Inhibition of human integrin alpha4beta7

Abstract

Small molecule antagonists of human [alpha] 4 [beta] 7 integrin and methods of using the small molecule antagonists in the treatment of various diseases and conditions are disclosed.

Description

[0001] This application is a divisional application of Chinese invention patent application 202080088450.4, entitled "Inhibition of human integrin α4β7", filed on October 16, 2020.

[0002] Related applications

[0003] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 916,062, filed on October 16, 2019. Technical Field

[0004] Novel compounds and related methods for inhibiting α4β7 integrin are disclosed herein. The compounds and methods disclosed herein are applicable to the development of drugs for the treatment of α4β7 integrin-mediated conditions such as inflammatory bowel disease (IBD), ulcerative colitis (UC), and Crohn's disease (CD). Background Technology

[0005] Integrins are non-covalently associated α / β heterodimeric cell surface receptors involved in many cellular processes. Different expression of integrins can modulate cell adhesion properties, allowing for the recruitment of different leukocyte populations to specific organs in response to different inflammatory signals. α4-integrin, containing α4β7, plays a role in lymphocyte migration throughout the gastrointestinal tract. This integrin is expressed on most leukocytes, including B and T lymphocytes, where it mediates cell adhesion through selective binding to its primary ligand, mucosal addressing cell adhesion molecule 1 (MAdCAM). Memory T lymphocytes expressing α4β7 integrin preferentially migrate into the gastrointestinal tract via strong adhesion to mucosal vascular addressing cell adhesion molecule 1 (MAdCAM-1).

[0006] Inhibitors of specific integrin-ligand interactions have been used to treat a variety of diseases. For example, monoclonal antibodies exhibiting high binding affinity for α4β7 have shown therapeutic benefits for gastrointestinal autoinflammatory / autoimmune diseases such as Crohn's disease and ulcerative colitis. However, these therapies also have certain undesirable characteristics for patients. Monoclonal antibody α4β7 integrin inhibitors are administered via parenteral administration, have long half-lives, cannot be rapidly modified for exposure, and their activity is reduced due to the formation of anti-drug antibodies. Monoclonal antibody therapies can be challenging to manufacture compared to small molecule therapies. Furthermore, some therapies that inhibit α4β7 also interfere with α4β1 integrin-ligand interactions, resulting in dangerous side effects for patients. In immunosuppressed patients, activity at the α4β1 integrin level is involved in the development of progressive multifocal leukoencephalopathy (PML), a life-threatening and progressive brain infection.

[0007] There remains a medical need for effective and safe oral α4β7 integrin inhibitors as an important complement to therapeutic medical devices for α4β7 integrin-mediated conditions such as inflammatory bowel disease (IBD), ulcerative colitis (UC), and Crohn's disease (CD). Summary of the Invention

[0008] In some embodiments, the present invention relates to compounds of formula (I):

[0009]

[0010] in

[0011] R a R b and R c Independently selected from the group consisting of: H, Me, halogen, CF3, C(H)F2, C(F)H2, -CN, -OCF3, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C1-C5)-alkoxy, -CH2CF3, and substituted or unsubstituted –(C 1- C5)alkylene-N-(R x (R) y ); the condition is R a R b and R c At least one of them is –(C 1- C5)alkylene-N-(R x (R) y );

[0012] R x and R y 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 it connects to, they form a 4- to 6-membered ring;

[0013] R1 is a substituted or unsubstituted (C1-C6)-alkyl, a substituted or unsubstituted (C1-C4)-alkylene-(C3-C6)-cycloalkyl, or a substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy.

[0014] R2 is

[0015] R 3a and R 3bIndependently selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3, and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; provided that R 3a and R 3b None of them are H;

[0016] R 3c Select from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, hydroxyl, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3-CN and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy;

[0017] R 3d Choose from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl, halogen and -(C1-C4)-alkoxy;

[0018] R4 is H or a substituted or unsubstituted (C1-C4)-alkyl group;

[0019] R 5a and R 5e Independently selected from the group consisting of: H, CN, halogens, CF3, C(H)F2, C(F)H2, -CH2CF3, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, hydroxyl, and (C1-C4)-alkoxy; and

[0020] R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogen, 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 heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy;

[0021] Or its pharmaceutically acceptable salt.

[0022] In some aspects of the invention, the compound of formula (I) can be a compound in which R a R b and R c One and only one of them is a substituted or unsubstituted -(C1-C5)alkylene-N-(R x (R) y R1 is a (C1-C6) alkyl group (e.g., isobutyl); R 3a and R 3b Independently selected from the group consisting of: H, (C1-C4)-alkyl (e.g., methyl), halogen (e.g., F or Cl), CF3, C(H)F2, and C(F)H2, provided that R 3a and R 3b None of them are H; and R4 is H.

[0023] In some instances, a compound of formula (I) can be a compound in which R a R b and R c One and only one of them is a substituted or unsubstituted -(C1-C5)alkylene-N-(R x (R) y ); R x and R y Each is independently an unsubstituted (C1-C6)-alkyl (e.g., methyl) or R x and R y Together with the N to which it is attached, it forms a substituted or unsubstituted 4- to 6-membered heterocyclic ring; R1 is an unsubstituted (C1-C6) alkyl group (e.g., isobutyl); R 3a and R 3b Independently selected from the group consisting of: H, unsubstituted (C1-C4)-alkyl (e.g., methyl, ethyl, etc.), halogen (e.g., F or Cl), CF3, C(H)F2 and C(F)H2, provided that R 3a and R 3b Neither of them are H; R 3c 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 The group consisting of H, halogens (e.g., F or Cl), substituted or unsubstituted (C1-C4)-alkyl (e.g., methyl), and hydroxyl groups is selected; and R4 is H. In some instances, compounds of formula (I), (Ia), and / or (Ib) can be compounds in which R a R band R c One and only one of them is a substituted or unsubstituted -(C1-C5)alkylene-N-(R x (R) y ); R x and R y Each is independently an unsubstituted methyl or R x and R y Together with the N group to which it is attached, it forms a substituted or unsubstituted 4- to 6-membered heterocyclic ring; R1 is isobutyl; R 3a and R 3b Independently selected from the group consisting of: unsubstituted (C1-C4)-alkyl (e.g., methyl), halogen (e.g., F or Cl), CF3, C(H)F2 and C(F)H2, R 3c and R 3d Neither of them is H; and R4 is H. For example, a compound of formula (I), formula (Ia), and / or formula (Ib) can be a compound in which R1 is isobutyl; R 3a and R 3b Independently selected from the group consisting of: unsubstituted (C1-C4)-alkyl (e.g., methyl), halogen (e.g., F or Cl), CF3, C(H)F2 and C(F)H2, R 3c and R 3d None of them are H; R4 is H; and R 5a and R 5e Each is a substituted or unsubstituted (C1-C4)-alkyl group (e.g., methyl). A compound of formula (I) can be a compound in which R... a R b and R c One and only one of them is a substituted or unsubstituted -(C1-C5)alkylene-N-(R x (R) y ); R x and R y Each is independently an unsubstituted methyl or R x and R y Together with the N-membered ring it is attached to, it forms a 4- to 6-membered heterocyclic ring, which is optionally substituted with a halogen (e.g., F); R1 is isobutyl; R 3a and R 3b Independently selected from the group consisting of: unsubstituted (C1-C4)-alkyl (e.g., methyl), halogen (e.g., F or Cl), CF3, C(H)F2 and C(F)H2, R 3c and R 3d None of them are H; R4 is H; R 5a and R 5eEach is a substituted or unsubstituted (C1-C4)-alkyl group (e.g., methyl), and R 5b R 5c and R 5d Each compound is independently selected from the group consisting of: H, CN, halogens (e.g., F, Cl), CF3, C(H)F2, C(F)H2, (C1-C5)-alkyl, hydroxyl, and (C1-C4)-alkoxy. In some embodiments, the present invention relates to a method for treating autoinflammatory / autoimmune diseases such as Crohn's disease and ulcerative colitis; said method comprising the step of administering to a subject in need a therapeutically effective amount of any of the compounds described herein.

[0024] In some embodiments, the compound of formula (I) can be a compound of formula (Ia):

[0025]

[0026] Or a pharmaceutically acceptable salt thereof, wherein R in formula (Ia) a R b R c R1, R 3a R 3b R 3c R 3d R 5a R 5b R 5c R 5d R 5e R and R4 are each defined independently as described above with respect to equation (I).

[0027]

[0028] Or a pharmaceutically acceptable salt thereof, wherein R in formula (Ia) a R b R c R1, R 3a R 3b R 3c R 3d R 5a R 5b R 5c R 5d R 5e R and R4 are each defined independently as described above with respect to equation (I).

[0029] This article also provides methods for preparing and isolating compounds of formula (I), formula (Ia) and / or formula (Ib). Attached Figure Description

[0030] Figure 1This is a table (Table 1) summarizing the in vitro inhibition of α4β7 integrin by exemplary compounds (i.e., data obtained from fluorescence polarization assays in Example 5 and ligand binding assays in Example 6).

[0031] Figure 2 A table (Table 2) provides additional exemplary compounds.

[0032] Figure 3 Table 5 summarizes the in vitro inhibition of α4β7 integrin by exemplary compounds (i.e., data obtained from fluorescence polarization assays in Example 5 and ligand binding assays in Example 6).

[0033] Figure 4 Table 6 summarizes the in vitro inhibition of α4β7 integrin by exemplary compounds (i.e., data obtained from fluorescence polarization assays in Example 5 and ligand binding assays in Example 6). Detailed Implementation

[0034] In some embodiments, the present invention relates to compounds that antagonize α4β7 integrin. These compounds could be used to treat diseases that can be treated by inhibiting α4β7 integrin (e.g., Crohn's disease (CD) and ulcerative colitis (UC)).

[0035] definition

[0036] For convenience, certain terms used in the specification, examples, and appended claims are collected herein before further description of the invention. These definitions should be understood in accordance with the remainder of this disclosure and as will be understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0037] To make the invention easier to understand, certain terms and phrases are defined below and throughout the specification.

[0038] The article “a / kind” is used in this text to refer to one / kind or more / kinds (i.e., at least one / kind) of grammatical objects. For example, “a element” means one or more elements.

[0039] As used herein in the specification and claims, the phrase “and / or” should be understood to mean “any one or both” of the elements thus combined, i.e., elements that coexist in some cases and exist separately in others. Multiple elements listed with “and / or” should be interpreted in the same way, i.e., “one or more” of the elements thus combined. Other elements may optionally be present, whether related to or unrelated to those specifically identified by the “and / or” clause. 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 only to A (optionally including elements other than B); in another embodiment, refer only to B (optionally including elements other than A); in yet another embodiment, refer to both A and B (optionally including other elements); and so on.

[0040] As used herein in this specification and claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when items in a list are separated, “or” or “and / or” should be interpreted as inclusive, i.e., including a plurality of elements or at least one element in a list of elements, but also including more than one element and optionally other items not listed. Only explicitly indicating the opposite terms, such as “only one of…” or “exact one of…” or, when used in claims, “consisting of…” will refer to including a plurality of elements or exactly one element in a list of elements. Generally, when preceded by an exclusive term such as “any one,” “one of…,” “only one of…,” or “exact one of…,” the term “or” as used herein should be interpreted only as indicating an exclusive alternative (i.e., “one or the other, not two”). When used in claims, “consisting substantially of…” should have the ordinary meaning as used in the field of patent law.

[0041] As used herein in the specification and claims, the phrase "at least one" relating to a list having one or more elements should be understood to mean at least one element selected from any one or more elements in the element list, but not necessarily including at least one of every element specifically listed in the element list, and does not exclude any combination of elements in the element list. This definition also allows for the optional presence of elements other than those specifically identified in the element list referred to by the phrase "at least one," whether or not they are related to those specifically identified elements. Thus, as a 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") in one embodiment may mean at least one, optionally including more than one A, without B (and optionally including elements other than B); in another embodiment, it may mean at least one, optionally including more than one B, without A (and optionally including elements other than A); in yet another embodiment, it may mean at least one, optionally including more than one A, and at least one, optionally including more than one B (and optionally including other elements); and so on.

[0042] It should also be understood that, unless explicitly stated otherwise, in any method claimed herein that comprises more than one step or operation, the order of the steps or operations of the method is not necessarily limited to the order of the steps or operations of the method described herein.

[0043] In the claims and the foregoing description, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “accommodating,” “constituting,” “comprises of,” etc., shall be understood as open-ended, meaning that they include, but are not limited to, those described in Section 2111.03 of the Patent Examination Procedure Manual of the U.S. Patent Office. Only the transitional phrases “comprises of” and “substantially constitutes of” shall be closed or semi-closed transitional phrases, respectively.

[0044] Certain compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. Additionally, the polymers of the present invention may also be optically active. The present invention considers all such compounds, including cis and trans isomers, R- and S enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, to fall within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents (such as alkyl groups). All such isomers and mixtures thereof are intended to be included in the present invention.

[0045] For example, if a specific enantiomer of the compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary groups are cleaved to produce the pure desired enantiomer. Alternatively, in the case where the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, and the resulting diastereomeric isomer is then reduced by stepwise crystallization or chromatographic methods well known in the art, and the pure enantiomer is subsequently recovered.

[0046] The structures described herein also refer to compounds that differ only in the presence of one or more isotopically enriched atoms. For example, by substituting hydrogen or deuterium with deuterium or tritium. 13 C- or 14 Compounds produced by C-enrichment of carbon to replace carbon are within the scope of this invention.

[0047] As used in this article, the terms “α4β7”, “a4B7”, “a4b7”, “α-4β-7”, and “α4β7” all refer to α4β7.

[0048] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulation material, that carries or transports the subject chemical from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable," harmless to the patient, and substantially pyrogen-free in the sense of compatibility with the other components of the formulation. Examples of materials 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 gum; (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) diols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; and (18) Ringer's solution. (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic and compatible substances used in the pharmaceutical formulation. In some embodiments, the pharmaceutical compositions of the present invention are pyrogen-free when administered to a patient, i.e., do not induce a significant increase in temperature.

[0049] The term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic and organic acid addition salt of one or more compounds. These salts can be prepared in situ during the final isolation and purification of one or more compounds, or by reacting one or more purified compounds, in their free base form, alone with a suitable organic or inorganic acid and isolating the resulting salt. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, lysinate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, glucono-p-ethyl, lacturonate, and lauryl sulfonate, etc. (See, for example, Berge et al., (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19.).

[0050] In other cases, compounds that can be used in the methods of the present invention may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic and organic base addition salt of one or more compounds. These salts can also be prepared in situ during the final separation and purification of one or more compounds, or by reacting one or more purified compounds in their free acid form with a suitable base (such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation), with ammonia, or alone with a pharmaceutically acceptable primary, secondary, or tertiary organic amine. Representative bases or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, etc. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (see, for example, Berge et al., ibid.).

[0051] The "therapeutic effective amount" (or "effective amount") of a compound used in treatment refers to the amount of the compound in a formulation that, when administered as part of a desired dosing regimen (to a mammal, preferably a human), relieves symptoms, improves condition, or slows the onset of disease symptoms for the purpose of treating the condition or symptom or for cosmetic purposes, according to clinically acceptable criteria (e.g., a reasonable benefit / risk ratio applicable to any medical treatment).

[0052] The term "preventive or therapeutic" treatment is recognized in the art and includes the administration of one or more of the subject compositions to a host. A treatment is preventive (i.e., it protects the host from developing the undesirable condition) if it is administered before the clinical manifestation of an undesirable symptom (e.g., disease or other undesirable condition in the host animal), and therapeutic (i.e., it aims to alleviate, improve, or stabilize the existing undesirable symptom or its side effects) if it is administered after the manifestation of the undesirable symptom.

[0053] The term "patient" refers to a mammal that requires specific treatment. In some embodiments, the patient is a primate, dog, cat, or horse. In some embodiments, the patient is a human.

[0054] Aliphatic chains include several classes of alkyl, alkenyl, and alkynyl groups as defined below. Straight-chain aliphatic chains are limited to the unbranched carbon chain portion. As used herein, the term "aliphatic group" refers to a straight-chain, branched, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups such as alkyl, alkenyl, or alkynyl groups.

[0055] "Alkyl" refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having a specified number of carbon atoms or (if not specified) 1 to 30 carbon atoms. For example, an alkyl group with 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as those that are positional isomers of these moieties. Alkyl groups with 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, eicosyl, dodecyl, tridecyl, and tetradecyl. In some embodiments, straight-chain or branched alkyl groups have 30 or fewer carbon atoms in their backbone (e.g., for straight-chain C1-C...). 30 For C3-C branches 30 (and preferably 20 or fewer.) Alkyl groups may be substituted or unsubstituted. As used herein, “Me” and –CH3 both refer to methyl.

[0056] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbon atoms (e.g., 2 to 12 carbon atoms) and containing two attachment sites extending to the remainder of the compound on its longest carbon chain. Non-limiting examples of alkylenes include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, etc. Alkylenes can be cyclic or acyclic, branched or unbranched carbon chain moieties, and may optionally be substituted with one or more substituents.

[0057] "Cycloalkyl" refers to a saturated carbon ring, whether monocyclic, bicyclic, bridged, spirocyclic, or polycyclic, having 3 to 12 carbon atoms. Preferably, cycloalkyl groups have 3-10 carbon atoms in their ring structure, and more preferably 3-6 carbon atoms. The cycloalkyl group can be substituted or unsubstituted.

[0058] Unless otherwise specified, "lower alkyl" as used herein means an alkyl group as defined above but having one to ten carbon atoms, more preferably one to six carbon atoms, in its main chain structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout this application, preferred alkyl groups are lower alkyl groups. In some embodiments, substituents designated as alkyl herein are lower alkyl groups.

[0059] As used herein, the term "aryl" comprises a 3- to 12-membered substituted or unsubstituted monocyclic aromatic group, wherein each atom of the ring is a carbon (i.e., carbocyclic aryl) or one or more of the atoms are heteroatoms (i.e., heteroaryl). Preferably, the aryl comprises a 5- to 12-membered ring, more preferably a 6- to 10-membered ring. The term "aryl" also comprises a polycyclic ring system having two or more cyclic rings, wherein two or more carbons are common to two adjacent rings, wherein at least one of the rings is aromatic; for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic. Carbocyclic aryl comprises benzene, naphthalene, phenanthrene, phenol, aniline, etc. Heteroaryl comprises a substituted or unsubstituted aromatic 3- to 12-membered ring structure, more preferably a 5- to 12-membered ring, more preferably a 5- to 10-membered ring, whose ring structure comprises one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl and heteroaryl groups can be monocyclic, bicyclic, or polycyclic.

[0060] As used herein, the terms “halogen,” “halogen,” or “halide” mean halogen and include, for example, but not limited to, fluorine, chlorine, bromine, iodine, etc., in radioactive and non-radioactive forms. In a preferred embodiment, the halogen is selected from the group consisting of fluorine, chlorine, and bromine.

[0061] The term "heterocyclyl" or "heterocyclic group" refers to a 3- to 12-membered ring structure, more preferably a 5- to 12-membered ring, and even more preferably a 5- to 10-membered ring, whose ring structure contains one to four heteroatoms. The heterocycle can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclic groups include, for example, thiophene, thiathracene, furan, pyran, isobenzofuran, benzopyran, oxanthracene, oxothionthanthracene, pyrrole, imidazole, pyrazole, isothiazol, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indazine, isoindole, indole, indazole, purine, quinazine, isoquinoline, quinoline, phthalazine, naphthidine, quinoxaline, quinoxaline, cinnamic acid, pteridine, carbazole, caroline, phenanthridine, acridine, pyrimidine, phenanthroxaline, phenazine, phenpyrazine, phenthiazine, furazine, phenoxazine, pyrrolidine, oxacyclopentane, thiocyclopentane, oxazole, piperidine, piperazine, morpholine, lactone, lactam (such as azacyclobutanone and pyrrolidone), sulfonamide, sulfonyl lactone, etc. The heterocycle may be substituted at one or more positions with such substituents as described above (e.g., halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, mercapto, imino, amide, phosphate, phosphonate, hypophosphonate, carbonyl, carboxyl, silyl, aminosulfonyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3, -CN, etc.).

[0062] The term "carbonyl" is recognized in the art and includes such a portion that can be represented by the following formula:

[0063] or

[0064] Where X' is a bond or represents oxygen or sulfur, and R 15 Indicates hydrogen, alkyl, alkenyl, -(CH2) m -R 10 Or a pharmaceutically acceptable salt, R 16 Indicates hydrogen, alkyl, alkenyl, or -(CH2). m -R 10 , where m and R 10 As defined above. Where X' is oxygen and R... 15 Or R 16 In the absence of hydrogen, the formula represents "ester". Where X' is oxygen and R... 15 As defined above, the part is referred to herein as a carboxyl group, and specifically when R... 15 When X' is hydrogen, the formula represents "carboxylic acid". In the case of X' being oxygen and R... 16 In the case of hydrogen, the formula represents "formate ester". On the other hand, when X' is a bond and R... 15 If it is not hydrogen, the above formula represents a "ketone" group. Where X' is a bond and R...15 In the case of hydrogen, the above formula represents an "aldehyde" group.

[0065] As used herein, the term "substituted" is contemplated to encompass all permissible substituents of an organic compound. In a broad sense, permissible substituents encompass acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Illustrative substituents include, for example, the substituents described above, and are substituted, for example, by one or more substituents selected from: alkyl, cycloalkyl, heterocyclic alkyl, halogen, OH, OMe, C(H)F2, C(F)H2, CF3, C(H)2CF3, SF5, CHFCH2amine, CH2amine, and CN. For a suitable organic compound, permissible substituents may be one or more and may be the same or different. For the purposes of this invention, heteroatoms (such as nitrogen) may have hydrogen substituents of the organic compounds described herein and / or any permissible substituents that will satisfy the valence of the heteroatom. This invention is not intended to be limited in any way to the permissible substituents of organic compounds. It should be understood that “substitution” or “being substituted” implies the condition that such substitution is based on the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, that does not spontaneously undergo transformation as by rearrangement, cyclization, elimination, etc.

[0066] As used herein, the term “nitro” means -NO2; the term “halogen” specifies -F, -Cl, -Br or -I; the term “hydroxyl” means -OH; and the term “cyano” means -CN.

[0067] As used herein, for each expression, such as the definition of alkyl, m, n, etc., when it appears more than once in any structure, it is intended to be independent of its definition elsewhere in the same structure.

[0068] As used herein, the term "prodrug" encompasses compounds that are converted into therapeutically active agents under physiological conditions. A common method for preparing prodrugs involves hydrolyzing selected portions of the molecule under physiological conditions to reveal the desired molecule. In other embodiments, prodrugs are converted via enzymatic activity in a host animal.

[0069] For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 67th edition, 1986-87, inner pages.

[0070] Exemplary compounds

[0071] In some embodiments, the present invention relates to compounds of formula (I), formula (Ia), or formula (Ib):

[0072]

[0073] Or its pharmaceutically acceptable salt;

[0074] in

[0075] R a R b and R c Independently selected from the group consisting of: H, Me, halogen, CF3, C(H)F2, C(F)H2, -CN, -OCF3, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C1-C5)-alkoxy, -CH2CF3, and substituted or unsubstituted –(C 1- C5)alkylene-N-(R x (R) y ); the condition is R a R b and R c At least one of them is –(C 1- C5)alkylene-N-(R x (R) y );

[0076] R x and R y 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 it connects to, they form a 4- to 6-membered ring;

[0077] R1 is a substituted or unsubstituted (C1-C6)-alkyl, a substituted or unsubstituted (C1-C4)-alkylene-(C3-C6)-cycloalkyl, or a substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy.

[0078] R2 is

[0079] R 3a and R 3bIndependently selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3, and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; provided that R 3a and R 3b None of them are H;

[0080] R 3c Select from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, hydroxyl, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3-CN and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy;

[0081] R 3d Choose from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl, halogen and -(C1-C4)-alkoxy;

[0082] R4 is H or a substituted or unsubstituted (C1-C4)-alkyl group;

[0083] R 5a and R 5e Independently selected from the group consisting of: H, CN, halogens, CF3, C(H)F2, C(F)H2, -CH2CF3, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, hydroxyl, and (C1-C4)-alkoxy; and

[0084] R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogen, 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 heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy.

[0085] In some embodiments, a compound of formula (Ia) can be a compound in which: R a It is Me; R bIs it substituted or unsubstituted – (C 1- C5)alkylene-N-(R x (R) y ); R x and R y 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 it connects to, they form a 4- to 6-membered ring; R c It is H; R1 is (C1-C6)-alkyl; R 3a It is halogen; R 3b It is (C1-C5)-alkyl; R 3c It is H; R 3d It is H; R4 is H; R 5a and R 5e It is (C1-C5)-alkyl; and R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogen, 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 heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy or pharmaceutically acceptable salts thereof.

[0086] In some embodiments, a compound of formula (Ia) can be a compound in which: R a It is Me; R b Is it substituted or unsubstituted – (C 1- C5)alkylene-N-(R x (R) y ); R x and R y 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 it connects to, they form a 4- to 6-membered ring; R c It is H; R1 is (C1-C6)-alkyl; R 3a It is halogen; R 3b It is halogen; R 3c It is H; R 3d It is H; R4 is H; R 5a and R 5e It is (C1-C5)-alkyl; and R 5b R 5c and R 5dIndependently selected from the group consisting of: H, CN, halogen, 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 heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy or pharmaceutically acceptable salts thereof.

