodiments, the present invention relates to a compound of formula (I), formula (Ia), or formula (Ib), or a pharmaceutically acceptable salt thereof: [Chemical formula] TIFF0007702004000140.tif47157 wherein, R a 、R b and R c are independently selected from the group consisting of H, Me, halide, CF3, C(H)F2, C(F)H2, -CN, -OCF3, substituted or unsubstituted (C1-C5)-alkyl, (C1-C5)-alkoxy, -CH2CF 3、and substituted or unsubstituted -(C 1- C5)alkylene-N-(R x )(R y ), selected from the group consisting of, provided that R a , R b , and at least one of R c is -(C 1- C5)alkylene-N-(R x )(R y ); wherein the substituted (C1-C5)-alkyl is substituted with a halide, amino or (C1-C4)-alkylamino; and the substituted -(C 1- C5)alkylene-N-(R x )(R y ) is substituted with a halide, (C1-C5)-alkyl, (C1-C5)-alkyl-OCH3, (C1-C4)-haloalkyl, (C3-C6)-cycloalkyl, (C1-C4)-alkoxy, or heterocyclyl; R x and R y are independently selected from the group consisting of H and (C1-C6)-alkyl, or R x and R y form a 4- to 6-membered ring together with the N to which they are attached; R1 is substituted or unsubstituted (C1-C6)-alkyl, (C1-C4)-alkylene-(C3-C6)-cycloalkyl, or (C1-C4)-alkylene-(C1-C4)-alkoxy, wherein the substituted (C1-C6)-alkyl is substituted with a halide or (C3-C6)-cycloalkyl; R2 is

Chemical formula

[0602] In one embodiment of the above formula (Ib), the compound is not a compound listed in Figure 1.

[0603] In one embodiment of the above formula (Ib), the compound is a compound listed in Figure 2 and / or Figure 3.

[0604] In some embodiments, the compound of formula (I) may be a compound of formula (Ib): [Chemical Formula] wherein R a is selected from the group consisting of hydrogen and (C1-C5)-alkyl optionally substituted with a halide; R b is -(C 1- C5)alkylene-N-(R x )(R y ); R x and R y are independently selected from the group consisting of (C1-C6)-alkyl; or R x and R y together with the N to which they are attached form a 4- to 6-membered ring optionally substituted with a halide or (C1-C4)alkoxy; R c is selected from the group consisting of hydrogen and (C1-C5)-alkyl optionally substituted with a halide; R1 is (C1-C6)-alkyl; R 3a is a halide; R 3b is selected from the group consisting of (C1-C5)-alkyl optionally substituted with a halide and (C3-C6)-cycloalkyl; R 3c is hydrogen; R 3d is selected from the group consisting of H and a halide; R4 is hydrogen; R 5a and R 5e are each (C1-C5)-alkyl; and R 5b , R 5c , and R 5dis independently selected from the group consisting of (C1-C5)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocycloalkyl, hydroxyl, and (C1-C4)-alkoxy, each optionally substituted with H, CN, halide, halide (e.g., CF3, C(H)F2, C(F)H2, -CH2CF3).

[0605] In some embodiments, the compound of formula (I) may be a compound of formula (Ia):

Chemical formula

[0606] In some embodiments, the compound of formula (I) may be a compound of formula (Ia):

Chemical formula

[0607] In some embodiments, the compound of formula (I) is a compound of formula (Ia):

Chemical formula

Chemical formula

[0608] In some embodiments, the compound of formula (I) is a compound of formula (Ib):

Chemical formula

Chemical formula

[0609] In some embodiments, the compound may be a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Chemical formula

Chemical formula

[0610] In some embodiments, the compound may be a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

Chemical formula

Chemical formula

[0611] In some embodiments, the compound may be a compound of formula (Ib) or a pharmaceutically acceptable salt thereof:

Chemical formula

[0612] Example 1. General Scheme for the Synthesis of α4β7 Inhibitors Synthesis of β - Amino Acids The synthesis of β - amino acids can be carried out using known procedures described in the literature such as, for example, but not limited to, "Enantioselective Synthesis of β‐Amino Acids," Second Edition, Editors: Eusebio Juaristi, Vadim A. Soloshonok, First published: 27 January 2005, John Wiley & Sons, Inc.; Ellman et. Al Acc.Chem. Res.2002.35,984 - 995; Franklin A. Davis and Bang - Chi Chen Chem.Soc.Rev.,1998,27,13 - 18; Jacobsen, M.F.; Skrydstrup, T. J.Org. Chem.2003,68,7122; Tang, T.P.; Ellman, J. A. J. Org. Chem.2002,67,7819; and Tang, T.P.; Ellman, J.A. J.Org.Chem.1999,64,12.

[0613] Reductive Amination [Chemical formula] Procedure A: A mixture of amine (1 equivalent), aldehyde (1.2 equivalents) in DCM (1 - 2 mL / mmol amine) was stirred at room temperature for 30 minutes. Then NaBH(OAc)3 (1.5 equivalents) was added portionwise several times and stirred at room temperature overnight. The solvent was concentrated in vacuo and the residue was purified by silica gel chromatography to obtain the desired amine.

[0614] Procedure B: A mixture of aldehyde (1 equiv), amine (1.05 - 2 equiv) in DCE (3 - 4 mL / mmol of aldehyde) was stirred at room temperature for 10 - 30 minutes. Then, NaBH(OAc)3 (3 - 4 equiv) was added portionwise and stirred at room temperature for 1 - 16 hours until LC / MS was complete. The solvent was concentrated in vacuo and the residue was purified by silica gel chromatography to afford the desired amine.

[0615] Procedure C: A mixture of aldehyde (1 equiv), AcOH (1.2 equiv), amine (1.05 - 2 equiv) in DCM (2 - 3 mL / mmol aldehyde) and MeOH (0.5 mL / mmol aldehyde) was stirred at room temperature for 15 - 30 minutes. Then, NaBH(OAc)3 (2 equiv) was added portionwise and stirred at room temperature for 1 - 16 hours until LC / MS was complete. The solvent was concentrated in vacuo and the residue was purified by silica gel chromatography to afford the desired amine.

[0616] Alkylation

Chem.

[0617]

Chem.

[0618] Phenol Deprotection

Chem.

[0619] Wittig reaction

Chem.

