Novel α4β7 inhibitors

Abstract

Novel compounds acting as inhibitors of α4β7 integrins are disclosed. Pharmaceutical compositions and methods for use as inhibitors of α4β7 integrins are disclosed. In particular, methods for using α4β7 inhibitors in the treatment of diseases or conditions associated with inflammatory bowel diseases, including ulcerative colitis and Crohn's disease.

Description

[Technical Field]

[0001] This disclosure relates to novel compounds that act as inhibitors of integrins, particularly α4β7 integrins. Furthermore, this disclosure relates to pharmaceutical compositions and methods for using α4β7 inhibitors in the treatment of diseases or conditions associated with inflammatory bowel diseases, including ulcerative colitis and Crohn's disease. [Background technology]

[0002] Integrins are involved in numerous cellular processes, including cell-cell and cell-extracellular matrix interactions. When integrins bind to extracellular ligands, they mediate intracellular signaling, leading to the capture, adhesion, and entry of lymphocytes into tissues. In fact, integrins are heterodimeric cell surface glycoprotein receptors composed of non-covalently bound α (alpha) and β (beta) subunits.

[0003] Using molecular biology and protein chemistry, 24 human integrins have been identified, and these integrins are known to contribute to a diverse range of human diseases, including platelet disorders, atherosclerosis, cancer, osteoporosis, fibrosis, diabetic neuropathy of the kidneys, macular degeneration, and autoimmune and chronic inflammatory diseases.

[0004] α4, α4β1, and α4β7 integrins play essential roles in lymphocyte migration in most leukocytes, including B and T lymphocytes. Specifically, α4β1 and α4β7 integrins are involved in the adhesion of α4β1 and α4β7 integrins to VCAM-1 (vascular cell adhesion molecule 1) and MAdCAM-1 (mucosal addressing cell adhesion molecule 1), respectively. MAdCAM-1 is an immunoglobulin superfamily adhesion receptor for lymphocytes and a selective ligand for the α4β7 receptor. MAdCAM-1 is involved in the selective homing of lymphocytes to normal mucosal tissue. In humans, MAdCAM-1 expression is associated with lymphocyte tissues of the gastrointestinal tract and associated lymphocyte tissues. Lymphocyte integrin α4β7 has been shown to mediate memory T cell adhesion to MAdCAM-1. During inflammation, MAdCAM-1 is upregulated in the intestine and is thought to play a crucial role in inflammatory bowel disease (IBD), a group of diseases including ulcerative colitis (UC) and Crohn's disease (CD). Inhibition of the interaction between integrins and their individual ligands has been proposed as an effective method for treating various autoimmune and inflammatory diseases, and blocking the interaction of AdCAM-1 has been shown to have therapeutic benefits in inflammatory bowel diseases such as ulcerative colitis and Crohn's disease (Hao Li et al., α4β7 integrin inhibitors: a patent review (2018), Vol.28, No.12, pp. 903-917).

[0005] Currently, injectable monoclonal antibodies are available as integrin inhibitors; see, for example, natalizumab (Tysabri®), approved for the treatment of highly active relapsing-remitting multiple sclerosis, or vedolizumab (Entyvio®), approved for both Crohn's disease and ulcerative colitis. However, no orally administered, bioavailable integrin inhibitors have yet been approved. [Prior art documents] [Non-patent literature]

[0006]

Non-Patent Document 1

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0007] Therefore, there is a need to provide an integrin inhibitor, preferably an α4β7 - selective inhibitor, useful for the prevention and / or treatment of diseases characterized by up - regulation of MAdCAM - 1 such as inflammatory bowel disease.

MEANS FOR SOLVING THE PROBLEMS

[0008] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof

CHEMICAL

MODE FOR CARRYING OUT THE INVENTION

[0009] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof

CHEMICAL

[0012] In some embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 2 is phenyl or a 5- to 10-membered heteroaryl, each of these groups being substituted by one, two or three groups independently selected from -CN, -C 1~6 alkyl, halogen, -C 1~6 haloalkyl.

[0013] In some embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 2 is substituted by one, two or three groups independently selected from -CN, -C 1~6 alkyl, halogen, -C 1~6 haloalkyl, and R 2 is

Chemical formula

[0014] In some embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 2 is substituted by one, two or three groups independently selected from methyl, fluorine or -CF3,

Chemical formula

[0015] In some embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, Y is -C(R 3 )=.

[0016] In some embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 3 is halogen, -CF3, methyl, ethyl, cyclopropyl.

[0017] In some embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, Y is -N=.

[0018] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 4 These are halogens or hydrogen.

[0019] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 4 It is a halogen.

[0020] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 4 It is fluorine.

[0021] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 5 It is either fluorine or hydrogen.

[0022] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 5 It is hydrogen.

[0023] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 6 is -C(O)-OR 8 And here, R 8 This is hydrogen, methyl, ethyl or isopropyl, -O-CH2-OC(O)-R 16 Or -OC(CH3)-OC(O)-R 16 And here, R 16 These are methyl, ethyl, isopropyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexane, neopentyl, or (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl.

[0024] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 6 is -C(O)-OR 8 And here, R 8 These are hydrogen, methyl, ethyl, or isopropyl.

[0025] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 6 is -C(O)-OR 8 And R 8 It is hydrogen.

[0026] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 -C is substituted with 0 or 1 phenyl or cyclopropyl group. 1~6 Is it alkyl? or R 7 is 0 or 1 -N(C 1~4 Is it a phenyl substituted with alkyl)2? or R 7 R 9 A 5-10 member heterocycline substituted with 0, 1, 2, or 3 groups independently selected from, R 9 These are halogen, =O, and -C respectively. 1~6 Alkyl, -C(O)-R 10 , -C 1~6 Haloalkyl, -SO2-C 1~6 Alkyl, -NH-C 1~4 Alkyl, -N(C 1~4 Alkyl)2,-C 3~6 Cycloalkyl, phenyl, 4-7 membered heterocycle, -OR 11 Selected independently from; R 9 These are R 17 It is independently replaced by 0, one or two, which are independently selected from; R 10 is -C 1~6 Alkyl, C 3~6 Cycloalkyl and -C 1~6 Alkyl-C 3~6 Selected independently from cycloalkyl groups; R 11 is -C 1~6 Alkyl, -C 1~6 Alkyl-N(-C) 1~6 Alkyl)2,-C 1~6 It is a haloalkyl or a 4- to 7-membered heterocycle; R17 is halogen, -OR 15 , -C(O)N(C 1~4 Alkyl)2,-N(R 12 R 13 ) and selected from 4- to 10-membered heterorings, R 17 However, if it is a 4- to 10-membered heterocycle, this is a halogen, -C 1~6 Alkyl or -C 1~6 Substituted by 0, 1, or 2 atoms, independently selected from the haloalkyl group; R 12 and R 13 is -C 1~6 Alkyl, -C 1~6 Independently selected from haloalkyl and cyclopropyl; R 15 is -C 1~6 Alkyl, -C 1~6 It is a haloalkyl or a 4- to 7-membered heterocycle, R 15 If it is a 4- to 7-member complex ring, then it is 0 or 1 -C 1~6 Substituted with alkyl; Here, -N(C 1~6 Alkyl)2 or -N(C 1~4 In each of alkyl)2, the two alkyl groups bonded to N may be the same or different. or R 7 -NHR 19 And R 19 is 0 or 1 -C 1~6 It is a five-membered heteroaryl compound substituted with an alkyl group.

[0027] In some embodiments of the compounds or pharmaceutically acceptable salts thereof of the present invention, R 7 -C is substituted with 0 or 1 phenyl or cyclopropyl group. 1~6 Is it alkyl? or R 7 is 0 or 1 -N(C 1~4 Is it a phenyl substituted with alkyl)2? or R 7 R9 A 5-10 member heterocycline substituted with 0, 1, 2, or 3 groups independently selected from, R 9 These are halogen, =O, and -C respectively. 1~6 Alkyl, -C(O)-R 10 , -C 1~6 A haloalkyl group is independently selected from 4- to 7-membered heterocycles; R 9 These are R 17 It is independently replaced by 0, one or two, which are independently selected from; R 10 is -C 1~6 It is alkyl; R 17 Halogen, -N(R 12 R 13 ) and selected from 4- to 10-membered heterorings, R 17 However, in the case of a 4- to 10-membered heterocycle, it is substituted by 0, 1, or 2 elements independently selected from the halogen; R 12 and R 13 is -C 1~6 It is an instance of alkyl; Here, -N(C 1~6 Alkyl)2 or -N(C 1~4 In each of alkyl)2, the two alkyl groups bonded to N may be the same or different; or R 7 -NHR 19 And R 19 is -C 1~6 It is a five-membered heteroaryl compound that is further substituted with alkyl groups.

[0028] In some embodiments of the compounds or pharmaceutically acceptable salts thereof of the present invention, R 7 is substituted or unsubstituted [ka] It is selected from the group consisting of the following.

[0029] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 is substituted or unsubstituted [ka] It is selected from the group consisting of the following.

[0030] In some embodiments of the compounds or pharmaceutically acceptable salts thereof of the present invention, R 7 teeth, [ka] A group consisting of is selected, and each is -F, -Cl, oxo, -Me, - i Bu, - i Pr, cyclobutyl, -CH2F, -CHF2, -CH2CF3, -CF3, -OMe, -OCF3, -O-azetidine-3-yl, -N(Me)2, -C(O)Me, -N(Me)2-C(O)cyclopropyl, 1-Me-azetidine-3-yl, 3-F-azetidine-1-yl, oxetane-3-yl, --C(O)CH2cyclopropyl, -CH2cyclopropyl, -CH2-CH2-azeditin-1-yl, -CH2-CH2-(3-F-azeditin-1-yl), -CH2-CH2-(3,3-diF-azeditin-1-yl), -CH2- Substituted with 0, 1, or 2 substituents independently selected from CH2-(3,3-diMe-azeditin-1-yl),-CH2-azeditin-1-yl,-CH2-(3-F-azeditin-1-yl),-CH2-(1-Me-azetidine-3-yl),-CH2-azetidine-3-yl,-CH2CH2-(3-F-pyrrolidine-1-yl),-CH2CH2OCH3,-CH2C(O)N(Me)2,-CH2CH2N(Me)2,-CH2CH2CH2N(Me)2-CH2CH2N(Me)CH2CF3,-CH2CH2N(Me)cyclopropyl, 4-F-phenyl, and -S(O)2Me.

[0031] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 The 0, 1, or 2 substituents are independently selected from the following: -F, -Cl, oxo, -Me, -N(Me)2, -C(O)Me, 3-F-azetidine-1-yl, oxetan-3-yl, -CH2-cyclopropyl, -CH2-CH2-azeditin-1-yl, and -CH2CH2N(Me)2.

[0032] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 1 These are: -C(O)-CH3, -S(O)2Me [ka] [ka] Selected from.

[0033] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 1 The following: [ka] Selected from.

[0034] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 2 These are -Br and -CF3, respectively. [ka] It is independently selected from the group consisting of [the specified elements].

[0035] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 3 It is independently selected from the group consisting of -F, -CF3, and -CH3.

[0036] In another embodiment, the present invention relates to a compound selected from any one of Examples 1 to 71 described herein.

[0037] In another embodiment, the present invention relates to a compound selected from any one of Examples 72 to 78 described herein.

[0038] In one embodiment, the present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0039] In one embodiment, the present invention relates to the use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product.

[0040] In one embodiment, the present invention relates to a compound of the present invention or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0041] In a particular embodiment, the present invention relates to a compound that inhibits α4β7-integrin.

[0042] In certain embodiments, the present invention relates to a prodrug of a compound that inhibits α4β7-integrin (i.e., a compound that is converted into an α4β7-integrin inhibitor under physiological conditions in a mammalian host or by enzymatic activity).

[0043] This compound is useful in the treatment of inflammatory bowel disease, ulcerative colitis, Crohn's disease, small intestinal bacterial overgrowth (SIBO), eosinophilic gastrointestinal disease (EGID), enteritis, gastrointestinal disorders associated with seronegative arthropathy, intestinal dysbiosis, microscopic colitis or collagenous colitis, cholecystitis, cholangitis, pericholangitis, familial adenomatous polyposis (FAP)-associated inflammatory gastrointestinal cancer, intestinal graft-versus-host disease (intestinal GVHD), celiac colitis, chronic cystitis, and checkpoint inhibitor-associated colitis.

[0044] In one embodiment, the present invention relates to a method for inhibiting the interaction between α4β7 integrin and MAdCAM-1 protein in a subject, comprising administering a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject requiring such inhibition.

[0045] In another embodiment, the present invention relates to a method for treating inflammatory bowel disease in a person in need thereof, comprising administering to the person a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0046] In another embodiment, the present invention relates to any of the compounds or pharmaceutically acceptable salts of the present invention described above for use in the treatment of inflammatory bowel disease.

[0047] In another embodiment, the present invention relates to any of the compounds or pharmaceutically acceptable salts of the present invention described above for use in the treatment of inflammatory bowel disease, wherein the inflammatory bowel disease is ulcerative colitis.

[0048] In another embodiment, the present invention relates to any of the compounds or pharmaceutically acceptable salts of the present invention described above for use in the treatment of inflammatory bowel disease, wherein the inflammatory bowel disease is Crohn's disease.

[0049] In another embodiment, the present invention relates to a method for treating ulcerative colon disease in humans, comprising administering a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a person in need thereof.

[0050] In another embodiment, the present invention relates to any of the compounds or pharmaceutically acceptable salts of the present invention described above for use in the treatment of ulcerative colon disease.

[0051] In another embodiment, the present invention relates to any of the compounds or pharmaceutically acceptable salts of the present invention described above for use in the treatment of ulcerative colon disease, wherein the ulcerative colon disease is ulcerative colitis.

[0052] In another embodiment, the present invention relates to any of the compounds or pharmaceutically acceptable salts of the present invention described above for use in the treatment of ulcerative colon disease, wherein the ulcerative colon disease is Crohn's disease.

[0053] In another embodiment, the present invention is as follows: a) One or more compositions, each comprising a pharmaceutically effective amount of a pharmaceutically acceptable salt of the compound of the present invention or any of the compound thereof, and a pharmaceutically acceptable carrier or excipient; and b) Instructions for use for administering one or more compositions to a person who needs them. Regarding the kit that includes this.

[0054] Terms used in this specification, description, examples, and claims are summarized herein. These definitions should be understood by those skilled in the art upon reading them in conjunction with the remainder of this disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art.

[0055] The terms and phrases defined below apply throughout this specification unless otherwise specified.

[0056] The articles “a,” “an,” and “the” are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of these articles, including multiple referents, unless the context specifically indicates otherwise. For example, “an element” means one element or more than one element.

[0057] The phrase "and / or" in this specification and in the claims should be understood, when used herein, to mean "one or both" of the elements thus coordinated.

[0058] In the claims and the above specification, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and “composed of” should be understood to be open-ended, meaning they include but are not limited to them. As described in Section 2111.03 of the U.S. Patent and Trademark Office Patent Examination Procedure Manual, only the transitional phrases “composed of” and “essentially made from” are closed transitional phrases or semi-closed transitional phrases, respectively.

[0059] Certain compounds included in the compositions of the present invention may exist, in particular, as geometric isomers or stereoisomers. The present invention intends to include all such compounds, within its scope, including cis and trans isomers, R-enantiomers and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Further chiral 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. Unless stereochemistry is explicitly indicated in the structure, the structure is intended to encompass all possible stereoisomers of the illustrated compound. If stereochemistry is explicitly indicated with respect to one or more parts of the molecule but not with respect to another or more parts of the molecule, the structure is intended to encompass all possible stereoisomers with respect to the part(s) whose stereochemistry is not explicitly indicated. For example, if a specific enantiomer of the compound of the present invention is desired, the desired enantiomer can be isolated from a racemic mixture using a chiral separation method known in the art, such as chiral chromatography. Alternatively, the enantiomer can be produced by asymmetric synthesis or derivatization with a chiral auxiliary agent, in which case the resulting diastereomer mixture is separated to cleave the auxiliary groups and obtain the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, a diastereomer salt can be formed using a suitable optically active acid or base, and then the diastereomer thus formed can be separated by fractional crystallization or chromatographic means known in the art, after which the pure enantiomer can be recovered.

[0060] Stereochemistry / Solvates / Hydrates: Unless otherwise specified, structural formulas or chemical names shown in this description or claims refer to the corresponding compounds themselves, mixtures of the forms previously specified herein (if such forms exist), and salts, in particular pharmaceutically acceptable salts thereof. The compounds and salts according to the present invention may exist in solvated forms (for example, with a pharmaceutically acceptable solvent such as water or ethanol) or in non-solvated forms. Generally, for the purposes of the present invention, solvated forms, such as hydrates, should be considered equivalent to non-solvated forms.

[0061] Aliphatic chains include the classes of alkyl, alkenyl, and alkynyl, as defined below. As used herein, the term “aliphatic group” means an unbranched or linear, branched or cyclic aliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups such as alkyl, alkenyl, or alkynyl groups.

[0062] The term "alkyl" refers to unbranched or branched hydrocarbons. For example, an alkyl group is a carbon chain with a specified number of carbon atoms, such as 1 to 6 carbon atoms (i.e., C1-C6 alkyl or C1-C6 alkyl). 1~6It may have an alkyl group. Examples of suitable alkyl groups are, but are not limited to, methyl (Me, --CH3), ethyl (Et, --CH2CH3), 1-propyl (n-Pr, n-propyl, --CH2CH2CH3), 2-propyl (i-Pr, i-propyl, --CH(CH3)2), 1-butyl (n-Bu, n-butyl, --CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, --CH2CH(CH3)2), 2-butyl (s-B u, s-butyl, --CH(CH3)CH2CH3), 2-methyl-2-propyl(t-Bu, t-butyl, --C(CH3)3), 1-pentyl(n-pentyl, --CH2CH2CH2CH2CH3), 2-pentyl(--CH(CH3)CH2CH2CH3), 3-pentyl(--CH(CH2CH3)2), 2-methyl-2-butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl(--CH(CH3)CH(CH3 )2), 3-methyl-1-butyl(--CH2CH2CH(CH3)2), 2-methyl-1-butyl(-CH2CH(CH3)CH2CH3), 1-hexyl(--CH2CH2CH2CH2CH2CH3), 2-hexyl(--CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl This includes ethyl(-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl(-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl(--C(CH3)(CH2CH3)2), 2-methyl-3-pentyl(-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl(--C(CH3)2CH(CH3)2), and 3,3-dimethyl-2-butyl(-CH(CH3)C(CH3)3).

[0063] 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, in which the longest carbon chain contains two bonding sites in the remainder of the compound. Non-limiting examples of alkylene groups include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, and others. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain portions, and may be optionally substituted with one or more substituents.

[0064] "Alkenyl" refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain portion having a specified number of carbon atoms, or up to 26 carbon atoms, unless otherwise specified, and having one or more double bonds in that portion. Alkenyls consisting of 6 to 26 carbon atoms are exemplified by their various isomers hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicocenyl, heneicosoenyl, dococenyl, tricocenyl, and tetracocenyl, in which the unsaturated bond can be located anywhere in the portion and can have either a (Z) configuration or an (E) configuration around the double bond.

[0065] "Alkinyl" refers to the hydrocarbyl portion of an alkenyl molecule, but specifically to the presence of one or more triple bonds in that portion.

[0066] The term "alkoxy" refers to a group having the formula "-O-alkyl" in which the alkyl group defined above is bonded to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group consists of a specified number of carbon atoms, such as 1 to 6 carbon atoms (i.e., C1-C6 alkoxy or C1-C6 alkoxy). 1~6It may have an alkoxy group. Suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), t-butoxy (-OC(CH3)3 or -OtBu), etc.

[0067] The term "haloalkyl" refers to a group in which the alkyl group defined above has one or more hydrogen atoms replaced by halogen atoms. The alkyl portion of a haloalkyl group consists of a specified number of carbon atoms, such as 1 to 6 carbon atoms (i.e., -C1 to C6 haloalkyl or -C 1~6 It may have a haloalkyl group. Examples include: -CFH2, -CF2H, -CF3, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, etc.

[0068] The term "carbonyl group" refers to C=O, that is, a carbon atom bonded to oxygen via a double bond, and further bonded to two other atoms. In this specification, the carbonyl group is denoted as -CO- or -C(O)-.

[0069] The term “carbocyclic ring” or “carbocyclic group” refers to a chemical ring containing only carbon atoms, including saturated rings, unsaturated rings, partially saturated rings, and aromatic rings. For clarity, “carbocyclic ring” includes “cycloalkyl” and “aryl” as defined herein.

[0070] "Cycloalkyl" means a monocyclic or bicyclic ring, or a bridging or spirocyclic ring, or a polycyclic saturated carbocyclic ring, each having 3 to 12 carbon atoms. Similarly, and unless otherwise specified, preferred cycloalkyls have 3 to 10 carbon atoms in their ring structure, and more preferably 3 to 6 carbon atoms in their ring structure. Cycloalkyls may be substituted or unsubstituted. In some embodiments, preferred cycloalkyls are monocyclic rings having 3 to 6 carbon atoms.