[0087] In some embodiments, a compound of formula (Ia) can be a compound in which: R a It is H; R b Is it substituted or unsubstituted – (C 1- C5)alkylene-N-(R x (R) y ); R x and R y 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 it connects to, they form a 4- to 6-membered ring; R c It is CH(F)2; R1 is (C1-C6)-alkyl; R 3a It is halogen; R 3b It is (C1-C5)-alkyl; R 3c It is H; R 3d It is H; R4 is H; R 5a and R 5e It is (C1-C5)-alkyl; and R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogen, 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 heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy or pharmaceutically acceptable salts thereof.

[0088] In some embodiments, a compound of formula (Ia) can be a compound in which: R a It is H; R b Is it substituted or unsubstituted – (C 1- C5)alkylene-N-(R x (R) y ); R x and R y Independently selected from the group consisting of: H and substituted or unsubstituted (C1-C6)-alkyl; or R x and R yTogether with the N it connects to, they form a 4- to 6-membered ring; R c It is a halogen; R1 is a (C1-C6)-alkyl; R 3a It is halogen; R 3b It is (C1-C5)-alkyl; R 3c It is H; R 3d It is H; R4 is H; R 5a and R 5e It is (C1-C5)-alkyl; and R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogen, 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 heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy or pharmaceutically acceptable salts thereof.

[0089] In some embodiments, a compound of formula (Ia) can be a compound in which: R a It's CF3; R b Is it substituted or unsubstituted – (C 1- C5)alkylene-N-(R x (R) y ); R x and R y 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 it connects to, they form a 4- to 6-membered ring; R c It is H; R1 is (C1-C6)-alkyl; R 3a It is halogen; R 3b It is (C1-C5)-alkyl; R 3c It is H; R 3d It is H; R4 is H; R 5a and R 5e It is (C1-C5)-alkyl; and R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogen, 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 heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy or pharmaceutically acceptable salts thereof.

[0090] In some embodiments, a compound of formula (Ia) can be a compound in which: R a It's CF3; R b Is it substituted or unsubstituted – (C 1- C5)alkylene-N-(R x (R) y ); R x and R y 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 it connects to, they form a 4- to 6-membered ring; R c It is H; R1 is (C1-C6)-alkyl; R 3a It is halogen; R 3b It's CF3; R 3c It is H; R 3d It is H; R4 is H; R 5a and R 5e It is (C1-C5)-alkyl; and R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogen, 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 heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy or pharmaceutically acceptable salts thereof.

[0091] In some embodiments, a compound of formula (Ia) can be a compound in which: R a It's CF3; R b Is it substituted or unsubstituted – (C 1- C5)alkylene-N-(R x (R) y ); R x and R y 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 it connects to, they form a 4- to 6-membered ring; R c It is H; R1 is (C1-C6)-alkyl; R 3a It is halogen; R 3b It is halogen; R 3c It is H; R 3d It is H; R4 is H; R 5a and R 5e It is (C1-C5)-alkyl; and R5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogen, 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 heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy or pharmaceutically acceptable salts thereof.

[0092] In some embodiments, a compound of formula (Ia) can be a compound in which: R a It's CF3; R b Is it substituted or unsubstituted – (C 1- C5)alkylene-N-(R x (R) y ); R x and R y 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 it connects to, they form a 4- to 6-membered ring; R c It is H; R1 is (C1-C6)-alkyl; R 3a It is halogen; R 3b It is (C3-C6)-cycloalkyl; R 3c It is H; R 3d It is a halogen; R4 is H; R 5a and R 5e It is (C1-C5)-alkyl; and R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogen, 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 heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy or pharmaceutically acceptable salts thereof.

[0093] In some embodiments, a compound of formula (Ia) can be a compound in which: R a It's CF3; R b Is it substituted or unsubstituted – (C 1- C5)alkylene-N-(R x (R) y ); R x and R yIndependently selected from the group consisting of: H and substituted or unsubstituted (C1-C6)-alkyl; or R x and R y Together with the N it connects to, they form a 4- to 6-membered ring; R c It is H; R1 is (C1-C6)-alkyl; R 3a It is halogen; R 3b It's CF3; R 3c It is H; R 3d It is a halogen; R4 is H; R 5a and R 5e It is (C1-C5)-alkyl; and R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogen, 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 heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy or pharmaceutically acceptable salts thereof.

[0094] In some embodiments, a compound of formula (Ia) can be a compound in which: R a It's CF3; R b Is it substituted or unsubstituted – (C 1- C5)alkylene-N-(R x (R) y ); R x and R y 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 it connects to, they form a 4- to 6-membered ring; R c It is H; R1 is (C1-C6)-alkyl; R 3a It is halogen; R 3b It is (C1-C5)-alkyl; R 3c It is H; R 3d It is a halogen; R4 is H; R 5a and R 5e It is (C1-C5)-alkyl; and R 5b R 5c and R 5dIndependently selected from the group consisting of: H, CN, halogen, 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 heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy or pharmaceutically acceptable salts thereof.

[0095] In some embodiments, the compound of formula (Ia) can be a compound in which R 5a It is a halogen or (C1-C5)-alkyl; R 5b It is H, halogen, or substituted or unsubstituted (C1-C5)-alkyl; R 5c It is H, halogen, substituted or unsubstituted (C1-C5)-alkyl or substituted or unsubstituted (C3-C6)-cycloalkyl; and R 5d The group consisting of H, halogen, 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 heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy; and R5e is halogen or (C1-C5)-alkyl.

[0096] In some embodiments, the compound of formula (I) can be a compound of formula (Ia), formula (Ib), formula (Ic), and / or formula (Id):

[0097]

[0098] In equations (Ia), (Ib), (Ic), and (Id), R a R b R c R1, R 3a R 3b R 3c R 3d R 5a R 5b R 5c R 5d R 5e R and R4 are each defined independently as described above with respect to equation (I).

[0099] In some embodiments, the compound of formula (I) may be a compound of formula (II), including compounds of formula (IIa), (IIb) or (IIc):

[0100]

[0101] Where R aR c R 3a R 3b R 3c R 3d R 5a R 5b R 5c R 5d and R 5e As described in equation (I); p is 1, 2, or 3; q is 0, 1, 2, or 3; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, 4, or 5; and each R d Independently selected from the group consisting of: halogen, (C1-C5)-alkyl, (C1-C4)-alkoxy, -CF3, -C(H)F2, -OCF3, and -CN. In some embodiments, R d At least one instance is F or Cl. In some embodiments, R d At least one instance is methyl. In some embodiments, R d At least one example is a methoxy group. In some embodiments, the invention relates to any of the compounds of formula (IIa) mentioned above, wherein q is 1. In some embodiments, the invention relates to any of the compounds of formula (IIb) mentioned above, wherein r is 1. In some embodiments, the invention relates to any of the compounds of formula (IIc) mentioned above, wherein s is 1.

[0102] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R1 is an unsubstituted (C1-C6)-alkyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R1 is a substituted (C1-C6)-alkyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R1 is a substituted or unsubstituted (C1-C4)-alkyl. In some embodiments, R1 is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R1 is selected from the group consisting of: In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R1 is a substituted (C1-C4)-alkylene-(C3-C6)-cycloalkyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R1 is an unsubstituted (C1-C4)-alkylene-(C3-C6)-cycloalkyl. In some embodiments, R1 is... In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R1 is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R1 is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, R1 is... In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R1 is In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R1 is

[0103] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3a It is H; the condition is R. 3a and R 3b None of them are H. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3a It is an unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3a It is a substituted (C1-C4)-alkyl group. In some embodiments, the substituted (C1-C5)-alkyl group is substituted with a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, R 3a It is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, or tert-butyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3a It is a substituted (C3-C6)-cycloalkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3a It is a substituted or unsubstituted (C3-C6)-cycloalkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3a It is cyclopropyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3a It is a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3a It is CF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3a It is C(H)F2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R3a It is C(F)H2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3a It is a substituted (C1-C4)-alkoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3a It is an unsubstituted (C1-C4)-alkoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3a It is -OCF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3a It is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3a It is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy group is –CH2OMe. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3a It is F.

[0104] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It is H; the condition is R. 3a and R 3b None of them are H. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It is an unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It is a substituted (C1-C4)-alkyl group. In some embodiments, the substituted (C1-C5)-alkyl group is substituted with a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, R 3b It is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, or tert-butyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It is a substituted (C3-C6)-cycloalkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It is a substituted or unsubstituted (C3-C6)-cycloalkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3bIt is cyclopropyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It is a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It is CF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It is C(H)F2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It is C(F)H2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It is a substituted (C1-C4)-alkoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It is an unsubstituted (C1-C4)-alkoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It is -OCF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy group is –CH2OMe. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b The compounds are selected from the group consisting of (C1-C4)-alkylene groups, optionally substituted with one or more halogens and (C3-C6)-cycloalkyl groups. In some embodiments, the invention relates to any of the compounds mentioned above, wherein R 3b The compounds are selected from the group consisting of methyl, cyclopropyl, and CF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It is methyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b The compounds are selected from the group consisting of halogens, (C1-C4)-alkylene groups, optionally substituted with one or more halogens and (C3-C6)-cycloalkyl groups. In some embodiments, the invention relates to any of the compounds mentioned above, wherein R 3bThe compounds are selected from the group consisting of: F, Cl, methyl, and CF3. In some embodiments, the present invention relates to any one of the compounds mentioned above, wherein R 3b It is methyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It is F. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It is Cl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3b It's CF3.

[0105] In some embodiments, R 3a and R 3b Independently selected from the following groups: H, (C1-C5)-alkyl, halogen, CF3, C(H)F2, and C(F)H2; condition R 3a and R 3b None of them are H. For example, R 3a and R 3b The following groups can be independently selected: H, methyl, Cl, F, CF3, C(H)F2, and C(F)H2; the condition is R. 3a and R 3b None of them are H. In some embodiments, R 3a It is halogen, and R 3b Selected from the group consisting of (C1-C4)-alkylene groups, optionally substituted with one or more halogens and (C3-C6)-cycloalkyl groups. In some embodiments, R 3a It is F, and R 3b Selected from the group consisting of (C1-C4)-alkylene groups, optionally substituted with one or more halogens and (C3-C6)-cycloalkyl groups. In some embodiments, R 3a It is F, and R 3b The group consisting of methyl, cyclopropyl, and CF3 is selected. In some embodiments, R 3a It is F, and R 3b The following groups are selected: F, Cl, methyl, and CF3. In some embodiments, R 3a It is F, and R 3b Choose from the following groups: F, Cl, methyl, cyclopropyl, and CF3.

[0106] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3cThe compounds are selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted cyclopropyl, hydroxyl, methoxy, halogen, CF3, C(H)F2, C(F)H2, and –CN. In some embodiments, the invention relates to any of the compounds mentioned above, wherein R 3c It is H. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3c It is an unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3c It is a substituted (C1-C4)-alkyl group. In some embodiments, the substituted (C1-C5)-alkyl group is substituted with a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, R 3c It is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, or tert-butyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3c It is a substituted (C3-C6)-cycloalkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3c It is a substituted or unsubstituted (C3-C6)-cycloalkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3c It is cyclopropyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3c It is a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3c It is CF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3c It is C(H)F2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3c It is C(F)H2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3c It is a substituted (C1-C4)-alkoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3c It is an unsubstituted (C1-C4)-alkoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3c It is -OCF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R3c It is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3c It is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy group is –CH2OMe.

[0107] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3c It is H; R 3a It is a halogen; and R 3b Selected from the group consisting of (C1-C4)-alkylene groups, optionally substituted with one or more halogens and (C3-C6)-cycloalkyl groups. In some embodiments, R 3c It is H; R 3a It is F; and R 3b Selected from the group consisting of (C1-C4)-alkylene groups, optionally substituted with one or more halogens and (C3-C6)-cycloalkyl groups. In some embodiments, R 3c It is H; R 3a It is F; and R 3b The group consisting of methyl, cyclopropyl, and CF3 is selected. In some embodiments, R 3c It is H; R 3a It is F; R 3b The following groups are selected: F, Cl, methyl, and CF3. In some embodiments, R 3c It is H; R 3a It is F; R 3b The compounds are selected from the group consisting of: F, Cl, methyl, cyclopropyl, and CF3. In some embodiments, the present invention relates to any one of the compounds mentioned above, wherein R 3d The compounds are selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl, halogen, methoxy, CF3, C(H)F2, and C(F)H2. In some embodiments, the invention relates to any of the compounds mentioned above, wherein R 3d It is H. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3d It is an unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3dIt is a substituted (C1-C4)-alkyl group. In some embodiments, the substituted (C1-C5)-alkyl group is substituted with a halogen. In some embodiments, the halogen is F. In some embodiments, R... 3d It is methyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3d It is a substituted (C3-C6)-cycloalkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3c It is a substituted or unsubstituted (C3-C6)-cycloalkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3d It is cyclopropyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3d It is a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3d It is CF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3d It is C(H)F2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3d It is C(F)H2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3d It is a substituted (C1-C4)-alkoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3d It is an unsubstituted (C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkoxy group is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3d It is -OCF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3d It is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3d It is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy group is –CH2OMe.

[0108] In some embodiments, R 3c and R 3d They are the same. In some embodiments, R 3cand R 3d All are H. In some embodiments, R 3c and R 3d Different. In some embodiments, R 3c It is H, and R 3d It is H or halogen. In some embodiments, R 3c It is H, and R 3d It is F.

[0109] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3c and R 3d Both are H; R 3a It is a halogen; and R 3b Selected from the group consisting of (C1-C4)-alkylene groups, optionally substituted with one or more halogens and (C3-C6)-cycloalkyl groups. In some embodiments, R 3c and R 3d Both are H; R 3a It is F; and R 3b Selected from the group consisting of (C1-C4)-alkylene groups, optionally substituted with one or more halogens and (C3-C6)-cycloalkyl groups. In some embodiments, R 3c and R 3d Both are H; R 3a It is F; and R 3b The group consisting of methyl, cyclopropyl, and CF3 is selected. In some embodiments, R 3c and R 3d Both are H; R 3a It is F; R 3b The following groups are selected: F, Cl, methyl, and CF3. In some embodiments, R 3c and R 3d Both are H; R 3a It is F; R 3b Choose from the following groups: F, Cl, methyl, cyclopropyl, and CF3.

[0110] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 3c It is H; R 3d It is F; R 3a It is a halogen; and R 3b Selected from the group consisting of (C1-C4)-alkylene groups, optionally substituted with one or more halogens and (C3-C6)-cycloalkyl groups. In some embodiments, R 3c It is H; R 3d It is F; R 3a It is F; and R 3bSelected from the group consisting of (C1-C4)-alkylene groups, optionally substituted with one or more halogens and (C3-C6)-cycloalkyl groups. In some embodiments, R 3c It is H; R 3d It is F; R 3a It is F; and R 3b The group consisting of methyl, cyclopropyl, and CF3 is selected. In some embodiments, R 3c It is H; R 3d It is F; R 3a It is F; R 3b The following groups are selected: F, Cl, methyl, and CF3. In some embodiments, R 3c It is H; R 3d It is F; R 3a It is F; R 3b Choose from the following groups: F, Cl, methyl, cyclopropyl, and CF3.

[0111] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R4 is H. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R4 is a substituted (C1-C4)-alkyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R4 is an unsubstituted (C1-C4)-alkyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R4 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R4 is methyl or ethyl.

[0112] In some embodiments, R 5a It is H. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5a It is a substituted or unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5a It is an unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5a It is a substituted (C1-C4)-alkyl group. In some embodiments, the substituted (C1-C5)-alkyl group is substituted with one or more halogens. In some embodiments, the halogen is Cl or F. In some embodiments, R 5a It is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, or tert-butyl. In some embodiments, R 5aIt is methyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5a It is a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, R 5a It is a substituted (C3-C6)-cycloalkyl group. In some embodiments, R 5a It is an unsubstituted (C3-C6)-cycloalkyl group. In some embodiments, the (C3-C6)-cycloalkyl group is a cyclopropyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5a It is CF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5a It is C(H)F2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5a It is C(F)H2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5a It is a (C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkoxy group is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5a It is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5a It is a hydroxyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5a Yes -OCF3. In some embodiments, R 5a It is CN. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5a It is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5a It is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy group is –CH2OMe. In some embodiments, R 5a It is CH2OH.

[0113] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is CN. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5bIt is an unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is a substituted (C1-C4)-alkyl group. In some embodiments, the substituted (C1-C5)-alkyl group is substituted with a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, R 5b It is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, or tert-butyl. In some embodiments, R 5a It is methyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, R 5b It is a substituted (C3-C6)-cycloalkyl group. In some embodiments, R 5b It is an unsubstituted (C3-C6)-cycloalkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is CF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is C(H)F2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is C(F)H2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is (C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is a hydroxyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is -OCF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy group is –CH2OMe. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is hydrogen.

[0114] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is CN. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is an unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is a substituted (C1-C4)-alkyl group. In some embodiments, the substituted (C1-C5)-alkyl group is substituted with a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, R 5c It is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, or tert-butyl. In some embodiments, R 5c It is methyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, R 5c It is a substituted (C3-C6)-cycloalkyl group. In some embodiments, R 5c It is cyclopropyl. In some embodiments, R 5c It is an unsubstituted (C3-C6)-cycloalkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is CF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is C(H)F2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is C(F)H2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is (C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is a hydroxyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is -OCF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5cIt is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy group is –CH2OMe. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is hydrogen.

[0115] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is CN. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is an unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is a substituted (C1-C4)-alkyl group. In some embodiments, the substituted (C1-C5)-alkyl group is substituted with a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, R 5d It is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, or tert-butyl. In some embodiments, R 5d It is methyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, R 5d It is a substituted (C3-C6)-cycloalkyl group. In some embodiments, R 5d It is an unsubstituted (C3-C6)-cycloalkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is CF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is C(H)F2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is C(F)H2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is (C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is a hydroxyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5dIt is -OCF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy group is –CH2OMe. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is hydrogen.

[0116] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is CN. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is an unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is a substituted (C1-C4)-alkyl group. In some embodiments, the substituted (C1-C5)-alkyl group is substituted with a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, R 5e It is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, or tert-butyl. In some embodiments, R 5e It is methyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, R 5e It is a substituted (C3-C6)-cycloalkyl group. In some embodiments, R 5e It is an unsubstituted (C3-C6)-cycloalkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is CF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is C(H)F2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is C(F)H2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is (C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5eIt is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is a hydroxyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is -OCF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy group is –CH2OMe. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is hydrogen.

[0117] In some embodiments, R 5b It is H. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is a substituted or unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is an unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is a substituted (C1-C4)-alkyl group. In some embodiments, the substituted (C1-C5)-alkyl group is substituted with one or more halogens. In some embodiments, the halogen is Cl or F. In some embodiments, R 5b It is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, or tert-butyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, R 5b It is a substituted (C3-C6)-cycloalkyl group. In some embodiments, R 5b It is an unsubstituted (C3-C6)-cycloalkyl group. In some embodiments, the (C3-C6)-cycloalkyl group is a cyclopropyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is CF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5bIt is C(H)F2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is C(F)H2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5a It is a (C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkoxy group is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is a hydroxyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b Yes -OCF3. In some embodiments, R 5b It is CN. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5b It is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy group is –CH2OMe. In some embodiments, R 5b It is CH2OH.

[0118] In some embodiments, R 5c It is H. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is a substituted or unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5a It is an unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is a substituted (C1-C4)-alkyl group. In some embodiments, the substituted (C1-C5)-alkyl group is substituted with one or more halogens. In some embodiments, the halogen is Cl or F. In some embodiments, R 5c It is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, or tert-butyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, R 5cIt is a substituted (C3-C6)-cycloalkyl group. In some embodiments, R 5c It is an unsubstituted (C3-C6)-cycloalkyl group. In some embodiments, the (C3-C6)-cycloalkyl group is a cyclopropyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is CF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is C(H)F2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is C(F)H2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is a (C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkoxy group is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is a hydroxyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c Yes -OCF3. In some embodiments, R 5c It is CN. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5a It is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5c It is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy group is –CH2OMe. In some embodiments, R 5c It is CH2OH.

[0119] In some embodiments, R 5d It is H. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is a substituted or unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is an unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5dIt is a substituted (C1-C4)-alkyl group. In some embodiments, the substituted (C1-C5)-alkyl group is substituted with one or more halogens. In some embodiments, the halogen is Cl or F. In some embodiments, R 5d It is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, or tert-butyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, R 5d It is a substituted (C3-C6)-cycloalkyl group. In some embodiments, R 5d It is an unsubstituted (C3-C6)-cycloalkyl group. In some embodiments, the (C3-C6)-cycloalkyl group is a cyclopropyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is CF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is C(H)F2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is C(F)H2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is a (C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkoxy group is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is a hydroxyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d Yes -OCF3. In some embodiments, R 5d It is CN. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5d It is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy group is –CH2OMe. In some embodiments, R 5d It is CH2OH.

[0120] In some embodiments, R 5eIt is H. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is a substituted or unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is an unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is a substituted (C1-C4)-alkyl group. In some embodiments, the substituted (C1-C5)-alkyl group is substituted with one or more halogens. In some embodiments, the halogen is Cl or F. In some embodiments, R 5e It is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, or tert-butyl. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, R 5e It is a substituted (C3-C6)-cycloalkyl group. In some embodiments, R 5e It is an unsubstituted (C3-C6)-cycloalkyl group. In some embodiments, the (C3-C6)-cycloalkyl group is a cyclopropyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is CF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is C(H)F2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is C(F)H2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is a (C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkoxy group is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is a hydroxyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e Yes -OCF3. In some embodiments, R 5e It is CN. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5eIt is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R 5e It is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy group is –CH2OMe. In some embodiments, R 5e It is CH2OH.

[0121] In some embodiments, R 5a and R 5e Same. For example, R 5a and R 5e They can all be substituted or unsubstituted (C1-C4)-alkyl groups. In some embodiments, R 5a and R 5e All are unsubstituted (C1-C4)-alkyl groups (e.g., methyl). In some instances, R 5a and R 5e All of them are unsubstituted methyl groups.

[0122] In some embodiments, R 5b and R 5d Same. For example, R 5a and R 5e Both can be hydrogen.

[0123] In some embodiments, R 5a and R 5e All were replaced, and R 5b and R 5d Both are hydrogen. For example, R 5a and R 5e They can all be (the same or different) substituted or unsubstituted (C1-C4)-alkyl groups. In some examples, R 5a and R 5e They can all be unsubstituted (C1-C4)-alkyl groups (e.g., methyl), and R 5b and R 5d Both are hydrogen. In some instances, R 5a and R 5e All are unsubstituted methyl groups, and R 5b and R 5d Both are hydrogen. In some embodiments, R 5a and R 5e The following groups are selected independently: H, CN, halogen, CF3, C(H)F2, C(F)H2, (C1-C5)-alkyl, hydroxyl and (C1-C4)-alkoxy.

[0124] In some embodiments, R5c It is hydrogen, halogen (e.g., F), substituted or unsubstituted (C1-C4)-alkoxy (e.g., methoxy) or substituted or unsubstituted (C1-C4)-alkyl (e.g., methyl).

[0125] In some embodiments, R 5a and R 5e All are substituted or unsubstituted (C1-C5)-alkyl groups, R 5b and R 5d Both are hydrogen, and R 5c It is hydrogen, halogen (e.g., F), substituted or unsubstituted (C1-C4)-alkoxy (e.g., methoxy), or substituted or unsubstituted (C1-C4)-alkyl (e.g., methyl). For example, R 5a and R 5e Both can be methyl groups; R 5b and R 5d Both are hydrogen; and R 5c Selected from the group consisting of: hydrogen, halogens (e.g., F), substituted or unsubstituted (C1-C4)-alkoxy groups (e.g., methoxy groups), and substituted or unsubstituted (C1-C4)-alkyl groups (e.g., methyl groups). In some instances, R 5a and R 5e Both can be methyl groups; R 5b and R 5d Both are hydrogen; and R 5c Choose from the group consisting of: hydrogen, F, Cl, methoxy, and methyl. In some instances, R 5a R 5c and R 5e Each is a methyl group; and R 5b and R 5d Both are hydrogen. In some embodiments, R 5b R 5c and R 5d The following groups are selected independently: H, CN, halogen, CF3, C(H)F2, C(F)H2, (C1-C5)-alkyl, hydroxyl and (C1-C4)-alkoxy.

[0126] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a R b and R c Including charged amines. R a R b and R c At least one of them can be substituted or unsubstituted –(C1-C5)alkylene-N-(R x (R) y); where R x and R y 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 it is attached, it forms a substituted or unsubstituted 4- to 6-membered heterocyclic base ring.

[0127] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a R b and R c Only one of them is substituted or unsubstituted –(C1-C5)alkylene-N-(R x (R) y ); where R x and R y 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 some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a R b and R c Only one of them is substituted or unsubstituted –(C1-C5)alkylene-N-(R x (R) y ); where R x and R y Independently selected from the group consisting of: substituted or unsubstituted (C1-C6)-alkyl or substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a R b and R c Only one of them is substituted or unsubstituted –(C1-C5)alkylene-N-(R x (R) y ); where R x and R y Independently selected from the group consisting of: substituted or unsubstituted (C1-C6)-alkyl groups.