[0620] Procedure B: A mixture of (methoxymethyl)triphenylphosphonium chloride (1.1 equiv), t-BuOK (2.5 equiv) in THF (4 mL / mmol of phosphonium salt) was stirred at 0 °C for 1 h. Then a solution of aldehyde (1 equiv) in THF (2 mL / mmol of aldehyde) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was worked up (diluted with water and extracted with EtOAc; the combined extracts were dried over Na2SO4, filtered, and concentrated) and purified by silica gel chromatography to afford the enol ether product.

[0621] From enol ether to aldehyde

Chem.

[0622] Procedure B: The enol ether (1 equivalent) was treated with HCOOH (2 mL / mmol) at 70 °C for 2 h. The solvent was removed in vacuo to afford the desired aldehyde.

[0623] Procedure C: To a DCM solution of enol ether (1 equivalent) (15 mL / mmol enol ether), TFA (2 mL / mmol) and water (0.25 mL / mmol enol ether) were added. The reaction mixture was stirred at 45 °C for 18 h. The reaction was completed (quenched with NaHCO3 and extracted with DCM; the combined extracts were dried over Na2SO4, filtered and concentrated) to afford the desired aldehyde.

[0624] Stille reaction

Chem.

[0625] From alkene to aldehyde

Chem.

[0626] From ester to acid

Chem.

[0627] Amine protection

Chem.

[0628] Preparation of aryl borane

Chem.

[0629] Suzuki coupling "Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds" N. Miyaura; A. Suzuki Chem. Rev. 1995, 957, 2457 - 2483。

[0630]

Chem.

[0631]

Chem.

Chem.

[0632] Boc Deprotection

Chem.

[0633] t-Butylsulfinyl Deprotection

Chem.

[0634] Amide Bond Formation “Peptide Coupling Reagents, More than a Letter Soup” A. El-Faham, F. Albericio Chem. Rev. 2011, 111, 11, 6557 - 6602; “Amide bond formation and peptide coupling” C. A. G. N. Montalbetti; V. Falque Tetrahedron 2005, 61, 10827 - 10852. [Chemistry] A mixture of an amine (1 equivalent), a carboxylic acid (1 equivalent), TCFH (2 equivalents), and NMI (4 equivalents) in CH3CN (10 mL / mmol amine) was stirred at room temperature for 1 - 2 hours until completion by LCMS. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography to obtain the desired amine product.

[0635] Ester hydrolysis [Chemistry] An ester (1 equivalent) was treated at room temperature for 1 - 5 hours with a solution of LiOH - H2O (3 - 5 equivalents) in MeOH (1 - 3 mL / mmol ester) and water (1 - 3 mL / mmol ester). The reaction mixture was acidified to pH = 4 - 5 using 1N HCl and concentrated. The residue was purified by preparative HPLC to obtain the desired carboxylic acid product.

[0636] Analytical methods LCMS analysis method The final compound was analyzed using LC / MS conditions with monitoring by UV detectors at 214 nm and 254 nm and mass spectrometry scanning from 110 - 800 amu in ESI+ ionization mode.

[0637] LC / MS A: Column: XBridge C18, 4.6 X 50 mm, 3.5 μm, Mobile phase: A water (10 mM ammonium bicarbonate), B CH3CN; Gradient: 5% - 95% B in 1.4 minutes, then hold for 1.6 minutes; Flow rate: 1.8 mL / min; Oven temperature 50 °C.

[0638] LC / MS B: Column: SunFire C18, 4.6 X 50 mm, 3.5 μm; Mobile phase: A water (0.01% TFA), B CH3CN; Gradient: 5% - 95% B in 1.5 minutes, then hold for 1.5 minutes; Flow rate: 2.0 mL / min; Oven temperature 50 °C.

[0639] LC / MS C: Column: XBridge C18, 4.6 X 50 mm, 3.5 μm, Mobile phase: A water (10 mM ammonium bicarbonate), B CH3CN; Gradient: 5% - 95% B in 1.5 min, then hold for 1.5 min; Flow rate: 1.8 mL / min; Oven temperature 50 °C.

[0640] LC / MS D: Column: Poroshell 120 EC-C138, 4.6 X 30 mm, 2.7 μm; Mobile phase: A water (0.01% TFA), B CH3CN (0.01% TFA); Gradient: 5% - 95% B in 1.2 min, then hold for 1.8 min; Flow rate: 2.2 mL / min; Oven temperature 50 °C.

[0641] Example 2A. Preparation of Intermediate Preparation of Ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-((tert-butoxycarbonyl)amino)propanoate Step 1: 5-Bromo-2-fluoro-3-methylbenzaldehyde [Chemical formula] Under a nitrogen atmosphere, at -78 °C, a solution of 4-bromo-1-fluoro-2-methylbenzene (10.0 g, 52.9 mmol, 1.0 equivalent) in anhydrous THF (100.0 mL) was added dropwise with lithium diisopropylamide (2.0 M, 39.7 mL, 79.4 mmol, 1.5 equivalents) over 10 minutes and stirred at -78 °C for 1 hour. DMF (15.0 mL) was added dropwise and the mixture was stirred at -78 °C for 2 hours. LCMS indicated that the reaction was complete. The reaction mixture was quenched at 0 °C with saturated aqueous NH4Cl solution (100 mL) and extracted with EtOAc (100 mL x 2). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column (petroleum ether:EtOAc 9:1) to obtain 5-bromo-2-fluoro-3-methylbenzaldehyde (8.0 g) as a white solid. Yield 70% (ESI 218.9 [M+H] + )

[0642] Step 2: (R,E)-N-(5-Bromo-2-fluoro-3-methylbenzylidene)-2-methylpropan-2-sulfinamide [Chemical formula] Under a nitrogen atmosphere, Ti(OEt)4 (12.6 g, 55.4 mmol, 1.50 equivalents) was added dropwise to a mixture of 5-bromo-2-fluoro-3-methylbenzaldehyde (8.0 g, 36.9 mmol, 1.00 equivalent) and (R)-2-methylpropan-2-sulfinamide (5.4 g, 44.3 mmol, 1.2 equivalents) in anhydrous THF (80 mL) at room temperature while maintaining the temperature below 30 °C. The reaction mixture was warmed to 40 °C and stirred for 1 hour. LCMS indicated that the reaction was complete. Water (80 mL) and EtOAc (80 mL) were added to the mixture, and the mixture was stirred at room temperature for 5 minutes. The mixture was filtered and washed with EtOAc (50 mL). The filtrate was separated. The organic layer was washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product (R,E)-N-(5-bromo-2-fluoro-3-methylbenzylidene)-2-methylpropan-2-sulfinamide (12.0 g, crude) as a yellow solid, which was used in the next step without further purification. Yield 100% (ESI 320.0 [M+H] + )