[0071] As used herein, the term "aryl" includes substituted or unsubstituted 6- to 12-membered monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of the rings is aromatic, for example, the other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclyl, in which case the bond site is located on the aromatic ring. Examples of aryl groups include benzene, naphthalene, phenanthrene, phenol, and aniline. Examples of aryl groups also include dihydrobenzofuran, indoline, isoindoline, quinoline, and isoquinoline, in which case the bond site is located on the phenyl ring.

[0072] The terms “heterocyclyl,” “heterocyclic,” or “heterocyclic group” refer to a ring structure with 3 to 12 members, more preferably 4 to 12 members, and more preferably 5 to 10 members, the ring structure containing 1 to 4 heteroatoms selected from N, O, S and their oxidized forms. Heterocyclyls can be saturated, partially saturated, unsaturated, and / or aromatic. Heterocyclics can be monocyclic, bicyclic, spirocyclic, or polycyclic. Examples of heterocyclyl groups include azetidine, aziridine, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxatiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indidine, isoindole, indole, indazole, purine, quinoridine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carborin, phenanthidine, acridine, pyrimidine, phenanthroline, phenazine, phenalsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolan, oxazole, piperidine, piperazine, morpholine, lactone, lactams such as azetidinone, pyridone and pyrrolidinenon, saltum, and sultone.

[0073] For clarity, "heterocyclyl" includes "heteroaryl" and "heterocycloalkyl".

[0074] The heterocyclic ring is substituted at one or more positions with the above substituents, such as halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, 5-amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, -CF3, -CN, etc.

[0075] The general terms relating to heterocycles as referenced herein are understood to include each isomer of the heterocycle, such as “dithianyl” including the 1,2-dithianyl, 1,3-dithianyl, and 1,4-dithianyl groups; “thiadiazinyl” including the 1,2,5-thiadiazinyl and 1,3,4-thiadiazinyl groups; “azaindyl” including the 4-azaindyl, 5-azaindyl, 6-azaindyl, and 7-azaindyl groups; and “benzothiophenyl” including the benzo[b]thiophenyl and benzo[c]thiophenyl groups.

[0076] Similarly, common heterocycle names include all different ones with one or more unsaturation points. For example, the term “dihydropyrrolyl” refers to the “2,3-dihydro-1H-pyrrolyl” group and the “2,5-dihydro-1H-pyrrolyl” group.

[0077] "Heterocycloalkyl" means a saturated heterocyclic ring, each having 3 to 12 ring-membered atoms, more preferably 4 to 10-membered rings, and more preferably 4 to 7-membered rings, the ring structure containing 1 to 4 heteroatoms selected from N, O, S and their oxidized forms. The heterocyclic ring can be monocyclic, bicyclic, spirocyclic, or polycyclic. Examples of heterocyclyl groups include azetidine, oxetane, tetrahydrofuran, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, dioxane, and azepane.

[0078] The heterocycloalkyl group may be substituted or unsubstituted. In some embodiments, the preferred heterocycloalkyl group is a monoring having 4 to 6 ring members and containing one or two heteroatoms.

[0079] A partially saturated heterocycle means a heterocyclic ring having at least one carbon-carbon double bond, preferably one, two, or three carbon-carbon double bonds, preferably one or two carbon-carbon double bonds, and preferably one carbon-carbon double bond.

[0080] A heteroaryl group comprises a substituted or unsubstituted 5- to 12-membered aromatic ring structure, more preferably a 5- to 10-membered ring, the ring structure containing 1 to 4 heteroatoms selected from N, O, S and their oxidized forms. The term “heteroaryl” also includes polycyclic ring systems having two or more cyclic rings, where two or more atoms are common to two adjacent rings, and at least one of the rings is aromatic, and the other cyclic ring may be, for example, a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl, where the bond site is located on the aromatic ring. Examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Heteroaryl groups also include benzofuran, benzothiophene, indole, benzothiazole, and others, regardless of the position of the bond site. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.

[0081] The term "halogen" refers to atoms selected from the group consisting of elements -F, -Cl, -Br, or -I, namely chlorine, fluorine, bromine, and iodine.

[0082] The term "oxo" refers to oxygen atoms with a double bond ("=O").

[0083] As used herein, the term "nitro" means -NO2; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; the term "sulfonyl" means -SO2-; the term "azide" means -N3; ​​the term "cyano" means -CN; the term "isocyanato" means -NCO; the term "thiocyanato" means -SCN; the term "isothiocyanato" means -NCS; and the term "cyanato" means -OCN.

[0084] As used herein, the term “substituted” is intended to include all permissible substituents of an organic compound. In broad embodiments, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Exemplary substituents include, for example, those listed above herein. There may be one or more permissible substituents, and they may be identical or different for a given organic compound. For the purposes of the present invention, a heteroatom such as nitrogen may have any permissible substituent of the organic compound described herein that satisfies the valence of the hydrogen substituent and / or the heteroatom. The present invention is by no means intended to be limited by the permissible substituents of an organic compound. It will be understood that “substituted” or “substituted by” implies that such substitutions conform to the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound, such as one that does not spontaneously undergo transformations such as rearrangement, cyclization, or elimination.

[0085] The term "prodrug," as used herein, encompasses compounds that are converted into therapeutic agents under physiological conditions. A common method for producing a prodrug is to include a selected moiety that undergoes hydrolysis under physiological conditions to reveal a desired molecule. In other embodiments, the prodrug is converted by enzymatic activity in a mammalian host. An example of a moiety that undergoes hydrolysis under physiological conditions to reveal a desired molecule includes a functionalized carboxyl group, which is an ester of a carboxylic acid, and is converted into the corresponding active molecule under physiological conditions. An example of a moiety that undergoes hydrolysis under physiological conditions to reveal a desired molecule is, for example, [ka] That is the case.

[0086] For the purposes of this invention, the chemical elements are identified according to the CAS version of the periodic table of elements inside the cover of the Handbook of Chemistry and Physics, 67th edition, 1986-87.

[0087] The terms “therapeutic dose” and “pharmaceutical dose” refer to an amount sufficient to produce the treatment defined below when administered to a subject (e.g., a mammal such as a human) that requires such treatment. The therapeutic dose or pharmaceutical dose will vary depending on the subject and disease state being treated, the subject’s weight and age, the severity of the disease state, the method of administration, etc., and this is readily determined by those skilled in the art. For example, the therapeutic dose or pharmacovigilance of the compound of formula (I) or a pharmaceutically acceptable salt or cocrystal thereof is sufficient to inhibit the pre-existing symptoms of the indication, thereby treating a subject (e.g., a human) suffering from the indication, or sufficient to improve or alleviate the aforementioned pre-existing symptoms.

[0088] "Treatment" or "doing treatment" is a method for obtaining beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes may include one or more of the following: (i) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the severity of the disease or condition); (ii) slowing or stopping the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis)); and / or (iii) alleviating the disease, i.e., causing a regression of clinical symptoms (e.g., improving the disease state, achieving partial or complete remission of the disease or condition, enhancing the effect of another medication, slowing the progression of the disease, improving the quality of life, and / or extending survival).

[0089] The term “inhibitor” refers to a compound of the present invention that selectively binds to α4β7 integrin to block the interaction between α4β7 integrin and the MAdCAM-1 protein. Therefore, “inhibiting” or “restriction” refers to a decrease in baseline activity of a biological activity, or a process regulated by the interaction between α4β7 integrin and the MAdCAM-1 protein. In some embodiments, inhibition of α4β7 integrin activity is compared in the same subject before treatment or in other untreated subjects. The term “inhibitor” is understood to refer to a compound or agent that achieves desired inhibitory activity when administered at a pharmaceutically effective or therapeutically effective dose to a human being requiring it.

[0090] Numerical values ​​in the specification and claims of this application should be understood to include numerical values ​​that, when aligned to the same number of significant figures, are identical, as well as numerical values ​​that differ from the specified values ​​by less than the experimental error of the type of conventional measurement technique described in this application that determines the values.

[0091] All scopes disclosed and / or claimed herein include the enumerated endpoints and those that can be independently combined (for example, the ranges “2 to 10” and “2-10” include the endpoints 2 and 10, as well as all the intermediate values ​​3, 4, 5, 6, 7, 8 and 9).

[0092] "Significant" refers to any statistically significant detectable change in a standard parametric test of statistical significance (in this case, p<0.05), such as the Student's T-test.

[0093] Salt: The term “pharmaceutically acceptable” is used herein to describe a compound, substance, composition and / or formulation that is suitable for use in conjunction with human and / or animal tissues, according to generally recognized medical findings, and that does not have or cause any excessive toxicity, irritation or immune response, or cause any other problems or complications, i.e., corresponds to an overall acceptable risk / benefit ratio. The term “pharmaceutically acceptable salt” refers to a derivative of a disclosed chemical compound in which the parent compound is modified by the addition of an acid or base. Examples of pharmaceutically acceptable salts include (but are not limited to) salts of inorganic or organic acids with respect to basic functional groups such as amines, alkali metals, or organic salts of acidic functional groups such as carboxylic acids. These salts include, in particular, acetate, ascorbate, benzenesulfonate, benzoate, besilate, bicarbonate, hydrogen tartrate, bromide / hydrobromide, calcium edetate / edetate, cansilate, carbonate, chloride / hydrochloride, citrate, edisylate, ethane disulfonate, estrulate, esylate, fumarate, gluceptinate, gluconate, glutamate, glycolate, glycolyl arsanylate, hexylresorcinate, hydravamin, hydroxymaleate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, and malic acid. Examples include salts, maleates, mandelates, methanesulfons, mesilates, methyl bromides, methylnitrates, methylsulfates, mucinates, napsylates, nitrates, oxalates, pamoates, pantothenates, phenylacetates, phosphates / diphosphates, polygalacturonates, propions, salicylates, stearates, basic acetates, succinates, sulfamides, sulfates, tannates, tartrates, theoclates, toluenesulfons, triethiozides, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, and procaine.Other pharmaceutically acceptable salts are formed with metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc (see also Pharmaceutical salts, Birge, SM et al., J. Pharm. Sci. (1977), 66, pp. 1-19).

[0094] As used herein, the terms “isotope” and “isotope” in relation to the compounds disclosed herein mean that one or more atoms of a compound are replaced by an isotope of such one or more atoms. “Isotope” refers to any two or more forms of a chemical element that have the same number of protons in the nucleus but different numbers of neutrons in the nucleus. For example, isotopic compounds include compounds in which one or more hydrogen atoms (H) are replaced by one or more deuterium atoms (D). In this example, deuterium is an isotope of hydrogen, and replacing a hydrogen atom with deuterium (at one or more positions) results in an isotopic compound. For example, referring to formula (I), replacing the two methyl groups of the isopropyl moiety (-CH(CH3)2) with fully deuterated methyl groups (-CH(CD3)2) results in the isotopic compound of formula (I). In addition to replacing hydrogen with deuterium, other stable (non-radioactive) isotopic substitutions include replacing carbon-12 with carbon-13, while unstable (radioactive) isotopes include replacing hydrogen with tritium, replacing carbon-12 with carbon-14, replacing iodine-127 with iodine-123 or iodine-125, and so on. Accordingly, all references to isotopic compounds of formula (I) in this specification, and all references to their various embodiments, refer to compounds having one or more isotopic substitutions, including (but not limited to) the substitution of one or more hydrogen atoms in the compound with one or more deuterium atoms, and any occurrences. For this purpose, the isotopic compounds disclosed herein offer improved advantages compared to their non-isotopic counterparts. For this purpose, isotopic modification offers a means to improve existing drugs and / or a tool in the design of novel drugs. For example, the design of isotopic drugs has demonstrated success in the context of deuterium(D) kinetic isotope effects. Because the mass of D is twice as high as that of H, the CD bond has considerable resistance to oxidative processes (such as its ability to be catalyzed by CYP450 or other enzymes involved in metabolism) while simultaneously maintaining very similar steric properties.Therefore, H-D isotopic substitution typically preserves the pharmacodynamics of a compound while simultaneously improving its pharmacokinetics, including its effects on half-life and / or area under the curve, and ultimately, its effects on dose and / or administration regimen. For example, drug exposure is enhanced by isotopic modification and / or reduced clearance. Such benefits are borne by the compounds disclosed herein through their isotopic derivatization.

[0095] Terms such as “subject” and “patient” refer to mammalian or other animal subjects who have been, or will be, subjects of treatment, observation, or experimentation. The methods described herein may be useful for both human therapeutic and veterinary applications. In some embodiments, the subject is a mammal; in some embodiments, the subject is a human; and in some embodiments, the subject is selected from cats and dogs. “Subject in need of it” or “human in need of it” refers to a human-like subject who may have, or is suspected of having, a disease or condition that would be beneficial from a particular treatment; for example, treatment with a compound of formula (I) described herein or a pharmaceutically acceptable salt or cocrystal thereof. This includes subjects who are at risk of, or are judged to be susceptible to, such diseases or conditions, and thus the treatment is expected to prevent the onset of the disease or condition.

[0096] The pharmaceutically acceptable salts of the present invention can be prepared by conventional chemical methods, starting from a parent compound having a basic or acidic functional group. Generally, such salts can be synthesized by reacting these compounds in the form of free acids or free bases with a sufficient amount of the corresponding base or acid in water or in an organic solvent such as ether, ethyl acetate, ethanol, isopropanol, acetonitrile (or a mixture thereof). Salts of acids other than the above-mentioned salts (e.g., trifluoroacetates), which are useful for, for example, purifying or isolating compounds from the reaction mixture, should also be considered part of the present invention.

[0097] The terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier", as used herein, mean a pharmaceutically acceptable substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in the transport or conveyance of the subject chemical substance from one organ or part of the body to another organ or part of the body. The carriers must each be "acceptable" in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially nonpyrogenic. Some examples of substances that can serve as pharmaceutically acceptable carriers include the following: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) celluloses and their derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, sesame oil, coconut oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the invention are nonpyrogenic, i.e., they do not induce a significant elevation in temperature upon administration to a patient.

[0098] The compounds of the present invention may optionally exist as a racemate, but can also be obtained as pure enantiomers, i.e., the (R) or (S) form. Compounds having a specific stereochemistry of formula Ia are preferred.

[0099] The present invention relates to the compounds in question, optionally in the form of individual optical isomers, diastereomers, mixtures of diastereomers, mixtures of individual enantiomers or racemates, in the form of tautomers, and in the form of corresponding acid addition salts with free bases or pharmaceutically acceptable acids (e.g., acid addition salts with hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), or organic acids (e.g., oxalic acid, fumaric acid, diglycolic acid or methanesulfonic acid, etc.)).

[0100] The present invention relates to the individual compounds of formula I in the form of their pharmaceutically acceptable salts. These pharmaceutically acceptable salts of the compounds of formula I and Ia may also exist in the form of their individual hydrates (e.g., monohydrate, dihydrate, etc.) and in the form of their individual solvates.

[0101] For the purposes of the present invention, the hydrate of the compound according to formula I is intended to be a crystalline salt of the compound according to formula I containing water of crystallization.

[0102] For the purposes of the present invention, the solvate of the compound according to formula I is intended to be a crystalline salt of the compound according to formula I containing solvent molecules (e.g., ethanol, methanol, etc.) in the crystal lattice.

[0103] Combination The compounds of formula I are used per se or in combination with other active substances of formula I according to the present invention. The compounds of formula I are also optionally used in combination with other pharmacologically active substances. Preferably, the active substances used here are selected, for example, from among anti-IL17, bispecific antibody IL23p19 / TNF, fecal transplantation, aminosalicylic acid (5-ASA), COX-2 inhibitors, corticosteroids, azathioprine, cyclosporine, tacrolimus, 6-mercaptopurine and / or antibiotics (ciprofloxacin, metronidazole, ampicillin, etc.).

[0104] Formulation The compound of formula I according to the present invention also possesses properties necessary for the production of suitable pharmaceutical dosage forms. These properties include, for example, those related to the efficient bioavailability of the active ingredient, particularly its sufficiently high solubility, such as a solubility of >2 μg / ml when measured in an aqueous solution at pH 6.8.

[0105] Suitable forms for administration include, for example, tablets, capsules, solutions, syrups, emulsions, or inhalation powders or aerosols. The content of the pharmaceutically effective compound should, in each case, be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight of the whole composition, i.e., an amount sufficient to achieve the dosage range specified herein.

[0106] The preparation is administered orally in the form of tablets, powder, powder in capsules (e.g., hard gelatin capsules), solution, or suspension. When administered by inhalation, the combination of active substances is administered as a powder, aqueous solution or aqueous ethanol solution, or using a propellant gas formulation.

[0107] Preferably, and therefore, the pharmaceutical formulation is characterized by the content of one or more compounds of formula I according to the preferred embodiments described above.

[0108] It is particularly preferred when the compound of formula I is administered orally, and also particularly preferred when the compound of formula I is administered once or twice daily. Suitable tablets can be obtained, for example, by mixing the active substance with known excipients, such as an inert diluent like calcium carbonate, calcium phosphate, or lactose; a disintegrant like corn starch or alginate; a binder like starch or gelatin; a lubricant like magnesium stearate or talc; and / or an agent for delayed release like carboxymethylcellulose, cellulose acetate or polyvinyl acetate. The tablets may also contain several layers.

[0109] Therefore, coated tablets can be manufactured by coating a core, which is produced in the same manner as a tablet, with a substance commonly used for tablet coatings, such as collidone or shellac, gum arabic, talc, titanium dioxide, or sugar. To achieve delayed release or prevent incompatibility, the core may also consist of several layers. Similarly, the tablet coating may also consist of several layers to achieve delayed release using the excipients described above for tablets.

[0110] The syrups containing the active substances or combinations thereof according to the present invention may further contain sweeteners such as saccharin, cyclamate, glycerin, or sugar, and flavor enhancers, such as vanillin or orange extract. They may also contain suspended adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as condensation products of fatty alcohols and ethylene oxide, or preservatives such as p-hydroxybenzoate.

[0111] Capsules containing one or more active substances or combinations of active substances can be manufactured, for example, by mixing the active substance with an inert carrier such as lactose or sorbitol and packaging them in gelatin capsules. Suitable suppositories are prepared, for example, by mixing with a carrier that achieves this purpose, such as a neutral fat or polyethylene glycol, or derivatives thereof.

[0112] Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents (paraffin (e.g., petroleum fraction), vegetable oils (e.g., peanut oil or sesame oil), monofunctional or polyfunctional alcohols (e.g., ethanol or glycerin), carriers (e.g., natural inorganic powders (e.g., kaolin, clay, talc, chalk), synthetic inorganic powders (e.g., highly dispersed silicic acid and silicates), sugars (e.g., sugarcane sugar, lactose and glucose), emulsifiers (e.g., lignin, sulfite pulp wastewater, methylcellulose, starch and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

[0113] For oral administration, tablets may, in addition to the carrier described above, contain additives such as sodium citrate, calcium carbonate, and dicalcium phosphate, along with various other additives such as starch, preferably potato starch, and gelatin. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc may be used simultaneously in the tableting process. In the case of aqueous suspensions, the active substance is combined with the above-mentioned excipients, along with various flavor enhancers or colorants.

[0114] It is also preferable, and particularly preferable, when the compound of formula I is administered by inhalation. For this purpose, the compound of formula I must be prepared to be available in a form suitable for inhalation. Inhalation preparations include inhalation powders, propellant-containing metered aerosols, or propellant-free inhalation solutions, which may be present in mixtures with physiologically acceptable conventional excipients.

[0115] Within the scope of the present invention, the term propellant-free inhalation solution also includes concentrates or ready-to-use sterile inhalation solutions. Preparations that can be used according to the present invention are described in more detail in the following parts of this specification.

[0116] Exemplary methods - Indications In certain embodiments, the present invention relates to a method of treating a disease or condition selected from the group consisting of inflammatory bowel disease, small intestinal bacterial overgrowth (SIBO), eosinophilic gastrointestinal disease (EGID), enteritis, gastrointestinal disorders associated with seronegative arthritis, intestinal dysbiosis, microscopic colitis or collagenous colitis, cholecystitis, cholangitis, pericholangitis, familial adenomatous polyposis related inflammation (FAP) gastrointestinal cancer, intestinal graft-versus-host disease (intestinal GVHD), celiac disease, chronic cholecystitis, checkpoint inhibitor-related colitis, the method comprising administering to a subject in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

[0117] In certain embodiments, the disease or condition is Crohn's disease.

[0118] In certain embodiments, the disease or condition is colitis.

[0119] In certain embodiments, the disease or condition is ulcerative colitis.

[0120] In certain embodiments, the present invention relates to any one of the aforementioned methods, wherein the subject is a mammal. In certain embodiments, the present invention relates to any one of the aforementioned methods, wherein the subject is a human.

[0121] Synthesis The compounds described herein can be prepared by methods known in the art and are exemplified by the following non-limiting description.

[0122] Unless otherwise specified, all reactions are typically carried out under an inert atmosphere (e.g., under nitrogen). The following abbreviations are used herein: s.s. = saturated solution ON = overnight

[0123] [Table 1-1] [Table 1-2]

[0124] Other features and advantages of the present invention will become apparent from the following more detailed embodiments, which illustrate the principles of the present invention without limiting their scope.

[0125] General synthesis Unless otherwise specified, all reactions are carried out using commercially available equipment and methods commonly used in chemical laboratories. Starting materials sensitive to air and / or moisture are stored under a protective gas, and corresponding reactions and operations are carried out under a protective gas (nitrogen or argon).