[0128] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a R b and R cOnly one of them is substituted or unsubstituted –(C1-C5)alkylene-N-(R x (R) y ); where R x and R y Together with the N-membered ring it is attached to, it forms a substituted or unsubstituted 4- to 6-membered heterocyclic ring. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a R b and R c Only one of them is substituted or unsubstituted –(C1-C5)alkylene-N-(R x (R) y ); where R x and R y Together with the N to which it is attached, it forms a 4- to 6-membered heterocyclic ring, which is optionally replaced by one or more halogens (e.g., F, Cl).

[0129] In some embodiments, R a R b and R c Independently selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, halogen, 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 them is --–(C1-C3)alkylene-N-(R x (R) y ), where R x and R y Independently selected from the group consisting of: H and (C1-C6)-alkyl; or R x and R y Together with the N to which it is attached, it forms a 4 to 6-membered heterocyclic ring, which is optionally replaced by one or more halogens (e.g., F or Cl).

[0130] In some embodiments, R a R b and R c Independently selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, halogen, 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 them is --–(C1-C3)alkylene-N-(R x (R) y), where R x and R y Independently selected from the group consisting of: (C1-C6)-alkyl (e.g., methyl); or R x and R y Together with the N to which it is attached, it forms a 4 to 6-membered heterocyclic ring, which is optionally replaced by one or more halogens (e.g., F or Cl).

[0131] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a R b and R c At least one of them is selected from the group consisting of: In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a R b and R c Only one of the following groups can be selected: In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a R b and R c Only one of the following groups can be selected:

[0132] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a The compounds are selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, halogen, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C4)-alkoxy, and -OCF3. In some embodiments, the invention relates to any of the compounds mentioned above, wherein R a Choose from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, halogen, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C4)-alkoxy and -OCF3; and R b and R c One of them is substituted or unsubstituted –(C1-C5)alkylene-N-(R x (R) y ); where R x and R yIndependently 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 it is attached, it forms a substituted or unsubstituted 4- to 6-membered heterocyclic base ring.

[0133] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a It is H. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a It is Me. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a It is a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a It is CF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a It is C(H)F2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a It is C(F)H2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a It is a substituted (C1-C4)-alkoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a It is an unsubstituted (C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkoxy group is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a It is -OCF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a It is a substituted –(C1-C5)alkylene-N-(R x (R) y In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a It is an unsubstituted –(C1-C5)alkylene-N-(R x (R) y In some embodiments, –(C1-C5)alkylene-N-(R x (R) yThe –(C1-C5)alkylene group is substituted with one or more halogens or –(C1-C4)alkyl groups. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein the ––(C1-C5)alkylene-N-(R x (R) y ) is ––(C1-C4)alkylene-N-(R x (R) y ).

[0134] In some embodiments, R a It 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 a halogen or (C1-C4)-alkoxy group. In some embodiments, R a It 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 F or methoxy. In some embodiments, R a Choose from the following groups: In some embodiments, R a In some embodiments, R a yes In some embodiments, R a It's CF3.

[0135] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R a Choose from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, halogen, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C4)-alkoxy and -OCF; and R b It is substituted or unsubstituted –(C1-C5)alkylene-N-(R x (R) y ); where R x and R y 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 it is attached, it forms a substituted or unsubstituted 4- to 6-membered heterocyclic base ring.

[0136] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R b It is H. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R b It is Me. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R b It is a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R b It is CF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R b It is C(H)F2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R b It is C(F)H2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R b It is a substituted (C1-C4)-alkoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R b It is an unsubstituted (C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkoxy group is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R b It is -OCF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R b It is a substituted –(C1-C5)alkylene-N-(R x (R) y In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R b It is an unsubstituted –(C1-C5)alkylene-N-(R x (R) y In some embodiments, –(C1-C5)alkylene-N-(R x (R) y The –(C1-C5)alkylene group is substituted with one or more halogens or –(C1-C4)alkyl groups. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein the ––(C1-C5)alkylene-N-(R x (R) y ) is ––(C1-C4)alkylene-N-(R x (R) y ).

[0137] In some embodiments, R b It 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 a halogen or (C1-C4)-alkoxy group. In some embodiments, R b It 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 F or methoxy. In some embodiments, R b It is –(C1-C5)alkylene-N-(R x (R) y ), where R x and R y Each is a methyl group, or R is one of them. x and R y Together with the N-membered ring it is attached to, it forms a 4- to 6-membered heterocyclic ring, which is optionally substituted with one or more halogens (e.g., F or Cl). In some embodiments, R b It is –(C2-C3)alkylene-N-(R x (R) y ), where R x and R y Each is a methyl group, or R is one of them. x and R y Together with the N-membered ring it is attached to, it forms a 4- to 6-membered heterocyclic ring, which is optionally substituted with one or more halogens (e.g., F or Cl). In some embodiments, R b It is –(C2-C3)alkylene-N-(R x (R) y ), where R x and R y Each is a methyl group, or R is one of them. x and R y Together with the N-membered ring it is attached to, it forms a 4-membered heterocyclic ring, which is optionally substituted with one or more halogens (e.g., F or Cl). In some embodiments, R b It is –(C2-C3)alkylene-N-(R x (R) y ), where R x and R y Each is a methyl group, or R is one of them. x and R yTogether with the N-membered ring it is attached to, it forms a 4- to 6-membered heterocyclic ring, which is optionally substituted with one or more halogens (e.g., F or Cl). In some embodiments, R b It is –(C2-C3)alkylene-N-(R x (R) y ), where R x and R y Each is a methyl group, or R is one of them. x and R y Together with the N to which it is attached, it forms a 4-membered heterocyclic ring, which is optionally replaced by one or more halogens (e.g., F or Cl).

[0138] In some embodiments, the present invention relates to any of the compounds mentioned above, R b yes Where x is 1 or 2; R6 is H, and R6′ is a (C1-C4) alkyl group, optionally substituted with one or more halogens (e.g., CF3), or R6 and R6′ together form a substituted or unsubstituted 3- to 6-membered cycloalkyl or heterocycloalkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, R b yes Where x is 1 or 2; R6 is H, and R6′ is a (C1-C4) alkyl group, optionally substituted with one or more halogens (e.g., CF3), or R6 and R6′ together form a 3- to 6-membered cycloalkyl or heterocycloalkyl group, optionally substituted with a halogen (e.g., F), a (C1-C4) alkyl group (e.g., methyl), a (C1-C4) alkoxy group (e.g., methoxy), a (C3-C6) cycloalkyl group (e.g., spiropropyl), or a (C3-C6) heterocycloalkyl group (e.g., azirospiro[3.3]heptyl). In some embodiments, R b Choose from the following groups: In some embodiments, R b In some embodiments, the present invention relates to any of the compounds mentioned above, R b Choose from the following groups: In some embodiments, R b yes In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R b Choose from the following groups:

[0139] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R cIt is H. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R c It is Me. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R c It is a halogen. In some embodiments, the halogen is Cl or F. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R c It is CF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R c It is C(H)F2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R c It is C(F)H2. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R c It is a substituted (C1-C4)-alkoxy group. In some embodiments, the (C1-C4)-alkoxy group is a methoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R c It is an unsubstituted (C1-C4)-alkoxy group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R c It is -OCF3. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R c It is a substituted –(C1-C5)alkylene-N-(R x (R) y In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R c It is an unsubstituted –(C1-C5)alkylene-N-(R x (R) y In some embodiments, –(C1-C5)alkylene-N-(R x (R) y The –(C1-C5)alkylene group is substituted with one or more halogens or –(C1-C4)alkyl groups. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein the ––(C1-C5)alkylene-N-(R x (R) y ) is ––(C1-C4)alkylene-N-(R x (R) y ).

[0140] In some embodiments, R cIt 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 a halogen or (C1-C4)-alkoxy group. In some embodiments, R c It 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 by F or methoxy.

[0141] In some embodiments, R c Choose from the following groups: In some embodiments, R c

[0142] In some embodiments, R a R b and R c At least one of them is H.

[0143] In some embodiments, R a R b and R c At least one of them is a charged amine; and R a R b and R c At least one of them is H.

[0144] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R x It is H. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R x It is a substituted (C1-C6)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R x It is an unsubstituted (C1-C6)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R x It is a substituted (C1-C4)-alkyl group. In some embodiments, the (C1-C6)-alkyl group is substituted with OMe, CN, or a halogen. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R x It is an unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R xIt is (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is –(CH2)2OMe. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R x It's me.

[0145] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R y It is H. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R y It is a substituted (C1-C6)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R y It is an unsubstituted (C1-C6)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R y It is a substituted (C1-C4)-alkyl group. In some embodiments, the (C1-C6)-alkyl group is substituted with OMe, CN, or a halogen. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R y It is an unsubstituted (C1-C4)-alkyl group. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R y It is (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is –(CH2)2OMe. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R y It's me.

[0146] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R x It is Me; and R y It's me.

[0147] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein R x and R yTogether with the N atom it is attached to, it forms a substituted or unsubstituted 4- to 6-membered ring. In some embodiments, the 4- to 6-membered ring is a substituted or unsubstituted heterocyclic alkyl group. In some embodiments, the substituted 4- to 6-membered heterocyclic alkyl group is substituted with a halogen of a (C1-C6) alkyl group. In some embodiments, the 4- to 6-membered ring is a substituted or unsubstituted heteroaryl group. In some embodiments, the substituted 4- to 6-membered heteroaryl group is substituted with a halogen of a (C1-C6) alkyl group. In some embodiments, the 4- to 6-membered ring is selected from... In some embodiments, R x and R y Together with the N it is connected to form In some embodiments, R x and R y Together with the N it is connected to, they form a formula The substituted or unsubstituted 4- to 6-membered ring, wherein y is 0, 1 or 2; and R7 is H, halogen, alkoxy, spirocyclic 3- to 5-membered cycloalkyl and spirocyclic 3- to 5-membered heterocyclic alkyl.

[0148] In some embodiments, R a It is a (C1-C5)-alkyl group, which is optionally substituted with a halogen; R b It is –(C1-C5)alkylene-N-(R x (R) y ), where R x and R y Each is a methyl group, or R is one of them. x and R y Together with the N-membered ring it is attached to, it forms a 4- to 5-membered heterocyclic ring, which is optionally substituted with one or more halogens or alkoxy groups (e.g., methoxy groups); and R c It is hydrogen, halogen, or (C1-C5)-alkyl, optionally substituted with a halogen. In some embodiments, R a It is a methyl group, which may optionally be substituted with a halogen; R b It is –(C2-C3)alkylene-N-(R x (R) y ), where R x and R y Each is a methyl group, or R is one of them. x and R y Together with the N to which it is attached, it forms a 4- to 5-membered heterocyclic ring, which is optionally substituted with one or more halogens (e.g., F); and R c It is hydrogen, halogen, or methyl, optionally substituted with a halogen. In some embodiments, R a It is methyl or CF3; R b It is –(C2-C3)alkylene-N-(R x (R)y ), where R x and R y Each is a methyl group, or R is one of them. x and R y Together with the N-membered ring it is attached to, it forms a 4- to 5-membered heterocyclic ring, which is optionally substituted with one or more F- or methoxy groups; and R c It consists of hydrogen, F, CH2F, CHF2, and CF3.

[0149] In some embodiments, the present invention relates to compounds of formula (Ia) or (Ib):

[0150]

[0151] in

[0152] R1, R 3c R 3d R 5a R 5b R 5c R 5d R 5e R a R b and R c As defined above regarding equation (I);

[0153] R4 is H; and

[0154] R a R b and R c At least one of them is –(C1-C3)alkylene-N(R x (R) y );

[0155] R x and R y Independently selected from the group consisting of H and methyl groups; or R x and R y Together with the N it connects to, they form a 4- to 6-membered ring; and

[0156] R 3a and R 3b Each is independently selected from the group consisting of methyl and F.

[0157] In some embodiments, the present invention relates to... Figure 1 Any one of the compounds described herein. In some embodiments, the present invention relates to... Figure 2 Any one of the compounds described herein. In some embodiments, the present invention relates to... Figure 3 Any one of the compounds described herein. In some embodiments, the present invention relates to... Figure 4Any one of the compounds described in it.

[0158] In some embodiments, the compound is a compound of formula (I), and the compound is not... Figure 1 The compounds described herein. In some embodiments, the compound is a compound of formula (I), and the compound is not... Figure 2 The compounds described herein. In some embodiments, the compound is a compound of formula (I), and the compound is not... Figure 3 The compounds described herein. In some embodiments, the compound is a compound of formula (I), and the compound is not... Figure 4 The compounds described herein. In some embodiments, the compound is a compound of formula (I), and the compound is not... Figure 2 , Figure 3 or Figure 4 The compounds described in the text.

[0159] In some embodiments, the present invention relates to compounds of formula (IIIa):

[0160]

[0161] Among them, R1, R a R x R y R 3b R 5b R 5c R 5d As defined above regarding equation (I).

[0162] In some embodiments, the present invention relates to compounds of formula (IVa):

[0163]

[0164] Among them, R1, R a R x R y R 3b R 5b R 5c R 5d As defined above regarding equation (I).

[0165] In some embodiments, the present invention relates to compounds selected from the group consisting of:

[0166] (3S)-3-(4,5-difluoro-2',6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluorozacricyclobutan-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid;

[0167] (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propionic acid;

[0168] (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[0169] (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[0170] (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-methylpentamido)propionic acid;

[0171] (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid;

[0172] (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propionic acid;

[0173] (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-methylpentamido)propionic acid;

[0174] (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propionic acid;

[0175] (3S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fluoroazacyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid; and

[0176] (3S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidine-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid.

[0177] Or its pharmaceutically acceptable salt.

[0178] In some embodiments, the present invention relates to compounds selected from the group consisting of:

[0179]

[0180]

[0181] Or its pharmaceutically acceptable salt.

[0182] In some embodiments, the present invention relates to compounds selected from the group consisting of:

[0183]

[0184]

[0185]

[0186] In some embodiments, the present invention relates to compounds selected from the group consisting of:

[0187] (S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazacyclobutan-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid;

[0188] (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionic acid;

[0189] (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[0190] (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[0191] (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-methylpentamido)propionic acid;

[0192] (S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid;

[0193] (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[0194] (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-methylpentamido)propionic acid;

[0195] (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexamido)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[0196] (S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazacyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid; and

[0197] (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-methylpentamido)propionic acid;

[0198] Or its pharmaceutically acceptable salt.

[0199] In some embodiments, the present invention relates to compounds selected from the group consisting of:

[0200]

[0201]

[0202] Or its pharmaceutically acceptable salt.

[0203] In some embodiments, the present invention relates to any of the compounds mentioned above, wherein the compounds are in the form of pharmaceutically acceptable salts.

[0204] In some embodiments, the present invention relates to compounds selected from the group consisting of:

[0205]

[0206]

[0207]

[0208]

[0209] Exemplary pharmaceutical compositions

[0210] Compounds of formula (I) can be formulated in a variety of pharmaceutical compositions. Compounds of formula (I) (including compounds of formulas (Ia) and (Ib) as provided herein) and their pharmaceutically acceptable salts can be active pharmaceutical ingredients (APIs) combined with one or more other ingredients to form a pharmaceutical substance (DS) pharmaceutical composition. A pharmaceutical substance (DS) pharmaceutical composition may include an API (i.e., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and one or more pharmaceutically acceptable carriers, diluents, and / or excipients. The carrier, diluent, or excipient may be selected to be compatible with other components of the formulation and to be appropriately safe and effective for the intended therapy. A desired weight concentration of the compound of formula (I) as an active pharmaceutical ingredient (API) can be combined with other inactive ingredients to form a pharmaceutical substance (DS) in a batch of formulation. Pharmaceutically acceptable compositions can be formulated for administration via an appropriate route, such as by oral delivery in unit dosage forms (including capsules or tablets). Such compositions can be prepared by associating an active pharmaceutical ingredient (API) comprising a compound of formula (I) with a carrier or excipient.

[0211] In some 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 formulated for oral therapeutic administration of the α4β7 integrin inhibitor compound.

[0212] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0213] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (Ia) or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0214] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (Ib) or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0215] In some embodiments, the present invention provides a pharmaceutical composition comprising (3S)-3-(4,5-difluoro-2',6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluorozacyclobutane-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0216] In some embodiments, the present invention provides a pharmaceutical composition comprising (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0217] In some embodiments, the present invention provides a pharmaceutical composition comprising (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0218] In some embodiments, the present invention provides a pharmaceutical composition comprising (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0219] In some embodiments, the present invention provides a pharmaceutical composition comprising (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-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0220] In some embodiments, the present invention provides a pharmaceutical composition comprising (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0221] In some embodiments, the present invention provides a pharmaceutical composition comprising (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0222] In some embodiments, the present invention provides a pharmaceutical composition comprising (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-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0223] In some embodiments, the present invention provides a pharmaceutical composition comprising (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0224] In some embodiments, the present invention provides a pharmaceutical composition comprising (3S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fluoroazacyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0225] In some embodiments, the present invention provides a pharmaceutical composition comprising (3S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(((R)-3-fluoropyrrolidine-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0226] In some embodiments, the present invention provides a pharmaceutical composition comprising (S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluorozacyclobutane-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0227] In some embodiments, the present invention provides a pharmaceutical composition comprising (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0228] In some embodiments, the present invention provides a pharmaceutical composition comprising (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0229] In some embodiments, the present invention provides a pharmaceutical composition comprising (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0230] In some embodiments, the present invention provides a pharmaceutical composition comprising (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-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0231] In some embodiments, the present invention provides a pharmaceutical composition comprising (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0232] In some embodiments, the present invention provides a pharmaceutical composition comprising (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-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0233] In some embodiments, the present invention provides a pharmaceutical composition comprising (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexamido)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0234] In some embodiments, the present invention provides a pharmaceutical composition comprising (S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazacyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0235] In some embodiments, the present invention provides a pharmaceutical composition comprising (S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidine-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0236] In some embodiments, the present invention relates to a pharmaceutical composition comprising compounds selected from the group consisting of:

[0237]

[0238]

[0239] Or its pharmaceutically acceptable salt.

[0240] In some embodiments, the present invention relates to a pharmaceutical composition comprising a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof, as an active pharmaceutical ingredient (API):

[0241]

[0242]

[0243]

[0244]

[0245]

[0246] Pharmaceutically acceptable compositions including compounds of formula (I) can be prepared by various procedures. For example, compounds of formula (I) can be formulated with suitable excipients, diluents or carriers and formed into tablets or capsules and other suitable dosage forms.

[0247] Pharmaceutical compositions may be provided in unit doses containing a predetermined amount of an API comprising a compound of formula (I) per unit dose. Such units may contain a desired amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, depending on the condition being treated, the route of administration, and the patient's age, weight, and condition. Therefore, such unit doses may be administered at desired dosing intervals. The concentration of the active compound in the pharmaceutical composition will depend on various applicable parameters and considerations, such as the rate of absorption, inactivation, and excretion of the drug, and other factors known to those skilled in the art. It should be noted that dose values ​​will also vary with the severity of the condition to be alleviated. It should be further understood that, for any particular subject, the specific dosing regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges set forth herein are merely exemplary and not intended to limit the scope and practice of the required compositions. The active ingredient may be administered once or divided into many smaller doses administered at different time intervals.

[0248] In some embodiments, the mode of administration of the active compound is oral. Oral compositions will typically contain an inert diluent or an edible carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be incorporated together with excipients and used in tablet, lozenge, or capsule form. Pharmaceutically compatible binder and / or adjuvant materials may be included as part of the composition. Pharmaceutical compositions comprising a compound of formula (I) formulated for oral delivery may be prepared in unit dosage forms, such as capsules at the desired dose strength of the compound of formula (I). For oral administration in liquid form, the oral pharmaceutical component may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, etc. For oral administration in tablet or capsule form, the compound of formula (I) may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier. Other examples of excipients, diluents, and carriers suitable for such formulations include: fillers and extenders such as starch and sugar; and binders such as cellulose derivatives. In addition, suitable binders, lubricants, disintegrants, and colorants may be incorporated into the mixture when desired or required. Suitable binders include starch, natural sugars, natural and synthetic gums, etc. Lubricants and / or flow aids may be used in these dosage forms.

[0249] Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds with similar properties: 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 silica; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavorings. When the dosage unit is in capsule form, in addition to the above types of materials, it may also contain a liquid carrier such as fatty oil. Furthermore, the dosage unit form may contain various other materials that alter the physical form of the dosage unit, such as coatings of sugar or other enteric solvents.

[0250] The compound can be applied as a component of elixirs, suspensions, syrups, flakes, etc. In addition to one or more active compounds, syrups may also contain sucrose or sweeteners as sweeteners, as well as certain preservatives, dyes and colorants, and flavorings.

[0251] Compounds can be formulated into solutions suitable for parenteral administration, such as via intramuscular, subcutaneous, or intravenous routes. For example, compounds of formula (I) can be dissolved in a suitable buffer solution. Pharmaceutical compositions comprising compounds of formula (I) at desired concentrations can be formulated into injectable drug solutions (useful, for example, in preclinical animal studies).

[0252] Exemplary methods

[0253] Compounds that inhibit α4β7 could be used to develop drugs for treating patients with ulcerative colitis and Crohn's disease. Patients with ulcerative colitis (UC) and Crohn's disease (CD) suffer from autoimmune inflammation of the digestive tract, and for many of these patients, CD4... + Memory T cells drive disease progression and onset through their ability to secrete pro-inflammatory and effector cytokines within the gut, thereby influencing peripheral immune cells and tissues. The progression and onset of these disease symptoms are believed to involve T cell extravasation, allowing blood to enter intestinal tissues and leading to inflammatory symptoms identified in UC and CD via integrin-associated mechanisms. Inhibition of α4β7 can disrupt this mechanism, preventing T cells from localizing to tissues and effectively treating and preventing diseases such as UC and CD. Gut-associated T cells require surface expression of integrin α4β7 and the chemokine receptor CCR9. While CCR9 is used by cells for gradient migration against CCL25 expressed in the small intestine, α4β7 is a binding ligand for the mucosal addressin cell adhesion molecule 1 (MAdCAM-1). Integrin α4β7 binds to MAdCAM-1 with high affinity, thereby promoting cell rolling and firm adhesion, followed by extravasation into tissues.

[0254] The pharmaceutical composition may include a compound that inhibits α4β7 integrin on inflammatory cells, the compound enabling these cells to adhere to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and inhibiting or preventing these cells from entering the lamina propria and gut-associated lymphoid tissue.

[0255] The compounds of formula (I), as described in Example 5, were evaluated using fluorescence polarization (FP) assays. FP assays were used to evaluate the potency of the compounds for purified proteins. FP assays consist of measuring the extracellular domain or headpiece of the purified integrin αβ-dihexadiomer bound to substituted or truncated ligands. Results of FP assays for exemplary compounds of formula (I) are provided herein.

[0256] Compound (I) was further evaluated using a ligand binding assay (LBA) as described in Example 6 to examine the potency of the compound in binding to the receptor expressed on the cell surface with the free ligand. The MAdCAM ligand binding assay measured the binding of fluorescently labeled MAdCAM-1-Fc to RPMI 8866 cells in the presence of Mn++ using flow cytometry. This assay assesses 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 distinguish the activity of potent compounds exceeding the functional sensitivity limit of the FP assay [Mn ~ 10 nM]. The ligand binding assay (LBA) is used to examine the potency of the compound and the selectivity of the binding of the free ligand to the receptor expressed on the cell surface.

[0257] In some embodiments, the compounds of the present invention may be selected from one or more of the embodiments numbered below:

[0258] 1. A compound of formula (I):

[0259]

[0260] in

[0261] R a R b and R c Independently select from the following groups: H, Me, halogens, CF3, C(H)F2, C(F)H2, and -(C 1- C5)alkylene-N-(R x (R) y ); the condition is R a R b and R c At least one of them is -(C 1- C5)alkylene-N-(R x (R) y );

[0262] R x and R y 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 it connects to, they form a 4- to 6-membered ring;

[0263] R1 is a substituted or unsubstituted (C1-C6)-alkyl, a substituted or unsubstituted (C1-C4)-alkylene-(C3-C6)-cycloalkyl, or a substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy.

[0264] R2 is

[0265] R 3a and R 3b Independently selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3, and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; provided that R 3a and R 3b None of them are H;

[0266] R3c and R 3d It is H;

[0267] R4 is H or a substituted or unsubstituted (C1-C4)-alkyl group;

[0268] R 5a and R 5e Independently selected from the group consisting of: H, CN, halogens, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl, and (C1-C4)-alkoxy; and

[0269] R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogen, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy;

[0270] Or its pharmaceutically acceptable salt.

[0271] 2. The compound according to Example 1, wherein R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0272] 3. The compound according to Example 2, wherein R1 is isobutyl.

[0273] 4. The compound according to Example 1, wherein R1 is

[0274] 5. The compound according to Example 1, wherein R1 is

[0275] 6. The compound according to any one of Examples 1 to 5, wherein R 3a and R 3b Independently selected from the group consisting of: halogens, 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.

[0276] 7. The compound according to Example 6, wherein R 3a and R 3b Independently selected from the group consisting of halogens and (C1-C4)-alkyl groups.

[0277] 8. The compound according to Example 7, wherein the halogen is Cl or F.

[0278] 9. The compound according to Example 7 or 8, wherein the (C1-C4)-alkyl group is methyl.

[0279] 10. The compound according to any one of Examples 1 to 7, wherein R 3a It is methyl; and R 3b It is F.

[0280] 11. The compound according to any one of Examples 1 to 7, wherein R 3a It is F; and R 3b It is a methyl group.

[0281] 12. The compound according to any one of Examples 1 to 11, wherein R4 is H.