[0643] Step 3: Ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate [Chemical formula] Under a nitrogen atmosphere, chlorotrimethylsilane (0.8 g, 7.5 mmol, 0.2 equivalent) was added dropwise to a THF mixture (200 mL) of Zn (12.2 g, 187.5 mmol, 5.0 equivalents) at room temperature. The mixture was stirred at 60 °C for 1 hour under a nitrogen atmosphere and then cooled to 20 - 30 °C. Ethyl 2-bromoacetate (1.57 g, 9.4 mmol, 0.25 equivalent) was added dropwise at 20 - 30 °C. When the reaction mixture began to exotherm, the remaining ethyl 2-bromoacetate (14.4 g, 86.3 mmol, 2.3 equivalents) was added dropwise while maintaining the reaction mixture at 50 - 60 °C. After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to 0 °C, and a solution of (R,E)-N-(5-bromo-2-fluoro-3-methylbenzylidene)-2-methylpropane-2-sulfinamide (12.0 g, 37.5 mmol) in anhydrous THF (30 mL) was added dropwise, and the mixture was stirred at 25 °C for 1 hour. LCMS indicated that the reaction was complete. MTBE (150 mL) and an aqueous solution of citric acid (3 g) (100 mL) were added to the mixture. The mixture was separated. The aqueous layer was extracted with MTBE (150 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 3:1) to obtain ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate (9.0 g). Yield 59% (ESI 408.0 [M+H] + )。

[0644] Step 4: Ethyl (S)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propanoate

Chemical Structure

[0645] Step 5: Ethyl (S)-ethyl 3-(5-bromo-2-fluoro-3-methylphenyl)-3-(tert-butoxycarbonylamino)propanoate [Chemical formula] To a solution of (S)-ethyl 3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propanoate (8.0 g, 19.6 mmol, 1.00 equiv) in DCM (100 mL) were added DIEA (7.6 g, 59.0 mmol, 3.00 equiv) and Boc2O (8.6 g, 39.2 mmol, 2.00 equiv). The reaction mixture was stirred at room temperature for 16 h. LCMS indicated the completion of the reaction. The reaction mixture was diluted with DCM (200 mL) and washed with 0.5 N HCl (50 mL×3), saturated NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 3:1) to give (S)-ethyl 3-(5-bromo-2-fluoro-3-methylphenyl)-3-((tert-butoxycarbonyl)amino)propanoate (6.0 g) as a brown oil. Yield 75% (ESI 404.1(M+H) + ).

[0646] (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate Preparation

Chem.

[0647] (S)-Ethyl 3-amino-3-(2’,4-difluoro-5,6’-dimethyl-[1,1’-biphenyl]-3-yl)propanoate Preparation Step 1: (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-3-(2’,4-difluoro-5,6’-dimethyl-[1,1’-biphenyl]-3-yl)propanoate

Chem.

[0648] Step 2: (S)-Ethyl 3-amino-3-(2’,4-difluoro-5,6’-dimethyl-[1,1’-biphenyl]-3-yl)propanoate [Chemical formula] (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-3-(2’,4-difluoro-5,6’-dimethyl-[1,1’-biphenyl]-3-yl)propanoate (210 mg, 0.48 mmol, 1.0 eq) in a stirred solution of DCM (2 mL) was treated with HCl-dioxane (4 M, 3.0 mL, 6.0 mmol, 12.5 eq). The mixture was stirred at room temperature for 2 h. LCMS indicated completion of the reaction. The mixture was concentrated in vacuo to afford (S)-ethyl 3-amino-3-(2’,4-difluoro-5,6’-dimethyl-[1,1’-biphenyl]-3-yl)propanoate (160 mg) as a colorless oil. Yield 99% ((ESI 334.1[M+H] + ).

[0649] Preparation of (S)-ethyl 3-amino-3-(2’-cyano-4-fluoro-5,6’-dimethyl-[1,1’-biphenyl]-3-yl)propanoate hydrochloride Step 1: (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-3-(2’-cyano-4-fluoro-5,6’-dimethyl-[1,1’-biphenyl]-3-yl)propanoate

Chemical formula

[0650] Step 2: (S)-Ethyl 3-amino-3-(2'-cyano-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride [Chemical formula] (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-3-(2'-cyano-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (230 mg, 0.52 mmol, 1.0 eq) in DCM (2 mL) was added to HCl-dioxane (4 M, 2.0 mL, 4.0 mmol, 7.7 eq). The mixture was stirred at room temperature for 1 h. LCMS indicated the completion of the reaction. The mixture was concentrated in vacuo to give (S)-ethyl 3-amino-3-(2'-cyano-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride (180 mg) as a yellow oil. Yield 91% (ESI 341.1 [M+H] + ).

[0651] Preparation of (S)-ethyl 3-amino-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate Step 1: (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate [Chemical formula] (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (1.0 g, 2.22 mmol, 1.00 equiv), 2-bromo-1-chloro-3-methylbenzene (543 mg, 2.66 mmol, 1.20 equiv), K2CO3 (613 mg, 4.44 mmol, 2.0 equiv) and Pd(dppf)Cl2 (81 mg, 0.11 mmol, 0.05 equiv) in a mixture of dioxane (10 mL) and H2O (2 mL) were stirred at 110 °C for 2 h under a nitrogen atmosphere. Water (30 mL) was added and the solution was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 2:1) to give (S)-ethyl 3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (800 mg) as a colorless oil. Yield 80% (ESI 450.18 [M+H] + ).

[0652] Step 2: (S)-Ethyl 3-amino-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate [Chemical formula] (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (300 mg, 0.67 mmol, 1.00 eq) in DCM (9 mL) was added with HCl-dioxane (4 M, 9.0 mL, 36.0 mmol, 53.73 eq), and stirred at room temperature for 1 h. LCMS indicated the completion of the reaction. The mixture was concentrated in vacuo to give (S)-ethyl 3-amino-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (200 mg) as a white solid, which was used directly in the next reaction without further purification. Yield 86% (ESI 350.1 [M+H] + ).