[0126] The compounds of Formula 1 described herein can be synthesized by amide coupling of the amino group of biaryl ester 2 with a suitable amino acid 3, as shown in the general route reported in Scheme 1. Biarylaminoester intermediate 2 can be synthesized by a multi-step procedure described in Scheme 2. Starting with a commercially available aromatic aldehyde 6, intermediate 5 can be produced using the chiral auxiliary tert-butylsulfoxamide, which can then be metal-catalyzed with commercially available aryl and heteroaryl boronates to produce intermediate 4, which can then be deprotected of the amine to yield compound 2.

[0127] [ka]

[0128] [ka]

[0129] Dimethylcyclopropylproline intermediate 3 can be synthesized by a two-step procedure starting with amino acid methyl ester 7, followed by amide coupling with acyl chloride or carboxylate 8, and then ester hydrolysis.

[0130] Alternatively, in the case of such compounds for which suitable building blocks are not commercially available, they can be synthesized in accordance with the general routes described herein as reported.

[0131] Other features and advantages of the present invention will become apparent from the following more detailed embodiments, which illustrate the principles of the present invention without limiting their scope.

[0132] The LCMS conditions for analysis are as follows: System 1 (S1): Acidic IPC method Analytical (MET / uPLC / 1704) uHPLC-MS was performed on a Waters Acquity uPLC system using a Waters UPLC® BEHTM C18 column (2.1 mm × 50 mm, 1.7 μm; temperature 40°C) and a gradient of B from 5 to 100% (A = 0.1% formic acid in H₂O₂-H: B = 0.1% formic acid in MeCN) over 1.1 minutes, followed by B becoming 100% over 0.25 minutes. Next, a second gradient of B from 100% to 5% was applied over 0.05 minutes at an injection volume of 1 μL and a flow rate of 0.9 mL / min, and held for 0.1 minutes. The UV spectrum at 215 nm was recorded in the spectral range of 200–400 nm using a Waters Acquity PDA. Mass spectra were obtained using a Waters QDa. Data are integrated and reported using Waters MassLynx and OpenLynx software, and retention times (Rt) are reported in minutes.

[0133] System 2 (S2): Basic IPC method Analytical (MET / uPLC / AB2010)(M15) UHPLC-MS was performed in reverse phase using a Waters UPLC™ BEH™ C18 column (2.1 mm × 30 mm, 1.7 μm; temperature 55 °C) with an injection volume of 1 μL and a flow rate of 1.0 mL / min, and a gradient of B from 1 to 100% over 1.10 minutes, followed by B to 100% over 0.25 minutes (A = 2 mM ammonium bicarbonate in water (buffered to pH 10) and B = acetonitrile). A second gradient of B from 100% to 1% was then applied over 0.05 minutes and held for 0.40 minutes. UV spectra were recorded at 215 nm; spectral range: 200–400 nm. Mass spectra were obtained using a Waters Quattro Premier XE or SQD2 with ionization mode: electrospray positive or negative. Data are integrated and reported using Waters MassLynx and OpenLynx software, and retention times (Rt) are reported in minutes.

[0134] System 3 (S3): Acidic final method Analytical (MET / uPLC / AB101) uHPLC-MS was performed on a Waters Acquity uPLC system using a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 μM; temperature: 40°C) and a gradient of B from 5 to 100% (A = 0.1% formic acid in H2O; B = 0.1% formic acid in MeCN) over 5.3 minutes, followed by B to 100% over 0.5 minutes. Next, a second gradient of B from 100% to 5% was applied over 0.02 minutes with an injection volume of 1 μL and a flow rate of 0.6 mL / min, and held for 1.18 minutes. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector with a spectral range of 200–400 nm. Mass spectra were obtained using Waters SQD or Waters Acquity QDA. Data are integrated and reported using Waters MassLynx and OpenLynx software, and retention times (Rt) are reported in minutes.

[0135] System 4 (S4): Basic final method Analytical (MET / uHPLC / AB105) uPLC-MS was performed on a Waters Acquity uPLC system using a Waters UPLC® BEHTM C18 column (2.1 mm × 100 mm, 1.7 μM column; temperature: 40°C) and a gradient of 5–100% (A = 2 mM ammonium bicarbonate (buffered to pH 10); B = MeCN) over 5.3 minutes, followed by a gradient of B to 100% over 0.5 minutes. Next, a second gradient of B from 100–5% was applied over 0.02 minutes with an injection volume of 1 μL and a flow rate of 0.6 mL / min, and held for 1.18 minutes. UV spectra were recorded at 215 nm using a Waters Acquity photodiode array detector with a spectral range of 200–400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector. Data are integrated and reported using Waters MassLynx and OpenLynx software, and retention times (Rt) are reported in minutes.

[0136] System 5 (S5): Neutral final method Analytical UHPLC-MS was performed on an Agilent 1260 system using an Agilent Poroshell 120EC-C18 column (2.1 mm × 50 mm, 1.9 μM; temperature 50°C) in binary gradient mode (A=10 mM NH4OAc in H2O:B=ACN) over 4.5 minutes at a flow rate of 0.8 mL / min (linearly increasing B to 1% over 0.25 minutes, then to 100% over 2.25 minutes, then to 100% B over 0.40 minutes, and then returning to the initial conditions over 0.1 minutes). The initial injection volume was 0.2 μL. UV spectra at 220 nm and 254 nm were recorded using an Agilent PDA in the spectral range of 190–400 nm. Mass spectra were obtained using either positive or negative electrospray ionization (Agilent Jet Stream source) with an Agilent 6490A QQQ. The data was used with the Agilent MassHunter software suite, and retention times (Rt) are reported in minutes.

[0137] System 6 (S6): Neutral IPC method Analytical UHPLC-MS was performed on an Agilent 1260 system using an Agilent Poroshell 120EC-C18 column (2.1 mm × 50 mm, 1.9 μm; temperature 50°C) in binary gradient mode (A=10 mM NH4OAc in H2O:B=ACN) over 4.2 minutes at a flow rate of 0.8 mL / min (linearly increasing B to 1% over 0.25 minutes, then to 100% over 2.25 minutes, then to 100% B over 0.40 minutes, and then back to the initial conditions over 0.1 minutes). The initial injection volume was 1 μL. UV spectra at 220 nm and 254 nm were recorded with an Agilent PDA in the spectral range of 190–400 nm. Mass spectra were obtained using an Agilent 6120B SQ with simultaneous positive or negative electrospray ionization. Agilent OpenLab software will be used to access the data, and retention time (Rt) will be reported in minutes.

[0138] System 4 (S7): Neutral IPC method Analytical UHPLC-MS was performed on an Agilent 1260 system using an Agilent Poroshell 120 EC-C18 column (2.1 mm × 50 mm, 2.7 μm; temperature 50°C) in binary gradient mode (A=10 mM NH4OAc in H2O:B=ACN) over 3.8 minutes at a flow rate of 1.0 mL / min (linearly increasing B to 0.5% for 0.10 minutes, then to 100% B over 1.6 minutes, then 100% B for 0.40 minutes, and returning to the initial condition over 0.1 minutes). The initial injection volume was 1 μL. UV spectra at 220 nm and 254 nm were recorded with an Agilent PDA in the spectral range of 190–400 nm. Mass spectra were obtained using an Agilent 6120B SQ with simultaneous positive and negative electrospray ionization. Agilent OpenLab software was used to access the data.

[0139] System 9 (S9): Acid IPC Method Analytical UHPLC-MS was performed on an Agilent 1290 system using an Agilent Poroshell 120EC-C18 column (2.1 mm × 50 mm, 1.9 μm; temperature 50°C) in binary gradient mode (A = 0.1% formic acid in H2O: B = 0.05% formic acid in ACN) over 2.5 minutes at a flow rate of 1.00 mL / min (linearly increasing B to 1% for 0.10 minutes, then to 100% for 1.3 minutes, then to 100% for 0.50 minutes, and then returning to the initial conditions for 0.1 minutes). The initial injection volume was 1 μL. UV spectra at 220 nm and 254 nm were recorded with an Agilent PDA in the spectral range of 190–400 nm. Mass spectra were obtained using an Agilent 6120B SQ with simultaneous positive and negative electrospray ionization. Agilent OpenLab software was used to access the data.

[0140] The purification method is as follows: The compounds were purified using the following methods: normal-phase or reverse-phase automated flash column chromatography on silica or C-18 silica (e.g., Biotage® Isolera or Selekt instruments); open-access reverse-phase preparative HPLC (methods are detailed below, pp. 1-4); and one of the custom-developed reverse-phase preparative HPLC methods.

[0141] Method 1: Acidic early elution method (P1) Purification (P1) LC was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm × 100 mm, 10 μM; temperature: room temperature) and a gradient of B from 10–95% (A = 0.1% formic acid in H2O; B = 0.1% formic acid in MeCN) over 14.44 minutes, followed by a gradient of B from 95% over 2.11 minutes. Next, a second gradient of B from 95–10% was applied over 0.2 minutes with an injection volume of 1500 μL and a flow rate of 40 mL / min. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0142] Method 2: Acidic standard method (P2) Purification (P2) LC was performed on a Waters Sunfire C18 column (30 mm × 10 mm, 10 μM; temperature: room temperature) using a Gilson LC system with a gradient of 30–95% B (A = 0.1% formic acid in water; B = 0.1% formic acid in MeCN) over 11.00 minutes, followed by a gradient of 95% B over 2.10 minutes. Next, a second gradient of 95–30% B was applied over 0.2 minutes with an injection volume of 1500 μL and a flow rate of 40 mL / min. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0143] Method 3: Basic early elution method (P3) Purified (P3)LC was performed in reverse phase using a Waters XBridge® C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature) with an injection volume of 1500 μL and a flow rate of 40 mL / min, applying a gradient of 10% B over 2.00 minutes, followed by a gradient of 10% B to 95% B over 14.00 minutes, and a retention period of 2.00 minutes (A = 0.2% NH4OH in water and B = MeCN). A second gradient of 95% to 10% B was then applied over 0.20 minutes and held for 1.25 minutes. The UV spectrum was recorded at 215 nm.

[0144] Method 4: Basic standard method (P4) Purified (P4)LC was performed in reverse phase using a Waters XBridge® C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature) with an injection volume of 1500 μL and a flow rate of 40 mL / min, applying a gradient of B to 30% over 2.00 minutes, followed by a gradient of B from 30% to 95% over 9.50 minutes, and a retention of 1.97 minutes (A = 0.2% NH4OH in water and B = MeCN). A second gradient of B from 95% to 30% was then applied over 0.33 minutes and held for 1.65 minutes. The UV spectrum was recorded at 215 nm.

[0145] Chiral separation method: LC method: Chiral separation using Gilson LC [column at room temperature; isocratic eluent; flow rate: 18 mL / min; detector wavelength: 215 / 254 nm; diluent: IPA; injection volume: 100-1000 μL]

[0146] SFC method: Chiral separation using Waters Thar SFC [column at 40°C; isocratic eluent; back pressure: 120 bar; flow rate: 15 mL / min; diluent: MeOH / acetonitrile; injection volume: 250 μL]

[0147] The NMR method is as follows: Method 1, NMR (N1) Unless otherwise specified, 1¹H NMR spectra were recorded at 500 MHz, 400 MHz, or 250 MHz using one of the following Bruker Avance III HD 500 MHz, Bruker Avance III HD 400 MHz, or Bruker Avance III HD 250 MHz spectrometers, respectively. Chemical shift δ is expressed in parts per million (ppm) and referenced to the residual solvent peak. The following abbreviations are used to represent multiplicity and general assignment: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublets of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), penta (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent), and br. (broad). The coupling constant J is quoted to the nearest 0.1 Hz.

[0148] Method 2, NMR: (N2) Unless otherwise specified, 1 The H NMR spectrum was obtained at 300K using dual z-gradation. 1 Recordings were made at 300 MHz or 500 MHz, respectively, using either a Bruker 300 MHz Fourier spectrometer equipped with an H / 13C probe or a Bruker 500 MHz AVIII HD spectrometer equipped with an N2-cooled z-grad broadband CPP BBO probe at 298 K. Chemical shift δ was expressed in parts per million (ppm) and referenced to the residual solvent peak. The following abbreviations are used to represent multiplicity and general assignment: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublets of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), penta (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent), and br. (broad). The coupling constant J is quoted to the nearest 0.1 Hz.

[0149] synthesis General Route 1 (Synthesis of biarylaminoester intermediates 1a-e)

[0150] [ka]

[0151] Intermediate 1a Process A: (R)-N-[(E)-(5-bromo-2,3-difluorophenyl)methylidene]-2-methylpropane-2-sulfinamide [ka] A stirred solution of 5-bromo-2,3-difluorobenzaldehyde (25.00 g, 0.113 mol) and (R)-2-methylpropane-2-sulfinamide (15.08 g, 0.124 mol) in anhydrous THF (300 mL) was treated dropwise with Ti(OiPr)4 (35 mL, 0.170 mol) under N2 at room temperature, and the mixture was stirred for 1 hour at room temperature and then for 1.5 hours at 40°C. The reaction mixture was poured into a mixture of water (300 mL) and pharmaceutically acceptable phosphate (200 mL) and vigorously stirred for 10 minutes. The suspension was then sonicated, filtered, and washed with pharmaceutically acceptable phosphate (200 mL). The organic components were separated, water was extracted using toluene (3 × 100 mL), the combined organic matter was washed with brine (2 × 100 mL), dehydrated with MgSO4, filtered, and concentrated to obtain the title compound (33.74 g, 87% yield) as a solid. LCMS m / z: 323.9 / 325.9 [M+H]+, (ESI+), Rt = 1.08 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.61 (s, 1H), 8.09 (ddd, J = 9.8, 7.1, 2.5 Hz, 1H), 7.95 (dt, J = 5.3, 2.2 Hz, 1H), 1.20 (s, 9H).

[0152] Process B: Ethyl(3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate [ka] A stirred suspension of activated zinc powder (26.91 g, 0.411 mol) in anhydrous THF (350 mL) was treated by adding ethyl 2-bromoethyl acetate (29 mL, 0.257 mol) dropwise over 20 minutes at 65°C under N2. This solution was stirred at 65°C for 1.5 hours, cooled, and allowed to precipitate for 30 minutes. This organozinc solution was added to a stirred solution of (R)-N-[(E)-(5-bromo-2,3-difluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (35.10 g, 0.103 mol) in anhydrous THF (350 mL) over 5 minutes at 65°C under N2, and the reaction mixture was then stirred at 65°C for 1.5 hours.

[0153] The reaction mixture was cooled and poured into a mixture of TBME (400 mL) and 10% citric acid (600 mL). The organic matter was separated and water was extracted with TBME (3 × 150 mL). The combined organic matter was washed with brine (2 × 150 mL), dehydrated with MgSO4, filtered, and concentrated to obtain the crude product. This was purified by silica dry flash chromatography (approximately 300 g of silica, 0-70% siRNA in heptane) to obtain the title compound (29.40 g, 55% yield) as an oily substance. LCMS m / z: 412.4 / 414.2 [M+H]+, (ESI+), Rt = 0.98 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: δ 7.74 (ddd, J = 9.6, 6.9, 2.4 Hz, 1H), 7.57 (dt, J = 5.4, 2.1 Hz, 1H), 5.85 (d, J = 7.0 Hz, 1H), 4.95 (d, J = 7.2 Hz, 1H), 4.07 - 3.97 (m, 2H), 3.02 (dd, J = 15.8, 7.2 Hz, 1H), 2.90 (dd, J = 15.8, 7.5 Hz, 1H), 1.13 (t, J = 7.1 Hz, 3H), 1.06 (s, 9H). (N1)

[0154] Process C: Ethyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate [ka] Ethyl(3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (20.00 g, 38.3 mmol), (2,6-dimethylphenyl)boronic acid (11.50 g, 76.6 mmol), and potassium carbonate (15.89 g, 0.115 mol) were mixed in 1,4-dioxane (110 mL) and water (8 mL), and nitrogen (N2) was sprayed over them for 10 minutes. Pd(dppf)Cl2 (1.57 g, 1.92 mmol) was added, and the reaction mixture was stirred under nitrogen at 100 °C for 4 hours. The reaction mixture was cooled and poured into water (400 mL), and extracted with SiO2 (4 × 150 mL). The combined organic matter was washed with brine (2 × 100 mL), dehydrated with MgSO4, filtered, and concentrated to obtain the crude product. This was purified by Biotage Isolera™ chromatography (350 g silica; 10% to 100% toluene in heptane, followed by 0 to 20% MeOH in toluene) to obtain the title compound (8.25 g, 44% yield) as an oily substance. LCMS m / z:438.4[M+H]+, (ESI+), Rt=1.14(S1)

[0155] Process D: Ethyl(3S)-3-amino-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride [ka] A stirred solution of ethyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (9.63 g, 18.3 mmol) in anhydrous DCM (100 mL) was treated with HCl [4 M in dioxane] (9.1 mL, 36.5 mmol) under N2 at room temperature and stirred for 2 hours at room temperature. The reaction mixture was concentrated under vacuum, and the residue was purified by FC (50 g silica, 0%~43% MeOH in ethylethanol) to obtain intermediate 1a (7.38 g, 94% yield) as a solid. LCMS m / z: 334.1 [M+H]+, (ESI+), Rt = 0.71 (S1) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: δ8.80 (s, 3H), 7.42 - 7.35 (m, 1H), 7.35 - 7.27 (m, 1H), 7.22 - 7.17 (m, 1H), 7.17 - 7.09 (m, 2H), 4.95 - 4.81 (m, 1H), 4.08 - 3.94 (m, 2H), 3.25 - 3.17 (m, 1H), 3.17 - 3.03 (m, 1H), 2.03 (s, 3H), 1.95 (s, 3H), 1.08 (t, J = 7.1 Hz, 3H). (N1)

[0156] Intermediate 1b Process E: Ethyl(3S)-3-amino-3-(5-bromo-2,3-difluorophenyl)propanoate hydrochloride [ka] A stirred solution of ethyl(3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (0.50 g, 0.958 mmol) from step E of general route 1 in anhydrous DCM (10 mL) was treated with HCl [4 M in dioxane] (1.0 mL, 4.00 mmol) at room temperature under N2 and stirred for 3 hours. The reaction mixture was then concentrated under vacuum and purified using a silica plug (4 CV of DCM flushed, then eluted with 4 CV of DCM-MeOH (1:1)). The filtrate was concentrated to obtain the title intermediate 1b as an oily substance. LCMS m / z:308.1 / 310.1[M+H]+, (ESI+), Rt=0.55(S1)

[0157] The following intermediates were prepared using the corresponding starting materials according to General Route 1, which is reported for intermediate 1a outlined in Scheme 3.