[0282] 13. The compound according to any one of Examples 1 to 11, wherein R4 is methyl, ethyl, n-propyl, or isopropyl.

[0283] 14. The compound according to any one of Examples 1 to 13, wherein R 5a and R 5e Independently selected from the group consisting of: halogens, CF3, C(H)F2, C(F)H2 and substituted or unsubstituted (C1-C4)-alkyl groups.

[0284] 15. The compound according to any one of Examples 1 to 14, wherein R 5a It is halogen.

[0285] 16. The compound according to Example 15, wherein R 5a It is either F or Cl.

[0286] 17. The compound according to any one of Examples 1 to 14, wherein R 5a It's CF3.

[0287] 18. The compound according to any one of Examples 1 to 14, wherein R 5a It is C(H)F2.

[0288] 19. The compound according to any one of Examples 1 to 14, wherein R 5a It is C(F)H2.

[0289] 20. The compound according to any one of Examples 1 to 14, wherein R 5a It is an unsubstituted (C1-C4)-alkyl group.

[0290] 21. The compound according to Example 20, wherein R 5a It is a methyl group.

[0291] 22. The compound according to any one of Examples 1 to 14, wherein R 5a It is a substituted (C1-C5)-alkyl group, which is substituted with at least one halogen.

[0292] 23. The compound according to any one of Examples 1 to 14, wherein R 5a It is an unsubstituted (C1-C4)-alkoxy group.

[0293] 24. The compound according to Example 23, wherein R 5a It's OMe.

[0294] 25. The compound according to any one of Examples 1 to 24, wherein R 5e It is halogen.

[0295] 26. The compound according to Example 25, wherein R 5e It is either F or Cl.

[0296] 27. The compound according to any one of Examples 1 to 24, wherein R 5e It's CF3.

[0297] 28. The compound according to any one of Examples 1 to 24, wherein R 5e It is C(H)F2.

[0298] 29. The compound according to any one of Examples 1 to 24, wherein R 5e It is C(F)H2.

[0299] 30. The compound according to any one of Examples 1 to 24, wherein R 5e It is an unsubstituted (C1-C4)-alkyl group.

[0300] 31. The compound according to Example 30, wherein R 5e It is a methyl group.

[0301] 32. The compound according to any one of Examples 1 to 24, wherein R 5e It is a substituted (C1-C5)-alkyl group, which is substituted with at least one halogen.

[0302] 33. The compound according to any one of Examples 1 to 24, wherein R 5e It is an unsubstituted (C1-C4)-alkoxy group.

[0303] 34. The compound according to Example 33, wherein R 5eIt's OMe.

[0304] 35. The compound according to any one of Examples 1 to 34, wherein R 5b R 5c and R 5d Independently selected from the group consisting of: H, halogens, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl and substituted or unsubstituted (C1-C4)-alkoxy.

[0305] 36. The compound according to any one of Examples 1 to 35, wherein R 5b It is H.

[0306] 37. The compound according to any one of Examples 1 to 35, wherein R 5b It is halogen.

[0307] 38. The compound according to Example 37, wherein R 5b It is either Cl or F.

[0308] 39. The compound according to any one of Examples 1 to 35, wherein R 5b It's CF3.

[0309] 40. The compound according to any one of Examples 1 to 35, wherein R 5b It is C(H)F2.

[0310] 41. The compound according to any one of Examples 1 to 35, wherein R 5b It is C(F)H2.

[0311] 42. The compound according to any one of Examples 1 to 35, wherein R 5b It is an unsubstituted (C1-C4)-alkyl group.

[0312] 43. The compound according to Example 37, wherein R 5b It is a methyl group.

[0313] 44. The compound according to any one of Examples 1 to 35, wherein R 5b It is an unsubstituted (C1-C4)-alkoxy group.

[0314] 45. The compound according to Example 44, wherein R 5b It's OMe.

[0315] 46. ​​The compound according to any one of Examples 1 to 35, wherein R 5b It is an unsubstituted (C3-C6)-cycloalkyl group.

[0316] 47. The compound according to Example 46, wherein R 5b It is cyclopropyl.

[0317] 48. The compound according to any one of Examples 1 to 47, wherein R 5c It is H.

[0318] 49. The compound according to any one of Examples 1 to 47, wherein R 5c It is halogen.

[0319] 50. The compound according to Example 49, wherein R 5c It is either Cl or F.

[0320] 51. The compound according to any one of Examples 1 to 47, wherein R 5c It's CF3.

[0321] 52. The compound according to any one of Examples 1 to 47, wherein R 5c It is C(H)F2.

[0322] 53. The compound according to any one of Examples 1 to 47, wherein R 5c It is C(F)H2.

[0323] 54. The compound according to any one of Examples 1 to 47, wherein R 5c It is an unsubstituted (C1-C4)-alkyl group.

[0324] 55. The compound according to Example 54, wherein R 5c It is a methyl group.

[0325] 56. The compound according to any one of Examples 1 to 47, wherein R 5c It is an unsubstituted (C1-C4)-alkoxy group.

[0326] 57. The compound according to Example 56, wherein R 5c It's OMe.

[0327] 58. The compound according to any one of Examples 1 to 47, wherein R 5c It is an unsubstituted (C3-C6)-cycloalkyl group.

[0328] 59. The compound according to Example 58, wherein R 5b It is cyclopropyl.

[0329] 60. The compound according to any one of Examples 1 to 59, wherein R 5d It is H.

[0330] 61. The compound according to any one of Examples 1 to 59, wherein R 5d It is halogen.

[0331] 62. The compound according to Example 61, wherein R 5d It is either Cl or F.

[0332] 63. The compound according to any one of Examples 1 to 59, wherein R 5d It's CF3.

[0333] 64. The compound according to any one of Examples 1 to 59, wherein R 5d It is C(H)F2.

[0334] 65. The compound according to any one of Examples 1 to 59, wherein R 5d It is C(F)H2.

[0335] 66. The compound according to any one of Examples 1 to 59, wherein R 5d It is an unsubstituted (C1-C4)-alkyl group.

[0336] 67. The compound according to Example 66, wherein R 5d It is a methyl group.

[0337] 68. The compound according to any one of Examples 1 to 67, wherein R 5d It is an unsubstituted (C1-C4)-alkoxy group.

[0338] 69. The compound according to Example 68, wherein R 5d It's OMe.

[0339] 70. The compound according to any one of Examples 1 to 67, wherein R 5d It is an unsubstituted (C3-C6)-cycloalkyl group.

[0340] 71. The compound according to Example 70, wherein R 5d It is cyclopropyl.

[0341] 72. The compound according to any one of Examples 1 to 35, wherein R 5b and R 5d Each is H.

[0342] 73. The compound according to any one of Examples 1 to 72, wherein R a It is H.

[0343] 74. The compound according to any one of Examples 1 to 72, wherein R a It's me.

[0344] 75. The compound according to any one of Examples 1 to 72, wherein R a It is halogen.

[0345] 76. The compound according to Example 75, wherein R a It is either Cl or F.

[0346] 77. The compound according to any one of Examples 1 to 72, wherein R a It's CF3.

[0347] 78. The compound according to any one of Examples 1 to 72, wherein R a It is C(H)F2.

[0348] 79. The compound according to any one of Examples 1 to 72, wherein R a It is C(F)H2.

[0349] 80. The compound according to any one of Examples 1 to 72, wherein R a It is an unsubstituted –(C1-C3)alkylene-N-(R x (R) y ).

[0350] 81. The compound according to any one of Examples 1 to 72, wherein R a It is a substituted –(C1-C3)alkylene-N-(R x (R) y ), which was replaced by F or OMe.

[0351] 82. The compound according to any one of Examples 1 to 81, wherein R b It is H.

[0352] 83. The compound according to any one of Examples 1 to 81, wherein R b It's me.

[0353] 84. The compound according to any one of Examples 1 to 81, wherein R b It is halogen.

[0354] 85. The compound according to Example 84, wherein R b It is either Cl or F.

[0355] 86. The compound according to any one of Examples 1 to 81, wherein R b It's CF3.

[0356] 87. The compound according to any one of Examples 1 to 81, wherein R b It is C(H)F2.

[0357] 88. The compound according to any one of Examples 1 to 81, wherein R b It is C(F)H2.

[0358] 89. The compound according to any one of Examples 1 to 81, wherein R b It is an unsubstituted –(C1-C3)alkylene-N-(R x (R) y ).

[0359] 90. The compound according to any one of Examples 1 to 81, wherein R b It is a substituted –(C1-C3)alkylene-N-(R x (R) y ), which was replaced by F or OMe.

[0360] 91. The compound according to any one of Examples 1 to 90, wherein R c It is H.

[0361] 92. The compound according to any one of Examples 1 to 90, wherein R c It's me.

[0362] 93. The compound according to any one of Examples 1 to 90, wherein R c It is halogen.

[0363] 94. The compound according to Example 93, wherein R c It is either Cl or F.

[0364] 95. The compound according to any one of Examples 1 to 90, wherein R c It's CF3.

[0365] 96. The compound according to any one of Examples 1 to 90, wherein R c It is C(H)F2.

[0366] 97. The compound according to any one of Examples 1 to 90, wherein R c It is C(F)H2.

[0367] 98. The compound according to any one of Examples 1 to 90, wherein R c It is an unsubstituted –(C1-C3)alkylene-N-(R x (R) y ).

[0368] 99. The compound according to any one of Examples 1 to 90, wherein R cIt is a substituted –(C1-C3)alkylene-N-(R x (R) y ), which was replaced by F or OMe.

[0369] 100. The compound according to any one of Examples 1 to 99, wherein R x It is H.

[0370] 101. The compound according to any one of Examples 1 to 99, wherein R x It is an unsubstituted (C1-C6)-alkyl group.

[0371] 102. The compound according to any one of Examples 1 to 100, wherein R y It is H.

[0372] 103. The compound according to any one of Examples 1 to 100, wherein R y It is an unsubstituted (C1-C6)-alkyl group.

[0373] 104. The compound according to any one of Examples 1 to 72, 80 to 81, 89 to 90 and 98-99, wherein R x and R y Together with the N it connects to, they form an unsubstituted 4 to 6-membered ring.

[0374] 105. The compound according to any one of Examples 1 to 72, 80 to 81, 89 to 90 and 98-99, wherein R x and R y Together with the N to which it is attached, it forms a substituted 4- to 6-membered ring, which is substituted by at least one halogen, substituted or unsubstituted (C1-C4) alkyl or OMe.

[0375] 106. The compound according to Example 104 or 105, wherein the 4 to 6 membered ring is a 3 to 6 membered heterocyclic alkyl group.

[0376] 107. The compound according to Example 104 or 105, wherein the 4 to 6-membered ring is a 4 to 5-membered heterocyclic alkyl group.

[0377] 108. The compound according to Example 1, wherein the compound is a compound of formula (Ia):

[0378]

[0379] in

[0380] R a R b and R c At least one of them is –(C1-C3)alkylene-N(Rx (R) y );

[0381] R x and R y Independently selected from the group consisting of H and methyl groups; or R x and R y Together with the N it is connected to, they form substituted or unsubstituted 4- to 6-membered rings; and

[0382] R 3a and R 3b Each is independently selected from the group consisting of methyl and F.

[0383] 109. The compound according to Example 108, wherein R 5a and R 5e It is independently an unsubstituted (C1-C4) alkyl group.

[0384] 110. The compound according to Example 108 or 109, wherein R b It is an unsubstituted –(C1-C3)alkylene-N(R) x (R) y ).

[0385] 111. The compound according to Example 1 or 108, wherein R a Choose from the following groups: H, C(H)F2, CF3, and Me.

[0386] 112. The compound according to Example 1 or 108, wherein R b Choose from the following groups:

[0387] 113. The compound according to Example 1 or 108, wherein R b Choose from the following groups:

[0388] 114. The compound according to Example 1 or 108, wherein R c It is H or F.

[0389] 115. The compound according to any one of Examples 1 and 108 to 114, wherein R1 is selected from the group consisting of:

[0390] 116. The compound according to any one of Examples 108 to 115, wherein R 5a It's CF3.

[0391] 117. The compound according to any one of Examples 108 to 115, wherein R 5a It is C(H)F2.

[0392] 118. The compound according to any one of Examples 108 to 115, wherein R 5a It is C(F)H2.

[0393] 119. The compound according to any one of Examples 108 to 115, wherein R 5a It is a methyl group.

[0394] 120. The compound according to any one of Examples 108 to 115, wherein R 5a It's OMe.

[0395] 121. The compound according to any one of Examples 108 to 115, wherein R 5a It is either F or Cl.

[0396] 122. The compound according to any one of Examples 108 to 121, wherein R 5b It is H.

[0397] 123. The compound according to any one of Examples 108 to 121, wherein R 5b It's CF3.

[0398] 124. The compound according to any one of Examples 108 to 121, wherein R 5b It is C(H)F2.

[0399] 125. The compound according to any one of Examples 108 to 121, wherein R 5b It is C(F)H2.

[0400] 126. The compound according to any one of Examples 108 to 121, wherein R 5b It is a methyl group.

[0401] 127. The compound according to any one of Examples 108 to 121, wherein R 5b It's OMe.

[0402] 128. The compound according to any one of Examples 108 to 121, wherein R 5b It is either F or Cl.

[0403] 129. The compound according to any one of Examples 108 to 128, wherein R 5c It is H.

[0404] 130. The compound according to any one of Examples 108 to 128, wherein R5c It's CF3.

[0405] 131. The compound according to any one of Examples 108 to 128, wherein R 5c It is C(H)F2.

[0406] 132. The compound according to any one of Examples 108 to 128, wherein R 5c It is C(F)H2.

[0407] 133. The compound according to any one of Examples 108 to 128, wherein R 5c It is a methyl group.

[0408] 134. The compound according to any one of Examples 108 to 128, wherein R 5c It's OMe.

[0409] 135. The compound according to any one of Examples 108 to 128, wherein R 5c It is either F or Cl.

[0410] 136. The compound according to any one of Examples 108 to 135, wherein R 5d It is H.

[0411] 137. The compound according to any one of Examples 108 to 135, wherein R 5d It's CF3.

[0412] 138. The compound according to any one of Examples 108 to 135, wherein R 5d It is C(H)F2.

[0413] 139. The compound according to any one of Examples 108 to 135, wherein R 5d It is C(F)H2.

[0414] 140. The compound according to any one of Examples 108 to 135, wherein R 5d It is a methyl group.

[0415] 141. The compound according to any one of Examples 108 to 135, wherein R 5d It's OMe.

[0416] 142. The compound according to any one of Examples 108 to 135, wherein R 5d It is either F or Cl.

[0417] 143. The compound according to any one of Examples 108 to 142, wherein R 5e It's CF3.

[0418] 144. The compound according to any one of Examples 108 to 142, wherein R 5e It is C(H)F2.

[0419] 145. The compound according to any one of Examples 108 to 142, wherein R 5e It is C(F)H2.

[0420] 146. The compound according to any one of Examples 108 to 142, wherein R 5e It is a methyl group.

[0421] 147. The compound according to any one of Examples 108 to 142, wherein R 5e It's OMe.

[0422] 148. The compound according to any one of Examples 108 to 142, wherein R 5e It is either F or Cl.

[0423] 149. The compound according to any one of Examples 1 and 108 to 121, wherein R 5b R 5c and R 5d At least one of them is H.

[0424] 150. The compound according to any one of Examples 1 and 108 to 121, wherein R 5b R 5c and R 5d At least two of them are H.

[0425] 151. The compound according to any one of Examples 1 and 108 to 121, wherein R 5b R 5c and R 5d It is H.

[0426] 152. The compound according to any one of Examples 1 and 108 to 151, wherein R 3a It is H.

[0427] 153. The compound according to any one of Examples 1 and 108 to 151, wherein R 3a It is a methyl group.

[0428] 154. The compound according to any one of Examples 1 and 108 to 151, wherein R 3a It is halogen.

[0429] 155. The compound according to any one of Examples 1 and 108 to 151, wherein R 3a It's CF3.

[0430] 156. The compound according to any one of Examples 1 and 108 to 151, wherein R 3a It is C(H)F2.

[0431] 157. The compound according to any one of Examples 1 and 108 to 151, wherein R 3a It is C(F)H2.

[0432] 158. The compound according to any one of Examples 1 and 108 to 151, wherein R 3a It's OMe.

[0433] 159. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It is H.

[0434] 160. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It is a methyl group.

[0435] 161. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It is halogen.

[0436] 162. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It's CF3.

[0437] 163. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It is C(H)F2.

[0438] 164. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It is C(F)H2.

[0439] 165. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It's OMe.

[0440] 166. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It is OCF3.

[0441] 167. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It is cyclopropyl.

[0442] 168. The compound according to any one of Examples 108 to 151, wherein R 3a It is methyl, and R 3b It is F.

[0443] 169. The compound according to any one of Examples 108 to 151, wherein R 3a It is F, and R 3b It is a methyl group.

[0444] 170. The compound according to Example 1, wherein the compound is selected from... Figure 1 Any of the compounds or their enantiomers.

[0445] 171. The compound according to Example 1, wherein the compound is a compound of formula (Ic).

[0446]

[0447] Or its pharmaceutically acceptable salt, wherein

[0448] R a R b and R c Independently selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, halogen, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C4)-alkoxy, -OCF3, and substituted or unsubstituted –(C1-C5)alkylene-N-(R x (R) y ); the condition is R a R b and R c One of them is –(C1-C5)alkylene-N-(R x (R) y );

[0449] R x and R y 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 it is attached to, it forms a substituted or unsubstituted 4- to 6-membered heterocyclic ring;

[0450] R 3a and R 3bIndependently selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3, and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; provided that R 3a and R 3b None of them are H;

[0451] R 3c Select from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, hydroxyl, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3-CN and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy;

[0452] R 3d Choose from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl, halogen and -(C1-C4)-alkoxy;

[0453] R 5a and R 5e Independently selected from the group consisting of: H, CN, halogens, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl, and (C1-C4)-alkoxy; and

[0454] R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogens, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl and (C1-C4)-alkoxy;

[0455] Or its pharmaceutically acceptable salt.

[0456] 172. A compound selected from the group consisting of:

[0457] (3S)-3-(4,5-difluoro-2',6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluorozacricyclobutan-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid;

[0458] (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propionic acid;

[0459] (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[0460] (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[0461] (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-methylpentamido)propionic acid;

[0462] (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid;

[0463] (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propionic acid;

[0464] (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-methylpentamido)propionic acid;

[0465] (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propionic acid;

[0466] (3S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fluoroazacyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid;

[0467] (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-methylpentamido)propionic acid; and

[0468] (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid;

[0469] Or its pharmaceutically acceptable salt.

[0470] 173. The compound according to Example 1, wherein the compound is one of the following compounds:

[0471]

[0472] Or its pharmaceutically acceptable salt.

[0473] 174. The compound according to Example 1, wherein the compound is one of the following compounds:

[0474]

[0475] Or its pharmaceutically acceptable salt.

[0476] 175. The compound according to Example 1, wherein the compound is one of the following compounds:

[0477]

[0478] Or its pharmaceutically acceptable salt.

[0479] 176. The compound according to Example 1, wherein the compound is one of the following compounds:

[0480] Or its pharmaceutically acceptable salt.

[0481] 177. The compound according to Example 1, wherein the compound is one of the following compounds:

[0482] Or its pharmaceutically acceptable salt.

[0483] 178. The compound according to Example 1, wherein the compound is one of the following compounds:

[0484] Or its pharmaceutically acceptable salt.

[0485] 179. The compound according to Example 1, wherein the compound is one of the following compounds:

[0486] Or its pharmaceutically acceptable salt.

[0487] 180. The compound according to Example 1, wherein the compound is one of the following compounds:

[0488] Or its pharmaceutically acceptable salt.

[0489] 181. The compound according to Example 1, wherein the compound is one of the following:

[0490] Or its pharmaceutically acceptable salt.

[0491] 182. The compound according to Example 1, wherein the compound is one of the following compounds:

[0492] Or its pharmaceutically acceptable salt.

[0493] 183. The compound according to Example 1, wherein the compound is one of the following compounds:

[0494]

[0495] Or its pharmaceutically acceptable salt.

[0496] 184. The compound according to Example 1, wherein the compound is one of the following compounds:

[0497]

[0498] Or its pharmaceutically acceptable salt.

[0499] 185. The compound according to Example 1, wherein the compound is (3S)-3-(4,5-difluoro-2',6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazacyclobutane-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0500] 186. The compound according to Example 1, wherein the compound is (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0501] 187. The compound according to Example 1, wherein the compound is (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0502] 188. The compound according to Example 1, wherein the compound is (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0503] 189. The compound according to Example 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-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0504] 190. The compound according to Example 1, wherein the compound is (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0505] 191. The compound according to Example 1, wherein the compound is (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0506] 192. The compound according to Example 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-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0507] 193. The compound according to Example 1, wherein the compound is (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0508] 194. The compound according to Example 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-fluoroazacyclobutane-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0509] 195. The compound according to Example 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-fluoropyrrolidine-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0510] 196. The compound according to Example 1, wherein the compound is (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0511] 197. The compound according to Example 1, wherein the compound is (S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazacyclobutane-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0512] 198. The compound according to Example 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0513] 199. The compound according to Example 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0514] 200. The compound according to Example 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0515] 201. The compound according to Example 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-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0516] 202. The compound according to Example 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-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0517] 203. The compound according to Example 1, wherein the compound is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0518] 204. The compound according to Example 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-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0519] 205. The compound according to Example 1, wherein the compound is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexamido)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0520] 206. The compound according to Example 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-fluoroazacyclobutane-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0521] 207. The compound according to Example 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-fluoropyrrolidine-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0522] 208. The compound according to Example 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-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0523] 209. A pharmaceutical composition comprising a compound according to any one of Examples 1 to 208; and a pharmaceutically acceptable excipient.

[0524] 210. A method for inhibiting α4β7 integrin in cells, the method comprising contacting the cells with a compound of any one of Examples 1 to 208 under conditions that effectively reduce cell adhesion to MAdCAM-1.

[0525] 211. A method for reducing cell adhesion to MAdCAM-1 comprising α4β7 integrin, the method comprising contacting the cells with a compound of any one of Examples 1 to 208 under conditions that effectively reduce cell adhesion to MAdCAM-1.

[0526] 212. A method for treating inflammatory bowel disease, ulcerative colitis, or Crohn's disease, the method comprising administering to a subject in need a therapeutically effective amount of any one of the compounds of Examples 1 to 208.

[0527] In some embodiments, the compounds of the present invention may be compounds of formula (I):

[0528]

[0529] in

[0530] R a R b and R c Independently select from the following groups: H, Me, halogens, CF3, C(H)F2, C(F)H2, and -(C 1- C5)alkylene-N-(R x (R) y ); the condition is R a R b and R c At least one of them is -(C 1- C5)alkylene-N-(R x (R) y );

[0531] R x and R y 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 it connects to, they form a 4- to 6-membered ring;

[0532] R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0533] R2 is

[0534] R 3a and R 3b Independently selected from the group consisting of: halogens, 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;

[0535] R 3c and R 3d It is H;

[0536] R4 is H;

[0537] R 5a It is methyl;

[0538] R 5b Select from the group consisting of: H, CN, halogen, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy;

[0539] R 5c It is methyl;

[0540] R 5d It is H;

[0541] R 5e Choose from the group consisting of: H, CN, halogen, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl and (C1-C4)-alkoxy;

[0542] Or its pharmaceutically acceptable salt.

[0543] In some embodiments, the compounds of the present invention may be compounds of formula (Ia):

[0544]

[0545] in

[0546] R a R b and R c Independently select from the following groups: H, Me, halogens, CF3, C(H)F2, C(F)H2, and -(C 1- C5)alkylene-N-(R x (R) y); the condition is R a R b and R c At least one of them is -(C 1- C5)alkylene-N-(R x (R) y );

[0547] R a R b and R c At least one of them is –(C1-C3)alkylene-N(R x (R) y );

[0548] R x and R y Independently selected from the group consisting of H and methyl groups; or R x and R y Together with the N it is connected to, they form substituted or unsubstituted 4- to 6-membered rings;

[0549] R1 is a substituted or unsubstituted (C1-C6)-alkyl, a substituted or unsubstituted (C1-C4)-alkylene-(C3-C6)-cycloalkyl, or a substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy.

[0550] R2 is

[0551] R 3a and R 3b Each is independently selected from the group consisting of methyl and F, and R 3a It is halogen;

[0552] R 3c and R 3d It is H;

[0553] R4 is H or a substituted or unsubstituted (C1-C4)-alkyl group;

[0554] R 5a Selected from the group consisting of: H, CN, halogens, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl, and (C1-C4)-alkoxy; and

[0555] R 5b and R 5cIndependently selected from the group consisting of: H, CN, halogens, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, hydroxyl, and (C1-C4)-alkoxy; and

[0556] R 5d It is H;

[0557] R 5e It is methyl;

[0558] Or its pharmaceutically acceptable salt.

[0559] In some embodiments, the compounds of the present invention may be compounds of formula (Ic).