[0653] Preparation of (S)-ethyl 3-amino-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate Step 1: (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate [Chemical formula] (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (500 mg, 1.12 mmol, 1.00 equiv), cyclopropylboronic acid (116 mg, 1.35 mmol, 1.20 equiv), K3PO4 (475 mg, 2.24 mmol, 2.00 equiv), PCy3 (31 mg, 0.11 mmol, 0.10 equiv) and Pd(OAc)2 (11 mg, 0.11 mmol, 0.10 equiv) in a mixture of dioxane (10 mL) and H2O (2 mL) were stirred at 110 °C for 36 h under a nitrogen atmosphere. Water (30 mL) was added and the solution was extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 2:1) to give (S)-ethyl 3-((tert-butoxycarbonyl)amino)-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (400 mg) as a colorless oil. Yield 79% (ESI 456.2 [M+H] + ).

[0654] Step 2: (S)-Ethyl 3-amino-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate [Chemical formula] (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (400 mg, 0.88 mmol, 1.0 equiv) in DCM (9 mL) was added to HCl-dioxane (4 M, 9.0 mL, 36.0 mmol, 40.9 equiv), and the mixture was stirred at room temperature for 1 hour. LCMS indicated that the reaction was complete. The mixture was concentrated in vacuo to give (S)-ethyl 3-amino-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (300 mg) as a white solid, which was used directly in the next reaction without further purification. Yield 96% (ESI 356.2 [M+H] + ).

[0655] Preparation of (S)-ethyl 3-amino-3-(4-fluoro-4'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride Step 1: (S)-Ethyl 3-amino-3-(2'-ethyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

Chemical Structure

[0656] Step 2: (S)-Ethyl 3-amino-3-(2'-ethyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

Chem.

[0657] Preparation of (S)-ethyl 3-amino-3-(4-fluoro-2’-methoxy-5,6’-dimethylbiphenyl-3-yl)propanoate Step 1: (S)-Ethyl 3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2’,4’,5,6’-tetramethyl-[1,1’-biphenyl]-3-yl)propanoate

Chemical Structure

[0658] Step 2: (S)-Ethyl 3-amino-3-(4-fluoro-2'-methoxy-5,6'-dimethylbiphenyl-3-yl)propanoate

Chemical Structure

[0659] Preparation of (S)-ethyl 3-amino-3-(4-fluoro-2'-methoxy-5-methyl-6'-(trifluoromethyl)biphenyl-3-yl)propanoate Step 1: 1-Methoxy-2-nitro-3-(trifluoromethyl)benzene [Chemical formula] To a mixture of 2-nitro-3-(trifluoromethyl)phenol (1.5 g, 7.25 mmol, 1.0 equiv) in acetone (20 mL) were added K2CO3 (3 g, 21.75 mmol, 3 equiv) and CH3I (5.15 g, 36.25 mmol, 5 equiv). The mixture was stirred at room temperature for 16 h. LCMS indicated completion of the reaction. The reaction mixture was filtered and washed with EtOAc (20 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column (petroleum ether:EtOAc 2:1) to give 1-methoxy-2-nitro-3-(trifluoromethyl)benzene (1.3 g) as a white solid. Yield 81%.

[0660] Step 2: 2-Methoxy-6-(trifluoromethyl)aniline [Chemical formula] A mixture of 1-methoxy-2-nitro-3-(trifluoromethyl)benzene (1.3 g, 5.88 mmol, 1.0 equiv) in EtOH (20 mL) was added with 10% Pd / C (700 mg), and stirred at room temperature for 16 h under H2 atmosphere (2 L, 1 atm). LCMS indicated that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to afford 2-methoxy-6-(trifluoromethyl)aniline (0.75 g) as a white solid. Yield 67% (ESI 192.1 [M+H] + ).

[0661] Step 3: 2-Bromo-1-methoxy-3-(trifluoromethyl)benzene

Chemical Structure

[0662] Step 4: (S)-Ethyl 3-(tert-butoxycarbonylamino)-3-(4-fluoro-2'-methoxy-5-methyl-6'-(trifluoromethyl)biphenyl-3-yl)propanoate

Chemical Structure

[0663] Step 5: (S)-ethyl 3-amino-3-(4-fluoro-2'-methoxy-5-methyl-6'-(trifluoromethyl)biphenyl-3-yl)propanoate

Chem.

[0664] (S)-Ethyl 3-amino-3-(2',6'-dichloro-4-fluoro-5-methylbiphenyl-3-yl)propanoate Step 1: (S)-Ethyl 3-(tert-butoxycarbonylamino)-3-(2',6'-dichloro-4-fluoro-5-methylbiphenyl-3-yl)propanoate

Chemical Structure

[0665] Step 2: (S)-Methyl 3-amino-3-(2’,6’-dichloro-4-fluoro-5-methylbiphenyl-3-yl)propanoate

Chemical formula

[0666] Preparation of Ethyl (S)-3-Amino-3-(2’,4-Difluoro-4’,5,6’-Trimethyl-[1,1’-Biphenyl]-3-Yl)Propanoate Step 1: 2-Fluoro-4,6-Dimethylaniline

Chemical Structure

[0667] Step 2: 2-Bromo-1-Fluoro-3,5-Dimethylbenzene

Chemical Structure

[0668] Step 3: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2’,4-difluoro-4’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoate [Chemical formula] (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (556 mg, 1.23 mmol, 1.0 equiv), 2-bromo-1-fluoro-3,5-dimethylbenzene (250 mg, 1.23 mmol, 1.0 equiv), Pd(dppf)Cl2 (45 mg, 0.062 mmol, 0.05 equiv) and K2CO3 (510 mg, 3.69 mmol, 3.0 equiv) in a mixture of dioxane (6 mL) and water (2 mL) were stirred at 110 °C for 2 h under a nitrogen atmosphere. Water (35 mL) was added and the solution was extracted with EtOAc (25 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 7:1) to give ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2’,4-difluoro-4’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoate (365 mg) as a yellow oil. Yield 66% (ESI 348.1 [M+H-100] + )