[0158] Intermediate 1c Process A: (R)-N-[(E)-[3-bromo-2,6-difluoro-5-(trifluoromethyl)phenyl]methylidene]-2-methylpropane-2-sulfinamide [ka] It was prepared from ethyl(3S)-3-[3-bromo-2,6-difluoro-5-(trifluoromethyl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate and 3-bromo-2,6-difluoro-5-(trifluoromethyl)benzaldehyde using the route outlined in step A of Scheme 3. LCMS m / z: 392.1 [M+H]+, (ESI+), Rt = 1.08, (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: δ 8.58 (s, 1H), 8.46 (t, J = 7.2 Hz, 1H), 1.25 - 1.13 (m, 9H). (N1)

[0159] Process B: Ethyl (3S)-3-[3-bromo-2,6-difluoro-5-(trifluoromethyl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate [ka] (R)-N-[(E)-[3-bromo-2,6-difluoro-5-(trifluoromethyl)phenyl]methylidene]-2-methylpropane-2-sulfinamide was prepared using the route outlined in step B of Scheme 3. LCMS m / z: 480.1 / 482.1 [M+H]+, (ESI+), Rt = 0.89, (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: δ 8.21 (t, J = 7.2 Hz, 1H), 5.96 (d, J = 5.0 Hz, 1H), 5.12 (q, J = 6.8 Hz, 1H), 4.01 (q, J = 7.1 Hz, 2H), 3.23 - 2.97 (m, 2H), 1.11 - 1.06 (m, 3H), 1.02 (s, 9H). (N1)

[0160] Process C: Ethyl (3S)-3-[2,4-difluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate [ka] It was prepared from ethyl(3S)-3-[3-bromo-2,6-difluoro-5-(trifluoromethyl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate using the route outlined in step C of Scheme 3. LCMS m / z:520.3[M+H]+, (ESI+), Rt=1.20, (S1)

[0161] Process D: Ethyl(3S)-3-amino-3-[2,4-difluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate hydrochloride [ka] It was prepared from ethyl(3S)-3-[2,4-difluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (EV-SBW001-785-001) using the route outlined in step D of Scheme 3. LCMS m / z:416.3[M+H]+, (ESI+), Rt=0.91, (S1)

[0162] Intermediate 1d Process C: Ethyl (3S)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-3-{4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate [ka] It was prepared from ethyl(3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate and 2-(4-fluoro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane using the route outlined in step C of Scheme 3. LCMS m / z:456.5[M+H]+, (ESI+), Rt=1.01, (S2)

[0163] Process D: Ethyl(3S)-3-amino-3-{4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride [ka] It was prepared from ethyl(3S)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-3-{4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate using the route outlined in step D of Scheme 3. LCMS m / z:352.3[M+H]+, (ESI+), Rt=0.89, (S2)

[0164] Intermediate 1e Process A - (R)-N-[(E)-(5-bromo-2-fluoro-3-methylphenyl)methylidene]-2-methylpropane-2-sulfinamide [ka] It was prepared from 5-bromo-2-fluoro-3-methylbenzaldehyde using the route outlined in step A of Scheme 3. LCMS m / z: 322.1 [M+H]+, (ESI+), Rt = 1.14, (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.62 (s, 1H), 7.95 - 7.87 (m, 1H), 7.82 - 7.74 (m, 1H), 2.33 - 2.26 (m, 3H), 1.19 (s, 9H). (N1)

[0165] Step B - Ethyl(3S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate [ka] It was prepared from (R)-N-[(E)-(5-bromo-2-fluoro-3-methylphenyl)methylidene]-2-methylpropane-2-sulfinamide using the route outlined in step B of Scheme 3. LCMS m / z: 408.2 [M+H]+, (ESI+), Rt = 1.02, (S1) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.53 - 7.47 (m, 1H), 7.45 - 7.38 (m, 1H), 5.73 (d, J = 7.0 Hz, 1H), 4.91 (q, J = 7.2 Hz, 1H), 4.01 (q, J = 7.1 Hz, 2H), 2.97 (dd, J = 15.5, 7.4 Hz, 1H), 2.81 (dd, J = 15.5, 7.4 Hz, 1H), 2.25 - 2.16 (m, 3H), 1.13 - 1.08 (m, 3H), 1.05 (s, 9H). (N1)

[0166] Process E - Ethyl(3S)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propanoate hydrochloride [ka] It was prepared from ethyl(3S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate using the route outlined in step E of Scheme 3. LCMS m / z:304.1[M+H]+, (ESI+), Rt=0.60, (S1)

[0167] Intermediate 1f Process C: Ethyl(3S)-3-{4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate [ka] It was prepared from ethyl(3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate and (2,4,6-trimethylphenyl)boronic acid using the route outlined in step C of Scheme 3. LCMS m / z: 452.3 [M+H]+, (ESI+), Rt = 1.21, (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: δ 6.95 - 6.86 (m, 4H), 5.16 - 5.07 (m, 1H), 4.79 (d, J = 6.2 Hz, 1H), 4.17 - 4.00 (m, 2H), 3.05 - 2.88 (m, 2H), 2.32 (s, 3H), 1.96 (d, J = 4.8 Hz, 6H), 1.24 - 1.17 (m, 12H). (N1)

[0168] Process D: Ethyl(3S)-3-amino-3-{4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride [ka] It was prepared from ethyl(3S)-3-{4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate using the route outlined in step D of Scheme 3. LCMS m / z: 348.2 [M+H]+, (ESI+), Rt = 0.84, (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: δ 8.94 (s, 3H), 7.08 (s, 1H), 6.96 (dd, J = 10.1, 6.7 Hz, 1H), 6.86 (d, J = 5.3 Hz, 2H), 5.02 (s, 1H), 4.06 (q, J = 6.9 Hz, 2H), 3.25 (d, J = 15.7 Hz, 1H), 3.07 (d, J = 15.6 Hz, 1H), 2.29 (s, 3H), 1.93 (d, J = 13.0 Hz, 6H), 1.16 (t, J = 6.4 Hz, 3H) (N1)

[0169] 1g of intermediate Step 1: Ethyl(3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(tert-butoxy)carbonyl]amino}propanoate [ka] To a solution of intermediate 1b (500 mg, 1.45 mmol) in methyltetrahydrofuran (5 ml), NEt3 (375 μL, 1.60 mmol) and Boc2O (349 mg, 3.05 mmol) were added. This solution was stirred at room temperature for 2 hours. After removing the solvent under vacuum, an oily substance was obtained. Purification by column chromatography (10 g silica, 0-40% ethyl phosphate in heptane) yielded the title product (600 mg, 90% yield) as an oily substance. LCMS m / z:309.9 [M-Boc+H] + (ESI+), Rt=0.96, (S2)

[0170] Step 2: Ethyl(3S)-3-{[(tert-butoxy)carbonyl]amino}-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate [ka] To a solution of ethyl(3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(tert-butoxy)carbonyl]amino}propanoate (600 mg, 1.47 mmol) in 1,4-dioxane (12 ml), KOAc (447 mg, 4.56 mmol), B2Pin2 (450 mg, 1.77 mmol), and Pd(dppf)2Cl2 (122 mg, 0.15 mmol) were added. This reaction mixture was heated at 80°C for 2 hours. When this reaction mixture was concentrated under vacuum, a brown gum-like substance was obtained. Purification by column chromatography (10 g silica, 0-50% acetone in heptane, then 10% MeOH in acetone) yielded the title product (520 mg, 89% yield) as an oily substance. LCMS m / z:356.3[M-Boc+H]+, (ESI+), Rt=0.79, (S1)

[0171] Step 3: Ethyl(3S)-3-{[(tert-butoxy)carbonyl]amino}-3-[5-(3,5-dimethylpyridine-4-yl)-2,3-difluorophenyl]propanoate [ka] To a solution of ethyl(3S)-3-{[(tert-butoxy)carbonyl]amino}-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (950 mg, 1.47 mmol) in 1,4-dioxane (1.8 mL) and water (1.8 mL), K2CO3 (813 mg, 5.88 mmol), 3,5-dimethyl-4-bromopyridine (590 mg, 2.65 mmol), and Pd(dppf)2Cl2 (256 mg, 0.3 mmol) were added. This reaction mixture was heated at 100 °C for 2 hours. When this reaction mixture was concentrated under vacuum, a brown gum-like substance was obtained. Purification by column chromatography (10 g silica, 0-100% ethyl acetate in heptane, followed by 10% MeOH in ethyl acetate) yielded the title product (800 mg, 52% yield) as an oily substance. LCMS m / z:435.3[M+H]+, (ESI+), Rt=0.91, (S1)

[0172] Step 4: Ethyl(3S)-3-amino-3-[5-(3,5-dimethylpyridine-4-yl)-2,3-difluorophenyl]propanoate hydrochloride [ka] It was manufactured using the route outlined in step D of Scheme 3, starting from intermediate 117. LCMS m / z:336.4[M+H]+, (ESI+), Rt=0.67(S1)

[0173] General Route 2 (Synthesis of N-acyl-(6,6-dimethylcyclopropyl)pyrrolidine-2-carboxylate intermediates 2a-b)

[0174] [ka]

[0175] Intermediate 2a Step A - Methyl(1R,2S,5S)-3-benzoyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka] To a stirred solution of methyl(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (96%, 253 mg, 1.18 mmol) and triethylamine (190 μL, 1.36 mmol) in DCM (2.2 mL), benzoyl chloride (125 μL, 1.08 mmol, 0°C) was added. The solution was then warmed to room temperature over 30 minutes and stirred for 1 hour. The reaction mixture was diluted with HCl (50 mL) and washed with HCl (1 M, 50 mL) and brine (50 mL). The organic layer was dehydrated with MgSO4 and concentrated under vacuum. Purification by FC (10 g silica, 0-60% ethyl phosphate in heptane) yielded the title compound (91.0%) (200 mg, 62% yield) as an oil. LCMS m / z: 274.2 [M+H]+, (ESI+), Rt = 0.87 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: δ 7.54 - 7.14 (m, 5H), 4.47 (s, 1H), 3.87 - 3.22 (m, 2H), 3.51 (s, 3H), 1.55 - 1.44 (m, 2H), 1.06 - 0.90 (m, 6H). (N1)

[0176] Step B - (1R,2S,5S)-3-benzoyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid [ka] To a stirred solution of methyl(1R,2S,5S)-3-benzoyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (200 mg, 0.549 mmol) from step A in THF (5 mL) and MeOH (0.1 mL), 2 M LiOH (aqueous solution) (1.7 mL, 3.40 mmol) was added. This mix was stirred at 50°C for 1.5 hours. Next, the solution was cooled for 45 minutes, after which water (10 mL) was added, and the mixture was concentrated under vacuum. The residual solution was acidified with HCl (1 M) to pH 3, and then extracted with DCM (3 × 15 mL). The combined organic layers were dehydrated with MgSO4 and concentrated under vacuum to obtain intermediate 2a (84.0%) (150 mg, 89% yield) as an oily substance. LCMS m / z: 260.2 [M+H]+, (ESI+), Rt = 0.74 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: δ 12.87 (s, 1H), 7.45 - 7.40 (m, 4H), 7.28 - 7.21 (m, 1H), 4.39 (s, 1H), 3.82 (dd, J = 10.7, 4.9 Hz, (N1), 3.23 (d, J = 10.8 Hz, 1H), 1.49 - 1.46 (m, 2H), 1.06 - 0.89 (m, 6H)

[0177] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate 2a outlined in general route 2 (Scheme 4).

[0178] Intermediate 2b Step A - Methyl(1R,2S,5S)-3-acetyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka] It was prepared from methyl(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate using the general route outlined in step A of Scheme 4. LCMS m / z: 212.2 [M+H]+, (ESI+), Rt = 0.64, (S1) 1 H NMR (400 MHz, Chloroform-d) δ [ppm]: 4.38 (s, 1H), 3.84 (dd, J = 10.2, 5.2 Hz, 1H), 3.75 (s, 3H), 3.46 (d, J = 10.2 Hz, 1H), 2.03 (s, 3H), 1.54 - 1.40 (m, 2H), 1.05 (s, 3H), 0.96 (s, 3H) (N1)

[0179] Step B - (1R,2S,5S)-3-acetyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid [ka] It was prepared from methyl(1R,2S,5S)-3-acetyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate using the general route outlined in step B of Scheme 4. LCMS m / z:324.4[M+H]+, (ESI+), Rt=1.11, (S1)

[0180] General Route 3 (Synthesis of Intermediates 3a-b)

[0181] [ka]

[0182] Intermediate 3a Step A - Ethyl 8-(3-fluoroazetidine-1-yl)imidazo[1,2-a]pyridine-2-carboxylate [ka] A suspension consisting of Cs2CO3 (593 mg, 1.82 mmol), ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (200 mg, 0.728 mmol), 3-fluoroazetidine hydrochloride (122 mg, 1.09 mmol), and XantPhos Pd G3 (69 mg, 0.0728 mmol) in dioxane (4 mL) was purged with nitrogen for 5 minutes and then heated at 100°C for 18 hours. The reaction mixture was partitioned between DCM (5 mL) and water (5 mL), the aqueous layer was extracted with DCM (5 mL), the combined organic matter was dried using hydrophobic frit, and then concentrated under vacuum to obtain a brown solid. This solid was triturated in MeCN (2 mL), and the resulting suspension was filtered. Washing this solid with MeCN (1 mL) yielded ethyl 8-(3-fluoroazetidine-1-yl)imidazo[1,2-a]pyridine-2-carboxylate (90 mg, 46% yield) as a solid. LCMS m / z: 264.1 [M+H]+, (ESI+), Rt = 0.74 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.47 (s, 1H), 7.99 - 7.92 (m, 1H), 6.85 - 6.77 (m, 1H), 6.11 - 6.04 (m, 1H), 5.63 - 5.34 (m, 1H), 4.56 - 4.42 (m, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.24 - 4.10 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H).

[0183] Step B - 8-(3-fluoroazetidine-1-yl)imidazo[1,2-a]pyridine-2-carboxylic acid [ka] A solution of ethyl 8-(3-fluoroazetidine-1-yl)imidazo[1,2-a]pyridine-2-carboxylate (90 mg, 0.342 mmol) from step A was stirred at 50°C for 72 hours in LiOH (2 M, aqueous, 205 μL, 0.410 mmol), THF (1 mL), and methanol (1 mL). The reaction mixture was loaded into a reverse-phase sample and purified by reverse-phase FC (12 g of C-18, 0-100% MeCN (0.1% formic acid) in water (0.1% formic acid)) to obtain intermediate 3a, 8-(3-fluoroazetidine-1-yl)imidazo[1,2-a]pyridine-2-carboxylic acid (55 mg, 68% yield), as a solid. LCMS m / z: 236.1 [M+H]+, (ESI+), Rt = 0.47 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 12.65 (br. s, 1H), 8.39 (s, 1H), 7.95 (dd, J = 6.7, 1.0 Hz, 1H), 6.83 - 6.74 (m, 1H), 6.09 - 6.02 (m, (N1)

[0184] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate 3a outlined in Scheme 5.

[0185] Intermediate 3b Step A - Ethyl 7-(3-fluoroazetidine-1-yl)imidazo[1,2-a]pyridine-2-carboxylate [ka] It was prepared from ethyl 7-bromoimidazo[1,2-a]pyridine-2-carboxylate and 3-fluoroazetidine hydrochloride using general route 3 outlined in step A of scheme 5. LCMS m / z: 264.1 [M+H]+, (ESI+), Rt = 0.49, (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.34 (d, J = 7.4 Hz, 1H), 8.24 (s, 1H), 6.52 - 6.45 (m, 1H), 6.24 (d, J = 2.2 Hz, 1H), 5.51 (dtt, J = (N1)

[0186] Step B - 7-(3-fluoroazetidine-1-yl)imidazo[1,2-a]pyridine-2-carboxylic acid [ka] It was prepared from ethyl 7-(3-fluoroazetidine-1-yl)imidazo[1,2-a]pyridine-2-carboxylate using general route 3 outlined in step B of scheme 5. LCMS m / z: 236.1 [M+H]+, (ESI+), Rt = 0.37, (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.39 - 8.32 (m, 1H), 8.06 (s, 1H), 6.50 (dd, J = 7.4, 2.3 Hz, 1H), 6.21 (d, J = 2.2 Hz, 1H), 5.51 (dtt, J = (N1)

[0187] General Route 10 (Synthesis of 1-alkylpyrazole RHS intermediate) [ka]

[0188] Intermediate 105 Step A: Methyl 6-(3-fluoroazetidine-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate [ka] A suspension consisting of discesium carbonate (958 mg, 2.94 mmol), methyl 6-bromopyrazolo[1,5-a]pyridine-3-carboxylate (300 mg, 1.18 mmol), 3-fluoroazetidine hydrochloride (1:1) (197 mg, 1.76 mmol), and XantPhos Pd G3 (112 mg, 0.118 mmol) was purged with nitrogen for 5 minutes and then heated at 100°C for 18 hours. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (10 mL). The resulting suspension was filtered. Washing the solid with water (5 mL) and ethyl acetate (5 mL) yielded the title product (130 mg, 0.516 mmol, 44% yield) as a gray solid.

[0189] The phases of the filtrate were separated, and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic matter was washed with brine (2 × 10 mL), dried over MgSO4, and concentrated under vacuum to obtain a brown oily substance. This oily substance was triturated with ethyl acetate / MeOH (approximately 2:1, 5 mL) and filtered. Washing this solid with ethyl acetate (2 mL) and MeOH (2 mL) yielded the title product (60 mg, 96% pure, 20% yield) as an off-white solid. The filtrate was concentrated under vacuum and purified by column chromatography (10 g silica, 0-100% ethyl acetate in heptane) to obtain the title (etotled) product (75 mg, 63% pure, 16% yield) as a white solid. LCMS m / z: 250.1 [M+H] + , (ESI+), Rt = 0.71 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.28 (s, 1H), 8.10 - 8.05 (m, 1H), 7.97 - 7.90 (m, 1H), 7.14 (dd, J = 9.4, 2.1 Hz, 1H), 5.61 - 5.40 (m, 1H), 4.21 (dddd, J = 20.5, 9.4, 5.7, 1.3 Hz, 2H), 3.96 (dddd, J = 24.0, 9.4, 3.3, 1.3 Hz, 2H), 3.80 (s, 3H).

[0190] Intermediate 106 Step B: 6-(3-fluoroazetidine-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid [ka] A solution of methyl 6-(3-fluoroazetidine-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (255 mg, 1.02 mmol) in 2 M aqueous lithium hydroxide (1023 μL, 2.05 mmol), THF (10.2 mL), and methanol (10.2 mL) was stirred at 40°C for 18 hours. An additional 2 M aqueous LiOH (3 mL, 3 mmol) was added, and the reaction mixture was stirred at 50°C for 6 hours. The reaction mixture was concentrated under vacuum and purified by reverse-phase column chromatography (6 g C-18 silica, 0-100% MeCN / H2O (containing 0.1% formic acid)) to obtain the title product (440 mg, 1.03 mmol, 101% yield) as a white solid. LCMS m / z: 236.1 [M+H] + , (ESI+), Rt = 0.57 (S1) 1H NMR (400 MHz, DMSO-d6) δ 8.12 [ppm]: (dd, J = 9.4, 0.8 Hz, 1H), 7.87 (s, 1H), 7.78 (dd, J = 2.0, 0.9 Hz, 1H), 6.81 (dd, J = 9.4, 2.0 Hz, 1H), 5.62 - 5.36 (m, 1H), 4.22 - 4.08 (m, 2H), 3.95 - 3.81 (m, 2H).

[0191] General Route 11 (Synthesis of 1-alkylpyrazole RHS intermediate) [ka]

[0192] Intermediate 100 Step A: Ethyl 1-{1-[(tert-butoxy)carbonyl]azetidine-3-yl}-1H-pyrazole-4-carboxylate [ka] To a solution of ethyl 1H-pyrazole-4-carboxylate (200 mg, 1.43 mmol) in acetonitrile (3 mL), tert-butyl 3-iodoazetidine-1-carboxylate (0.27 mL, 1.43 mmol) and K2CO3 (276 mg, 2.00 mmol) were added. This reaction mixture was heated at 80°C for 20 hours. The reaction product was cooled to room temperature and filtered. The filtrate was concentrated under vacuum to obtain an oily substance. Purification by column chromatography (10 g silica, 0-50% ethyl phosphate in heptane) yielded the title product (198 mg, 90% pure, 42% yield) as a colorless oil. LCMS m / z: 240.2 [M-butyl+H] + , (ESI+), Rt = 0.87 (S2) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.47 (d, J = 0.7 Hz, 1H), 7.97 (s, 1H), 5.30 - 5.21 (m, 1H), 4.31 - 4.25 (m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 4.13 (br. s, 2H), 1.40 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H).

[0193] Intermediate 101 Step B: 1-{1-[(tert-butoxy)carbonyl]azetidine-3-yl}-1H-pyrazole-4-carboxylic acid [ka] To a stirred solution of ethyl 1-(1-tert-butoxycarbonylazetidine-3-yl)pyrazole-4-carboxylate (90%, 198 mg, 0.603 mmol) in THF (2 mL) and methanol (0.2 mL), 2 M aqueous LiOH (0.40 mL, 0.800 mmol) was added. This reaction mixture was stirred at room temperature for 22 hours. The reaction mixture was concentrated under vacuum and diluted with water (5 mL), and the pH was adjusted to 4 using 10% aqueous citric acid solution. The resulting precipitate was extracted using DCM (2 × 20 mL), passed through hydrophobic frit, and concentrated under vacuum to obtain the title product (138 mg, 85% yield) as a white solid. LCMS m / z: 266.1 [M+H] + , (ESI+), Rt = 0.64 (S2) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 12.40 (br. s, 1H), 8.38 (d, J = 0.6 Hz, 1H), 7.92 (s, 1H), 5.29 - 5.20 (m, 1H), 4.31 - 4.24 (m, 2H), 4.12 (br. s, 2H), 1.40 (s, 9H).

[0194] General Route 4 (Synthesis of intermediates 4a-b) [ka]

[0195] Intermediate 4a Ethyl(3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(1R,2S,5S)-6,6-dimethyl-3-(1-methyl-1H-imidazole-4-carbonyl)-3-azabicyclo[3.1.0]hexane-2-yl]formamide}propanoate [ka] To a solution of intermediate 1b (470 mg, 0.955 mmol), intermediate 12 (282 mg, 1.05 mmol), and DIPEA (1.7 mL, 9.55 mmol) in DCM (10 mL), HATU (726 mg, 1.91 mmol) was added at room temperature and stirred for 16 hours. The reaction product was diluted with water (30 mL) and extracted with DCM (3 × 15 mL). The organic components were dehydrated with MgSO4, filtered, and concentrated to obtain a crude substance, which was purified with FC (50 g silica; 10% to 100% SiO in heptane, then 20% MeOH in SiO) to obtain a crude oily substance. When this was re-purified with basic reversed-phase FC (C18-D30g; 10%-100% MeCN in water (0.1% ammonium hydroxide)), the title intermediate (245 mg, 45% yield) was obtained as an oily substance. LCMS m / z:553.5 / 555.3[M+H]+, (ESI+), Rt=0.86(S1)

[0196] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate 4a outlined in Scheme 6.