[0560]

[0561] in

[0562] R a R b and R c Independently selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, halogen, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C4)-alkoxy, -OCF3, and substituted or unsubstituted –(C1-C5)alkylene-N-(R x (R) y ); the condition is R a R b and R c One of them is –(C1-C5)alkylene-N-(R x (R) y );

[0563] R x and R y 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 it is attached to, it forms a substituted or unsubstituted 4- to 6-membered heterocyclic ring;

[0564] R 3a It is halogen, and R 3bSelect from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3 and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy;

[0565] R 3c It is H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, hydroxyl, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3-CN and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy;

[0566] R 3d Choose from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl, halogen and -(C1-C4)-alkoxy;

[0567] R 5a and R 5e Independently selected from the group consisting of: H, CN, halogens, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl, and (C1-C4)-alkoxy; and

[0568] R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogens, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl and (C1-C4)-alkoxy;

[0569] Or its pharmaceutically acceptable salt.

[0570] In some embodiments, the compound of the present invention may be (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2-fluoro-3-methyl-5-((S)-2-methylpiperidin-1-yl)phenyl)propionic acid

[0571] Or its pharmaceutically acceptable salt.

[0572] In some embodiments, the present invention relates to any of the methods mentioned above, wherein the subject is a mammal. In some embodiments, the present invention relates to any of the compounds mentioned above, wherein the subject is a human.

[0573] Example

[0574] The invention described herein in general will be more readily understood by referring to the following examples, which are included only for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0575] Examples 1 to 4 describe Figure 1 The synthesis of certain compounds presented in the document includes compounds of formula (Ia) and formula (Ib). Figure 1 The compounds can be prepared as mixtures of diastereomers having a (3S) configuration (i.e., with the carboxylic acid moiety at the stereocenter β) (e.g., as disclosed in Examples 1-4), and mixtures of diastereomers covalently bonded at the chiral center to the nitrogen atom of the pyridone ring of formula (I) (e.g., as shown in formula (Ib)).

[0576] exist Figure 1 The diagram shows the stereochemistry of the compound with high activity in the fluorescence polarization (FP) assay of Example 5. Example 5 describes the fluorescence polarization (FP) assay. Example 6 describes the ligand binding (LB) assay. Example 7 describes the cell adhesion (CA) assay.

[0577] Other embodiments

[0578] In some embodiments, the compound may be selected from one or more of the examples listed below:

[0579] 1. A compound of formula (I):

[0580]

[0581] in

[0582] R a R b and R c Independently select from the following groups: H, Me, halogens, CF3, C(H)F2, C(F)H2, and -(C 1- C5)alkylene-N-(R x (R) y ); the condition is R a R b and R c At least one of them is -(C 1- C5)alkylene-N-(Rx (R) y );

[0583] R x and R y 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 it connects to, they form a 4- to 6-membered ring;

[0584] R1 is a substituted or unsubstituted (C1-C6)-alkyl, a substituted or unsubstituted (C1-C4)-alkylene-(C3-C6)-cycloalkyl, or a substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy.

[0585] R2 is

[0586] R 3a and R 3b Independently selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3, and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; provided that R 3a and R 3b None of them are H;

[0587] R 3c and R 3d It is H;

[0588] R4 is H or a substituted or unsubstituted (C1-C4)-alkyl group;

[0589] R 5a and R 5e Independently selected from the group consisting of: H, CN, halogens, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl, and (C1-C4)-alkoxy; and

[0590] R 5b R 5c and R 5dIndependently selected from the group consisting of: H, CN, halogen, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy;

[0591] Or its pharmaceutically acceptable salt.

[0592] 2. The compound according to Example 1, wherein R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0593] 3. The compound according to Example 2, wherein R1 is isobutyl.

[0594] 4. The compound according to Example 1, wherein R1 is

[0595] 5. The compound according to Example 1, wherein R1 is

[0596] 6. The compound according to any one of Examples 1 to 5, wherein R 3a and R 3b Independently selected from the group consisting of: halogens, 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.

[0597] 7. The compound according to Example 6, wherein R 3a and R 3b Independently selected from the group consisting of halogens and (C1-C4)-alkyl groups.

[0598] 8. The compound according to Example 7, wherein the halogen is Cl or F.

[0599] 9. The compound according to Example 7 or 8, wherein the (C1-C4)-alkyl group is methyl.

[0600] 10. The compound according to any one of Examples 1 to 7, wherein R 3a It is methyl; and R 3b It is F.

[0601] 11. The compound according to any one of Examples 1 to 7, wherein R 3a It is F; and R 3b It is a methyl group.

[0602] 12. The compound according to any one of Examples 1 to 11, wherein R4 is H.

[0603] 13. The compound according to any one of Examples 1 to 11, wherein R4 is methyl, ethyl, n-propyl, or isopropyl.

[0604] 14. The compound according to any one of Examples 1 to 13, wherein R 5a and R 5e Independently selected from the group consisting of: halogens, CF3, C(H)F2, C(F)H2 and substituted or unsubstituted (C1-C4)-alkyl groups.

[0605] 15. The compound according to any one of Examples 1 to 14, wherein R 5a It is halogen.

[0606] 16. The compound according to Example 15, wherein R 5a It is either F or Cl.

[0607] 17. The compound according to any one of Examples 1 to 14, wherein R 5a It's CF3.

[0608] 18. The compound according to any one of Examples 1 to 14, wherein R 5a It is C(H)F2.

[0609] 19. The compound according to any one of Examples 1 to 14, wherein R 5a It is C(F)H2.

[0610] 20. The compound according to any one of Examples 1 to 14, wherein R 5a It is an unsubstituted (C1-C4)-alkyl group.

[0611] 21. The compound according to Example 20, wherein R 5a It is a methyl group.

[0612] 22. The compound according to any one of Examples 1 to 14, wherein R 5a It is a substituted (C1-C5)-alkyl group, which is substituted with at least one halogen.

[0613] 23. The compound according to any one of Examples 1 to 14, wherein R 5a It is an unsubstituted (C1-C4)-alkoxy group.

[0614] 24. The compound according to Example 23, wherein R 5a It's OMe.

[0615] 25. The compound according to any one of Examples 1 to 24, wherein R 5e It is halogen.

[0616] 26. The compound according to Example 25, wherein R 5e It is either F or Cl.

[0617] 27. The compound according to any one of Examples 1 to 24, wherein R 5e It's CF3.

[0618] 28. The compound according to any one of Examples 1 to 24, wherein R 5e It is C(H)F2.

[0619] 29. The compound according to any one of Examples 1 to 24, wherein R 5e It is C(F)H2.

[0620] 30. The compound according to any one of Examples 1 to 24, wherein R 5e It is an unsubstituted (C1-C4)-alkyl group.

[0621] 31. The compound according to Example 30, wherein R 5e It is a methyl group.

[0622] 32. The compound according to any one of Examples 1 to 24, wherein R 5e It is a substituted (C1-C5)-alkyl group, which is substituted with at least one halogen.

[0623] 33. The compound according to any one of Examples 1 to 24, wherein R 5e It is an unsubstituted (C1-C4)-alkoxy group.

[0624] 34. The compound according to Example 33, wherein R 5e It's OMe.

[0625] 35. The compound according to any one of Examples 1 to 34, wherein R 5b R 5c and R 5d Independently selected from the group consisting of: H, halogens, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl and substituted or unsubstituted (C1-C4)-alkoxy.

[0626] 36. The compound according to any one of Examples 1 to 35, wherein R 5b It is H.

[0627] 37. The compound according to any one of Examples 1 to 35, wherein R5b It is halogen.

[0628] 38. The compound according to Example 37, wherein R 5b It is either Cl or F.

[0629] 39. The compound according to any one of Examples 1 to 35, wherein R 5b It's CF3.

[0630] 40. The compound according to any one of Examples 1 to 35, wherein R 5b It is C(H)F2.

[0631] 41. The compound according to any one of Examples 1 to 35, wherein R 5b It is C(F)H2.

[0632] 42. The compound according to any one of Examples 1 to 35, wherein R 5b It is an unsubstituted (C1-C4)-alkyl group.

[0633] 43. The compound according to Example 37, wherein R 5b It is a methyl group.

[0634] 44. The compound according to any one of Examples 1 to 35, wherein R 5b It is an unsubstituted (C1-C4)-alkoxy group.

[0635] 45. The compound according to Example 44, wherein R 5b It's OMe.

[0636] 46. ​​The compound according to any one of Examples 1 to 35, wherein R 5b It is an unsubstituted (C3-C6)-cycloalkyl group.

[0637] 47. The compound according to Example 46, wherein R 5b It is cyclopropyl.

[0638] 48. The compound according to any one of Examples 1 to 47, wherein R 5c It is H.

[0639] 49. The compound according to any one of Examples 1 to 47, wherein R 5c It is halogen.

[0640] 50. The compound according to Example 49, wherein R 5c It is either Cl or F.

[0641] 51. The compound according to any one of Examples 1 to 47, wherein R 5cIt's CF3.

[0642] 52. The compound according to any one of Examples 1 to 47, wherein R 5c It is C(H)F2.

[0643] 53. The compound according to any one of Examples 1 to 47, wherein R 5c It is C(F)H2.

[0644] 54. The compound according to any one of Examples 1 to 47, wherein R 5c It is an unsubstituted (C1-C4)-alkyl group.

[0645] 55. The compound according to Example 54, wherein R 5c It is a methyl group.

[0646] 56. The compound according to any one of Examples 1 to 47, wherein R 5c It is an unsubstituted (C1-C4)-alkoxy group.

[0647] 57. The compound according to Example 56, wherein R 5c It's OMe.

[0648] 58. The compound according to any one of Examples 1 to 47, wherein R 5c It is an unsubstituted (C3-C6)-cycloalkyl group.

[0649] 59. The compound according to Example 58, wherein R 5b It is cyclopropyl.

[0650] 60. The compound according to any one of Examples 1 to 59, wherein R 5d It is H.

[0651] 61. The compound according to any one of Examples 1 to 59, wherein R 5d It is halogen.

[0652] 62. The compound according to Example 61, wherein R 5d It is either Cl or F.

[0653] 63. The compound according to any one of Examples 1 to 59, wherein R 5d It's CF3.

[0654] 64. The compound according to any one of Examples 1 to 59, wherein R 5d It is C(H)F2.

[0655] 65. The compound according to any one of Examples 1 to 59, wherein R 5dIt is C(F)H2.

[0656] 66. The compound according to any one of Examples 1 to 59, wherein R 5d It is an unsubstituted (C1-C4)-alkyl group.

[0657] 67. The compound according to Example 66, wherein R 5d It is a methyl group.

[0658] 68. The compound according to any one of Examples 1 to 67, wherein R 5d It is an unsubstituted (C1-C4)-alkoxy group.

[0659] 69. The compound according to Example 68, wherein R 5d It's OMe.

[0660] 70. The compound according to any one of Examples 1 to 67, wherein R 5d It is an unsubstituted (C3-C6)-cycloalkyl group.

[0661] 71. The compound according to Example 70, wherein R 5d It is cyclopropyl.

[0662] 72. The compound according to any one of Examples 1 to 35, wherein R 5b and R 5d Each is H.

[0663] 73. The compound according to any one of Examples 1 to 72, wherein R a It is H.

[0664] 74. The compound according to any one of Examples 1 to 72, wherein R a It's me.

[0665] 75. The compound according to any one of Examples 1 to 72, wherein R a It is halogen.

[0666] 76. The compound according to Example 75, wherein R a It is either Cl or F.

[0667] 77. The compound according to any one of Examples 1 to 72, wherein R a It's CF3.

[0668] 78. The compound according to any one of Examples 1 to 72, wherein R a It is C(H)F2.

[0669] 79. The compound according to any one of Examples 1 to 72, wherein Ra It is C(F)H2.

[0670] 80. The compound according to any one of Examples 1 to 72, wherein R a It is an unsubstituted –(C1-C3)alkylene-N-(R x (R) y ).

[0671] 81. The compound according to any one of Examples 1 to 72, wherein R a It is a substituted –(C1-C3)alkylene-N-(R x (R) y ), which was replaced by F or OMe.

[0672] 82. The compound according to any one of Examples 1 to 81, wherein R b It is H.

[0673] 83. The compound according to any one of Examples 1 to 81, wherein R b It's me.

[0674] 84. The compound according to any one of Examples 1 to 81, wherein R b It is halogen.

[0675] 85. The compound according to Example 84, wherein R b It is either Cl or F.

[0676] 86. The compound according to any one of Examples 1 to 81, wherein R b It's CF3.

[0677] 87. The compound according to any one of Examples 1 to 81, wherein R b It is C(H)F2.

[0678] 88. The compound according to any one of Examples 1 to 81, wherein R b It is C(F)H2.

[0679] 89. The compound according to any one of Examples 1 to 81, wherein R b It is an unsubstituted –(C1-C3)alkylene-N-(R x (R) y ).

[0680] 90. The compound according to any one of Examples 1 to 81, wherein R b It is a substituted –(C1-C3)alkylene-N-(R x (R) y ), which was replaced by F or OMe.

[0681] 91. The compound according to any one of Examples 1 to 90, wherein R c It is H.

[0682] 92. The compound according to any one of Examples 1 to 90, wherein R c It's me.

[0683] 93. The compound according to any one of Examples 1 to 90, wherein R c It is halogen.

[0684] 94. The compound according to Example 93, wherein R c It is either Cl or F.

[0685] 95. The compound according to any one of Examples 1 to 90, wherein R c It's CF3.

[0686] 96. The compound according to any one of Examples 1 to 90, wherein R c It is C(H)F2.

[0687] 97. The compound according to any one of Examples 1 to 90, wherein R c It is C(F)H2.

[0688] 98. The compound according to any one of Examples 1 to 90, wherein R c It is an unsubstituted –(C1-C3)alkylene-N-(R x (R) y ).

[0689] 99. The compound according to any one of Examples 1 to 90, wherein R c It is a substituted –(C1-C3)alkylene-N-(R x (R) y ), which was replaced by F or OMe.

[0690] 100. The compound according to any one of Examples 1 to 99, wherein R x It is H.

[0691] 101. The compound according to any one of Examples 1 to 99, wherein R x It is an unsubstituted (C1-C6)-alkyl group.

[0692] 102. The compound according to any one of Examples 1 to 100, wherein R y It is H.

[0693] 103. The compound according to any one of Examples 1 to 100, wherein R y It is an unsubstituted (C1-C6)-alkyl group.

[0694] 104. The compound according to any one of Examples 1 to 72, 80 to 81, 89 to 90 and 98-99, wherein R x and R y Together with the N it connects to, they form an unsubstituted 4 to 6-membered ring.

[0695] 105. The compound according to any one of Examples 1 to 72, 80 to 81, 89 to 90 and 98-99, wherein R x and R y Together with the N to which it is attached, it forms a substituted 4- to 6-membered ring, which is substituted by at least one halogen, substituted or unsubstituted (C1-C4) alkyl or OMe.

[0696] 106. The compound according to Example 104 or 105, wherein the 4 to 6 membered ring is a 3 to 6 membered heterocyclic alkyl group.

[0697] 107. The compound according to Example 104 or 105, wherein the 4 to 6-membered ring is a 4 to 5-membered heterocyclic alkyl group.

[0698] 108. The compound according to Example 1, wherein the compound is a compound of formula (Ia):

[0699]

[0700] in

[0701] R a R b and R c At least one of them is –(C1-C3)alkylene-N(R x (R) y );

[0702] R x and R y Independently selected from the group consisting of H and methyl groups; or R x and R y Together with the N it is connected to, they form substituted or unsubstituted 4- to 6-membered rings; and

[0703] R 3a and R 3b Each is independently selected from the group consisting of methyl and F.

[0704] 109. The compound according to Example 108, wherein R 5a and R 5eIt is independently an unsubstituted (C1-C4) alkyl group.

[0705] 110. The compound according to Example 108 or 109, wherein R b It is an unsubstituted –(C1-C3)alkylene-N(R) x (R) y ).

[0706] 111. The compound according to Example 1 or 108, wherein R a Choose from the following groups: H, C(H)F2, CF3, and Me.

[0707] 112. The compound according to Example 1 or 108, wherein R b Choose from the following groups:

[0708] 113. The compound according to Example 1 or 108, wherein R b Choose from the following groups:

[0709] 114. The compound according to Example 1 or 108, wherein R c It is H or F.

[0710] 115. The compound according to any one of Examples 1 and 108 to 114, wherein R1 is selected from the group consisting of:

[0711] 116. The compound according to any one of Examples 108 to 115, wherein R 5a It's CF3.

[0712] 117. The compound according to any one of Examples 108 to 115, wherein R 5a It is C(H)F2.

[0713] 118. The compound according to any one of Examples 108 to 115, wherein R 5a It is C(F)H2.

[0714] 119. The compound according to any one of Examples 108 to 115, wherein R 5a It is a methyl group.

[0715] 120. The compound according to any one of Examples 108 to 115, wherein R 5a It's OMe.

[0716] 121. The compound according to any one of Examples 108 to 115, wherein R 5a It is either F or Cl.

[0717] 122. The compound according to any one of Examples 108 to 121, wherein R 5b It is H.

[0718] 123. The compound according to any one of Examples 108 to 121, wherein R 5b It's CF3.

[0719] 124. The compound according to any one of Examples 108 to 121, wherein R 5b It is C(H)F2.

[0720] 125. The compound according to any one of Examples 108 to 121, wherein R 5b It is C(F)H2.

[0721] 126. The compound according to any one of Examples 108 to 121, wherein R 5b It is a methyl group.

[0722] 127. The compound according to any one of Examples 108 to 121, wherein R 5b It's OMe.

[0723] 128. The compound according to any one of Examples 108 to 121, wherein R 5b It is either F or Cl.

[0724] 129. The compound according to any one of Examples 108 to 128, wherein R 5c It is H.

[0725] 130. The compound according to any one of Examples 108 to 128, wherein R 5c It's CF3.

[0726] 131. The compound according to any one of Examples 108 to 128, wherein R 5c It is C(H)F2.

[0727] 132. The compound according to any one of Examples 108 to 128, wherein R 5c It is C(F)H2.

[0728] 133. The compound according to any one of Examples 108 to 128, wherein R 5c It is a methyl group.

[0729] 134. The compound according to any one of Examples 108 to 128, wherein R5c It's OMe.

[0730] 135. The compound according to any one of Examples 108 to 128, wherein R 5c It is either F or Cl.

[0731] 136. The compound according to any one of Examples 108 to 135, wherein R 5d It is H.

[0732] 137. The compound according to any one of Examples 108 to 135, wherein R 5d It's CF3.

[0733] 138. The compound according to any one of Examples 108 to 135, wherein R 5d It is C(H)F2.

[0734] 139. The compound according to any one of Examples 108 to 135, wherein R 5d It is C(F)H2.

[0735] 140. The compound according to any one of Examples 108 to 135, wherein R 5d It is a methyl group.

[0736] 141. The compound according to any one of Examples 108 to 135, wherein R 5d It's OMe.

[0737] 142. The compound according to any one of Examples 108 to 135, wherein R 5d It is either F or Cl.

[0738] 143. The compound according to any one of Examples 108 to 142, wherein R 5e It's CF3.

[0739] 144. The compound according to any one of Examples 108 to 142, wherein R 5e It is C(H)F2.

[0740] 145. The compound according to any one of Examples 108 to 142, wherein R 5e It is C(F)H2.

[0741] 146. The compound according to any one of Examples 108 to 142, wherein R 5e It is a methyl group.

[0742] 147. The compound according to any one of Examples 108 to 142, wherein R 5e It's OMe.

[0743] 148. The compound according to any one of Examples 108 to 142, wherein R 5e It is either F or Cl.

[0744] 149. The compound according to any one of Examples 1 and 108 to 121, wherein R 5b R 5c and R 5d At least one of them is H.

[0745] 150. The compound according to any one of Examples 1 and 108 to 121, wherein R 5b R 5c and R 5d At least two of them are H.

[0746] 151. The compound according to any one of Examples 1 and 108 to 121, wherein R 5b R 5c and R 5d It is H.

[0747] 152. The compound according to any one of Examples 1 and 108 to 151, wherein R 3a It is H.

[0748] 153. The compound according to any one of Examples 1 and 108 to 151, wherein R 3a It is a methyl group.

[0749] 154. The compound according to any one of Examples 1 and 108 to 151, wherein R 3a It is halogen.

[0750] 155. The compound according to any one of Examples 1 and 108 to 151, wherein R 3a It's CF3.

[0751] 156. The compound according to any one of Examples 1 and 108 to 151, wherein R 3a It is C(H)F2.

[0752] 157. The compound according to any one of Examples 1 and 108 to 151, wherein R 3a It is C(F)H2.

[0753] 158. The compound according to any one of Examples 1 and 108 to 151, wherein R 3a It's OMe.

[0754] 159. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It is H.

[0755] 160. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It is a methyl group.

[0756] 161. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It is halogen.

[0757] 162. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It's CF3.

[0758] 163. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It is C(H)F2.

[0759] 164. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It is C(F)H2.

[0760] 165. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It's OMe.

[0761] 166. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It is OCF3.

[0762] 167. The compound according to any one of Examples 1 and 108 to 158, wherein R 3b It is cyclopropyl.

[0763] 168. The compound according to any one of Examples 108 to 151, wherein R 3a It is methyl, and R 3b It is F.

[0764] 169. The compound according to any one of Examples 108 to 151, wherein R 3a It is F, and R 3b It is a methyl group.

[0765] 170. The compound according to Example 1, wherein the compound is selected from... Figure 1 Any of the compounds or their enantiomers.

[0766] 171. The compound according to Example 1, wherein the compound is a compound of formula (Ic).

[0767]

[0768] Or its pharmaceutically acceptable salt, wherein

[0769] R a R b and R c Independently selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, halogen, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C4)-alkoxy, -OCF3, and substituted or unsubstituted –(C1-C5)alkylene-N-(R x (R) y ); the condition is R a R b and R c One of them is –(C1-C5)alkylene-N-(R x (R) y );

[0770] R x and R y 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 it is attached to, it forms a substituted or unsubstituted 4- to 6-membered heterocyclic ring;

[0771] R 3a and R 3b Independently selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3, and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; provided that R 3a and R 3b None of them are H;

[0772] R 3c Select from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, hydroxyl, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3-CN and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy;

[0773] R 3dChoose from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl, halogen and -(C1-C4)-alkoxy;

[0774] R 5a and R 5e Independently selected from the group consisting of: H, CN, halogens, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl, and (C1-C4)-alkoxy; and

[0775] R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogens, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl and (C1-C4)-alkoxy;

[0776] Or its pharmaceutically acceptable salt.

[0777] 172. A compound selected from the group consisting of:

[0778] (3S)-3-(4,5-difluoro-2',6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluorozacricyclobutan-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid;

[0779] (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propionic acid;

[0780] (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[0781] (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[0782] (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-methylpentamido)propionic acid;

[0783] (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid;

[0784] (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propionic acid;

[0785] (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-methylpentamido)propionic acid;

[0786] (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propionic acid;

[0787] (3S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fluoroazacyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid;

[0788] (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-methylpentamido)propionic acid; and

[0789] (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid;

[0790] Or its pharmaceutically acceptable salt.

[0791] 173. The compound according to Example 1, wherein the compound is one of the following compounds:

[0792]

[0793] Or its pharmaceutically acceptable salt.

[0794] 174. The compound according to Example 1, wherein the compound is one of the following compounds:

[0795]

[0796] Or its pharmaceutically acceptable salt.

[0797] 175. The compound according to Example 1, wherein the compound is one of the following compounds:

[0798]

[0799] Or its pharmaceutically acceptable salt.

[0800] 176. The compound according to Example 1, wherein the compound is one of the following compounds:

[0801] Or its pharmaceutically acceptable salt.

[0802] 177. The compound according to Example 1, wherein the compound is one of the following compounds:

[0803] Or its pharmaceutically acceptable salt.

[0804] 178. The compound according to Example 1, wherein the compound is one of the following compounds:

[0805] Or its pharmaceutically acceptable salt.

[0806] 179. The compound according to Example 1, wherein the compound is one of the following compounds:

[0807] Or its pharmaceutically acceptable salt.

[0808] 180. The compound according to Example 1, wherein the compound is one of the following compounds:

[0809] Or its pharmaceutically acceptable salt.

[0810] 181. The compound according to Example 1, wherein the compound is one of the following:

[0811] Or its pharmaceutically acceptable salt.

[0812] 182. The compound according to Example 1, wherein the compound is one of the following compounds:

[0813] Or its pharmaceutically acceptable salt.

[0814] 183. The compound according to Example 1, wherein the compound is one of the following compounds:

[0815]

[0816] Or its pharmaceutically acceptable salt.

[0817] 184. The compound according to Example 1, wherein the compound is one of the following compounds:

[0818]

[0819] Or its pharmaceutically acceptable salt.

[0820] 185. The compound according to Example 1, wherein the compound is (3S)-3-(4,5-difluoro-2',6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazacyclobutane-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0821] 186. The compound according to Example 1, wherein the compound is (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0822] 187. The compound according to Example 1, wherein the compound is (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0823] 188. The compound according to Example 1, wherein the compound is (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0824] 189. The compound according to Example 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-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0825] 190. The compound according to Example 1, wherein the compound is (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0826] 191. The compound according to Example 1, wherein the compound is (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0827] 192. The compound according to Example 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-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0828] 193. The compound according to Example 1, wherein the compound is (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0829] 194. The compound according to Example 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-fluoroazacyclobutane-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0830] 195. The compound according to Example 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-fluoropyrrolidine-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0831] 196. The compound according to Example 1, wherein the compound is (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0832] 197. The compound according to Example 1, wherein the compound is (S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazacyclobutane-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0833] 198. The compound according to Example 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0834] 199. The compound according to Example 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0835] 200. The compound according to Example 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0836] 201. The compound according to Example 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-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0837] 202. The compound according to Example 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-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0838] 203. The compound according to Example 1, wherein the compound is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0839] 204. The compound according to Example 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-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0840] 205. The compound according to Example 1, wherein the compound is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexamido)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0841] 206. The compound according to Example 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-fluoroazacyclobutane-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0842] 207. The compound according to Example 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-fluoropyrrolidine-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0843] 208. The compound according to Example 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-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0844] 209. A pharmaceutical composition comprising a compound according to any one of Examples 1 to 208; and a pharmaceutically acceptable excipient.