[0669] Step 4: Ethyl (S)-3-amino-3-(2’,4-difluoro-4’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoate TIFF0007702004000204.tif41140 Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2’,4-difluoro-4’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoate (720 mg, 1.29 mmol, 1.0 eq) in DCM (2 mL) was stirred and HCl-dioxane (4 M, 2.0 mL, 4.0 mmol, 3.1 eq) was added. The mixture was stirred at room temperature for 1 h. LCMS indicated completion of the reaction. The mixture was concentrated in vacuo to give ethyl (S)-3-amino-3-(2’,4-difluoro-4’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoate (450 mg) as a yellow oil. Yield 93% (ESI 348.1 [M+H] + )

[0670] Preparation of (S)-ethyl 3-amino-3-(2’,6’-dichloro-4-fluoro-4’,5-dimethylbiphenyl-3-yl)propanoate Step 1: 1,3-Dichloro-2-iodo-5-methylbenzene [Chemical formula] To a mixture of 2,6-dichloro-4-methylaniline (2.5 g, 14.3 mmol, 1.0 equiv) in acetonitrile (10 mL) and water (1 mL) was added 4-methylbenzenesulfonic acid (9.8 g, 57.1 mmol, 4 equiv), and the mixture was stirred at 0 °C for 10 min. A solution of NaNO2 (2.0 g, 28.6 mmol, 2 equiv) in H2O (2 mL) was added dropwise, and the mixture was stirred at 0 °C for 30 min. Then, a solution of potassium iodide (3.0 g, 17.9 mmol, 1.5 equiv) in H2O (2 mL) was added, and the mixture was heated at 50 °C for 2 h under a nitrogen atmosphere. Water (20 mL) was added, and the solution was extracted with EtOAc (20 mL × 3). The combined organic layers were concentrated in vacuo, and the residue was purified by silica gel column (petroleum ether:EtOAc 1:1) to give 1,3-dichloro-2-iodo-5-methylbenzene (1.8 g) as a colorless oil. Yield 44.2% (ESI 286.9 [M+H]+).

[0671] Step 2: (S)-Ethyl 3-(tert-butoxycarbonylamino)-3-(2’,6’-dichloro-4-fluoro-4’,5-dimethylbiphenyl-3-yl)propanoate [Chemical formula] Methyl (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (1.5 g, 3.43 mmol, 1 equiv) and 1,3-dichloro-2-iodo-5-methylbenzene (2.0 g, 6.86 mmol, 2 equiv) in dioxane (10 mL) were added with an aqueous solution of K2CO3 (1.9 g, 13.72 mmol, 4 equiv) in H2O (2 mL) and Pd(dppf)Cl2 (250 mg, 0.343 mmol, 0.1 equiv). The mixture was heated at 110 °C for 2 h under a nitrogen atmosphere. Water (20 mL) was added and the solution was extracted with EtOAc (20 mL × 3). The combined organic layers were concentrated in vacuo and the residue was purified by silica gel column (petroleum ether:EtOAc 1:1) to give methyl (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2’,6’-dichloro-4-fluoro-4’,5-dimethylbiphenyl-3-yl)propanoate (1.3 g) as a colorless oil. Yield 78.3% (ESI 484.4 [M+H] + ).

[0672] Step 3: (S)-Ethyl 3-amino-3-(2’,6’-dichloro-4-fluoro-4’,5-dimethylbiphenyl-3-yl)propanoate

Chemical formula

[0673] Preparation of (S)-ethyl 3-amino-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoate Step 1: (S)-ethyl 3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoate

Chemical formula

[0674] Step 2: (S)-Ethyl 3-amino-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoate [Chemical formula] To a stirred solution of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoate (4.0 g, 9.2 mmol, 1.00 eq) in DCM (6 mL) was added HCl-dioxane (4 M, 4 mL, 16.0 mmol, 1.7 eq). The mixture was stirred at room temperature for 30 minutes. LCMS indicated completion of the reaction. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18 / 120 g column (A: water 10 mM NH4HCO3, B: MeOH, 0 - 100%) to give ethyl (S)-3-amino-3-(4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoate (2.0 g) as a colorless oil. Yield 61% (ESI 330.1 [M+H] + ).

[0675] Preparation of Ethyl (S)-3-Amino-3-(4,4’-difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoate Step 1: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,4’-difluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoate [Chemical formula] (S)-Ethyl 3-((R)-tert-butylsulfinyl)amino-3-(5-bromo-2-fluoro-3-methylphenyl)propanoate (6.0 g, 14.7 mmol, 1.00 equiv), (4-fluoro-2,6-dimethylphenyl)boronic acid (3.7 g, 22.1 mmol, 1.5 equiv), K2CO3 (6.1 g, 44.1 mmol, 3.0 equiv) and Pd(dppf)Cl2 (1.1 g, 1.47 mmol, 0.01 equiv) in a mixture of dioxane (50 mL) and H2O (5 mL) were stirred at 110 °C for 1 h under a nitrogen atmosphere. LCMS indicated that the reaction was complete. The mixture was cooled to room temperature. Water (50 mL) was added and the solution was extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 1:1) to give (S)-ethyl 3-((R)-tert-butylsulfinyl)amino-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (5.5 g) as a yellow oil. Yield 83% (ESI 452.0 (M+H) + )

[0676] Step 2: (S)-Ethyl 3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

Chemical Structure

[0677] Preparation of ethyl (S)-3-amino-3-(4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate Step 1: 2-(4-Chloro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [Chemical formula] Under a nitrogen atmosphere, n-BuLi (2 N, 11.0 mL, 22.0 mmol, 1.2 equivalents) was added to a solution of 2-bromo-5-chloro-1,3-dimethylbenzene (4.0 g, 18.2 mmol, 1.0 equivalent) in anhydrous THF (40 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 40 minutes, and a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.1 g, 27.5 mmol, 1.5 equivalents) in anhydrous THF (40 mL) was added, and the mixture was stirred at -78 °C for 3 hours. After completion, saturated aqueous NH4Cl (100 mL) was added. The mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel (petroleum ether:EtOAc 2:1) to obtain the desired 2-(4-chloro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.4 g) as a white solid. Yield 90%.