[0197] Intermediate 4b Ethyl(3S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-{[(1R,2S,5S)-6,6-dimethyl-3-(1-methyl-1H-imidazole-4-carbonyl)-3-azabicyclo[3.1.0]hexane-2-yl]formamide}propanoate [ka] The intermediate 1e and (1R,2S,5S)-6,6-dimethyl-3-(1-methyl-1H-imidazole-4-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid were prepared using the route outlined in General Route 4. LCMS m / z:549.5 / 550.3[M+H]+, (ESI+), Rt=0.86(S1)

[0198] Intermediate 4c Ethyl(3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(1R,2S,5S)-3-{imidazo[1,2-a]pyrazine-2-carbonyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-yl]formamide}propanoate [ka] Intermediate 1b and intermediate 12c (1R,2S,5S)-3-{imidazo[1,2-a]pyrazine-2-carbonyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid were prepared using the route outlined in general route 4. LCMS m / z:592.2[M+H]+, (ESI+), Rt=0.89(S1)

[0199] General Route 5 (Suzuki coupling synthesis of intermediate 5a) [ka]

[0200] Intermediate 5a Ethyl(3S)-3-{[(1R,2S,5S)-6,6-dimethyl-3-(1-methyl-1H-imidazole-4-carbonyl)-3-azabicyclo[3.1.0]hexane-2-yl]formamide}-3-{4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl}propanoate [ka] In a pressure-resistant vial, a suspension consisting of intermediate 4a (115 mg, 0.205 mmol) of dioxane (1.5 mL) and water (0.05 mL), (2,4,6-trimethylphenyl)boronic acid (50 mg, 0.305 mmol), and K2CO3 (85 mg, 0.615 mmol) was sprayed with N2 for 3 minutes, and then Pd(dppf)Cl2 (15 mg, 0.0205 mmol) was added. The reaction mixture was stirred under N2 at 100°C for 2 hours. HCl (5 mL) and water (10 mL) were added to the reaction mixture. The water was extracted with HCl (3 × 5 mL), the combined organic matter was washed with brine (10 mL), dehydrated with MgSO4, and concentrated under vacuum to obtain the title intermediate 5a (200 mg, 56% yield) as an oily substance. LCMS m / z:589.4[M+H]+, (ESI+), Rt=1.08(S1)

[0201] General Route 6 (Amide coupling with biarylaminoesters, synthesis of intermediates 6a-e) [ka]

[0202] Intermediate 6a tert-butyl(1R,2S,5S)-2-{[(1S)-1-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-ethoxy-3-oxopropyl]carbamoyl}6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate [ka] (1R,2S,5S)-3-[(tert-butoxy)carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (3.91 g, 15.3 mmol), intermediate 1a (90%, 6.00 g, 14.6 mmol), and HATU (6.11 g, 16.1 mmol) were dissolved in DCM (100 mL), to which DIPEA (6.4 mL, 36.5 mmol) was added and the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, and the resulting aqueous layer was extracted with DCM (50 mL). The combined organic matter was dried using hydrophobic frit and concentrated under vacuum. The residual material was purified by FC (100 g, eluted with 0-50% ELISA in heptane) to obtain the title intermediate (6.40 g, 77% yield) as a glassy substance. LCMS m / z: 471.5 [M+H]+, (ESI+), Rt = 1.26 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: δ 7.80 - 7.27 (m, 1H), 7.18 - 7.10 (m, 1H), 7.10 - 7.02 (m, 2H), 6.95 - 6.81 (m, 2H), 5.71 - 5.59 (m, 1H), 4.15 - 3.96 (m, 3H), 3.71 - 3.40 (m, 2H), 2.99 - 2.79 (m, 2H), 2.02 - 1.97 (m, 3H), 1.97 - 1.93 (m, 3H), 1.60 - 1.50 (m, 1H), 1.33 - 1.13 (m, 13H), 1.04 - 0.98 (m, 3H), 0.89 - 0.85 (m, 3H). (N1)

[0203] The following intermediates were prepared using the corresponding starting materials in a similar manner to intermediate 6a outlined in Scheme 8.

[0204] Intermediate 6b tert-butyl(1R,2S,5S)-2-{[(1S)-1-[2,4-difluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-ethoxy-3-oxopropyl]carbamoyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate [ka] Starting with ethyl(3S)-3-amino-3-[2,4-difluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate hydrochloride (synthesized according to general route 1) and (1R,2S,5S)-3-[(tert-butoxy)carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid synthesized according to general route 5, the product was prepared according to general route 6 as reported in scheme 7. LCMS m / z:675.5[M+H]+, (ESI+), Rt=1.28(S1)

[0205] Intermediate 6c Ethyl(3S)-3-{[(1R,2S,5S)-3-benzoyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-yl]formamide}-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate [ka] Starting with (1R,2S,5S)-3-benzoyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, which was synthesized according to Intermediate 1a (synthesized according to General Route 1) and General Route 5, the product was prepared according to General Route 6 as reported in Scheme 7. LCMS m / z: 575.4 [M+H]+, (ESI+), Rt = 1.17 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: δ 8.71 - 8.43 (m, 1H), 7.51 - 6.93 (m, 10H), 5.63 - 5.39 (m, 1H), 4.43 - 3.89 (m, 1H), 4.07 - 3.94 (m, 2H), 3.88 - 3.55 (m, 2H), 3.25 - 2.79 (m, 2H), 2.67 - 2.57 (m, 1H), 2.00 - 1.88 (m, 6H), 1.42 - 1.31 (m, 1H), 1.13 - 1.07 (m, 3H), 0.95 - 0.79 (m, 6H). (N1)

[0206] Intermediate 6d Ethyl(3S)-3-{[(1R,2S,5S)-3-acetyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-yl]formamide}-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate [ka] Starting with intermediate 1a (synthesized according to general route 1) and (1R,2S,5S)-3-acetyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (synthesized according to general route 2), the product was prepared according to general route 6 as reported in Scheme 7. LCMS m / z: 513.3 [M+H]+, (ESI+), Rt = 4.12 (S3) 1H NMR (500 MHz, CDCl3) δ [ppm]: 7.77 (d, J = 8.4 Hz, 1H), 7.21 - 7.13 (m, 1H), 7.10 - 7.06 (m, 2H), 6.96 - 6.86 (m, 2H), 5.72 - 5.60 (m, 1H), 4.33 (s, 1H), 4.09 - 4.01 (m, 2H), 3.86 - 3.74 (m, 1H), 3.46 (d, J = 10.5 Hz, 1H), 2.94 - 2.83 (m, 2H), 2.01 (s, 3H), 2.00 (s, 3H), 2.00 (s, 3H), 1.59 (d, (N1)

[0207] Intermediate 6e tert-butyl(1R,2S,5S)-2-{[(1S)-3-ethoxy-3-oxo-1-{4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propyl]carbamoyl}6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate [ka] The compound was prepared from intermediate 1d and (1R,2S,5S)-3-[(tert-butoxy)carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid using the route outlined in general route 5. LCMS m / z: 611.3 [M+H]+, (ESI+), Rt = 1.19 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.85 - 7.28 (m, 1H), 6.93 - 6.70 (m, 4H), 5.71 - 5.59 (m, 1H), 4.14 - 3.95 (m, 3H), 3.71 - 3.43 (m, 2H), 3.03 - 2.79 (m, 2H), 2.02 - 1.91 (m, 6H), 1.41 - 1.27 (m, 7H), 1.21 - 1.14 (m, 7H), 1.04 - 1.00 (m, 3H), 0.87 (d, J = 5.3 Hz, 3H). (N1)

[0208] Intermediate 6f tert-butyl(1R,2S,5S)-2-{[(1S)-1-{4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-ethoxy-3-oxopropyl]carbamoyl}6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate [ka] The compound was prepared from intermediate 1f and (1R,2S,5S)-3-[(tert-butoxy)carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid using the route outlined in general route 5. LCMS m / z: 585.5 [M+H]+, (ESI+), Rt = 1.09 (S2) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.60 - 8.52 (m, 1H), 7.20 - 7.08 (m, 1H), 7.00 (d, J = 5.7 Hz, 1H), 6.95 - 6.88 (m, 2H), 5.59 - 5.49 (m, 1H), 4.06 - 3.95 (m, 2H), 3.89 (d, J = 20.4 Hz, 1H), 3.48 (ddd, J = 19.0, 11.0, 5.2 Hz, 1H), 3.27 (t, J = 10.5 Hz, 1H), 2.88 - 2.78 (m, 2H), 2.24 (s, 3H), 1.93 (s, 2H), 1.90 (t, J = 5.1 Hz, 4H), 1.29 (s, 3H), 1.26 (dd, J = 7.4, 5.2 Hz, 1H), 1.18 (s, 6H), 1.11 (q, J = 7.3 Hz, 3H), 1.04 (d, J = 7.5 Hz, 1H), 0.91 (d, J = 2.3 Hz, 3H), 0.84 (s, 3H). (N1)

[0209] General Route 7 (Boc deprotection, synthesis of intermediates 7a-c) [ka]

[0210] Intermediate 7a Ethyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-yl]formamide}propanoate hydrochloride [ka] Intermediate 6a (6.40 g, 11.2 mmol) was dissolved in DCM (80 mL) and HCl (4 M dioxane, 11 mL, 45.6 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum to obtain a crude oily substance, which was purified using an SCX cartridge (70 g) eluted with MeOH and NH3 in MeOH (7 M). A methanol solution was loaded onto a second SCX cartridge (70 g) eluted with NH3 in MeOH (7 M), yielding the title intermediate 7a (4.93 g, 92% yield) as a sticky glassy substance. LCMS m / z: 471.2 [M+H]+, (ESI+), Rt = 0.91 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: δ 8.81 (d, J = 9.2 Hz, 1H), 7.21 - 7.10 (m, 1H), 7.08 (d, J = 7.5 Hz, 2H), 6.88 (ddd, J = 10.0, 7.4, 2.0 Hz, 1H), 6.87 - 6.80 (m, 1H), 5.61 (dt, J = 9.3, 6.1 Hz, 1H), 4.13 - 3.99 (m, 2H), 3.58 - 3.46 (m, 1H), 3.19 (dd, J = 11.4, 4.9 Hz, 1H), 3.02 - 2.82 (m, 3H), 1.99 (d, J = 6.2 Hz, 6H), 1.68 (d, J = 7.1 Hz, 1H), 1.24 (dd, J = 7.1, 4.7 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H), 1.03 (s, 3H), 0.97 (s, 2H). (N1)

[0211] The following intermediates were prepared using the corresponding starting materials in a manner similar to 7a outlined in Scheme 9.

[0212] Intermediate 7b Ethyl(3S)-3-[2,4-difluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-{[(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-yl]formamide}propanoate hydrochloride [ka] Starting with intermediate 6b synthesized according to general route 5, the product was manufactured according to general route 7 outlined in scheme 9. LCMS m / z:553.3[M+H]+, (ESI+), Rt=1.02, (S1)

[0213] Intermediate 7c Ethyl(3S)-3-{[(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-yl]formamide}-3-{4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride [ka] Starting with intermediate 6e, the product was manufactured in accordance with the general route 7 outlined in Scheme 9. LCMS m / z: 489.3 [M+H]+, (ESI+), Rt = 2.77, (S3) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.90 (s, 1H), 9.52 (d, J = 7.6 Hz, 1H), 8.92 (s, 1H), 7.25 (ddd, J = 11.0, 7.3, 2.0 Hz, 1H), 7.11 - 7.04 (m, 1H), 7.01 (d, J = 9.8 Hz, 2H), 5.56 (q, J = 7.5 Hz, 1H), 4.10 - 3.97 (m, 3H), 3.57 - 3.53 (m, 1H), 3.35 (s, 2H), 3.06 (d, J = 12.2 Hz, 1H), 2.96 (dd, J = 7.6, 2.8 Hz, 2H), 1.97 (d, J = 13.4 Hz, 6H), 1.73 - 1.60 (m, 1H), 1.29 (dd, J = 7.9, 1.7 Hz, 1H), 1.11 (t, J = 7.1 Hz, 3H), 1.05 (s, 3H), 0.94 (s, 3H).] (N1)

[0214] intermediate 7d Ethyl(3S)-3-{4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-yl]formamide}propanoate hydrochloride [ka]

[0215] Starting with intermediate 1f, the product was manufactured in accordance with general route 7 outlined in Scheme 9. LCMS m / z: 485.4 [M+H]+, (ESI+), Rt = 3.02, (S3) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 9.37 (s, 2H), 8.96 (s, 1H), 7.25 - 7.12 (m, 1H), 7.02 (d, J = 5.6 Hz, 1H), 6.93 (d, J = 8.2 Hz, 2H), 5.54 (q, J = 7.6 Hz, 1H), 4.09 - 3.98 (m, 2H), 3.97 (s, 1H), 3.55 - 3.49 (m, 1H), 3.06 (d, J = 12.3 Hz, 1H), 2.99 - 2.87 (m, 2H), 2.25 (s, 3H), 1.93 (s, 3H), 1.90 (s, 3H), 1.64 (t, J = 7.0 Hz, 1H), 1.32 - 1.27 (m, 1H), 1.14 - 1.07 (m, 3H), 1.04 - 0.99 (m, 3H), 0.94 (d, J = 1.6 Hz, 3H). (N1)

[0216] General Route 8 (Coupling of carboxylic acid with intermediates 7a-c for the synthesis of intermediates 8a-m) [ka]

[0217] Intermediate 8a Ethyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-6,6-dimethyl-3-(2-methyl-1,3-oxazole-4-carbonyl)-3-azabicyclo[3.1.0]hexane-2-yl]formamide}propanoate [ka] A mixture consisting of 2-methyl-1,3-oxazole-4-carboxylic acid (28 mg, 0.220 mmol), intermediate 7a (90 mg, 0.191 mmol), and HATU (80 mg, 0.210 mmol) in DCM (1 mL) was mixed with DIPEA (85 μL, 0.488 mmol), and the reaction was stirred at room temperature for 2 hours. Water (2 mL) and DCM (2 mL) were added. The layers were separated, and the aqueous layer was extracted with DCM (3 × 2 mL). The organic components were dried using hydrophobic frit and concentrated under vacuum. The resulting oily substance was purified with FC (10 g silica, 0-100% ethyl phosphate in heptane) to obtain intermediate 8a (115 mg, 91% yield) as a solid. LCMS m / z: 580.6 [M+H]+, (ESI+), Rt = 1.14 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: δ 8.76 - 8.53 (m, 1H), 8.36 - 8.22 (m, 1H), 7.24 - 6.98 (m, 5H), 5.61 - 5.41 (m, 1H), 5.08 - 4.21 (m, 1H), 4.07 - 3.93 (m, 3H), 3.67 - 3.57 (m, 1H), 2.89 - 2.70 (m, 2H), 2.46 - 2.31 (m, 3H), 2.06 - 1.77 (m, 6H), 1.50 - 1.41 (m, 1H), 1.33 - 0.97 (m, 4H), 0.96 - 0.78 (m, 6H). (N1)

[0218] The intermediates listed in Table 1 were prepared using the corresponding starting materials in a manner similar to that of intermediate 8a outlined in Scheme 10.

[0219] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9]

[0220] Synthesis of other intermediates Intermediate 9a [ka]

[0221] Step A: Ethyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-6,6-dimethyl-3-{1H,2H,3H,4H-pyrrolo[1,2-a]pyrazine-6-carbonyl}-3-azabicyclo[3.1.0]hexane-2-yl]formamide}propanoate hydrochloride [ka] To a solution of tert-butyl 6-[(1R,2S,5S)-2-{[(1S)-1-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-ethoxy-3-oxopropyl]carbamoyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-1H,2H,3H,4H-pyrrolo[1,2-a]pyrazine-2-carboxylate (139 mg, 0.162 mmol) in DCM (1 mL), HCl (4 M dioxane, 0.40 mL, 1.60 mmol) was added for 2 hours. Upon removal of the solvent under reduced pressure, ethyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-6,6-dimethyl-3-{1H,2H,3H,4H-pyrrolo[1,2-a]pyrazine-6-carbonyl}-3-azabicyclo[3.1.0]hexane-2-yl]formamide}propanoate hydrochloride (136 mg, 100% yield) was obtained as a foamy substance. LCMS m / z: 619.5 [M+H]+, (ESI+), Rt = 0.92 (S1) 1H NMR (500 MHz, CDCl3) δ [ppm]: δ 7.78 (d, J = 8.5 Hz, 1H), 7.19 - 7.14 (m, 1H), 7.09 - 7.02 (m, 3H), 6.90 - 6.84 (m, 2H), 6.65 (d, J = 4.1 Hz, 1H), 6.04 (d, J = 4.0 Hz, 1H), 5.67 - 5.63 (m, 1H), 4.81 - 4.73 (m, 1H), 4.63 (s, 1H), 4.41 - 4.36 (m, 2H), 4.24 - 4.16 (m, 1H), 4.04 - 3.95 (m, 3H), 3.78 (d, J = 10.8 Hz, 1H), 3.49 - 3.42 (m, 2H), 2.91 - 2.85 (m, 2H), 1.99 (s, 3H), 1.95 (s, 4H), 1.59 (d, J = 7.5 Hz, 1H), 1.52 - 1.49 (m, 1H), 1.12 (t, J = 7.0 Hz, 3H), 1.02 (s, 3H), 0.87 (s, 3H) (N1)

[0222] Step B: Ethyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-6,6-dimethyl-3-{2-methyl-1H,2H,3H,4H-pyrrolo[1,2-a]pyrazine-6-carbonyl}-3-azabicyclo[3.1.0]hexane-2-yl]formamide}propanoate [ka] To a stirred DCE (0.8 mL) solution of ethyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-6,6-dimethyl-3-{1H,2H,3H,4H-pyrrolo[1,2-a]pyrazine-6-carbonyl}-3-azabicyclo[3.1.0]hexane-2-yl]formamide}propanoate hydrochloride (78%, 136 mg, 0.161 mmol), aqueous formaldehyde (37%, 0.10 mL, 1.34 mmol) was added. The reaction mixture was vigorously stirred at room temperature for 5 minutes, then STAB (137 mg, 0.646 mmol) was added, followed by stirring at room temperature for 2.5 hours. The mixture was then diluted with DCM (1 mL), and NaHCO3 (1 M, aqueous) was added until the solution became basic. The aqueous component was extracted with DCM (2 × 10 mL). The combined organic components were dried (to form hydrophobic frit) and concentrated to obtain the title intermediate 9a (156 mg, 99% yield) as an oily substance. LCMS m / z: 633.5 [M+H]+, (ESI+), Rt = 0.94 (S1) 1 H NMR (500 MHz, CDCl3) δ [ppm]: δ 7.76 (d, J = 8.4 Hz, 1H), 7.17 - 7.13 (m, 1H), 7.07 - 7.05 (m, 2H), 6.90 - 6.85 (m, 2H), 6.58 (d, J = 3.9 Hz, 1H), 5.84 (d, J = 3.9 Hz, 1H), 5.66 - 5.61 (m, 1H), 4.70 (s, 1H), 4.50 - 4.44 (m, 1H), 3.99 - 3.90 (m, 4H), 3.60 (s, 1H), 2.88 - 2.83 (m, 2H), 2.74 - 2.68 (m, 2H), 2.44 (s, 3H), 2.00 (s, 3H), 1.95 (s, 3H), 1.68 - 1.57 (m, 4H), 1.09 (t, J = 7.2 Hz, 3H), 1.02 (s, 3H), 0.83 (s, 3H). (N1)

[0223] Intermediate 103 Process D: Ethyl(3S)-3-{[(1R,2S,5S)-3-[1-(azetidine-3-yl)-1H-pyrazole-4-carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-yl]formamide}-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate [ka] To a stirred solution of tert-butyl 3-[4-[(1R,2S,5S)-2-[[(1S)-1-[5-(2,6-dimethylphenyl)-2,3-difluorophenyl]-3-ethoxy-3-oxopropyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]pyrazole-1-yl]azetidine-1-carboxylate (90%, 180 mg, 0.225 mmol) in DCM (1.8 mL), TFA (0.19 mL, 2.48 mmol) was added. The reaction mixture was stirred under nitrogen at room temperature for 18 hours. The reaction mixture was concentrated under vacuum, sonicated with RINKAN, and concentrated under vacuum again. Purification by SCX chromatography (25g SCX, 0-100% 7M NH3 in MeOH) yielded the title product (134mg, 83% pure, 80% yield) as a colorless gum-like substance. LCMS m / z:620.1[M+H] + (ESI+), Rt=0.83(S2)

[0224] Intermediate 104 Step E: Ethyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-6,6-dimethyl-3-[1-(1-methylazetidine-3-yl)-1H-pyrazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-2-yl]formamide}propanoate [ka] To a stirred solution of ethyl(3S)-3-[[(1R,2S,5S)-3-[1-(azetidine-3-yl)pyrazole-4-carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-3-[5-(2,6-dimethylphenyl)-2,3-difluorophenyl]propanoate (83%, 134 mg, 0.179 mmol) in DCE (0.85 mL), aqueous formaldehyde (37%, 0.11 mL, 1.44 mmol) was added. The reaction mixture was vigorously stirred under nitrogen at room temperature for 5 minutes, after which STAB (152 mg, 0.718 mmol) was added. The reaction mixture was stirred under nitrogen at room temperature for 2 hours. The residue was diluted with DCM (20 mL), and saturated NaHCO3 (aqueous solution) was added until it became basic. The organic layer was separated, and the aqueous layer was further extracted using DCM (2 × 20 ml). The combined organic layers were dried (to form hydrophobic frit) and concentrated under vacuum to obtain the title product (132 mg, 55% pure, 64% yield) as a yellow gum-like substance. LCMS m / z: 634.4 [M+H] + , (ESI+), Rt = 0.89 (S2) 1 H (500 MHz, DMSO-d6) δ [ppm]: 8.83 - 8.55 (m, 1H), 8.26 - 7.94 (m, 1H), 7.85 - 7.51 (m, 1H), 7.27 - 6.98 (m, 5H), 5.53 (q, J = 7.8 Hz, 1H), 5.02 - 4.87 (m, 1H), 4.38 - 4.28 (m, 1H), 4.04 - 3.94 (m, 3H), 3.76 - 3.53 (m, 3H), 3.40 - 3.35 (m, 2H), 2.89 - 2.75 (m, 2H), 2.33 - 2.26 (m, 3H), 1.98 - 1.90 (m, 6H), 1.55 - 1.44 (m, 1H), 1.34 - 1.19 (m, 1H), 1.13 - 1.04 (m, 3H), 0.95 - 0.89 (m, 3H), 0.83 - 0.79 (m, 3H).