[0845] 210. A method for inhibiting α4β7 integrin in cells, the method comprising contacting the cells with a compound of any one of Examples 1 to 208 under conditions that effectively reduce cell adhesion to MAdCAM-1.

[0846] 211. A method for reducing cell adhesion to MAdCAM-1 comprising α4β7 integrin, the method comprising contacting the cells with a compound of any one of Examples 1 to 208 under conditions that effectively reduce cell adhesion to MAdCAM-1.

[0847] 212. A method for treating inflammatory bowel disease, ulcerative colitis, or Crohn's disease, the method comprising administering to a subject in need a therapeutically effective amount of any one of the compounds of Examples 1 to 208.

[0848] In some embodiments, compounds of formula (I) are used:

[0849]

[0850] in

[0851] R a R b and R c Independently select from the following groups: H, Me, halogens, CF3, C(H)F2, C(F)H2, and -(C 1- C5)alkylene-N-(R x (R) y ); the condition is R a R b and R c At least one of them is -(C 1- C5)alkylene-N-(R x (R) y );

[0852] R x and R y 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 it connects to, they form a 4- to 6-membered ring;

[0853] R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0854] R2 is

[0855] R 3a and R 3b Independently selected from the group consisting of: H, (C1-C5)-alkyl, (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3, and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; provided that R 3a and R 3b None of them are H;

[0856] R 3c and R 3d It is H;

[0857] R4 is H;

[0858] R 5a and R 5e It is methyl on its own;

[0859] R 5b and R 5c Independently selected from the group consisting of: H, CN, halogen, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy;

[0860] R 5d It is H; and

[0861] The compound of formula (I) is selected from the group consisting of:

[0862] a. (S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazacyclobutan-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid;

[0863] b. (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionic acid;

[0864] c. (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[0865] d. (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[0866] e. (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-methylpentamido)propionic acid;

[0867] f. (S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid;

[0868] g. (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[0869] h. (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-methylpentamido)propionic acid;

[0870] i. (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexamido)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[0871] j. (S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazacyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid; and

[0872] k.(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-methylpentamido)propionic acid;

[0873] Or its pharmaceutically acceptable salt.

[0874] 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-fluoroazacyclobutane-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0875] In some embodiments, the compound is (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0876] In some embodiments, the compound is (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0877] In some embodiments, the compound is (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0878] 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-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0879] 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-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0880] In some embodiments, the compound is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0881] 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-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0882] In some embodiments, the compound is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexamido)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

[0883] 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-fluoroazacyclobutane-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0884] 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-fluoropyrrolidine-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid or a pharmaceutically acceptable salt thereof.

[0885] In some embodiments, a pharmaceutical composition includes a compound of formula (I) as an active pharmaceutical ingredient:

[0886]

[0887] in

[0888] R a R b and R c Independently select from the following groups: H, Me, halogens, CF3, C(H)F2, C(F)H2, and -(C 1-C5)alkylene-N-(R x (R) y ); the condition is R a R b and R c At least one of them is -(C 1- C5)alkylene-N-(R x (R) y );

[0889] R x and R y 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 it connects to, they form a 4- to 6-membered ring;

[0890] R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0891] R2 is

[0892] R 3a and R 3b Independently selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3, and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; provided that R 3a and R 3b None of them are H;

[0893] R 3c and R 3d It is H;

[0894] R4 is H;

[0895] R 5a and R 5e It is methyl on its own;

[0896] R 5b and R 5c Independently selected from the group consisting of: H, CN, halogen, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy;

[0897] R5d It is H; and

[0898] The compound of formula (I) is selected from the group consisting of:

[0899]

[0900]

[0901] Or its pharmaceutically acceptable salt.

[0902] In some embodiments, the compound is

[0903] Or its pharmaceutically acceptable salt.

[0904] In some embodiments, the compound is

[0905] Or its pharmaceutically acceptable salt.

[0906] In some embodiments, the compound is

[0907] Or its pharmaceutically acceptable salt.

[0908] In some embodiments, the compound is

[0909] Or its pharmaceutically acceptable salt.

[0910] In some embodiments, the compound is

[0911] Or its pharmaceutically acceptable salt.

[0912] In some embodiments, the compound is

[0913] Or its pharmaceutically acceptable salt.

[0914] In some embodiments, the compound is

[0915] Or its pharmaceutically acceptable salt.

[0916] In some embodiments, the compound is

[0917] Or its pharmaceutically acceptable salt.

[0918] In some embodiments, the compound is

[0919] Or its pharmaceutically acceptable salt.

[0920] In some embodiments, the compound is

[0921] Or its pharmaceutically acceptable salt.

[0922] In some embodiments, the compound is

[0923] Or its pharmaceutically acceptable salt.

[0924] In some embodiments, the compound of formula (Ia):

[0925]

[0926] in:

[0927] R a It's CF3;

[0928] R b Is it substituted or unsubstituted? -(C 1- C5)alkylene-N-(R x (R) y );

[0929] R x and R y Independently, it is a substituted or unsubstituted (C1-C6)-alkyl group; or R x and R y Together with the N it connects to, they form a 4- to 6-membered ring;

[0930] R c It is H;

[0931] R1 is a substituted or unsubstituted (C1-C6)-alkyl group;

[0932] R2 is

[0933] R 3a and R 3b Independently selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3, and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; provided that R 3a and R 3b None of them are H;

[0934] R3c It is H;

[0935] R 3d It is halogen;

[0936] R4 is H;

[0937] R 5a and R 5e Each is independently selected from (C1-C5)-alkyl groups; and

[0938] R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogen, 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 heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy;

[0939] The compound of formula (I) is selected from the group consisting of:

[0940]

[0941]

[0942]

[0943]

[0944]

[0945] In some embodiments, the compound is

[0946] Or its pharmaceutically acceptable salt.

[0947] In some embodiments, the compound is

[0948] Or its pharmaceutically acceptable salt.

[0949] In some embodiments, the compound is

[0950] Or its pharmaceutically acceptable salt.

[0951] In some embodiments, the compound is

[0952] Or its pharmaceutically acceptable salt.

[0953] In some embodiments, the compound is

[0954] Or its pharmaceutically acceptable salt.

[0955] In some embodiments, the compound is

[0956] Or its pharmaceutically acceptable salt.

[0957] In some embodiments, the compound is

[0958] Or its pharmaceutically acceptable salt.

[0959] The compound according to claim 25, wherein the compound is

[0960] Or its pharmaceutically acceptable salt.

[0961] The compound according to claim 25, wherein the compound is

[0962] Or its pharmaceutically acceptable salt.

[0963] In some embodiments, the compound is

[0964] Or its pharmaceutically acceptable salt.

[0965] In some embodiments, the compound is

[0966] Or its pharmaceutically acceptable salt.

[0967] In some embodiments, a pharmaceutical composition comprises a compound of the present application or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient. In some embodiments, the present invention relates to compounds of formula (I), formula (Ia), or formula (Ib):

[0968]

[0969] Or its pharmaceutically acceptable salt;

[0970] in

[0971] R a R b and R cIndependently selected from the group consisting of: H, Me, halogen, CF3, C(H)F2, C(F)H2, -CN, -OCF3, substituted or unsubstituted (C1-C5)-alkyl, (C1-C5)-alkoxy, -CH2CF3, and substituted or unsubstituted –(C 1- C5)alkylene-N-(R x (R) y ); the condition is R a R b and R c At least one of them is –(C 1- C5)alkylene-N-(R x (R) y ),

[0972] The substituted (C1-C5)-alkyl group is substituted with a halogen, an amino group, or a (C1-C4)-alkylamino group; and the substituted –(C 1- C5)alkylene-N-(R x (R) y () is replaced by halogen or (C1-C4)-alkoxy;

[0973] R x and R y Independently selected from the group consisting of: H and (C1-C6)-alkyl; or R x and R y Together with the N it connects to, they form a 4- to 6-membered ring;

[0974] R1 is (C1-C6)-alkyl, (C1-C4)-alkylene-(C3-C6)-cycloalkyl, or (C1-C4)-alkylene-(C1-C4)-alkoxy;

[0975] R2 is

[0976] R 3a and R 3b Independently selected from the group consisting of: H, (C1-C5)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclic alkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3, and (C1-C4)-alkylene-(C1-C4)-alkoxy; condition R 3a and R 3b None of them are H;

[0977] R 3cSelected from the group consisting of: H, (C1-C5)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclic alkyl, hydroxyl, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3-CN and (C1-C4)-alkylene-(C1-C4)-alkoxy;

[0978] R 3d Choose from the group consisting of: H, (C1-C5)-alkyl, hydroxyl, halogen and -(C1-C4)-alkoxy;

[0979] R4 is H or (C1-C4)-alkyl;

[0980] R 5a and R 5e Independently selected from the group consisting of: H, CN, halogens, CF3, C(H)F2, C(F)H2, -CH2CF3, (C3-C6)-cycloalkyl, (C1-C5)-alkyl, 3- to 6-membered heterocyclic alkyl, hydroxyl, and (C1-C4)-alkoxy; and

[0981] R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogen, CF3, C(H)F2, C(F)H2, -CH2CF3, (C1-C5)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy.

[0982] In one embodiment of the above formula (Ib), the compound is not Figure 1 The compounds described in the text.

[0983] In one embodiment of the above formula (Ib), the compound is Figure 2 And / or the compounds described in 3.

[0984] In some embodiments, the present invention relates to compounds of formula (I), formula (Ia), or formula (Ib):

[0985]

[0986]

[0987] Or its pharmaceutically acceptable salt;

[0988] in

[0989] R a R b and R cIndependently selected from the group consisting of: H, Me, halogen, CF3, C(H)F2, C(F)H2, -CN, -OCF3, substituted or unsubstituted (C1-C5)-alkyl, (C1-C5)-alkoxy, -CH2CF3, and substituted or unsubstituted –(C 1- C5)alkylene-N-(R x (R) y ); the condition is R a R b and R c At least one of them is –(C 1- C5)alkylene-N-(R x (R) y ),

[0990] The substituted (C1-C5)-alkyl group is substituted with a halogen, an amino group, or a (C1-C4)-alkylamino group; and the substituted –(C 1- C5)alkylene-N-(R x (R) y ) is substituted by halogen, (C1-C5)-alkyl, (C1-C5)-alkyl-OCH3, (C1-C4)-haloalkyl, (C3-C6)-cycloalkyl, (C1-C4)-alkoxy or heterocyclic group;

[0991] R x and R y Independently selected from the group consisting of: H and (C1-C6)-alkyl; or R x and R y Together with the N it connects to, they form a 4- to 6-membered ring;

[0992] R1 is a substituted or unsubstituted (C1-C6)-alkyl, (C1-C4)-alkylene-(C3-C6)-cycloalkyl, or (C1-C4)-alkylene-(C1-C4)-alkoxy group.

[0993] The substituted (C1-C6)-alkyl group is replaced by a halogen or a (C3-C6)-cycloalkyl group;

[0994] R2 is

[0995] R 3a and R 3b Independently selected from the group consisting of: (C1-C5)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclic alkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3, and (C1-C4)-alkylene-(C1-C4)-alkoxy; condition R 3a and R3b None of them are H;

[0996] R 3c Selected from the group consisting of: H, (C1-C5)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclic alkyl, hydroxyl, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3-CN and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy;

[0997] R 3d Choose from the group consisting of: H, (C1-C5)-alkyl, hydroxyl, halogen and -(C1-C4)-alkoxy;

[0998] R4 is H or (C1-C4)-alkyl;

[0999] R 5a and R 5e Independently selected from the group consisting of: H, CN, halogens, CF3, C(H)F2, C(F)H2, -CH2CF3, (C3-C6)-cycloalkyl, (C1-C5)-alkyl, 3- to 6-membered heterocyclic alkyl, hydroxyl, and (C1-C4)-alkoxy; and

[1000] R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogen, CF3, C(H)F2, C(F)H2, -CH2CF3, (C1-C5)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy.

[1001] In one embodiment of the above formula (Ib), the compound is not Figure 1 The compounds described in the text.

[1002] In one embodiment of the above formula (Ib), the compound is Figure 2 And / or the compounds described in 3.

[1003] In some embodiments, the compound of formula (I) can be a compound of formula (Ib).

[1004]

[1005] in

[1006] R a Choose from the group consisting of hydrogen and (C1-C5)-alkyl groups optionally substituted with halogens;

[1007] R b Yes – (C1- C5)alkylene-N-(R x (R) y );

[1008] R x and R y Independently selected from the group consisting of (C1-C6)-alkyl groups; or R x and R y Together with the N to which it is attached, it forms a 4 to 6-membered ring, which is optionally substituted with a halogen or (C1-C4)-alkoxy group;

[1009] R c Choose from the group consisting of hydrogen and (C1-C5)-alkyl groups optionally substituted with halogens;

[1010] R1 is a (C1-C6)-alkyl;

[1011] R 3a It is halogen;

[1012] R 3b Choose from the group consisting of (C1-C5)-alkyl and (C3-C6)-cycloalkyl groups that are optionally substituted with halogens;

[1013] R 3c It is hydrogen;

[1014] R 3d Choose from the following groups: H and halogens;

[1015] R4 is hydrogen;

[1016] R 5a and R 5e Each is a (C1-C5)-alkyl group; and

[1017] R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogen, (C1-C5)-alkyl, which is optionally substituted with halogen (e.g., CF3, C(H)F2, C(F)H2, -CH2CF3), (C3-C6)-cycloalkyl, 3 to 6-membered heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy.

[1018] In some embodiments, the compound of formula (I) may be a compound of formula (Ia).

[1019]

[1020] in

[1021] R a The group consisting of hydrogen and methyl groups optionally substituted with halogens;

[1022] R b Yes – (C 1- C5)alkylene-N-(R x (R) y );

[1023] R x and R y Independently selected from the group consisting of methyl and ethyl groups; or R x and R y Together with the N to which it is attached, it forms a 4- to 5-membered ring, which is optionally substituted with F or methoxy group;

[1024] R c The group consisting of hydrogen and methyl groups optionally substituted with halogens;

[1025] R1 is selected from the group consisting of free isobutyl and isopentyl groups;

[1026] R 3a It is F;

[1027] R 3b Choose from the group consisting of (C1-C5)-alkyl and (C3-C6)-cycloalkyl groups optionally substituted with F;

[1028] R 3c It is hydrogen;

[1029] R 3d Choose from the following groups: H and F;

[1030] R4 is hydrogen;

[1031] R 5a and R 5e Each is a methyl group;

[1032] R 5b and R 5d Independently selected from the group consisting of: H, F, methyl, and methoxy; and

[1033] R 5c Choose from the following groups: F, methyl, and cyclopropyl.

[1034] In some embodiments, the compound of formula (I) may be a compound of formula (Ia).

[1035]

[1036] in

[1037] R a The group consisting of hydrogen and methyl groups optionally substituted with halogens;

[1038] Rb Yes – (C 1- C5)alkylene-N-(R x (R) y );

[1039] R x and R y It is methyl; or R x and R y Together with the N to which it is attached, it forms a 4- to 5-membered ring, which is optionally substituted with F or methoxy group;

[1040] R c The group consisting of hydrogen and methyl groups optionally substituted with halogens;

[1041] R1 is selected from the group consisting of free isobutyl and isopentyl groups;

[1042] R 3a It is F;

[1043] R 3b Choose from the group consisting of (C1-C5)-alkyl and (C3-C6)-cycloalkyl groups optionally substituted with F;

[1044] R 3c It is hydrogen;

[1045] R 3d It is F;

[1046] R4 is hydrogen;

[1047] R 5a and R 5e Each is a methyl group;

[1048] R 5b and R 5d Independently selected from the group consisting of: H, F, methyl, and methoxy; and

[1049] R 5c Choose from the following groups: F, methyl, and cyclopropyl.

[1050] In some embodiments, the compound of formula (I) can be a compound of formula (Ia):

[1051]

[1052] Or a pharmaceutically acceptable salt thereof, wherein R in formula (Ia) a R b R c R1, R 3a R 3b R 3c R 3d R 5a R5b R 5c R 5d R 5e R1 and R2 are each independently as defined above with respect to formula (I), provided that the compound of formula (Ia) is not a compound selected from the group consisting of:

[1053]

[1054]

[1055] In some embodiments, the compound of formula (I) can be a compound of formula (Ib):

[1056]

[1057] Or a pharmaceutically acceptable salt thereof, wherein R in formula (Ia) a R b R c R1, R 3a R 3b R 3c R 3d R 5a R 5b R 5c R 5d R 5e R1 and R2 are each independently as defined above with respect to formula (I), provided that the compound of formula (Ia) is not a compound selected from the group consisting of:

[1058]

[1059]

[1060] In some embodiments, the compound may be a compound of formula (I).

[1061]

[1062] in

[1063] R a R b and R c Independently select from the following groups: H, Me, halogens, CF3, C(H)F2, C(F)H2, and -(C 1- C5)alkylene-N-(R x (R) y ); the condition is R a R b and R c At least one of them is -(C 1- C5)alkylene-N-(Rx (R) y );

[1064] R x and R y 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 it connects to, they form a 4- to 6-membered ring;

[1065] R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[1066] R2 is

[1067] R 3a and R 3b Independently selected from the group consisting of: H, (C1-C5)-alkyl, (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3, and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; provided that R 3a and R 3b None of them are H;

[1068] R 3c and R 3d It is H;

[1069] R4 is H;

[1070] R 5a and R 5e It is methyl on its own;

[1071] R 5b and R 5c Independently selected from the group consisting of: H, CN, halogen, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy;

[1072] R 5d It is H; and

[1073] The condition is that the compound of formula (I) is not a compound selected from the group consisting of:

[1074] a. (S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazacyclobutan-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid;

[1075] b. (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionic acid;

[1076] c. (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[1077] d. (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[1078] e. (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-methylpentamido)propionic acid;

[1079] f. (S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazacyclobutane-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid;

[1080] g. (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[1081] h. (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-methylpentamido)propionic acid;

[1082] i. (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexamido)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid;

[1083] j. (S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazacyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)propionic acid; and

[1084] k.(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-methylpentamido)propionic acid;

[1085] Or its pharmaceutically acceptable salt.

[1086] In some embodiments, the compound may be a compound of formula (Ia).

[1087]

[1088] in:

[1089] R a It's CF3;

[1090] R b Is it substituted or unsubstituted? -(C 1- C5)alkylene-N-(R x (R) y );

[1091] R x and R y Independently, it is a substituted or unsubstituted (C1-C6)-alkyl group; or R x and R y Together with the N it connects to, they form a 4- to 6-membered ring;

[1092] R c It is H;

[1093] R1 is a substituted or unsubstituted (C1-C6)-alkyl group;

[1094] R 3a and R 3b Independently selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3, and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; provided that R 3a and R 3b None of them are H;

[1095] R 3c It is H;

[1096] R 3d It is halogen;

[1097] R4 is H;

[1098] R 5a and R 5e Each is independently selected from (C1-C5)-alkyl groups; and

[1099] R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogen, 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 heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy;

[1100] Or its pharmaceutically acceptable salt;

[1101] The condition is that the compound of formula (Ia) is not selected from the group consisting of the following:

[1102]

[1103]

[1104] In some embodiments, the compound may be a compound of formula (Ib).

[1105]

[1106] in:

[1107] R a It's CF3;

[1108] R b Is it substituted or unsubstituted? -(C 1- C5)alkylene-N-(R x (R) y );

[1109] R x and R y Independently, it is a substituted or unsubstituted (C1-C6)-alkyl group; or R x and R y Together with the N it connects to, they form a 4- to 6-membered ring;

[1110] R c It is H;

[1111] R1 is a substituted or unsubstituted (C1-C6)-alkyl group;

[1112] R 3a and R 3b Independently selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3, and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; provided that R 3a and R 3b None of them are H;

[1113] R 3c It is H;

[1114] R 3d It is halogen;

[1115] R4 is H;

[1116] R 5a and R 5e Each is independently selected from (C1-C5)-alkyl groups; and

[1117] R 5b R 5c and R 5d Independently selected from the group consisting of: H, CN, halogen, 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 heterocyclic alkyl, hydroxyl and (C1-C4)-alkoxy;

[1118] Or its pharmaceutically acceptable salt;

[1119] The condition is that the compound of formula (Ib) is not selected from the group consisting of the following:

[1120]

[1121] Example 1. A general scheme for synthesizing α4β7 inhibitors

[1122] β-amino acid synthesis

[1123] The synthesis of β-amino acids can be achieved using well-known procedures described in the literature, such as, but not limited to, “Enantioselective Synthesis of β-Amino Acids,” 2nd ed., edited by Eusebio Juaristi and Vadim A. Soloshonok, first published January 27, 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, MF; Skrydstrup, T., *J. Org. Chem.*, 2003, 68, 7122; Tang, TP; Ellman, JA, *J. Org. Chem.*, 2002, 67, 7819; and Tang, TP; Ellman, JA, *J. Org. Chem.*, 1999, 64, 12.

[1124] Reductive amination

[1125]

[1126] Procedure A: A mixture of amine (1 equivalent) and aldehyde (1.2 equivalent) in DCM (1-2 mL / mmol amine) was stirred at room temperature for 30 minutes. Then, NaBH(OAc)3 (1.5 equivalent) was added in portions, and the mixture was stirred overnight at room temperature. The solvent was concentrated under vacuum, and the residue was purified by silica gel chromatography to produce the desired amine.

[1127] Procedure B: A mixture of aldehyde (1 equivalent) and amine (1.05–2 equivalents) in DCE (3–4 mL / mmol aldehyde) was stirred at room temperature for 10–30 minutes. NaBH(OAc)₃ (3–4 equivalents) was then added in portions, and the mixture was stirred at room temperature for 1–16 minutes until the reaction was complete by LC / MS. The solvent was concentrated under vacuum, and the residue was purified by silica gel chromatography to yield the desired amine.

[1128] Procedure C: Aldehyde (1 equivalent), AcOH (1.2 equivalent), and amine (1.05–2 equivalents) were added to a mixture of DCM (2–3 mL / mmol aldehyde) and MeOH (0.5 mL / mmol aldehyde) and stirred at room temperature for 15–30 minutes. Then, NaBH(OAc)₃ (2 equivalents) was added in portions, and the mixture was stirred at room temperature for 1–16 minutes until the reaction was complete by LC / MS. The solvent was concentrated under vacuum, and the residue was purified by silica gel chromatography to yield the desired amine.

[1129] Alkylation

[1130]

[1131] Procedure A: Add methanesulfonate (1.5 equivalents) and K₂CO₃ (3 equivalents) to a solution of amine (1 equivalent) in MeCN (3-4 mL / mmol amine). Stir the reaction mixture at 80 °C for 16 hours. Concentrate the reaction mixture under vacuum and purify the residue by reversed-phase HPLC to obtain the desired alkylated product.

[1132]

[1133] Procedure B: Add alkyl bromide (2 equivalents) and K₂CO₃ (2 equivalents) to a solution of amine (1 equivalent) in MeCN (3-4 mL / mmol amine). Stir the reaction mixture at 80 °C for 16 hours. Concentrate the reaction mixture under vacuum and purify the residue by reversed-phase HPLC to obtain the desired alkylated product.

[1134] Phenol deprotection

[1135]

[1136] The mixture of methoxypyridine (1 equivalent) in 44% HBr / AcOH (10 mL / mmol substrate) was heated at 55–75 °C for 5–16 hours until complete by LC-MS. The reaction was concentrated under vacuum, and the residue was purified by reversed-phase HPLC to give the desired phenolated product.

[1137] Wittig Reaction

[1138]

[1139] Procedure A: A mixture of (methoxymethyl)triphenylphosphine chloride (1.5 equivalents), t-BuOK (2.5 equivalents), and dioxane (2 mL / mmol phosphate) was stirred at room temperature for 15 minutes. Then, THF (1 mL / mmol aldehyde) containing an aldehyde (1 equivalent) was added. The mixture was stirred at room temperature for 2–16 hours. The reaction mixture was treated (diluted with water and extracted with EtOAc; the extracts were combined, dried over Na₂SO₄, filtered, and concentrated), and purified by silica gel chromatography to obtain the enol ether product.

[1140] Procedure B: A mixture of (methoxymethyl)triphenylphosphine chloride (1.1 equivalents), t-BuOK (2.5 equivalents), and THF (4 mL / mmol phosphate) was stirred at 0 °C for 1 hour. Then, THF containing an aldehyde (1 equivalent) (2 mL / mmol aldehyde) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was treated (diluted with water and extracted with EtOAc; the extracts were combined, dried over Na2SO4, filtered, and concentrated), and purified by silica gel chromatography to give the enol ether product.

[1141] Enol ethers to aldehydes

[1142]

[1143] Procedure A: Treat the enol ether (1 equivalent) with TFA (2 mL / mmol) at room temperature for 4 hours. Remove the solvent under vacuum to produce the desired aldehyde.

[1144] Procedure B: Treat the enol ether (1 equivalent) with HCOOH (2 mL / mmol) at 70 °C for 2 hours. Remove the solvent under vacuum to produce the desired aldehyde.