[0678] Step 2: Ethyl (S)-3-amino-3-(4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate [Chemical formula] (S)-Ethyl 3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propanoate (500 mg, 1.7 mmol, 1.0 equiv), 2-(4-chloro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (544 mg, 2.04 mmol, 1.2 equiv), Pd(dppf)Cl2 (62 mg, 0.085 mmol, 0.05 equiv) and K2CO3 (704 mg, 5.1 mmol, 3.0 equiv) in a mixture of 1,4-dioxane (10 mL) and water (2 mL) were stirred at 110 °C for 2 h under a nitrogen atmosphere. Water (20 mL) was added and the solution was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 1:2) to give (S)-ethyl 3-amino-3-(4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (250 mg) as a colorless oil. Yield 41% (ESI 364.2 [M+H] + ).

[0679] Preparation of (S)-Ethyl 3-amino-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoate Step 1: (S)-Ethyl 3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoate

Chemical Structure

[0680] Step 2: (S)-Ethyl 3-amino-3-(4-fluoro-2’,4’,5,6’-tetramethyl-[1,1’-biphenyl]-3-yl)propanoate

Chemical formula

[0681] Example: Preparation of (S)-ethyl 3-amino-3-(4-fluoro-2’,5,6’-trimethyl-4’-(trifluoromethyl)-[1,1’-biphenyl]-3-yl)propanoate hydrochloride Step 1: 2,6-Dimethyl-4-(trifluoromethyl)aniline [Chemical formula] A mixture of 2,6-dibromo-4-(trifluoromethyl)aniline (638 mg, 2.00 mmol, 1.0 equiv), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (TFH, 3.5 M, 3.43 mL, 12.00 mmol, 6.0 equiv), K2CO3 (1.10 g, 7.96 mmol, 3.98 equiv) and Pd(dppf)Cl2 (245 mg, 0.30 mmol, 0.15 equiv) in dioxane (6 mL) and water (1 mL) was stirred at 90 °C for 8 h under a nitrogen atmosphere. The mixture was filtered through a Celite bed, washed with ethyl acetate (100 mL), and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column (petroleum ether:EtOAc 20:1) to give 2,6-dimethyl-4-(trifluoromethyl)aniline (1.63 g) as a colorless oil. Yield 48% (ESI 190.1 (M+H) + ).

[0682] Step 2: 2-Bromo-1,3-dimethyl-5-(trifluoromethyl)benzene

Chem.

[0683] Step 3: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2’,5,6’-trimethyl-4’-(trifluoromethyl)-[1,1’-biphenyl]-3-yl)propanoate

Chem.

[0684] High and low 5: Ethyl (S)-3-amino-3-(4-fluoro-2’,5,6’-trimethyl-4’-(trifluoromethyl)-[1,1’-biphenyl]-3-yl)propanoate hydrochloride [Chemical formula] (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2’,5,6’-trimethyl-4’-(trifluoromethyl)-[1,1’-biphenyl]-3-yl)propanoate (308 mg, 0.62 mmol, 1.0 equiv) in a stirred solution of DCM (4 mL) was added HCl-dioxane (4 M, 4.0 mL, 16.0 mmol, 25.8 equiv). The mixture was stirred at room temperature for 2 h. LCMS indicated that the reaction was complete. The mixture was concentrated in vacuo to give (S)-ethyl 3-amino-3-(4-fluoro-2’,5,6’-trimethyl-4’-(trifluoromethyl)-[1,1’-biphenyl]-3-yl)propanoate hydrochloride (260 mg) as a yellow oil. Yield 97% (ESI 398.1 [M+H] + ).

[0685] Preparation of (S)-ethyl 3-amino-3-(4’-cyclopropyl-4-fluoro-2’,5,6’-trimethyl-[1,1’-biphenyl]-3-yl)propanoate High-low 1:4-cyclopropyl-2,6-dimethylaniline [Chemical formula] Under a nitrogen atmosphere, to a mixture of 4-bromo-2,6-dimethylaniline (2.0 g, 10.0 mmol, 1.0 equiv) and cyclopropylboronic acid (1.03 g, 12.0 mmol, 1.2 equiv) in toluene (15 mL) was added a solution of K3PO4 (4.2 g, 20.0 mmol, 2.0 equiv) in H2O (3 mL), PCy3 (280.0 mg, 1.0 mmol, 0.1 equiv) and Pd(OAc)2 (224.0 mg, 1.0 mmol, 0.1 equiv). The mixture was stirred at 100 °C for 4 h under a nitrogen atmosphere. Water (30 mL) was added and the solution was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 2:1) to give 4-cyclopropyl-2,6-dimethylaniline (0.8 g), which was used in the next step without further purification. Yield 93% (ESI 162.2[M+H]+ )。

[0686] Step 2: 2-Bromo-5-cyclopropyl-1,3-dimethylbenzene

Chem.

[0687] Step 3: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-cyclopropyl-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

Chem.

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, R ａ , R ｂ and R ｃ are independently H, Me, halide, CF ３ , C(H)F ２ , C(F)H ２ , -CN, -OCF ３ , substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C １ -C ５ )-alkoxy, -CH ２ CF ３、 and substituted or unsubstituted -(C １－ C ５ ) alkylene-N-(R ｘ ) (R ｙ ), with the proviso that R ａ , R ｂ , and R ｃ At least one of the groups is -(C １－ C ５ ) alkylene-N-(R ｘ ) (R ｙ ) and R ｘ and R ｙ are independently H and substituted or unsubstituted (C １ -C ６ )-alkyl, or R ｘ and R ｙ form a 4-6 membered ring together with the N to which they are attached; R １ is a substituted or unsubstituted (C １ -C ６ )-alkyl, substituted or unsubstituted (C １ -C ４ )-alkylene-(C ３ -C ６ )-cycloalkyl, or substituted or unsubstituted (C １ -C ４ )-alkylene-(C １ -C ４ )-alkoxy; R ２ teeth, 【Chemistry 2】 and R ３ａ and R ３ｂ are independently H, substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -OH, -CN, halide, CF ３ , C(H)F ２ , C(F)H ２、 - (C １ -C ４ )-alkoxy, -OCF ３ and substituted or unsubstituted (C １ -C ４ )-alkylene-(C １ -C ４ )-alkoxy, with the proviso that R ３ａ and R ３ｂ may not both be H; R ３ｃ is H, substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, halide, CF ３ , C(H)F ２ , C(F)H ２ , -(C １ -C ４ )-alkoxy, -OCF ３ -CN, and substituted or unsubstituted (C １ -C ４ )-alkylene-(C １ -C ４ )-alkoxy; R ３ｄ is H, substituted or unsubstituted (C １ -C ５ )-alkyl, hydroxyl, halide, and -(C １ -C ４ )-alkoxy; R ４ is H or a substituted or unsubstituted (C １ -C ４ ) alkyl; R ５ａ and R ５ｅ are independently H, CN, halide, CF ３ , C(H)F ２ , C(F)H ２ , -CH ２ CF ３、 Substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkylhydroxyl, and (C １ -C ４ )-alkoxy; and R ５ｂ , R ５ｃ , and R ５ｄ are independently H, CN, halide, CF ３ , C(H)F ２ , C(F)H ２ , -CH ２ CF ３ , substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, hydroxyl, and (C １ -C ４ )-alkoxy; However, the compounds of formula (I) exclude the following compounds: 【Chemistry 3】 【change】 The compound or a pharma- ceutically acceptable salt thereof, 4 β 7 Medicaments for treating integrin-mediated conditions.