[0225] Intermediate 110 2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole [ka] To a degassed suspension consisting of 1,4-dioxane (4.1 mL) and 4-bromo-2,5-dimethylindazole (300.0 mg, 1.33 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (B2Pin2) (507.599 mg, 2.0 mmol), and potassium acetate (392.596 mg, 4.0 mmol) in one drop of DMF, Pd(dppf)2Cl2 (81.133 mg, 0.11 mmol) was added. The reaction mixture was heated under MW irradiation at 150°C for 15 minutes. The reaction mixture was passed through a thiol cartridge and washed with ELISA (2 × 10 mL). The solvent was concentrated under vacuum to obtain the title product (410 mg, 71% pure, 80% yield) as a black oil. LCMS m / z:273.2[M+H] + (ESI+), Rt=1.00(S2)

[0226] Intermediate 111 (1R,2S,5S)-3-{imidazo[1,2-a]pyrazine-2-carbonyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid [ka] A stirred solution of imidazo[1,2-a]pyrazine-2-carboxylic acid (542.518 mg, 3.21 mmol) and HATU (1.44 g, 3.79 mmol) in 10 mL of DMF was stirred for 30 minutes. Methyl(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (600 mg, 2.92 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (5.08 mL, 29.2 mmol) were added, and the reaction mixture was stirred at room temperature for 17 hours. The reaction product was diluted with water (40 mL), and the organic layer was separated. The aqueous layer was extracted with SiO2 (4 × 10 mL), and the combined organic layers were washed with saturated LiCl aqueous solution, dehydrated with MgSO4, and concentrated under vacuum to obtain an orange oily substance. The crude oily substance was dissolved in THF (6.0 mL) and treated with lithium hydroxide (140 mg, 5.83 mmol) at room temperature for 18 hours. The reaction mixture was acidified to pH 3 with citric acid (10 mL) and extracted with IPC / CHCl3 1:3 (4 × 10 mL). The combined organic layers were concentrated under vacuum to obtain the title product (1.15 g, 77% pure, 101% yield) as a clear oily substance. LCMS m / z:301.0[M+H] + (ESI+), Rt=0.27(S2)

[0227] Intermediate 10a Ethyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-6,6-dimethyl-3-[(1-methyl-1H-pyrazole-4-yl)carbamoyl]-3-azabicyclo[3.1.0]hexane-2-yl]formamide}propanoate [ka] Under N2 conditions, a stirred THF (2 mL) solution of 1-methyl-1H-pyrazole-4-amine (0.049 mL, 0.574 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (200 μL, 1.15 mmol) was treated with 4-nitrophenyl chloroformate (116 mg, 0.574 mmol) at 0°C, and then warmed to room temperature and stirred for 2 hours. An anhydrous THF (1 mL) solution of intermediate 7a (90%, 100 mg, 0.191 mmol) was added, and the reaction mixture was stirred at 50°C for 4 hours.

[0228] The reaction mixture was concentrated, resuspended in SiO2 (30 mL), and washed sequentially with water (2 × 15 mL), saturated NaHCO3 solution (4 × 10 mL), and then brine (20 mL). After dehydration with MgSO4 and filtration, the mixture was concentrated to obtain the title intermediate 10a (254 mg, 100% yield) as an oily substance. LCMS m / z:594.4[M+H]+, (ESI+), Rt=1.01(S1)

[0229] Intermediate 11a [ka]

[0230] Step A: Methyl(1R,2S,5S)-6,6-dimethyl-3-(1H-pyrazole-4-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka] To a stirred solution of methyl(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (350 mg, 1.70 mmol) and 1H-pyrazole-4-carboxylic acid (98%, 200 mg, 1.75 mmol) in DCM (25 mL), DIPEA (1.0 mL, 5.73 mmol) was added, followed by HATU (800 mg, 2.10 mmol). The resulting mixture was stirred at room temperature for 18 hours, and then allowed to stand at room temperature for 3 days. The reaction mixture was washed with water (20 mL), and the resulting aqueous layer was extracted with DCM (2 × 20 mL). The combined organic components were dehydrated with Na₂SO₄ and concentrated under vacuum to obtain a crude oily product. When this was purified by FC (50 g silica, 0-100% acetone in heptane, followed by 0-10% MeOH in acetone), methyl (1R,2S,5S)-6,6-dimethyl-3-(1H-pyrazole-4-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate (497 mg, 100% yield) was obtained as an oily substance. LCMS m / z:264.2[M+H]+, (ESI+), Rt=0.64(S1)

[0231] Step B: Methyl(1R,2S,5S)-6,6-dimethyl-3-[1-(oxetan-3-yl)-1H-pyrazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka] To a suspension of methyl(1R,2S,5S)-6,6-dimethyl-3-(1H-pyrazole-4-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate (490 mg, 1.73 mmol) and 3-bromooxetane (262 mg, 1.91 mmol) from step A, stirred in anhydrous DMF (7 mL), Cs2CO3 (1.21 g, 3.71 mmol) was added, and the resulting mixture was stirred at 90°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ELISA (3 × 20 mL). The combined organic components were washed with water (20 mL) and brine (30 mL), dehydrated with Na2SO4, and concentrated under vacuum. Purification of the crude substance by FC (25g silica column, gradient of 0-100% ethyl acetate in heptane and 0-10% MeOH in ethyl acetate) yielded methyl(1R,2S,5S)-6,6-dimethyl-3-[1-(oxetan-3-yl)-1H-pyrazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate (188mg, 28% yield) as an oily substance. LCMS m / z: 320.2 [M+H]+, (ESI+), Rt = 0.64 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: δ 8.07 - 8.05 (m, 1H), 7.96 - 7.91 (m, 1H), 5.49 - 5.40 (m, 1H), 5.07 - 5.01 (m, 4H), 4.65 - 4.51 (m, 1H), 4.10 (dd, J = 9.8, 5.4 Hz, 1H), 3.80 - 3.73 (m, 4H), 1.62 - 1.54 (m, 1H), 1.52 - 1.47 (m, 1H), 1.09 - 1.06 (m, 3H), 0.98 - 0.94 (m, 3H).(N1)

[0232] Step C: (1R,2S,5S)-6,6-dimethyl-3-[1-(oxetan-3-yl)-1H-pyrazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid [ka] To a stirred solution of methyl(1R,2S,5S)-6,6-dimethyl-3-[1-(oxetan-3-yl)-1H-pyrazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate (180 mg, 0.468 mmol) from step B in THF (5 mL) and MeOH (0.4 mL), LiOH (2 M, aqueous, 1.2 mL, 2.40 mmol) was added. This mixture was stirred at room temperature for 1.5 hours and then concentrated under vacuum. The residue was suspended in MeCN (10 mL) and concentrated under vacuum to obtain the crude residue. This was partitioned between ELISA (20 mL) and citric acid (aqueous, 10% w / w, 20 mL). The aqueous layer was extracted with SiO2 (2 × 20 mL), and the combined organic components were dehydrated with Na2SO4 and concentrated under vacuum to obtain (1R,2S,5S)-6,6-dimethyl-3-[1-(oxetan-3-yl)-1H-pyrazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (intermediate 11a) (128 mg, 81% yield) as a gum-like substance. LCMS m / z: 306.2 [M+H]+, (ESI+), Rt = 0.56 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: δ 8.10 (s, 1H), 7.93 (s, 1H), 5.47 (p, J = 6.8 Hz, 1H), 5.06 (d, J = 6.9 Hz, 4H), 4.68 (s, 1H), 4.04 (dd, J = 10.1, 5.4 Hz, 1H), 3.80 (d, J = 10.1 Hz, 1H), 1.89 (d, J = 7.7 Hz, 1H), 1.64 (dd, J = 7.7, 5.4 Hz, 1H), 1.11 (s, 3H), 0.93 (s, 3H). (N1)

[0233] General Route 12 (Coupling of dimentylbicyclopropylproline with carboxylic acid) Intermediate 12a [ka]

[0234] Step A: Methyl(1R,2S,5S)-6,6-dimethyl-3-(1-methyl-1H-imidazole-4-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka] To a solution of methyl(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (2.21 g, 17.5 mmol) and HATU (6.10 g, 16.0 mmol) in DCM (45 mL), DIPEA (6.4 mL, 36.5 mmol) was added and the mixture was stirred at room temperature for 5 hours. This reaction mixture was diluted with ¼ (5 mL) and water (5 mL). Water was extracted with SiO2 (3 × 5 mL), the combined organic components were washed with brine (10 mL), dehydrated with MgSO4, and concentrated under vacuum to obtain a crude residue. This residue was purified by FC (50 g silica column, 10-100% SiO2 in heptane, then 100% MeOH) to obtain methyl (1R,2S,5S)-6,6-dimethyl-3-(1-methyl-1H-imidazole-4-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate (4.60 g, 100% yield) as an oily substance. LCMS m / z:306.2[M+H]+, (ESI+), Rt=0.56(S1)

[0235] Step B: (1R,2S,5S)-6,6-dimethyl-3-(1-methyl-1H-imidazole-4-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid [ka] To a stirred THF (44 mL) solution of methyl(1R,2S,5S)-6,6-dimethyl-3-(1-methyl-1H-imidazole-4-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate (4.60 g, 14.6 mmol) from step A, 2 M LiOH (aqueous solution) (42 mL, 84.6 mmol) was added, and the mixture was stirred at 45°C for 1 hour and then cooled. Water (10 mL) was added, and the mixture was concentrated under vacuum to remove organic matter. This solution was acidified with HCl (1 M) to pH 3 and extracted by DCM (3 × 15 mL). The organic components were concentrated under vacuum and purified by reverse-phase FC (50 g silica C18, 15 CV, 10-100% [0.1% NH3 in water] in [0.1% NH3 in MeCN]). The product was dissolved in water (20 mL), acidified to pH 3, extracted with DCM (5 × 15 mL), dried using MgSO4, and concentrated under vacuum to obtain intermediate 12a (1.60 g, 41% yield) as an oily substance. LCMS m / z: 264.2 [M+H]+, (ESI+), Rt = 0.44 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: δ 12.54 (br s, 1H), 7.68 - 7.56 (m, 2H), 4.33 - 4.23 (m, 1H), 3.70 - 3.62 (m, 4H), 3.61 - 3.52 (m, (N1)

[0236] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate 12a outlined in Scheme 13.

[0237] Intermediate 12b Methyl(1R,2S,5S)-3-{imidazo[1,2-a]pyrazine-2-carbonyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka] Starting with methyl(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride) and imidazo[1,2-a]pyrazine-2-carboxylic acid, the preparation was carried out in accordance with general route 12 outlined in scheme 13. LCMS m / z:315.2[M+H]+, (ESI+), Rt=0.70, (S1)

[0238] Intermediate 12c (1R,2S,5S)-3-{imidazo[1,2-a]pyrazine-2-carbonyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid [ka] Starting with methyl(1R,2S,5S)-3-{imidazo[1,2-a]pyrazine-2-carbonyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate, the preparation was carried out in accordance with general route 12 outlined in scheme 12. LCMS m / z: 301.2 [M+H]+, (ESI+), Rt = 0.58, (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.20 - 8.99 (m, 1H), 8.63 - 8.57 (m, 1H), 8.52 (dd, J = 9.9, 0.8 Hz, 1H), 7.96 (t, J = 4.9 Hz, 1H), 4.43 - 4.32 (m, 1H), 4.23 - 4.08 (m, 1H), 3.77 - 3.61 (m, 2H), 1.69 - 1.57 (m, 1H), 1.52 - 1.41 (m, 1H), 1.09 - 1.01 (m, 3H), 1.01 - 0.89 (m, 3H).

[0239] Intermediate 13a [ka]

[0240] Step A: Ethyl 1-[(1,3-dioxolan-2-yl)methyl]-1H-pyrazole-3-carboxylate [ka] Under a nitrogen atmosphere, 2-(bromomethyl)-1,3-dioxolane (97%, 419 μL, 3.93 mmol) was added to a stirred mixture of ethyl 1H-pyrazole-3-carboxylate (500 mg, 3.57 mmol) and CsCO3 (1.74 g, 5.35 mmol) in MeCN (10 mL), and the reaction mixture was stirred at room temperature for 44 hours. The reaction mixture was heated to 60°C for 1 hour, then to 80°C for 3 hours, then cooled and filtered through a Celite pad. The filter cake was washed with SiO2 (100 mL), and the filtrate was collected and concentrated under vacuum to obtain a crude oil. This was purified with FC (25 g, silica, 0-80% SiO2 in heptane) to obtain the title compound (223 mg, 27% yield) as an oil. LCMS m / z: 227.3 [M+H]+, (ESI+), Rt = 0.62 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.81 (d, J = 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 5.19 (t, J = 4.2 Hz, 1H), 4.34 (d, J = 4.3 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.87 - 3.77 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H).

[0241] Step B: Ethyl 1-(2-oxoethyl)-1H-pyrazole-3-carboxylate [ka] To a solution of ethyl 1-[(1,3-dioxolan-2-yl)methyl]-1H-pyrazole-3-carboxylate (70 mg, 0.306 mmol) from step A in THF (1.5 mL), HCl (2 M, 1.5 mL, 3.00 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. HCl (12 M, 50 μL, 0.600 mmol) was added, and the reaction mixture was heated to 40°C and stirred for a further 30 minutes, then heated to 50°C and stirred for 2 hours. Further HCl (12 M, 150 μL, 1.80 mmol) was added, and the reaction mixture was stirred at 50°C for 17 hours, then further HCl (12 M, 150 μL, 1.80 mmol) was added, and the reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature and extracted with DCM (3 × 2 mL). The organic matter was combined with the aqueous layer, dried using a phase separator, and concentrated under vacuum. The aqueous layer was neutralized with saturated NaHCO3 (pH 7), extracted with DCM (3 × 5 mL), dried using a phase separator, and the combined organic matter was concentrated to obtain ethyl 1-(2-oxoethyl)-1H-pyrazole-3-carboxylate (EV-HYY001-793-001) (49 mg, 53% yield) as an oily substance. LCMS m / z:201.1[M+H]+, (ESI+), Rt=0.37(S2)

[0242] Process C: Ethyl 1-[2-(azetidine-1-yl)ethyl]-1H-pyrazole-3-carboxylate [ka] To a solution of ethyl 1-(2-oxoethyl)-1H-pyrazole-3-carboxylate (161 mg, 0.307 mmol) from step B in anhydrous THF (1.5 mL), acetic acid (19 μL, 0.332 mmol) and azetidine (31 μL, 0.460 mmol) were added, and the mixture was stirred at room temperature for 20 minutes, after which STAB (98 mg, 0.462 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, and then allowed to stand at room temperature for 2 days. The reaction mixture was diluted with MeOH, purified using an SCX cartridge (1 g) eluted with NH3 (3.5 M) in MeOH, concentrated under vacuum, and dried in a vacuum oven to obtain a mixture of ethyl 1-[2-(azetidine-1-yl)ethyl]-1H-pyrazole-3-carboxylate and 1-[2-(azetidine-1-yl)ethyl]-1H-pyrazole-3-carboxylic acid (8.8 mg, 13.7% yield) (1:1) as a gum-like substance. LCMS m / z: 224.2 [M+H]+, (ESI+), Rt = 0.51 (S2) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.88 - 7.81 (m, 1H), 6.70 (d, J = 2.3 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.10 (t, J = 6.2 Hz, 2H), 3.07 - 3.02 (m, 4H), 2.73 (t, J = 6.2 Hz, 2H), 1.95 - 1.87 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H).

[0243] Step D 1-[2-(azetidine-1-yl)ethyl]-1H-pyrazole-3-carboxylate lithium [ka] To a solution of ethyl 1-[2-(azetidine-1-yl)ethyl]-1H-pyrazole-3-carboxylate (27 mg, 0.106 mmol) in THF (0.5 mL) and MeOH (50 μL), LiOH (2 M, 265 μL, 0.530 mmol) was added, and the reaction mixture was stirred at room temperature for 1.5 hours; then, upon concentration to dryness, lithium 1-[2-(azetidine-1-yl)ethyl]-1H-pyrazole-3-carboxylate (intermediate 13) (35 mg, 100% yield) was obtained as a solid. LCMS m / z: 196.1 [M+H]+, (ESI+), Rt = 0.14 (S2) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.53 (d, J = 2.2 Hz, 1H), 6.28 (d, J = 2.2 Hz, 1H), 3.93 (t, J = 6.4 Hz, 2H), 3.05 (t, J = 7.0 Hz, 4H), 2.70 (t, J = 6.4 Hz, 2H), 1.91 (p, J = 6.9 Hz, 2H).

[0244] Intermediate 14a [ka]

[0245] Step A - Ethyl 1-[2-(dimethylamino)ethyl]-1H-imidazole-5-carboxylate [ka] Ethyl 1H-imidazole-4-carboxylate (500 mg, 3.57 mmol) was dissolved in DMF (17.8 mL), and then (2-chloroethyl)dimethylamine hydrochloride (2.06 g, 14.3 mmol) and Cs2CO3 (2.32 g, 7.14 mmol) were added sequentially. This mixture was heated in a microwave at 150 °C for 3 hours, after which it was quenched with water and extracted twice with SiO2. The combined organic matter was washed with brine, dried over Na2SO4, and concentrated under vacuum. The crude residue was purified by FC (elution with a gradient of 0-5% MeOH in 24 g silica in DCM), yielding a mixture of two isomers (including ethyl 1-[2-(dimethylamino)ethyl]-1H-imidazole-5-carboxylate) as a gum-like substance (210 mg, 23% yield). LCMS m / z:212.2[M+H]+, (ESI+), Rt=1.56(S7)

[0246] Process B - Lithium 1-[2-(dimethylamino)ethyl]-1H-imidazole-5-carboxylic acid [ka] Ethyl 1-[2-(dimethylamino)ethyl]-1H-imidazole-5-carboxylate (209 mg, 0.811 mmol) from step A was dissolved in THF (9 mL) at room temperature. LiOH hydrate (170 mg, 4.06 mmol) in water (3 mL) was added, and the mixture was stirred for 16 hours. When this mixture was concentrated under vacuum, intermediate 14 (153 mg, 49% yield) was obtained. No mass ions were observed. Rt=0.18(S6)

[0247] Intermediate 16a 7-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylic acid [ka]

[0248] Step A - Methyl 5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate hydrochloride [ka] To a solution of 7-tert-butyl2-methyl5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2,7-dicarboxylate (150 mg, 0.523 mmol) in DCM (4.9 mL), HCl (4 M in dioxane, 1.4 mL, 5.60 mmol) was added. The resulting mixture was stirred under N2 at room temperature for 3 hours. When the reaction mixture was concentrated, 7-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylic acid (EV-YQP001-022-001) (120 mg, 99% yield) was obtained as a solid. LCMS m / z: 182.1 [M+H]+, (ESI+), Rt = 0.27 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.82 (br. s, 2H), 7.98 (s, 1H), 4.38 (s, 2H), 4.27 (t, J = 5.7 Hz, 2H), 3.75 (s, 3H), 3.61 (d, J = 5.8 Hz, 2H). (N1)

[0249] Step B - Methyl 7-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate [ka] To a stirred DCE (2 mL) solution of 7-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylic acid (60 mg, 0.273 mmol) and acetic acid (125 μL, 2.19 mmol) from step A, paraformaldehyde (52 mg, 1.68 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydriide (106 mg, 1.69 mmol) was added, and the mixture was stirred for a further 3 hours. The reaction product was cooled and quenched by stirring with sodium bicarbonate (saturated aqueous solution, 2 mL). The organic phase was separated using a phase separator. The aqueous components were extracted using DCM (2 × 2 mL), and the combined organic components were concentrated under vacuum to obtain a crude residue. This residue was purified using FC (11 g KP-silica, 0-15% SiO in heptane) to obtain methyl 7-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (28 mg, 44% yield) as a semi-solid. LCMS m / z: 196.3 [M+H]+, (ESI+), Rt = 0.52 (S1) 1 H NMR (400 MHz, CD3CN) δ [ppm]: 7.68 (s, 1H), 4.29 - 4.20 (m, 2H), 4.13 - 3.98 (m, 2H), 3.78 (s, 3H), 3.56 - 3.36 (m, 2H), 2.82 (s, 3H). (N1)