[1145] Procedure C: Add TFA (2 mL / mmol) and water (0.25 mL / mmol) to a solution of enol ether (1 equivalent) in DCM (15 mL / mmol enol ether). Stir the reaction at 45 °C for 18 hours. Treat the reaction (quench with NaHCO3, extract with DCM; combine the extracts, dry with Na2SO4, filter and concentrate) to produce the desired aldehyde.

[1146] Stille reaction

[1147]

[1148] Pd(PPh3)4 (0.1 equivalent) was added to a solution of aryl bromide (1 equivalent) and allyl bromide (1.2 equivalent) in DMF (3 mL / mmol aryl bromide) under N2 conditions. The reaction was stirred at 100 °C for 16 h. The reaction was concentrated under vacuum, diluted with EtOAc, poured into a 20% KF aqueous solution, stirred for 1 h, and extracted. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography to yield the desired product.

[1149] Olefin to Aldehyde

[1150]

[1151] K₂O₄⁻ 2H₂O (0.01 equivalents) was added to a solution of olefin (1 equivalent) in THF / H₂O (1:1) (10 mL / mmol olefin) at 0 °C. The mixture was stirred at 0 °C for 5 min, and then H₂O (1 mL / mmol olefin) containing NaIO₄ (3 equivalents) was added dropwise. The mixture was stirred at 0 °C for 1 h, then warmed to room temperature and stirred until complete by LC-MS. The reaction was then treated (diluted with water and extracted with EtOAc; the combined organic layers were dried over Na₂SO₄, filtered, and concentrated) to obtain the desired aldehyde.

[1152] Ester to acid

[1153]

[1154] The ester (1 equivalent) was treated with MeOH (1-3 mL / mmol ester) containing LiOH-H₂O (3-5 equivalents) and water (1-3 mL / mmol ester) at room temperature for 1-5 hours. The reaction was acidified to pH 3 with 1N HCl and concentrated. The residue was purified by preparative HPLC to give the desired carboxylic acid product.

[1155] Amine protection

[1156]

[1157] A mixture of amine (1 equivalent), DIEA (3 equivalents), and Boc₂O (2 equivalents) was stirred in DCM (5 mL / mmol) at room temperature for 16 hours until complete as measured by LC-MS. The reaction was then treated (washed with 0.5 N HCl, saturated NaHCO₃, and brine; extracted with DCM; the combined organic layers were dried over Na₂SO₄, filtered, and concentrated), and purified by silica gel chromatography.

[1158] Preparation of arylboranes

[1159]

[1160] A mixture of aryl bromide (1 equivalent), B2pin2 (1.2 equivalent), Pd(dppf)Cl2 (0.05 equivalent), and KOAc (3 equivalent) in dioxane (10 mL / mmol aryl bromide) was stirred at 110 °C for 2–5 hours under N2 until complete by LCMS. The reaction was filtered, concentrated under vacuum, and purified by silica gel chromatography to yield the desired arylborane.

[1161] Suzuki Couple

[1162] "Palladium-catalyzed cross-coupling reactions of organoboron compounds" N. Miyaura; A. Suzuki, Chem. Rev., 1995, 957, 2457-2483.

[1163]

[1164] Procedure A: An aryl bromide (1.2 equivalents), Pd(dppf)Cl2 (0.1 equivalents), K2CO3 (2 equivalents), and water (2 mL / mmol) were added to a solution of arylborane (1 equivalent) in dioxane (10 mL / mmol arylborane). The reaction was stirred at 110 °C for 3 hours under N2. The reaction was then treated (washed with brine and extracted with EtOAc; the extracts were combined, dried over Na2SO4, filtered, and concentrated) and purified by silica gel chromatography to yield the desired diaryl product.

[1165]

[1166] Procedure B: A solution of aryl bromide (1 equivalent) and arylborane (1.1 equivalent) in dioxane (10 mL / mmol aryl bromide) was added to water (2 mL / mmol) containing K₂CO₃ (2 equivalents) and Pd(dppf)Cl₂ (0.1 equivalent). The reaction was stirred at 110 °C for 2 hours under N₂. The reaction was then treated (washed with brine and extracted with EtOAc; the extracts were combined, dried over Na₂SO₄, filtered, and concentrated) and purified by silica gel chromatography to yield the desired diaryl product.

[1167]

[1168] Procedure C: A mixture of aryl bromide (1 equivalent), arylborane (2.0 equivalent), K₂CO₃ (3 equivalent), and Pd(dppf)Cl₂ (0.05 equivalent) in dioxane (10 mL / mmol aryl bromide) and water (1 mL / mmol) was stirred at 110 °C for 2 hours under N₂ until complete by LC-MS. The reaction was treated (washed with brine and extracted with EtOAc; the extracts were combined, dried over Na₂SO₄, filtered, and concentrated) and purified by silica gel chromatography to yield the desired diaryl product.

[1169] Boc deprotection

[1170]

[1171] Add 4M HCl-dioxane (12 equivalents) to DCM (4 mL / mmol amine) containing a Boc-protected amine (1 equivalent). Stir the reaction for 1–2 hours until complete by LC-MS. Concentrate the reaction under vacuum to obtain the desired amine.

[1172] tert-butylsulfinyl deprotection

[1173]

[1174] Add 4M HCl-dioxane (1.7 equivalents) to a solution of tert-butylsulfinylamine (1 equivalent) in DCM (0.5 mL / mmol amine). Stir the reaction for 0.5–1 h until complete by LC-MS. Concentrate the reaction mixture and purify it by preparative HPLC to obtain the desired amine.

[1175] amide bond formation

[1176] "Peptide Coupling Reagents, More Than a Letter Soup" A. El-Faham, F. Albericio, *Chemical Review*, 2011, 111, 11, 6557-6602; "Amide Bond Formation and Peptide Coupling" CAGN Montalbetti, V. Falque, *Tetrahedron*, 2005, 61, 10827-10852.

[1177]

[1178] A mixture of amine (1 equivalent), 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 complete by LCMS. The reaction was concentrated under vacuum and purified by silica gel chromatography to obtain the desired amide product.

[1179] Ester hydrolysis

[1180]

[1181] The ester (1 equivalent) was treated with MeOH (1-3 mL / mmol ester) containing LiOH-H₂O (3-5 equivalents) and water (1-3 mL / mmol ester) at room temperature for 1-5 hours. The reaction was acidified to pH 4-5 with 1N HCl and concentrated. The residue was purified by preparative HPLC to obtain the desired carboxylic acid product.

[1182] Analytical methods

[1183] LCMS Analysis Method

[1184] The final compounds were analyzed using LC / MS conditions with UV detectors at 214 nm and 254 nm, and mass spectrometry scans of 110–800 amu in ESI+ ionization mode.

[1185] LC / MS A: Column: XBridge C18, 4.6 x 50 mm, 3.5 μm; Mobile phase: Water (10 mM ammonium bicarbonate), BCH3CN; Gradient: 5% - 95% B, 1.4 min, then hold for 1.6 min; Flow rate: 1.8 mL / min; Oven temperature: 50 °C.

[1186] LC / MS B: Column: SunFire C18, 4.6 x 50 mm, 3.5 μm; Mobile phase: Water (0.01% TFA), B CH3CN; Gradient: 5%-95% B, 1.5 min, then hold for 1.5 min; Flow rate: 2.0 mL / min; Oven temperature: 50 °C.

[1187] LC / MS C: Column: XBridge C18, 4.6 x 50 mm, 3.5 μm; Mobile phase: Water (10 mM ammonium bicarbonate), BCH3CN; Gradient: 5% - 95% B, 1.5 min, then hold for 1.5 min; Flow rate: 1.8 mL / min; Oven temperature: 50 °C.

[1188] LC / MSD: Column: Poroshell 120EC-C138, 4.6 x 30 mm, 2.7 μm; Mobile phase: Water (0.01% TFA), B CH3CN (0.01% TFA); Gradient: 5%-95% B, 1.2 min, then hold for 1.8 min; Flow rate: 2.2 mL / min; Oven temperature: 50 °C.

[1189] Example 2A. Preparation of intermediates

[1190] Preparation of ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-((tert-butoxycarbonyl)amino)propionate

[1191] Step 1: 5-Bromo-2-fluoro-3-methylbenzaldehyde

[1192]

[1193] Over a 10-minute period, diisopropylaminolithium (2.0 M, 39.7 mL, 79.4 mmol, 1.5 equivalence) was added dropwise to a mixture of 4-bromo-1-fluoro-2-methylbenzene (10.0 g, 52.9 mmol, 1.0 equivalence) and anhydrous THF (100.0 mL) at -78 °C under a nitrogen atmosphere, and the mixture was stirred at -78 °C for 1 hour. DMF (15.0 mL) was then added dropwise, and the mixture was stirred at -78 °C for 2 hours. LC-MS showed the reaction was complete. The reaction mixture was quenched at 0 °C with saturated NH4Cl solution (aqueous) (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 under vacuum. The obtained residue was purified by silica gel column chromatography (petroleum ether: EtOAc 9:1) to yield 8.0 g of 5-bromo-2-fluoro-3-methylbenzaldehyde as a white solid. Yield 70% (ESI 218.9 [M+H]). + ).

[1194] Step 2: (R,E)-N-(5-bromo-2-fluoro-3-methylbenzyl)-2-methylpropane-2-sulfinamide

[1195]

[1196] Ti(OEt)₄ (12.6 g, 55.4 mmol, 1.50 equivalent) 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-methylpropane-2-sulfinamide (5.4 g, 44.3 mmol, 1.2 equivalent) in anhydrous THF (80 mL) at room temperature under a nitrogen atmosphere, while maintaining the temperature below 30 °C. The reaction mixture was warmed to 40 °C and stirred for 1 hour. LCMS showed 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 under vacuum to give a crude product (R,E)-N-(5-bromo-2-fluoro-3-methylbenzyl)-2-methylpropane-2-sulfinamide (12.0 g, crude product) as a yellow solid, which was used in the next step without further purification. Yield 100% (ESI 320.0 [M+H]). + ).

[1197] Step 3: Ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propionate

[1198]

[1199] Trimethylchlorosilane (0.8 g, 7.5 mmol, 0.2 equivalence) was added dropwise to a mixture of Zn (12.2 g, 187.5 mmol, 5.0 equivalence) in anhydrous THF (200 mL) at room temperature under a nitrogen atmosphere. 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 equivalence) 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 equivalence) was added dropwise, while maintaining the reaction mixture at 50–60 °C during this period. 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 anhydrous THF (30 mL) containing (R,E)-N-(5-bromo-2-fluoro-3-methylbenzyl)-2-methylpropane-2-sulfinamide (12.0 g, 37.5 mmol) was added dropwise, and the mixture was stirred at 25°C for 1 hour. LCMS showed that the reaction was complete. A solution of MTBE (150 mL) and citric acid (3 g) in water (100 mL) was added to the mixture. The mixture was separated. The aqueous layer was extracted with MTBE (150 mL x 2). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 3:1) to yield ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propionate (9.0 g). Yield 59% (ESI 408.0 [M+H]) + ).

[1200] Step 4: Ethyl (S)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propionate

[1201]

[1202] Ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propionate (8.0 g, 19.6 mmol, 1.00 equivalent) in DCM (20 mL) was added to a solution of ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)propionate (20 mL, 4 M, 80.0 mmol, 4.08 equivalent) and stirred at room temperature for 4 hours. LC-MS showed the reaction was complete. The mixture was filtered and concentrated under vacuum to give crude (S)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propionate (8.0 g) as a yellow oil, which was used in the next step without further purification. Yield 100% (ESI 304.2 [M+H]). + ).

[1203] Step 5: Ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(tert-butoxycarbonylamino)propionate

[1204]

[1205] DIEA (7.6 g, 59.0 mmol, 3.00 equivalent) and Boc₂O (8.6 g, 39.2 mmol, 2.00 equivalent) were added to a solution of ethyl (S)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propionate (8.0 g, 19.6 mmol, 1.00 equivalent) in DCM (100 mL). The reaction mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction mixture was diluted with DCM (200 mL) and washed with 0.5 N HCl (50 mL x 3), saturated NaHCO₃ (50 mL), and brine (50 mL). The organic phase was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 3:1) to yield ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-((tert-butoxycarbonyl)amino)propionate (6.0 g), which was a brown oil. Yield 75% (ESI 404.1 (M+H)). + ).

[1206] Preparation of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl)propionate

[1207]

[1208] Ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-((tert-butoxycarbonyl)amino)propionate (1.0 g, 2.48 mmol, 1.0 equivalent), bis(pinacol)diboron (756.28 mg, 2.98 mmol, 1.2 equivalent), Pd(dppf)Cl2 (90.65 mg, 0.13 mmol, 0.05 equivalent), and KOAc (729.12 mg, 7.44 mmol, 3.0 equivalent) in 1,4-dioxane (20 mL) was stirred at 110 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc 2:1) to give ethyl (S)-3-(tert-butoxycarbonylamino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl)propionate (1.0 g) as a colorless oil. Yield 89% (ESI 452.2(M+H)). + ).

[1209] Preparation of ethyl (S)-3-amino-3-(2',4-difluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate

[1210] Step 1: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2',4-difluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate

[1211]

[1212] To a solution of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl)propionate (300 mg, 0.66 mmol, 1.0 equivalent) in dioxane (5 mL), 2-bromo-1-fluoro-3-methylbenzene (150 mg, 0.79 mmol, 1.2 equivalent), Pd(dppf)Cl2 (48 mg, 0.066 mmol, 0.1 equivalent), K2CO3 (182 mg, 1.32 mmol, 2.0 equivalent), and water (1 mL) were added. The reaction mixture was stirred at 110 °C for 3 hours under a nitrogen atmosphere. Water (10 mL) was added, and the solution was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 8:1) to yield ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2',4-difluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate (210 mg) as a colorless oil. Yield 73% (ESI 334.1 [M+H-100] + ).

[1213] Step 2: Ethyl (S)-3-amino-3-(2',4-difluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate

[1214]

[1215] Ethyl (S)-3-amino-3-(2',4-difluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate (210 mg, 0.48 mmol, 1.0 equivalent) in a stirred solution of (S)-3-((tert-butoxycarbonyl)amino)-3-(2',4-difluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate (2 mL) was added to HCl-dioxane (4 M, 3.0 mL, 6.0 mmol, 12.5 equivalent). The mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. The mixture was concentrated under vacuum to produce ethyl (S)-3-amino-3-(2',4-difluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate (160 mg) as a colorless oil. Yield 99% (ESI 334.1 [M+H]). + ).

[1216] Preparation of (S)-3-amino-3-(2'-cyano-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate ethyl hydrochloride

[1217] Step 1: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-cyano-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate

[1218]

[1219] To a solution of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl)propionate (350 mg, 0.77 mmol, 1.0 equivalent) in dioxane (10 mL), 2-bromo-3-methylbenzylnitrile (226 mg, 1.16 mmol, 1.5 equivalent), Pd(dppf)Cl2 (56 mg, 0.077 mmol), K2CO3 (193 mg, 1.4 mmol, 1.8 equivalent), and water (2 mL) were added. The reaction mixture was stirred at 110 °C for 3 hours under a nitrogen atmosphere. Water (20 mL) was added, and the solution was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 4:1) to yield ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-cyano-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate (260 mg) as a colorless oil. Yield 76% (ESI 341.1 [M+H-100]). + ).

[1220] Step 2: Ethyl (S)-3-amino-3-(2'-cyano-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate hydrochloride

[1221]

[1222] HCl-dioxane (4 M, 2.0 mL, 4.0 mmol, 7.7 equivalences) was added to a stirred solution of (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-cyano-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate (230 mg, 0.52 mmol, 1.0 equivalences) in DCM (2 mL). The mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The mixture was concentrated under vacuum to produce (S)-3-amino-3-(2'-cyano-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate hydrochloride (180 mg) as a yellow oil. Yield 91% (ESI 341.1 [M+H]). + ).

[1223] Preparation of ethyl (S)-3-amino-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate

[1224] Step 1: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate

[1225]

[1226] Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl)propionate (1.0 g, 2.22 mmol, 1.00 equivalent), 2-bromo-1-chloro-3-methylbenzene (543 mg, 2.66 mmol, 1.20 equivalent), K₂CO₃ (613 mg, 4.44 mmol, 2.0 equivalent), and Pd(dppf)Cl₂ (81 mg, 0.11 mmol, 0.05 equivalent) in dioxane (10 mL) and H₂O (2 mL) were stirred at 110 °C for 2 hours under a nitrogen atmosphere. Water (30 mL) was added, and the solution was extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc 2:1) to yield ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate (800 mg) as a colorless oil. Yield 80% (ESI 450.18 [M+H] + ).

[1227] Step 2: Ethyl (S)-3-amino-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate

[1228]

[1229] Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate (300 mg, 0.67 mmol, 1.00 equivalent) in a mixture of DCM (9 mL) was added with HCl-dioxane (4 M, 9.0 mL, 36.0 mmol, 53.73 equivalent) and stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The mixture was concentrated under vacuum to yield ethyl (S)-3-amino-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate (200 mg) as a white solid, which was used directly in the next reaction without further purification. Yield 86% (ESI 350.1 [M+H)). + ).

[1230] Preparation of ethyl (S)-3-amino-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate

[1231] Step 1: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate

[1232]

[1233] Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate (500 mg, 1.12 mmol, 1.00 equivalent), cyclopropylboronic acid (116 mg, 1.35 mmol, 1.20 equivalent), K3PO4 (475 mg, 2.24 mmol, 2.00 equivalent), PCy3 (31 mg, 0.11 mmol, 0.10 equivalent), and Pd(OAc)2 (11 mg, 0.11 mmol, 0.10 equivalent) in dioxane (10 mL) and H2O (2 mL) were stirred at 110 °C for 36 hours under a nitrogen atmosphere. Water (30 mL) was added, and the solution was extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc₂:1) to yield ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate (400 mg) as a colorless oil. Yield 79% (ESI 456.2 [M+H)). + ).

[1234] Step 2: Ethyl (S)-3-amino-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate

[1235]

[1236] Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate (400 mg, 0.88 mmol, 1.0 equivalent) in a mixture of DCM (9 mL) was added with HCl-dioxane (4 M, 9.0 mL, 36.0 mmol, 40.9 equivalent) and stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The mixture was concentrated under vacuum to yield ethyl (S)-3-amino-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate (300 mg) as a white solid, which was used directly in the next reaction without further purification. Yield 96% (ESI 356.2 [M+H)). + ).

[1237] Preparation of (S)-3-amino-3-(4-fluoro-4'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate ethyl hydrochloride

[1238] Step 1: (S)-3-amino-3-(2'-ethyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate ethyl hydrochloride

[1239]

[1240] To a solution of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl)propionate (350 mg, 0.77 mmol, 1.0 equivalent) in dioxane (10 mL), 1-ethyl-2-iodo-3-methylbenzene (286 mg, 1.16 mmol, 1.5 equivalent), Pd(dppf)Cl2 (56 mg, 0.077 mmol, 0.1 equivalent), K2CO3 (193 mg, 1.4 mmol, 1.8 equivalent), and water (2 mL) were added. The reaction mixture was stirred at 110 °C for 3 hours under a nitrogen atmosphere. Water (10 mL) was added, and the solution was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (60 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc 4:1) to yield ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-ethyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate (240 mg) as a colorless oil. Yield 70% (ESI 344.2 [M+H-100] + ).

[1241] Step 2: (S)-3-amino-3-(2'-ethyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate ethyl hydrochloride

[1242]

[1243] HCl-dioxane (4 M, 3.0 mL, 6.0 mmol, 12.8 equivalences) was added to a stirred solution of (S)-3-amino-3-(2'-ethyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate (210 mg, 0.47 mmol, 1.0 equivalences) in DCM (2 mL). The mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The mixture was concentrated under vacuum to produce (S)-3-amino-3-(2'-ethyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propionate hydrochloride (170 mg) as a colorless oil. Yield 94% (ESI 344.1 [M+H]). + ).

[1244] Preparation of ethyl (S)-3-amino-3-(4-fluoro-2'-methoxy-5,6'-dimethylbiphenyl-3-yl)propionate

[1245] Step 1: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate

[1246]

[1247] Ethyl (S)-3-(tert-butoxycarbonylamino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl)propionate (1 g, 2.22 mmol, 1.0 equivalent), 2-bromo-1-methoxy-3-methylbenzene (666 mg, 3.33 mmol, 1.5 equivalent), K₂CO₃ (919 mg, 6.66 mmol, 3.0 equivalent), and Pd(dppf)Cl₂ (162 mg, 0.222 mmol, 0.1 equivalent) in dioxane (15 mL) and H₂O (1.5 mL) were stirred at 100 °C for 3 hours under a nitrogen atmosphere. LC-MS showed that the reaction was complete. The reaction mixture was cooled to room temperature. Water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc 2:1) to yield ethyl (S)-3-(tert-butoxycarbonylamino)-3-(4-fluoro-2'-methoxy-5,6'-dimethylbiphenyl-3-yl)propionate (0.96 g), which was a yellow oil. Yield 97% (ESI 346.1 [M+H]). + ).

[1248] Step 2: Ethyl (S)-3-amino-3-(4-fluoro-2'-methoxy-5,6'-dimethylbiphenyl-3-yl)propionate

[1249]

[1250] Ethyl (S)-3-(tert-butoxycarbonylamino)-3-(4-fluoro-2'-methoxy-5,6'-dimethylbiphenyl-3-yl)propionate (0.96 g, 2.15 mmol, 1.0 equivalent) in a stirred solution of DCM (7 mL) was added with HCl-dioxane (4 M, 2.15 mL, 4 equivalent) and stirred at 25 °C for 2 h. LC-MS showed the reaction was complete. The mixture was concentrated under vacuum, and the residue was purified by reversed-phase HPLC on a C18 / 40 g column (A: 10 mM water NH4HCO3, B: MeOH, 0–100%) to yield ethyl (S)-3-amino-3-(4-fluoro-2'-methoxy-5,6'-dimethylbiphenyl-3-yl)propionate (0.6 g) as a yellow oil. Yield 81% (ESI 346.1 [M+H)). + ).

[1251] Preparation of ethyl (S)-3-amino-3-(4-fluoro-2'-methoxy-5-methyl-6'-(trifluoromethyl)biphenyl-3-yl)propionate

[1252] Step 1: 1-Methoxy-2-nitro-3-(trifluoromethyl)benzene

[1253]

[1254] K₂CO₃ (3 g, 21.75 mmol, 1.0 equivalent) and CH₃I (5.15 g, 36.25 mmol, 5 equivalent) were added to a mixture of 2-nitro-3-(trifluoromethyl)phenol (1.5 g, 7.25 mmol, 1.0 equivalent) and acetone (20 mL), and the mixture was stirred at room temperature for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was filtered and washed with EtOAc (20 mL). The filtrate was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 2:1) to yield 1-methoxy-2-nitro-3-(trifluoromethyl)benzene (1.3 g) as a white solid. Yield: 81%.

[1255] Step 2: 2-Methoxy-6-(trifluoromethyl)aniline

[1256]

[1257] 10% Pd / C (700 mg) was added to a mixture of 1-methoxy-2-nitro-3-(trifluoromethyl)benzene (1.3 g, 5.88 mmol, 1.0 equivalent) in EtOH (20 mL), and the mixture was stirred at room temperature for 16 h under a H2 atmosphere (2 L, 1 atm). LC-MS showed the reaction was complete. The reaction mixture was filtered and concentrated under vacuum to yield 0.75 g of 2-methoxy-6-(trifluoromethyl)aniline as a white solid. Yield 67% (ESI 192.1 [M+H]). + ).

[1258] Step 3: 2-Bromo-1-methoxy-3-(trifluoromethyl)benzene

[1259]

[1260] t-BuONO (565 mg, 5.49 mmol, 1.5 equivalence) and CuBr (628 mg, 4.39 mmol, 1.2 equivalence) were added to a mixture of 2-methoxy-6-(trifluoromethyl)aniline (700 mg, 3.66 mmol, 1.0 equivalence) in MeCN (15 mL). The mixture was stirred at 60 °C for 2 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 10:1) to yield 400 mg of 2-bromo-1-methoxy-3-(trifluoromethyl)benzene as a colorless oil. Yield: 43%.

[1261] Step 4: Ethyl (S)-3-(tert-butoxycarbonylamino)-3-(4-fluoro-2'-methoxy-5-methyl-6'-(trifluoromethyl)biphenyl-3-yl)propionate

[1262]

[1263] A mixture of 2-bromo-1-methoxy-3-(trifluoromethyl)benzene (400 mg, 1.57 mmol, 1.00 equivalent), ethyl (S)-3-(tert-butoxycarbonylamino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl)propionate (708 mg, 1.57 mmol, 1.0 equivalent), K₂CO₃ (650 mg, 4.71 mmol, 3.0 equivalent), and Pd(dppf)Cl₂ (115 mg, 0.157 mmol, 0.1 equivalent) in dioxane (8 mL) and H₂O (0.8 mL) was stirred at 110 °C for 4 hours under a nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was cooled to room temperature. Water (30 mL) was added, and the mixture was extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 10:1) to yield ethyl (S)-3-(tert-butoxycarbonylamino)-3-(4-fluoro-2'-methoxy-5-methyl-6'-(trifluoromethyl)biphenyl-3-yl)propionate (400 mg) as a colorless oil. Yield 51% (ESI 400.1 [M-Boc]). + ).