2. A compound of formula (I) or a pharma- ceutically acceptable salt thereof: 【Chemistry 4】 During the ceremony, R ａ is H, Me, halide, C(H)F ２ , C(F)H ２ , -CN, -OCF ３ , substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C １ -C ５ )-alkoxy, -CH ２ CF ３、 and substituted or unsubstituted -(C １－ C ５ ) alkylene-N-(R ｘ ) (R ｙ ) selected from the group consisting of; R ｂ and R ｃ are independently H, Me, halide, CF ３ , C(H)F ２ , C(F)H ２ , -CN, -OCF ３ , substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C １ -C ５ )-alkoxy, -CH ２ CF ３、 and substituted or unsubstituted -(C １－ C ５ ) alkylene-N-(R ｘ ) (R ｙ ), with the proviso that R ａ , R ｂ , and R ｃ At least one of the groups is -(C １－ C ５ ) alkylene-N-(R ｘ ) (R ｙ ) and R ｘ and R ｙ are independently H and substituted or unsubstituted (C １ -C ６ )-alkyl, or R ｘ and R ｙ form a 4-6 membered ring together with the N to which they are attached; R １ is a substituted or unsubstituted (C １ -C ６ )-alkyl, substituted or unsubstituted (C １ -C ４ )-alkylene-(C ３ -C ６ )-cycloalkyl, or substituted or unsubstituted (C １ -C ４ )-alkylene-(C １ -C ４ )-alkoxy; R ２ teeth, 【Chemistry 5】 and R ３ａ and R ３ｂ are independently H, substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -OH, -CN, halide, CF ３ , C(H)F ２ , C(F)H ２、 - (C １ -C ４ )-alkoxy, -OCF ３ and substituted or unsubstituted (C １ -C ４ )-alkylene-(C １ -C ４ )-alkoxy, with the proviso that R ３ａ and R ３ｂ may not both be H; R ３ｃ is H, substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, halide, CF ３ , C(H)F ２ , C(F)H ２ , -(C １ -C ４ )-alkoxy, -OCF ３ -CN, and substituted or unsubstituted (C １ -C ４ )-alkylene-(C １ -C ４ )-alkoxy; R ３ｄ is H, substituted or unsubstituted (C １ -C ５ )-alkyl, hydroxyl, halide, and -(C １ -C ４ )-alkoxy; R ４ is H or a substituted or unsubstituted (C １ -C ４ ) alkyl; R ５ａ and R ５ｅ are independently H, CN, halide, CF ３ , C(H)F ２ , C(F)H ２ , -CH ２ CF ３、 Substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkylhydroxyl, and (C １ -C ４ )-alkoxy; and R ５ｂ , R ５ｃ , and R ５ｄ are independently H, CN, halide, CF ３ , C(H)F ２ , C(F)H ２ , -CH ２ CF ３ , substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, hydroxyl, and (C １ -C ４ )-alkoxy; However, the compounds of formula (I) exclude the following compounds: 【Chemistry 6】 The compound or a pharma- ceutically acceptable salt thereof, 4 β 7 Medicaments for treating integrin-mediated conditions.

3. A compound of formula (I) or a pharma- ceutically acceptable salt thereof: 【Chemistry 7】 During the ceremony, R ａ , R ｂ and R ｃ are independently H, Me, halide, CF ３ , C(H)F ２ , C(F)H ２ , -CN, -OCF ３ , substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C １ -C ５ )-alkoxy, -CH ２ CF ３、 and substituted or unsubstituted -(C １－ C ５ ) alkylene-N-(R ｘ ) (R ｙ ), with the proviso that R ａ , R ｂ , and R ｃ At least one of the groups is -(C １－ C ５ ) alkylene-N-(R ｘ ) (R ｙ ) and R ｘ and R ｙ are independently H and substituted or unsubstituted (C １ -C ６ )-alkyl, or R ｘ and R ｙ form a 4-6 membered ring together with the N to which they are attached; R １ is a substituted or unsubstituted (C １ -C ６ )-alkyl, substituted or unsubstituted (C １ -C ４ )-alkylene-(C ３ -C ６ )-cycloalkyl, or substituted or unsubstituted (C １ -C ４ )-alkylene-(C １ -C ４ )-alkoxy; R ２ teeth, 【Chemistry 8】 and R ３ａ is H, substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -OH, -CN, CF ３ , C(H)F ２ , C(F)H ２、 - (C １ -C ４ )-alkoxy, -OCF ３ and substituted or unsubstituted (C １ -C ４ )-alkylene-(C １ -C ４ )-alkoxy; R ３ｂ is H, substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -OH, -CN, halide, CF ３ , C(H)F ２ , C(F)H ２、 - (C １ -C ４ )-alkoxy, -OCF ３ and substituted or unsubstituted (C １ -C ４ )-alkylene-(C １ -C ４ )-alkoxy, with the proviso that R ３ａ and R ３ｂ may not both be H; R ３ｃ is H, substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, halide, CF ３ , C(H)F ２ , C(F)H ２ , -(C １ -C ４ )-alkoxy, -OCF ３ -CN, and substituted or unsubstituted (C １ -C ４ )-alkylene-(C １ -C ４ )-alkoxy; R ３ｄ is H, substituted or unsubstituted (C １ -C ５ )-alkyl, hydroxyl, halide, and -(C １ -C ４ )-alkoxy; R ４ is H or a substituted or unsubstituted (C １ -C ４ ) alkyl; R ５ａ and R ５ｅ are independently H, CN, halide, CF ３ , C(H)F ２ , C(F)H ２ , -CH ２ CF ３、 Substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkylhydroxyl, and (C １ -C ４ )-alkoxy; and R ５ｂ , R ５ｃ , and R ５ｄ are independently H, CN, halide, CF ３ , C(H)F ２ , C(F)H ２ , -CH ２ CF ３ , substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, hydroxyl, and (C １ -C ４ )-alkoxy; The compound or a pharma- ceutically acceptable salt thereof, 4 β 7 Medicaments for treating integrin-mediated conditions.