[0250] Step C - Ethyl(3S)-3-{[(1R,2S,5S)-6,6-dimethyl-3-{7-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carbonyl}-3-azabicyclo[3.1.0]hexane-2-yl]formamide}-3-{4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate [ka] To a THF (1 mL) solution of methyl 7-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate from step B, LiOH (2 M, aqueous, 75 μL, 0.150 mmol) was added, and the solution was stirred at room temperature for 1 hour. Next, the reaction product was concentrated under vacuum to obtain a crude intermediate. This was dissolved in DCM (1 mL) together with intermediate 7c (60 mg, 0.0937 mmol), and then DIPEA (40 μL, 0.229 mmol) and HATU (44 mg, 0.116 mmol) were added, and the resulting mixture was stirred at room temperature for 48 hours. Water (1 mL) was added to this reaction mixture, and then it was separated using a phase separator. The retained water was extracted with DCM (2 × 2 mL), and the combined organic components were concentrated under vacuum. When the residue was purified by FC (11g KP-silica, 0-10% MeOH in DCM), intermediate 16a (40mg, 25% yield) was obtained as a solid. LCMS m / z:652.5[M+H]+, (ESI+), Rt=3.02(S3)

[0251] Intermediate 17a [ka]

[0252] Step A: Methyl(1R,2S,5S)-3-[(2R)-1-acetylpyrrolidine-2-carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka] (2R)-1-acetylpyrrolidine-2-carboxylic acid (80 mg, 0.509 mmol) and methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (100 mg, 0.467 mmol) were dissolved in DCM (9 mL), to which DIPEA (203 μL, 1.16 mmol) and then HATU (195 mg, 0.513 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water (10 mL) and passed through a phase separator. The organic components were collected and concentrated under vacuum to obtain a crude oily substance. This was purified by flash column chromatography on silica (10 g, 0-100% ethyl acetate in heptane, then 0-40% MeOH in ethyl acetate) to obtain a gum-like substance. Further purification of this gum-like substance by basic reverse-phase column chromatography (6g of C18 silica, 10-100% MeCN (+0.1% ammonia) in water (+0.1% ammonia)) yielded methyl (1R,2S,5S)-3-[(2R)-1-acetylpyrrolidine-2-carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (100 mg, 69% yield) as a gum-like substance. LCMS m / z: 309.2 [M+H]+, (ESI+), Rt = 0.56 (S2) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 4.62 - 4.46 (m, 1H), 4.23 - 4.08 (m, 1H), 3.95 - 3.87 (m, 1H), 3.67 - 3.60 (m, 3H), 3.58 - 3.46 (m, 3H), 2.39 - 2.27 (m, 1H), 2.17 - 2.03 (m, 1H), 1.97 - 1.88 (m, 3H), 1.78 - 1.65 (m, 2H), 1.62 - 1.53 (m, 1H), 1.46 - 1.34 (m, 1H), 1.05 - 1.03 (m, 3H), 0.94 - 0.90 (m, 3H). (N1)

[0253] Step B (1R,2S,5S)-3-[(2R)-1-acetylpyrrolidine-2-carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid [ka] To a stirred solution of methyl(1R,2S,5S)-3-[(2R)-1-acetylpyrrolidine-2-carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (100 mg, 0.321 mmol) in THF (1.5 mL) and methanol (0.2 mL), LiOH (2 M, aqueous, 803 μL, 1.61 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum and then diluted with water (2 mL). The mixture was acidified to approximately pH 0-1 using HCl (2M, aqueous solution), extracted with HCl (3 × 5 mL), dehydrated with Na₂SO₄ along with the organic matter, filtered, and concentrated under vacuum to obtain the intermediate 17(1R,2S,5S)-3-[(2R)-1-acetylpyrrolidine-2-carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (74 mg, 64% yield) as a glassy substance. LCMS m / z: 295.3 [M+H]+, (ESI+), Rt = 0.61 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 4.47 (dd, J = 7.9, 5.5 Hz, 1H), 4.44 - 4.41 (m, 1H), 4.17 (dd, J = 10.2, 5.5 Hz, 1H), 3.71 - 3.62 (m, 1H), 3.58 - 3.46 (m, 2H), 2.26 - 2.19 (m, 1H), 2.17 - 2.13 (m, 1H), 2.11 (s, 3H), 2.02 - 1.89 (m, 2H), 1.78 (d, J = 7.5 Hz, 1H), 1.51 (dd, J = 7.5, 5.4 Hz, 1H), 1.07 (s, 3H), 0.94 (s, 3H). (N1)

[0254] Example compound Scheme for general route 1: (Hydrolysis of carboxyl esters) [ka]

[0255] [Example 1] (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-6,6-dimethyl-3-(2-methyl-1,3-oxazole-4-carbonyl)-3-azabicyclo[3.1.0]hexane-2-yl]formamide}propanoic acid [ka] To a solution of intermediate 8a (110 mg, 0.180 mmol) in THF (1 mL), LiOH (2 M, aqueous, 0.20 mL, 0.400 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction product was concentrated under vacuum to remove organic matter, and the resulting water was acidified to pH 1 with HCl (aqueous, 2 M, 0.3 mL). Water (1.5 mL) and HCl (3 mL) were added, and this aqueous layer was extracted with HCl (2 × 3 mL). The combined organic components were washed with water (1 mL) and brine (1 mL), dehydrated with MgSO4, filtered, and concentrated under vacuum to obtain a crude oily substance. Purification of this substance using preparative HPLC (P2) yielded the title compound (67 mg, 65% yield) as a solid. LCMS m / z: 552.5 [M+H]+, (ESI+), Rt = 3.81 (S3) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 12.41 (br. s, 1H), 8.78 - 8.54 (m, 1H), 8.28 (s, 1H), 7.23 - 7.07 (m, 4H), 7.00 (t, J = 6.3 Hz, 1H), 5.54 - 5.38 (m, 1H), 5.10 - 4.26 (m, 1H), 4.08 - 3.88 (m, 1H), 3.68 - 3.55 (m, 1H), 2.78 - 2.63 (m, 2H), 2.45 - 2.30 (m, 3H), 2.00 - 1.85 (m, 6H), 1.50 - 1.27 (m, 1H), 1.22 - 0.98 (m, 1H), 0.96 - 0.77 (m, 6H). (N1)

[0256] The examples in Table 2 were synthesized using the corresponding intermediates in accordance with General Route 1, as illustrated by Example 1, and purified using one of the methods listed above (P1-5). The diastereomers were separated either during final purification or, if necessary, by chiral separation. The examples were obtained as the title compound or a salt thereof.

[0257] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15]

[0258] Scheme for general route 2: (Combination of amide coupling and ester hydrolysis to carboxylate salts) [ka]

[0259] [Example 22] Step a: (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-6,6-dimethyl-3-(5-methylpyrazine-2-carbonyl)-3-azabicyclo[3.1.0]hexane-2-yl]formamide}propanoic acid [ka] To a stirred solution of intermediate 7a (26 mg, 0.188 mmol) in DCM (5 mL), DIPEA (100 μL, 0.573 mol) was added, followed by HATU (80 mg, 0.210 mmol). The resulting mixture was stirred in a sealed tube at room temperature for 2 hours, after which it was concentrated under vacuum, and the residue was dissolved in THF (3.5 mL) and MeOH (0.3 mL). LiOH (2 M, aqueous, 0.50 mL, 1.00 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, the residue was dissolved in water (3 mL), and the pH was acidified to 1 using HCl (2 M, aqueous). The resulting precipitate was collected by filtration and air-dried, and then purified by preparative HPLC (P2) to obtain the title compound (72 mg, 71% yield) as a solid. LCMS m / z: 563.2 [M+H]+, (ESI+), Rt = 3.71 (S3) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 12.39 (br. s, 1H), 8.81 - 8.33 (m, 3H), 7.20 - 7.13 (m, 2H), 7.13 - 7.07 (m, 2H), 7.05 - 6.94 (m, 1H), 5.53 - 5.26 (m, 1H), 4.83 - 4.39 (m, 1H), 3.99 - 3.67 (m, 2H), 2.79 - 2.52 (m, 5H), 1.97 - 1.87 (m, 6H), 1.44 - 1.34 (m, 1H), 1.22 - 0.99 (m, 1H), 0.95 - 0.88 (m, 6H). (N1)

[0260] The examples in Table 3 were synthesized using the corresponding starting materials, in accordance with General Route 2, as illustrated by Example 22, and purified using one of the methods listed above (P1-5). The diastereomers were separated either during final purification or, if necessary, by chiral separation. The examples were obtained as the title compound or a salt thereof.

[0261] [Table 4-1] Table 4-2 Table 4-3 Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 Table 4-9 Table 4-10 Table 4-11 Table 4-12 Table 4-13 Table 4-14 Table 4-15 Table 4-16 Table 4-17 Table 4-18 [Table 4-19] [Table 4-20]

[0262] Scheme for general pathway 3: (Continuous acylamide formation and hydrolysis of chlorides) [ka]

[0263] [Example 48] (3S)-3-[[(1R,2S,5S)-6,6-dimethyl-3-methylsulfonyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-3-[5-(2,6-dimethylphenyl)-2,3-difluorophenyl]propanoic acid (Example 48) [ka] To a solution of intermediate 7a (100%, 50 mg, 0.106 mmol) in DCM (5 mL), DIPEA (0.037 mL, 0.213 mmol) and then methanesulfonyl chloride (13 mg, 0.117 mmol) were added, and the reaction mixture was stirred at room temperature for 18 hours. Further methanesulfonyl chloride (13 mg, 0.117 mmol) and DIPEA (0.037 mL, 0.213 mmol) were added, and the reaction mixture was stirred at room temperature for 4 hours. Next, the reaction mixture was concentrated under vacuum, the residue was dissolved in THF (5 mL), and LiOH (2 M, aqueous, 0.27 mL, 0.531 mmol) was added at room temperature. After 3 hours, HCl (2 M) was added to adjust the pH to 1, and the reaction mixture was extracted using DCM (2 × 25 ml). The combined organic components were dried using a phase separator and concentrated under vacuum to obtain a residue. This residue was then purified by preparative HPLC (P2) to obtain the title compound (27 mg, 49% yield) as a powder. LCMS m / z: 521.2[M+H]+, (ESI+), Rt = 3.75, (S3) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 12.46 (s, 1H), 8.96 - 8.67 (m, 1H), 7.22 - 7.15 (m, 2H), 7.14 - 7.08 (m, 2H), 6.99 (d, J = 5.7 Hz, 1H), 5.52 (dd, J = 7.6, 7.6 Hz, 1H), 4.08 (s, 1H), 3.59 (dd, J = 9.0, 5.1 Hz, 1H), 3.31 - 3.27 (m, 1H), 2.87 (s, 3H), 2.75 (d, J = 7.5 Hz, 2H), 1.95 (d, J = 18.5 Hz, (N1)

[0264] The examples in Table 4 were synthesized using the corresponding starting materials, in accordance with General Route 3 as illustrated by Example 48, and purified using one of the methods listed above (P1-5). The diastereomers were separated either during final purification or, if necessary, by chiral separation. The examples were obtained as the title compound or a salt thereof.

[0265] [Table 5-1] [Table 5-2]

[0266] Scheme for general route 4: (One-pot Suzuki and hydrolysis) [ka]

[0267] [Example 52] (3S)-3-{4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-6,6-dimethyl-3-(1-methyl-1H-imidazole-4-carbonyl)-3-azabicyclo[3.1.0]hexane-2-yl]formamide}propanoic acid [ka] Intermediate 4a (65 mg, 0.117 mmol), (2,4,6-trimethylphenyl)boronic acid (21 mg, 0.129 mmol), and K3PO4 (76 mg, 0.359 mmol) were dissolved in 1,4-dioxane (0.7 mL) and water (94 μL). After purging with N2 for 5 minutes, (Pd(dppf)Cl2 (13 mg, 0.0155 mmol) was added, and the mixture was stirred at 90°C for 2 hours and then cooled to room temperature. This mixture was diluted with SiO2 (15 mL). The mixture was washed with water (15 mL), and the aqueous components were extracted with toluene (3 × 10 mL). The combined organic matter was washed with brine (15 mL), dried (MgSO4), and concentrated under vacuum. THF (1 mL) and LiOH (2 M, 0.30 mL, 0.593 mmol) were added to the dried residue, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was acidified to pH 1 with HCl (1 M, aqueous), and the precipitate obtained by sonication was collected by filtration. This solid was purified by high pH HPLC (P3) to obtain the title compound (19 mg, 28% yield) as a solid. LCMS m / z: 565.3[M+H]+, (ESI+), Rt = 2.38, (S3) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 9.13 - 8.79 (m, 1H), 7.54 - 7.34 (m, 1H), 7.64 - 7.17 (m, 1H), 7.10 - 7.00 (m, 1H), 6.99 - 6.88 (m, 3H), 5.43 - 5.26 (m, 1H), 5.25 - 4.27 (m, 1H), 4.35 - 3.95 (m, 1H), 3.74 - 3.53 (m, 4H), 2.68 - 2.49 (m, 2H), 2.26 (s, 3H), 1.94 - 1.82 (m, 6H), 1.45 - 0.99 (m, 2H), 0.96 - 0.80 (m, 6H). (N1)

[0268] The examples in Table 5 were synthesized using the corresponding starting materials, in accordance with general route 4 as illustrated by Example 52, and purified using one of the methods listed above (P1-5). The diastereomers were separated either during final purification or, if necessary, by chiral separation. The examples were obtained as the title compound or a salt thereof.

[0269] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8]

[0270] Ray-integrin cell adhesion assay a4b7 cell adhesion assay: A clear, unbound v-bottom plate was used to dispense the compound from a 10 mM storage solution. The compound was dispensed and reconstituted in 250 mL of PBS to obtain a 200 mg / mL solution. This was then further diluted to 6 mg / mL in 5 mL of carbonate buffer (150 mL of storage solution + 4850 mL of carbonate buffer). In a black, highly binding maxisorp plate, 50 mL of this protein solution was added to the compound well, and 50 mL of carbonate buffer was added to the control well, and the plate was incubated overnight at 4°C. This plate is called Plate 2. RPMI8866 cells were prepared as a semi-logarithmic dilution series and normalized to 0.1% DMSO. This plate is called Plate 1. Recombinant human MAdCAM (storage solution: 50 mg of protein) was reconstituted at a density of 75,000 cells / well in plate culture medium (PBS, 50 mM HEPES, 3 mM MgCl2, 1 mM CaCl2, 1% BSA) with 1:1000 calcein AM. Cells were added to the compound plate prepared above (Plate 1) and incubated at 370C and 5% CO2 for 1 hour. Before adding 100 mL of cell suspension using Via Flo (96-well format), the protein-coated plate (Plate 2) was washed with PBS and blocked with 4% BSA for 2 hours. This plate was incubated at 370C and 5% CO2 for 1 hour. The supernatant was aspirated from this plate and rotated at 450 g for 30 seconds to remove unbound cells. The plate, including residual adherent cells, was then read using fluorescence reading mode with excitation wavelength 485 nm and emission wavelength 385 nm.

[0271] a4b1 cell adhesion assay: A clear, unbound v-bottom plate was used to dispense compounds from a 10 mM storage solution. Compounds were dispensed in a semi-logarithmic dilution series and normalized to 0.1% DMSO. Recombinant human VCAM (storage solution: 100 mg protein) was reconstituted in 1000 mL of PBS to obtain a 100 mg / mL solution. This was then further diluted to 3 mg / mL in 5 mL of carbonate buffer (150 mL storage solution + 4850 mL carbonate buffer). In a black, highly binding maxisorp plate, 50 mL of this protein solution was added to the compound well, and 50 mL of carbonate buffer was added to the control well, and incubated overnight at 4°C. Jurkat cells were reconstituted at a density of 50,000 cells / well in plate culture medium (PBS, 50 mM HEPES, 3 mM MgCl2, 1 mM CaCl2, 1% BSA) with 1:1000 calcein AM. Cells were added to the compound plates prepared above and incubated at 37°C and 5% CO2 for 1 hour. Before adding 100 mL of cell suspension using a Via Flo (96-well format), the protein-coated plates were washed with PBS and incubated at 37°C and 5% CO2 for 1 hour. The supernatant was aspirated from this plate and rotated at 450 g for 30 seconds to remove unbound cells. The plates, including residual adherent cells, were then read using fluorescence reading mode with excitation wavelength 485 nm and emission wavelength 385 nm.

[0272] The activity of the compound of the present invention is reported in Table 6 and explained as follows: C=IC 50 >1μM; B=1μM≧IC 50 ≥0.01μM; A=IC 50 <0.01 μM.

[0273] [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8]

[0274] Selected Embodiments Embodiment 1. Compound of Formula I or a pharmaceutically acceptable salt thereof: [ka] (In the formula: R x is hydrogen or methyl; R 1 is -SO2-C 1~6 Alkyl or -C(O)-R 7 and; Here, R 7 -C is substituted with 0 or 1 substituent selected from pyridine, phenyl, and cyclopropyl. 1~6 Is it alkyl? or R 7 These are phenyl or 5-10 membered heterocyclines, each with 0, 1, 2, or 3 R groups. 9 It is independently replaced by instances of; R 9 These are halogen, =O, and -C respectively. 1~6 Alkyl, -C(O)-R 10 , -C 1~6 Haloalkyl, -SO2-C 1~6 Alkyl, -NH-C 1~4 Alkyl, -N(C 1~4 Alkyl)2,-C 3~6 Cycloalkyl, -OR 11, independently selected from phenyl and 4-10 membered heterocycles; R 9 These are R 17 It is independently replaced by 0, 1, 2, or 3 instances of it; R 17 is halogen, -C 1~6 Alkyl, -OR 15 -C(O)-N(C 1~4 Alkyl)2,-N(R 12 R 13 ), selected from 4- to 10-membered complex rings, where R 17 If it is a heterocycle, then this is a halogen, -C 1~6 Alkyl, =O, -C(O)-R 14 , -C 1~6 Haloalkyl, -SO2-C 1~6 Alkyl, -NH-C 1~4 Alkyl, -N(C 1~4 Alkyl)2,-C 3~6 Cycloalkyl, -OR 18 It is further replaced by 0, one, or two elements selected independently of it; R 10 is -C 1~6 Alkyl, -C 1~6 Alkyl-C 3~6 Cycloalkyl and C 3~6 Selected independently from cycloalkyl groups; R 11 is -C 1~6 Alkyl, -C 1~6 Haloalkyl or 4-10 membered heterocycle or -C 1~6 Alkyl-N(C 1~6 Alkyl)2, where the 4-10 membered heterocycle has 0 or 1 -C 1~6 Substituted with alkyl; R 12 and R 13 is -C 1~6 Alkyl, -C 1~6 Independently selected from haloalkyl and cyclopropyl; R 14 is -C 1~6 Alkyl and C 3~6 Selected independently from cycloalkyl groups; R 15 is -C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Alkyl-N(C 1~6 A heterocycle with 2 or 4 to 10 members (alkyl), R 15 If it is a 4- to 10-member complex ring, then it is 0 or 1 -C 1~6 Substituted with alkyl; R 18 is -C 1~6 Alkyl or -C 1~6 It is a haloalkyl; Here, -N(C 1~6 Alkyl)2 or -N(C 1~4 In each of alkyl)2, the two alkyl groups bonded to N may be the same or different; or R 7 -NHR 19 And R 19 is 0 or 1 -C 1~6 It is a 4- to 10-membered heterocycle substituted with alkyl groups; R 2 These are selected from the group consisting of Br, phenyl, naphthyl, and 5-10 membered heteroaryls, which are respectively -CN, -C 1~6 Alkyl, halogen, -C 1~6 Haloalkyl, -OC 1~6 Alkyl, phenyl, 5-6 member heteroaryl, -OC 3~6 It is independently substituted with 0, 1, 2, or 3 groups independently selected from cycloalkyl, -O-phenyl, and -O-(5-6 membered heterocycloalkyl); Y is -N= or -C(R 3 )= and; R 3 is halogen, -C 1~6 Haloalkyl, -C 1~4 Alkyl, -C 3~6 It is a cycloalkyl; R 4 is a halogen or hydrogen; R 5 is a halogen or hydrogen; R 6 is -C(O)-OR 8 And, Here, R 8 is hydrogen or -C 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-R 16 And, R 16 is -C 1~6 These are alkyl, 3-6 cycloalkyl, and 4-6 membered partially saturated heterocycles, where the partially saturated heterocycle is defined as =O or -C. 1~4 (Further substitution with one or two groups independently selected from the alkyl group).

[0275] Embodiment 2. The compound of Embodiment 1 or a pharmaceutically acceptable salt thereof having formula Ia. [ka] (In the formula, R 1 ~R 6 (and Y are as defined in Embodiment 1).

[0276] Embodiment 3. R x That is hydrogen. The compound of Embodiment 1 or a pharmaceutically acceptable salt thereof.

[0277] Embodiment 4. R 2 However, these are phenyl or 5-10 member heteroaryl groups, and these groups are -CN, -C, respectively. 1~6 Alkyl, halogen, -C 1~6 Substituted by one, two, or three groups independently selected from the haloalkyl group. Any one of the compounds or pharmaceutically acceptable salts thereof from the above embodiments.

[0278] Embodiment 5. R 2 However, -CN, -C 1~6 Alkyl, halogen, -C 1~6 Substituted by one, two, or three groups independently selected from the haloalkyl group, R 2but, [ka] Selected from, Any one of the compounds or pharmaceutically acceptable salts thereof from the above embodiments.