[1264] Step 5: Ethyl (S)-3-amino-3-(4-fluoro-2'-methoxy-5-methyl-6'-(trifluoromethyl)biphenyl-3-yl)propionate

[1265]

[1266] Ethyl (S)-3-(tert-butoxycarbonylamino)-3-(4-fluoro-2'-methoxy-5-methyl-6'-(trifluoromethyl)biphenyl-3-yl)propionate (400 mg, 0.8 mmol, 1.00 equivalent) in a stirred solution of DCM (6 mL) was added with HCl-dioxane (4 M, 0.8 mL, 3.2 mmol, 4 equivalent) and stirred at room temperature for 2 h. LCMS showed that the reaction was complete. The mixture was concentrated under vacuum and the residue was purified by reversed-phase HPLC on a C18 / 120 g column (A: 10 mM water NH4HCO3, B: MeOH, 0–100%) to produce ethyl (S)-3-amino-3-(4-fluoro-2'-methoxy-5-methyl-6'-(trifluoromethyl)biphenyl-3-yl)propionate (280 mg) as a colorless oil. Yield 87% (ESI 400.1 [M+H]) + ).

[1267] Preparation of ethyl (S)-3-amino-3-(2',6'-dichloro-4-fluoro-5-methylbiphenyl-3-yl)propionate

[1268] Step 1: Ethyl (S)-3-(tert-butoxycarbonylamino)-3-(2',6'-dichloro-4-fluoro-5-methylbiphenyl-3-yl)propionate

[1269]

[1270] A solution of K₂CO₃ (0.34 g, 2.48 mmol, 2 equivalents) in H₂O (2 mL) and Pd(dppf)Cl₂ (90 mg, 0.124 mmol, 0.1 equivalents) was added to a mixture of (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(tert-butoxycarbonylamino)propionate (0.5 g, 1.29 mmol, 1 equivalent) in dioxane (10 mL). The mixture was heated to 110 °C under a nitrogen atmosphere for 2 hours. The mixture was then cooled to room temperature. Water (20 mL) was added, and the solution was extracted with EtOAc (20 mL x 3). The combined organic phases were concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether:EtOAc 1:1) to yield ethyl (S)-3-(tert-butoxycarbonylamino)-3-(2',6'-dichloro-4-fluoro-5-methylbiphenyl-3-yl)propionate (0.550 g) as a colorless oil. Yield 94% (ESI 470.4 [M+H]). + ).

[1271] Step 2: Methyl (S)-3-amino-3-(2',6'-dichloro-4-fluoro-5-methylbiphenyl-3-yl)propionate

[1272]

[1273] To a mixture of (S)-3-(tert-butoxycarbonylamino)-3-(2',6'-dichloro-4-fluoro-5-methylbiphenyl-3-yl)propionate ethyl methyl ester (0.55 g, 1.21 mmol, 1 equivalent) in DCM (6 mL), HCl-dioxane (4 M, 3 mL, 12 mmol, 10 equivalent) was added. The mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The mixture was concentrated under vacuum to give crude (S)-3-amino-3-(2',6'-dichloro-4-fluoro-5-methylbiphenyl-3-yl)propionate ethyl ester (0.42 g) as a white solid, which was used directly in the next reaction without further purification. Yield 98% (ESI 370.3 [M+H]). + ).

[1274] Preparation of ethyl (S)-3-amino-3-(2',4-difluoro-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate

[1275] Step 1: 2-Fluoro-4,6-Dimethylaniline

[1276]

[1277] A mixture of 2,4-dibromo-6-fluoroaniline (5.0 g, 18.59 mmol, 1.0 equivalent), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaboranecyclohexane (3.5 M in THF, 21.2 mL, 74.36 mmol, 4.0 equivalent), Pd(dppf)Cl2 (680 mg, 0.93 mmol, 0.05 equivalent), and K2CO3 (7.71 g, 55.78 mmol, 3.0 equivalent) in dioxane (60 mL) and H2O (8 mL) was stirred at 110 °C for 12 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. Water (30 mL) was added, and the solution was extracted with EtOAc (35 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 20:1) to yield 2-fluoro-4,6-dimethylaniline (2.16 g) as a yellow oil. Yield 83.5% (ESI 140.2 [M+H]). + ).

[1278] Step 2: 2-Bromo-1-fluoro-3,5-dimethylbenzene

[1279]

[1280] 1.68 g (14.4 mmol, 2.0 equivalent) of tert-butyl nitrite was added to a stirred solution of 2-fluoro-4,6-dimethylaniline (1.0 g, 7.2 mmol, 1.0 equivalent) and CuBr2 (4.8 g, 21.6 mmol, 3.0 equivalent) in MeCN (7 mL), and the mixture was stirred at 60 °C for 1 h under a nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether) to yield 560 mg of 2-bromo-1-fluoro-3,5-dimethylbenzene as a yellow oil. Yield: 38%.

[1281] Step 3: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2',4-difluoro-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate

[1282]

[1283] Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl)propionate (556 mg, 1.23 mmol, 1.0 equivalent), 2-bromo-1-fluoro-3,5-dimethylbenzene (250 mg, 1.23 mmol, 1.0 equivalent), Pd(dppf)Cl2 (45 mg, 0.062 mmol, 0.05 equivalent), and K2CO3 (510 mg, 3.69 mmol, 3.0 equivalent) in dioxane (6 mL) and water (2 mL) were stirred at 110 °C for 2 hours under a nitrogen atmosphere. Water (35 mL) was added, and the solution was extracted with EtOAc (25 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 7:1) to yield ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2',4-difluoro-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (365 mg), a yellow oil. Yield 66% (ESI 348.1 [M+H-100]). + ).

[1284] Step 4: Ethyl (S)-3-amino-3-(2',4-difluoro-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate

[1285]

[1286] Ethyl (S)-3-amino-3-(2',4-difluoro-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (720 mg, 1.29 mmol, 1.0 equivalent) in a stirred solution of (S)-3-((tert-butoxycarbonyl)amino)-3-(2',4-difluoro-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (450 mg) as a yellow oil. Yield 93% (ESI 348.1 [M+H] + ).

[1287] Preparation of ethyl (S)-3-amino-3-(2',6'-dichloro-4-fluoro-4',5-dimethylbiphenyl-3-yl)propionate

[1288] Step 1: 1,3-Dichloro-2-iodo-5-methylbenzene

[1289]

[1290] Add 4-methylbenzenesulfonic acid (9.8 g, 57.1 mmol, 4 equivalents) to a mixture of 2,6-dichloro-4-methylaniline (2.5 g, 14.3 mmol, 1.0 equivalents) in acetonitrile (10 mL) and water (1 mL), and stir at 0 °C for 10 min. Add dropwise a solution of NaNO2 (2.0 g, 28.6 mmol, 2 equivalents) in H2O (2 mL), and stir the mixture at 0 °C for 30 min. Then add a solution of potassium iodide (3.0 g, 17.9 mmol, 1.5 equivalents) in H2O (2 mL), and heat to 50 °C for 2 h under a nitrogen atmosphere. Add water (20 mL), and extract the solution with EtOAc (20 mL x 3). The combined organic phases were concentrated under vacuum, and the residue was purified by silica gel column chromatography (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]+).

[1291] Step 2: Ethyl (S)-3-(tert-butoxycarbonylamino)-3-(2',6'-dichloro-4-fluoro-4',5-dimethylbiphenyl-3-yl)propionate

[1292]

[1293] A solution of methyl ethyl (S)-3-(tert-butoxycarbonylamino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl)propionate (1.5 g, 3.43 mmol, 1 equivalent) in dioxane (10 mL) was added to a mixture of K₂CO₃ (1.9 g, 13.72 mmol, 4 equivalent) in H₂O (2 mL) and Pd(dppf)Cl₂ (250 mg, 0.343 mmol, 0.1 equivalent). The mixture was heated to 110 °C under a nitrogen atmosphere for 2 hours. Water (20 mL) was added, and the solution was extracted with EtOAc (20 mL x 3). The combined organic phases were concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether:EtOAc 1:1) to give ethyl (S)-3-(tert-butoxycarbonylamino)-3-(2',6'-dichloro-4-fluoro-4',5-dimethylbiphenyl-3-yl)propionate (1.3 g) as a colorless oil. Yield 78.3% (ESI 484.4 [M+H])+ ).

[1294] Step 3: Ethyl (S)-3-amino-3-(2',6'-dichloro-4-fluoro-4',5-dimethylbiphenyl-3-yl)propionate

[1295]

[1296] To a mixture of (S)-3-(tert-butoxycarbonylamino)-3-(2',6'-dichloro-4-fluoro-4',5-dimethylbiphenyl-3-yl)propionate methyl ethyl ester (1.3 g, 2.76 mmol, 4 equivalents) in DCM (6 mL), HCl-dioxane (4 M, 3 mL, 12 mmol, 4.3 equivalents) was added. The mixture was stirred at room temperature for 1 hour. LC-MS showed the reaction was complete. The mixture was concentrated under vacuum to give crude (S)-3-amino-3-(2',6'-dichloro-4-fluoro-4',5-dimethylbiphenyl-3-yl)propionate ethyl ester (1.0 g) as a white solid, which was used directly in the next reaction without further purification. Yield 91% (ESI 384.3 [M+H]). + ).

[1297] Preparation of ethyl (S)-3-amino-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate

[1298] Step 1: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate

[1299]

[1300] A mixture of (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propionate (4.0 g, 9.8 mmol, 1.00 equivalent), (2,6-dimethylphenyl)boronic acid (2.9 g, 19.6 mmol, 2.00 equivalent), K₂CO₃ (4.1 g, 29.4 mmol, 3.0 equivalent), and Pd(dppf)Cl₂ (717 mg, 0.98 mmol, 0.05 equivalent) in dioxane (24 mL) and H₂O (9 mL) was stirred at 110 °C for 2 h under a nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was cooled to room temperature. Water (30 mL) was added, and the solution was extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 1:1) to yield ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (4.0 g), a yellow oil. Yield 94% (ESI 434.1 [M+H] + ).

[1301] Step 2: Ethyl (S)-3-amino-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate

[1302]

[1303] Ethyl (S)-3-amino-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (4.0 g, 9.2 mmol, 1.00 equivalent) in a stirred solution of (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (6 mL) was added to HCl-dioxane (4 M, 4 mL, 16.0 mmol, 1.7 equivalent). The mixture was stirred at room temperature for 30 min. LCMS showed that the reaction was complete. The mixture was concentrated under vacuum, and the residue was purified by reversed-phase HPLC on a C18 / 120 g column (A: 10 mM water NH4HCO3, B: MeOH, 0–100%) to produce ethyl (S)-3-amino-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (2.0 g) as a colorless oil. Yield 61% (ESI 330.1 [M+H]) + ).

[1304] Preparation of ethyl (S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate

[1305] Step 1: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate

[1306]

[1307] Ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propionate (6.0 g, 14.7 mmol, 1.00 equivalent), (4-fluoro-2,6-dimethylphenyl)boronic acid (3.7 g, 22.1 mmol, 1.5 equivalent), K₂CO₃ (6.1 g, 44.1 mmol, 3.0 equivalent), and Pd(dppf)Cl₂ (1.1 g, 1.47 mmol, 0.01 equivalent) in dioxane (50 mL) and H₂O (5 mL) were stirred at 110 °C for 1 hour under a nitrogen atmosphere. LC-MS showed 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 x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc 1:1) to yield ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (5.5 g), a yellow oil. Yield 83% (ESI 452.0 (M+H)). + )

[1308] Step 2: Ethyl (S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate

[1309]

[1310] Ethyl (S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (5.5 g, 12.2 mmol, 1.00 equivalent) in DCM (6 mL) was added to a solution of (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (4.0 g) and stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and the residue was purified by reversed-phase HPLC on a C18 / 120 g column (A: water / 0.01% TFA, B: MeOH, 0–100%) to produce ethyl (S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (4.0 g) as a yellow solid. Yield 95% (ESI 348.1(M+H)) + ).

[1311] Preparation of ethyl (S)-3-amino-3-(4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate

[1312] Step 1: 2-(4-chloro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane

[1313]

[1314] n-BuLi (2N, 11.0 mL, 22.0 mmol, 1.2 equivalence) was added to a solution of 2-bromo-5-chloro-1,3-dimethylbenzene (4.0 g, 18.2 mmol, 1.0 equivalence) in anhydrous THF (40 mL) at -78 °C under a nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 40 min, and anhydrous THF (40 mL) containing 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxane (5.1 g, 27.5 mmol, 1.5 equivalence) was added, and the mixture was stirred at -78 °C for 3 h. After completion, a saturated NH4Cl solution (aqueous solution) (100 mL) was added. The mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The obtained residue was purified by silica gel (petroleum ether: EtOAc 2:1) to give the desired 2-(4-chloro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (4.4 g) as a white solid. Yield: 90%.

[1315] Step 2: Ethyl (S)-3-amino-3-(4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate

[1316]

[1317] Ethyl (S)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propionate (500 mg, 1.7 mmol, 1.0 equivalent), 2-(4-chloro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (544 mg, 2.04 mmol, 1.2 equivalent), Pd(dppf)Cl2 (62 mg, 0.085 mmol, 0.05 equivalent), and K2CO3 (704 mg, 5.1 mmol, 3.0 equivalent) in 1,4-dioxane (10 mL) and water (2 mL) were stirred at 110 °C for 2 hours under a nitrogen atmosphere. Water (20 mL) was added, and the solution was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc 1:2) to yield ethyl (S)-3-amino-3-(4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (250 mg) as a colorless oil. Yield 41% (ESI 364.2 [M+H) + ).

[1318] Preparation of ethyl (S)-3-amino-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate

[1319] Step 1: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate

[1320]

[1321] Ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propionate (3.8 g, 9.3 mmol, 1.0 equivalent), trimethylphenylboronic acid (3.05 g, 18.6 mmol, 2.0 equivalent), K₂CO₃ (3.85 g, 27.9 mmol, 3.0 equivalent), and Pd(dppf)Cl₂ (340 mg, 0.465 mmol, 0.05 equivalent) were stirred in dioxane (30 mL) and H₂O (5 mL) under a nitrogen atmosphere at 110 °C for 2 h. The reaction was shown to be complete by LC-MS. The reaction mixture was cooled to room temperature. Water (80 mL) was added, and the mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 1:1) to yield ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate (3.1 g), a yellow oil. Yield 75% (ESI 448.2 [M+H) + ).

[1322] Step 2: Ethyl (S)-3-amino-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate

[1323]

[1324] Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate (3.1 g, 6.94 mmol, 1.0 equivalent) in a stirred solution of DCM (7 mL) was added with HCl-dioxane (4 M, 6.8 mL, 3.9 equivalent) and stirred at 25 °C for 2 h. LCMS showed that the reaction was complete. The mixture was concentrated under vacuum and the residue was purified by reversed-phase HPLC on a C18 / 40 g column (A: 10 mM water NH4HCO3, B: MeOH, 0–100%) to produce ethyl (S)-3-amino-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propionate (1.6 g) as a yellow oil. Yield 67% (ESI 344.2 [M+H]) + ).

[1325] Example: Preparation of ethyl (S)-3-amino-3-(4-fluoro-2',5,6'-trimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionate hydrochloride

[1326] Step 1: 2,6-Dimethyl-4-(trifluoromethyl)aniline

[1327]

[1328] A mixture of 2,6-dibromo-4-(trifluoromethyl)aniline (638 mg, 2.00 mmol, 1.0 equivalent), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaboranecyclohexane (3.5 M, 3.43 mL, 12.00 mmol, 6.0 equivalent in THF), K₂CO₃ (1.10 g, 7.96 mmol, 3.98 equivalent), and Pd(dppf)Cl₂ (245 mg, 0.30 mmol, 0.15 equivalent) in dioxane (6 mL) and water (1 mL) was stirred at 90 °C for 8 hours under a nitrogen atmosphere. The mixture was filtered through a diatomaceous earth mat, washed with ethyl acetate (100 mL), and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 20:1) to yield 1.63 g of 2,6-dimethyl-4-(trifluoromethyl)aniline as a colorless oil. Yield 48% (ESI 190.1 (M+H)). + ).

[1329] Step 2: 2-Bromo-1,3-dimethyl-5-(trifluoromethyl)benzene

[1330]

[1331] A mixture of 2,6-dimethyl-4-(trifluoromethyl)aniline (793 mg, 4.19 mmol, 1.0 equivalent), tert-butyl nitrite (0.94 mL, 7.84 mmol, 1.9 equivalent), and copper(I) bromide (794 mg, 5.53 mmol, 1.3 equivalent) in anhydrous acetonitrile (16 mL) was stirred at 60 °C for 2 h under a nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 6:1) to yield 2-bromo-1,3-dimethyl-5-(trifluoromethyl)benzene (975 mg) as a colorless oil. Yield: 46%. 1 H NMR (400MHz, DMSO-d6) δ: 7.55 (s, 2H), 2.42 (s, 6H).

[1332] Step 3: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2',5,6'-trimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionate

[1333]

[1334] Ethyl (519 mg, 1.15 mmol, 1.0 equivalent) of (S)-3-(tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl)propionate in dioxane (36 mL) was added to a solution of dioxane (306 mg, 1.21 mmol, 1.1 equivalent), Pd(dppf)Cl2 (188 mg, 0.23 mmol, 0.2 equivalent), K2CO3 (477 mg, 3.45 mmol, 3.0 equivalent), and water (3.6 mL). The reaction mixture was stirred at 110 °C for 18 hours under a nitrogen atmosphere. The mixture was filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 6:1) to yield ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2',5,6'-trimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionate (308 mg), a pale brown oil. Yield: 54%. (ESI 398.1 [M+H-100]) + ).

[1335] Step 5: Ethyl (S)-3-amino-3-(4-fluoro-2',5,6'-trimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionate hydrochloride

[1336]

[1337] HCl-dioxane (4M, 4.0 mL, 16.0 mmol, 25.8 equivalences) was added to a stirred solution of (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2',5,6'-trimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionate (308 mg, 0.62 mmol, 1.0 equivalences) in DCM (4 mL). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated under vacuum to produce (S)-3-amino-3-(4-fluoro-2',5,6'-trimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionate hydrochloride (260 mg) as a yellow oil. Yield 97% (ESI 398.1 [M+H]). + ).

[1338] Preparation of ethyl (S)-3-amino-3-(4'-cyclopropyl-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate

[1339] Step 1: 4-Cyclopropyl-2,6-Dimethylaniline

[1340]

[1341] A solution of K3PO4 (4.2 g, 20.0 mmol, 2.0 equivalent) in H2O (3 mL), PCy3 (280.0 mg, 1.0 mmol, 0.1 equivalent), and Pd(OAc)2 (224.0 mg, 1.0 mmol, 0.1 equivalent) was added to a mixture of 4-bromo-2,6-dimethylaniline (2.0 g, 10.0 mmol, 1.0 equivalent) in toluene (15 mL) under a nitrogen atmosphere. The mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere. Water (30 mL) was added, and the solution was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc 2:1) to yield 0.8 g of 4-cyclopropyl-2,6-dimethylaniline, which was used in the next step without further purification. Yield 93% (ESI 162.2 [M+H]). + ).

[1342] Step 2: 2-Bromo-5-cyclopropyl-1,3-dimethylbenzene

[1343]

[1344] Toluenesulfonic acid (3.4 g, 19.8 mmol, 4.0 equivalent) was added to a mixture of 4-cyclopropyl-2,6-dimethylaniline (800.0 mg, 4.9 mmol, 1.0 equivalent) in ACN (10 mL) and H₂O (1 mL). The mixture was stirred at 0 °C for 10 min under a nitrogen atmosphere. A solution of NaNO₂ (685.0 mg, 9.93 mmol, 2.0 equivalent) in H₂O (2 mL) was added dropwise, and the mixture was stirred at 0 °C for 30 min. CuBr (4.4 g, 19.8 mmol, 4.0 equivalent) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 h. Water (50 mL) was added, and the solution was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 19:1) to yield 800.0 mg of 2-bromo-5-cyclopropyl-1,3-dimethylbenzene as a yellow oil, which was used in the next step without further purification. Yield 49% (ESI 225.1 (M+H)). + 227.1(M+H) + ).

[1345] Step 3: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-cyclopropyl-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate

[1346]

[1347] A solution of K₂CO₃ (1.0 g, 7.2 mmol, 2.0 equivalent) in H₂O (1 mL) and Pd(dppf)Cl₂ (260 mg, 0.36 mmol, 0.1 equivalent) was added to a mixture of 2-bromo-5-cyclopropyl-1,3-dimethylbenzene (800 mg, 3.6 mmol, 1.0 equivalent) and (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl)propionate (1.6 g, 3.6 mmol, 1.0 equivalent) in 1,4-dioxane (10 mL) under a nitrogen atmosphere. The mixture was stirred at 110 °C for 2 hours under a nitrogen atmosphere. Water (30 mL) was added, and the solution was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel c...

Claims

1. A compound of formula (I): in R a , R b and R c independently selected from the group consisting of H, Me, halogen, CF3, C(H)F2, C(F)H2 and -(C 1- C5)alkylene-N-(R x )(R y ); the condition is R a , R b and R c At least one of them is -(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 it is attached, it forms a 4- to 6-membered ring; R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; R2 is R 3a and R 3b is independently selected from the group consisting of H, (C1-C5)-alkyl, (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3 and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; provided that R 3a and R 3b None of them are H; R 3c and R 3d It is H; R4 is H; R 5a and R 5e are independently methyl; R 5b and R 5c independently selected from the group consisting of H, CN, halogen, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl and (C1-C4)-alkoxy; R 5d is H; and Wherein the compound of formula (I) is selected from the group consisting of: a. (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; b. (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoic acid; c. (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid; d. (S)-3-((S)-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; e. (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-methylpentanamido)propanoic acid; f. (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-methylpentanamido)propanoic acid; g. (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoic acid; h. (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-methylpentanamido)propanoic acid; i. (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamido)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid; j. (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-methylpentanamido)propanoic acid; and k. (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-methylpentanamido)propanoic acid; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 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-methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof.

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

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

5. The compound according to claim 1, wherein the compound is (S)-3-((S)-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 or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 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-methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 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-methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof.

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

9. The compound according to claim 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-methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof.

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

11. The compound according to claim 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-methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 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-methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound of formula (I) as an active pharmaceutical ingredient: in R a , R b and R c independently selected from the group consisting of H, Me, halogen, CF3, C(H)F2, C(F)H2 and -(C 1- C5)alkylene-N-(R x )(R y ); the condition is R a , R b and R c At least one of them is -(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 it is attached, it forms a 4- to 6-membered ring; R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; R2 is R 3a and R 3b is independently selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6-membered heterocycloalkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3 and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; provided that R 3a and R 3b None of them are H; R 3c and R 3d It is H; R4 is H; R 5a and R 5e are independently methyl; R 5b and R 5c independently selected from the group consisting of H, CN, halogen, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl and (C1-C4)-alkoxy; R 5d is H; and Wherein the compound of formula (I) is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

14. The composition according to claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof.

15. The composition of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof.

16. The composition of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof.

17. The composition of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof.

18. The composition of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof.

19. The composition of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof.

20. The composition of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof.

21. The composition of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof.

22. The composition of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof.

23. The composition of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof.

24. The composition of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof.

25. A compound of formula (Ia): in: R a It is CF3; R b is substituted or unsubstituted-(C 1- C5)alkylene-N-(R x )(R y ); R x and R y is independently substituted or unsubstituted (C1-C6)-alkyl; or R x and R y Together with the N to which it is attached, it forms a 4- to 6-membered ring; R c It is H; R1 is substituted or unsubstituted (C1-C6)-alkyl; R2 is R 3a and R 3b is independently selected from the group consisting of: H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6-membered heterocycloalkyl, -OH, -CN, halogen, CF3, C(H)F2, C(F)H2, -(C1-C4)-alkoxy, -OCF3 and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy; provided that R 3a and R 3b None of them are H; R 3c It is H; R 3d It is a halogen; R4 is H; R 5a and R 5e are each independently selected from (C1-C5)-alkyl; and R 5b , R 5c and R 5d independently selected from the group consisting of H, CN, halogen, CF3, C(H)F2, C(F)H2, -CH2CF3, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl and (C1-C4)-alkoxy; Wherein the compound of formula (I) is selected from the group consisting of:

26. The compound according to claim 25, wherein the compound is or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 25, wherein the compound is or a pharmaceutically acceptable salt thereof.

28. The compound according to claim 25, wherein the compound is or a pharmaceutically acceptable salt thereof.

29. The compound according to claim 25, wherein the compound is or a pharmaceutically acceptable salt thereof.

30. The compound according to claim 25, wherein the compound is or a pharmaceutically acceptable salt thereof.

31. The compound according to claim 25, wherein the compound is or a pharmaceutically acceptable salt thereof.

32. The compound according to claim 25, wherein the compound is or a pharmaceutically acceptable salt thereof.

33. The compound according to claim 25, wherein the compound is or a pharmaceutically acceptable salt thereof.

34. The compound according to claim 25, wherein the compound is or a pharmaceutically acceptable salt thereof.

35. The compound according to claim 25, wherein the compound is or a pharmaceutically acceptable salt thereof.

36. The compound according to claim 25, wherein the compound is or a pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition comprising the compound according to any one of claims 25 to 36 or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient.

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