4. R ａ , R ｂ , and R ｃ are independently H, Me, halide, CF ３ , C(H)F ２ , C(F)H ２ , and -(C １－ C ５ ) alkylene-N-(R ｘ ) (R ｙ ) selected from the group consisting of; ａ , R ｂ , and R ｃ At least one of the groups is -(C １－ C ５ ) alkylene-N-(R ｘ ) (R ｙ ) and R ３ｃ and R ３ｄ is H; R ５ａ and R ５ｅ are independently H, CN, halide, CF ３ , C(H)F ２ , C(F)H ２ , substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted (C １ -C ５ )-alkyl, hydroxyl, and (C １ -C ４ )-alkoxy; and R ５ｂ , R ５ｃ and R ５ｄ are independently H, CN, halide, CF ３ , C(H)F ２ , C(F)H ２ , substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, hydroxyl, and (C １ -C ４ 2. The pharmaceutical of claim 1, wherein said aryloxy group is selected from the group consisting of aryloxy group and aryloxy group.

5. The compound is of formula (Ia): 【Chemistry 9】 During the ceremony, R ａ , R ｂ and R ｃ At least one of the groups is -(C １ -C ３ ) alkylene-N(R ｘ ) (R ｙ ) and R ｘ and R ｙ is independently selected from the group consisting of H and methyl; or R ｘ and R ｙ form, together with the N to which they are attached, a substituted or unsubstituted 4-6 membered ring; and R ３ａ and R ３ｂ are each independently selected from the group consisting of methyl and F; The pharmaceutical composition according to claim 4.

6. R ａ , R ｂ , and R ｃ are independently H, Me, halide, CF ３ , C(H)F ２ , C(F)H ２ , and -(C １－ C ５ ) alkylene-N-(R ｘ ) (R ｙ ) selected from the group consisting of; ａ , R ｂ , and R ｃ At least one of the groups is -(C １－ C ５ ) alkylene-N-(R ｘ ) (R ｙ ) and R ｘ and R ｙ are independently H and substituted or unsubstituted (C １ -C ６ )-alkyl, or R ｘ and R ｙ form a 4-6 membered ring together with the N to which they are attached; R １ is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl; R ２ teeth, 【Chemistry 10】 and R ３ａ and R ３ｂ are independently H, (C １ -C ５ )-alkyl, (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -OH, -CN, halide, CF ３ , C(H)F ２ , C(F)H ２、 - (C １ -C ４ )-alkoxy, -OCF ３ and substituted or unsubstituted (C １ -C ４ )-alkylene-(C １ -C ４ )-alkoxy; provided that R ３ａ and R ３ｂ may not both be H; R ３ｃ and R ３ｄ is H; R ４ is H; R ５ａ and R ５ｅ is independently methyl; R ５ｂ and R ５ｃ are independently H, CN, halide, CF ３ , C(H)F ２ , C(F)H ２ , substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, hydroxyl, and (C １ -C ４ )-alkoxy; R ５ｄ is H, The pharmaceutical composition according to claim 1.

7. α, comprising a compound according to any one of claims 1 to 6 or a pharma- ceutically acceptable salt thereof, and one or more other ingredients. 4 β 7 Compositions for treating integrin-mediated conditions.

8. The compound is a compound of formula (Ia): 【Chemistry 11】 During the ceremony, R ａ CF ３ and R ｂ is a substituted or unsubstituted -(C １－ C ５ ) alkylene-N-(R ｘ ) (R ｙ ) and R ｘ and R ｙ are independently substituted or unsubstituted (C １ -C ６ )-alkyl; or R ｘ and R ｙ form a 4-6 membered ring together with the N to which they are attached; R ｃ is H; R １ is a substituted or unsubstituted (C １ -C ６ ) alkyl; R ２ teeth, 【Chemistry 12】 and R ３ａ and R ３ｂ are independently H, substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -OH, -CN, halide, CF ３ , C(H)F ２ , C(F)H ２、 - (C １ -C ４ )-alkoxy, -OCF ３ and substituted or unsubstituted (C １ -C ４ )-alkylene-(C １ -C ４ )-alkoxy, with the proviso that R ３ａ and R ３ｂ may not both be H; R ３ｃ is H; R ３ｄ is a halide; R ４ is H; R ５ａ and R ５ｅ are each independently １ -C ５ )-alkyl; and R ５ｂ , R ５ｃ , and R ５ｄ are independently H, CN, halide, CF ３ , C(H)F ２ , C(F)H ２ , -CH ２ CF ３ , substituted or unsubstituted (C １ -C ５ )-alkyl, substituted or unsubstituted (C ３ -C ６ )-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, hydroxyl, and (C １ -C ４ )-alkoxy; The pharmaceutical according to claim 1 , which is a compound having the above structure or a pharma- ceutically acceptable salt thereof.

9. 10. A pharmaceutical composition comprising the compound of claim 8, or a pharma- ceutically acceptable salt thereof, and one or more other ingredients. 4 β 7 Compositions for treating integrin-mediated conditions.

10. The a 4 β 7 9. The method of claim 1, wherein the integrin-mediated condition is a gastrointestinal autoinflammatory or autoimmune disease.

11. 10. The composition of claim 7 or 9, wherein the one or more other ingredients are pharma- ceutically acceptable excipients.

12. The a 4 β 7 12. The composition of any one of claims 7, 9 and 11, wherein the integrin-mediated condition is a gastrointestinal autoinflammatory or autoimmune disease.

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