[0279] Embodiment 6. R 2 However, it is substituted with one, two, or three groups independently selected from methyl, fluorine, or -CF3. [ka] Selected from, Any one of the compounds or pharmaceutically acceptable salts thereof from the above embodiments.

[0280] Embodiment 7. A compound from any of the embodiments or a pharmaceutically acceptable salt thereof, wherein Y is -N=.

[0281] Embodiment 8. Y is -C(R 3 ) = any one of the compounds or pharmaceutically acceptable salts thereof of the above embodiments.

[0282] Embodiment 9. R 3 However, these are halogen, -CF3, methyl, ethyl, and cyclopropyl; Any one of the compounds or pharmaceutically acceptable salts thereof from the above embodiments.

[0283] Embodiment 10. R 4 However, it is a halogen or hydrogen. Any one of the compounds or pharmaceutically acceptable salts thereof from the above embodiments.

[0284] Embodiment 11. R 4 The compound of Embodiment 10, wherein is a halogen.

[0285] Embodiment 12. R 4 A compound or pharmaceutically acceptable salt thereof of any one of the embodiments, wherein fluorine is present.

[0286] Embodiment 13. R 5 A compound from any one of Embodiments 1 to 7, wherein the compound is either fluorine or hydrogen.

[0287] Embodiment 14. R 5 A compound from any one of embodiments 1 to 7, wherein the compound is hydrogen.

[0288] Embodiment 15. R 6 ga -C(O)-OR 8 And here, R 8 However, hydrogen, methyl, ethyl or isopropyl, -O-CH2-OC(O)-R 16 Or -OC(CH3)-OC(O)-R 16 And here, R 16 The compound of any one of the embodiments is methyl, ethyl, isopropyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexane, neopentyl, or (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl.

[0289] Embodiment 16. R 6 However, -C(O)-OR 8 And here, R 8 The compound is one of any one of Embodiments 1 to 8, wherein the compound is hydrogen, methyl, ethyl, or isopropyl.

[0290] Embodiment 17. R 8 The compound of Embodiment 9, wherein the compound is hydrogen.

[0291] Embodiment 18. R 7 However, -C is substituted with 0 or 1 phenyl or cyclopropyl group. 1~6 Is it alkyl? or R 7 However, 0 or 1 -N(C 1~4 Is it a phenyl substituted with alkyl)2? or R 7 However, R 9A 5-10 member heterocycline substituted with 0, 1, 2, or 3 groups independently selected from, R 9 These are halogen, =O, and -C respectively. 1~6 Alkyl, -C(O)-R 10 , -C 1~6 Haloalkyl, -SO2-C 1~6 Alkyl, -NH-C 1~4 Alkyl, -N(C 1~4 Alkyl)2,-C 3~6 Cycloalkyl, phenyl, 4-7 membered heterocycle, -OR 11 Selected independently from; R 9 Each of these is R 17 It is independently replaced by 0, one or two, which are independently selected from; R 10 However, -C 1~6 Alkyl, C 3~6 Cycloalkyl and -C 1~6 Alkyl-C 3~6 Selected independently from cycloalkyl groups; R 11 However, -C 1~6 Alkyl, -C 1~6 Alkyl-N(-C) 1~6 Alkyl)2,-C 1~6 It is a haloalkyl or a 4- to 7-membered heterocycle; R 17 However, halogen, -OR 15 , -C(O)N(C 1~4 Alkyl)2,-N(R 12 R 13 ) and selected from 4- to 10-membered heterorings, R 17 However, if it is a 4- to 10-membered heterocycle, this is a halogen, -C 1~6 Alkyl or -C 1~6 Substituted by 0, 1, or 2 atoms, independently selected from the haloalkyl group; R 12 and R 13 However, -C 1~6 Alkyl, -C 1~6 Independently selected from haloalkyl and cyclopropyl; R 15 However, -C1~6 Alkyl, -C 1~6 It is a haloalkyl or a 4- to 7-membered heterocycle, R 15 If it is a 4- to 7-member complex ring, then it is 0 or 1 -C 1~6 Substituted with alkyl; Here, -N(C 1~6 Alkyl)2 or -N(C 1~4 In each of alkyl)2, the two alkyl groups bonded to N may be the same or different. or R 7 However, -NHR 19 And R 19 However, 0 or 1 -C 1~6 It is a 5-membered heteroaryl substituted with an alkyl group. A compound from any one of the above embodiments.

[0292] Embodiment 19. R 7 However, -C is substituted with 0 or 1 phenyl or cyclopropyl group. 1~6 Is it alkyl? or R 7 However, 0 or 1 -N(C 1~4 Is it a phenyl substituted with alkyl)2? or R 7 However, R 9 A 5-10 member heterocycline substituted with 0, 1, 2, or 3 groups independently selected from, R 9 These are halogen, =O, and -C respectively. 1~6 Alkyl, -C(O)-R 10 , -C 1~6 A haloalkyl group is independently selected from 4- to 7-membered heterocycles; R 9 Each of these is R 17 It is independently replaced by 0, one or two, which are independently selected from; R 10 However, -C 1~6 It is alkyl; R 17 However, halogen, -N(R 12 R 13) and selected from 4- to 10-membered heterorings, R 17 However, in the case of a 4- to 10-membered heterocycle, it is substituted by 0, 1, or 2 elements independently selected from the halogen; R 12 and R 13 However, -C 1~6 It is an instance of alkyl; Here, -N(C 1~6 Alkyl)2 or -N(C 1~4 In each of alkyl)2, the two alkyl groups bonded to N may be the same or different; or R 7 However, -NHR 19 And R 19 However, -C 1~6 It is a five-membered heteroaryl that is further substituted with alkyl. A compound from any one of the above embodiments.

[0293] Embodiment 20. R 7 However, if it is substituted or unsubstituted [ka] A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of the above embodiments.

[0294] Embodiment 21. R 7 However, if it is substituted or unsubstituted [ka] A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of the above embodiments.

[0295] Embodiment 22. R 7 but, [ka] A group consisting of the following is selected, and each is: -F, -Cl, oxo, -Me, - i Bu, - iPr, cyclobutyl, -CH2F, -CHF2, -CH2CF3, -CF3, -OMe, -OCF3, -O-azetidine-3-yl, -N(Me)2, -C(O)Me, -N(Me)2-C(O)cyclopropyl, 1-Me-azetidine-3-yl, 3-F-azetidine-1-yl, oxetane-3-yl, --C(O)CH2cyclopropyl, -CH2cyclopropyl, -CH2-CH2-azeditin-1-yl, -CH2-CH2-(3-F-azeditin-1-yl), -CH2-CH2-(3,3-diF-azeditin-1-yl), -CH2-CH2-(3,3-diMe-azeditin A compound from any of the embodiments or a pharmaceutically acceptable salt thereof, substituted with one or two substituents independently selected from -1-yl), -CH2-azeditin-1-yl, -CH2-(3-F-azeditin-1-yl), -CH2-(1-Me-azetidine-3-yl), -CH2-azetidine-3-yl, -CH2CH2-(3-F-pyrrolidine-1-yl), -CH2CH2OCH3, -CH2C(O)N(Me)2, -CH2CH2N(Me)2, -CH2CH2CH2N(Me)2-CH2CH2N(Me)CH2CF3, -CH2CH2N(Me)cyclopropyl, 4-F-phenyl, and -S(O)2Me.

[0296] Embodiment 23.0, the compound of Embodiment 21 or 22, wherein one or two substituents are independently selected from: -F, -Cl, oxo, -Me, -N(Me)2, -C(O)Me, 3-F-azetidine-1-yl, oxetan-3-yl, -CH2-cyclopropyl, -CH2-CH2-azeditin-1-yl, and -CH2CH2N(Me)2.

[0297] Embodiment 24. R 1 However, the following: -C(O)-CH3, -S(O)2Me [ka] [ka] A compound or a pharmaceutically acceptable salt thereof selected from any one of the embodiments described above.

[0298] Embodiment 25. R 2 These are -Br and -CF3, respectively. [ka] A compound from any one of the embodiments or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of the above.

[0299] Embodiment 26. R 3 However, one of the compounds or pharmaceutically acceptable salts thereof from the embodiments, independently selected from the group consisting of -F, -CF3, and -CH3.

[0300] Embodiment 27. The following [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] A compound or a pharmaceutically acceptable salt thereof, selected from the above.

[0301] Embodiment 28. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound selected from any of the embodiments or a pharmaceutically acceptable salt of any of the above, and a pharmaceutically acceptable carrier or excipient.

[0302] Embodiment 29. Use of a compound selected from any of the embodiments or any pharmaceutically acceptable salt described above in the manufacture of a pharmaceutical product.

[0303] Embodiment 30. A compound selected from any of the embodiments above, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0304] Embodiment 31. A method for inhibiting the interaction between α4β7 integrin and MAdCAM-1 protein in a subject, comprising administering to a subject requiring such inhibition a pharmaceutically effective amount of a compound selected from any of the embodiments, a compound selected from any of the embodiments, or a pharmaceutically acceptable salt thereof.

[0305] Embodiment 32. A method for treating inflammatory bowel disease in a person in need thereof, comprising administering to the person a pharmaceutically effective amount of a compound selected from any one of Embodiments 1 to 27 or a pharmaceutically acceptable salt thereof.

[0306] Embodiment 33. A compound selected from any of the embodiments, a compound selected from any one of embodiments 1 to 27, or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory bowel disease.

[0307] Embodiment 34. The method of Embodiment 32 or 33, wherein the inflammatory bowel disease is ulcerative colitis.

[0308] Embodiment 35. The method of Embodiment 32 or 33, wherein the inflammatory bowel disease is Crohn's disease.

[0309] Embodiment 36. A method for treating ulcerative colon disease in a human, comprising administering to a human in need a pharmaceutically effective amount of a compound selected from any one of Embodiments 1 to 27 or a pharmaceutically acceptable salt thereof.

[0310] Embodiment 37. A compound selected from any one of Embodiments 1 to 27 or a pharmaceutically acceptable salt thereof for use in the treatment of ulcerative colon disease.

[0311] Embodiment 38. The method of Embodiment 37, wherein the ulcerative colon disease is ulcerative colitis.

[0312] Embodiment 39. The method of Embodiment 37, wherein the ulcerative colon disease is Crohn's disease.

[0313] Embodiment 40. A kit, the following: a) One or more compositions, each comprising a pharmaceutically effective amount of a compound selected from any one of Embodiments 1 to 27 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient; and b) Instructions for use for administering one or more compositions to a person who needs them. A kit that includes this.

Claims

1. Compounds of formula I or pharmaceutically acceptable salts thereof: 【Chemistry 1】 (In the formula: R ｘ is hydrogen or methyl; R １ is, -SO ２ -C １～６ Alkyl or -C(O)-R ７ And; Here, R ７ -C is substituted with 0 or 1 substituent selected from pyridine, phenyl, and cyclopropyl. １～６ Is it alkyl? or R ７ is phenyl or a 5- to 10-member heterocyclyl, each of which is independently substituted by 0, 1, 2 or 3 instances of R ９ ; R ９ These are halogen, =O, and -C respectively. １～６ Alkyl, -C(O)-R １０ , -C １～６ Haloalkyl, -SO ２ -C １～６ Alkyl, -NH-C １～４ Alkyl, -N(C) １～４ Alkyl) ２ , -C ３～６ Cycloalkyl, -O-R １１ , independently selected from phenyl and 4- to 10-membered heterocycles; R ９ These are R １７ It is independently replaced by 0, 1, 2, or 3 instances of it; R １７ is halogen, -C １～６ Alkyl, -O-R １５ , -C(O)-N(C １～４ Alkyl) ２ , -N(R １２ R １３ ), selected from 4- to 10-membered complex rings, where R １７ If it is a heterocycle, then this is a halogen, -C １～６ Alkyl, =O, -C(O)-R １４ , -C １～６ Haloalkyl, -SO ２ -C １～６ Alkyl, -NH-C １～４ Alkyl, -N(C) １～４ Alkyl) ２ , -C ３～６ Cycloalkyl, -O-R １８ It is further substituted by 0, one or two elements selected independently of it; R １０ is, -C １～６ Alkyl, -C １～６ Alkyl-C ３～６ Cycloalkyl and C ３～６ Selected independently from cycloalkyl; R １１ is, -C １～６ Alkyl, -C １～６ Haloalkyl or 4-10 membered heterocycle or -C １～６ Alkyl-N(C) １～６ Alkyl) ２ Here, a 4- to 10-membered complex ring has 0 or 1 -C １～６ Substituted with alkyl; R １２ and R １３ is, -C １～６ Alkyl, -C １～６ Independently selected from haloalkyl and cyclopropyl; R １４ is, -C １～６ Alkyl and C ３～６ Selected independently from cycloalkyl; R １５ is, -C １～６ Alkyl, -C １～６ Haloalkyl, -C １～６ Alkyl-N(C) １～６ Alkyl) ２ Or a 4- to 10-membered complex ring, R １５ If it is a 4- to 10-membered complex ring, then it has 0 or 1 -C １～６ Substituted with alkyl; R １８ is, -C １～６ Alkyl or -C １～６ It is a haloalkyl; Here, -N(C) １～６ Alkyl) ２ or -N(C) １～４ Alkyl) ２ In each of these, the two alkyl groups bonded to N may be the same or different; or R ７ -NHR １９ And R １９ is 0 or 1 -C １～６ It is a 4- to 10-membered heterocycle substituted with an alkyl group; R ２ The group is selected from the group consisting of Br, phenyl, naphthyl, and 5- to 10-membered heteroaryl groups, where these groups are -CN and -C, respectively. １～６ Alkyl, halogen, -C １～６ Haloalkyl, -O-C １～６ Alkyl, phenyl, 5-6 member heteroaryl, -O-C ３～６ It is independently substituted with 0, 1, 2, or 3 groups independently selected from cycloalkyl, -O-phenyl, and -O- (5-6 membered heterocycloalkyl); Y is -N = or -C(R ３ ) = and; R ３ is halogen, -C １～６ Haloalkyl, -C １～４ Alkyl, -C ３～６ It is a cycloalkyl; R ４ is a halogen or hydrogen; R ５ is halogen or hydrogen; R ６ is -C(O)-O-R ８ And, Here, R ８ is hydrogen or -C １～４ Alkyl, -C １～４ Alkyl-O-C(O)-R １６ And, R １６ is -C １～６ alkyl, 3-6 cycloalkyl, or a 4-6 member partially saturated heterocyclic ring, where the partially saturated heterocyclic ring is further substituted by one or two groups independently selected from =O or -C １～４ alkyl).

2. A compound according to claim 1 having formula Ia, or a pharmaceutically acceptable salt thereof. 【Chemistry 2】 (In the formula, R １ ~R ６ , R ｘ (and Y are as defined in claim 1).

3. R ｘ That is hydrogen. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R ２ However, these are phenyl or a 5-10 member heteroaryl, where these groups are -CN and -C respectively. １～６ Alkyl, halogen, -C １～６ Substituted by one, two, or three groups independently selected from the haloalkyl group. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3.

5. R ２ However, -CN, -C １～６ Alkyl, halogen, -C １～６ Substituted by one, two, or three groups independently selected from haloalkyl groups, R ２ but, 【Transformation 3】 Selected from, A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4.

6. R ２ However, methyl, fluorine or -CF ３ It is replaced by one, two, or three groups independently selected from it. 【Chemistry 4】 Selected from, A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5.

7. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein Y is -N =

8. Y is -C(R ３ A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein ) =

9. R ３ However, halogen, -CF ３ These are methyl, ethyl, and cyclopropyl; A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8.

10. R ４ However, it is a halogen or hydrogen. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9.

11. R ４ The compound according to claim 10, wherein is a halogen.

12. R ４ A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein is fluorine.

13. R ５ The compound according to any one of claims 1 to 7, wherein the compound is fluorine or hydrogen.

14. R ５ The compound according to any one of claims 1 to 7, wherein is hydrogen.

15. R ６ ga-C(O)-O-R ８ And here, R ８ However, hydrogen, methyl, ethyl or isopropyl, -O-CH ２ -O-C(O)-R １６ or -O-C(CH ３ )-OC(O)-R １６ And here, R １６ The compound according to any one of claims 1 to 14, wherein the compound is methyl, ethyl, isopropyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexane, neopentyl, or (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl.

16. R ６ However, -C(O)-O-R ８ And here, R ８ The compound according to any one of claims 1 to 8, wherein the compound is hydrogen, methyl, ethyl, or isopropyl.

17. R ８ The compound according to claim 9, wherein is hydrogen.

18. R ７ However, it is substituted with 0 or 1 phenyl or cyclopropyl -C １～６ Is it alkyl? or R ７ However, 0 or 1 -N(C) １～４ Alkyl) ２ Is it a phenyl substituted by, or R ７ However, R ９ A 5- to 10-membered heterocycline substituted with 0, 1, 2, or 3 groups independently selected from, R ９ These are halogen, =O, and -C respectively. １～６ Alkyl, -C(O)-R １０ , -C １～６ Haloalkyl, -SO ２ -C １～６ Alkyl, -NH-C １～４ Alkyl, -N(C) １～４ Alkyl) ２ , -C ３～６ Cycloalkyl, phenyl, 4-7 membered heterocycle, -O-R １１ Selected independently from; R ９ Each of them is R １７ It is independently replaced by one or two 0s, which are independently selected from; R １０ However, -C １～６ Alkyl, C ３～６ Cycloalkyl and -C １～６ Alkyl-C ３～６ Selected independently from cycloalkyl; R １１ However, -C １～６ Alkyl, -C １～６ Alkyl-N(-C) １～６ Alkyl) ２ , -C １～６ It is a haloalkyl or a 4- to 7-membered heterocycle; R １７ However, halogen, -OR-R １５ , -C(O)N(C １～４ Alkyl) ２ , -N(R １２ R １３ ) and selected from 4- to 10-membered heterorings, R １７ However, in the case of a 4- to 10-membered heterocycle, this is a halogen, -C １～６ Alkyl or -C １～６ Substituted by 0, 1, or 2 atoms, independently selected from haloalkyl groups; R １２ and R １３ However, -C １～６ Alkyl, -C １～６ Independently selected from haloalkyl and cyclopropyl; R １５ However, -C １～６ Alkyl, -C １～６ It is a haloalkyl or a 4- to 7-membered heterocycle, R １５ If it is a complex ring with 4 to 7 members, then it has 0 or 1 -C １～６ Substituted with alkyl; Here, -N(C) １～６ Alkyl) ２ or -N(C) １～４ Alkyl) ２ In each of these, the two alkyl groups bonded to N may be the same or different. or R ７ However, -NHR １９ And R １９ However, 0 or 1 -C １～６ It is a five-membered heteroaryl substituted with alkyl. The compound according to any one of claims 1 to 17.

19. R ７ However, it is substituted with 0 or 1 phenyl or cyclopropyl -C １～６ Is it alkyl? or R ７ However, 0 or 1 -N(C) １～４ Alkyl) ２ Is it a phenyl substituted by, or R ７ However, R ９ A 5- to 10-membered heterocycline substituted with 0, 1, 2, or 3 groups independently selected from, R ９ These are halogen, =O, and -C respectively. １～６ Alkyl, -C(O)-R １０ , -C １～６ A haloalkyl group is independently selected from 4- to 7-membered heterocycles; R ９ Each of them is R １７ It is independently replaced by one or two 0s, which are independently selected from; R １０ However, -C １～６ It is alkyl; R １７ However, halogen, -N(R １２ R １３ ) and selected from 4- to 10-membered heterorings, R １７ However, in the case of a 4- to 10-membered heterocycle, it is substituted by 0, one, or two elements independently selected from the halogen; R １２ and R １３ However, -C １～６ It is an instance of alkyl; Here, -N(C) １～６ Alkyl) ２ or -N(C) １～４ Alkyl) ２ In each of these, the two alkyl groups bonded to N may be the same or different; or R ７ However, -NHR １９ And R １９ However, -C １～６ It is a five-membered heteroaryl that is further substituted with alkyl. The compound according to any one of claims 1 to 18.

20. R ７ However, if it is substituted or unsubstituted 【Transformation 5】 A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

21. R ７ However, if it is substituted or unsubstituted 【Transformation 6】 A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following:

22. R ７ but, 【Transformation 7】 A group consisting of the following is selected, and each is: -F, -Cl, oxo, -Me, - ｉ Bu, - ｉ Pr, cyclobutyl, -CH ２ F, -CHF ２ ien-CH ２ CF ３ , -CF ３ , -OMe, -OCF ３ -O-azetidine-3-yl, -N(Me) ２ , -C(O)Me, -N(Me) ２ -C(O)cyclopropyl, 1-Me-azetidine-3-yl, 3-F-azetidine-1-yl, oxetane-3-yl, --C(O)CH ２ Cyclopropyl, -CH ２ Cyclopropyl, -CH ２ -CH ２ -Azeditin-1-yl, -CH ２ -CH ２ -(3-F-azeditin-1-yl),-CH ２ -CH ２ - (3-CF) ３ -Azeditin-1-yl), -CH ２ -CH ２ -(3,3-diF-azeditin-1-yl),-CH ２ -CH ２ -(3,3-diMe-azeditin-1-yl),-CH ２ -Azeditin-1-yl, -CH ２ -(3-F-azeditin-1-yl),-CH ２ -(1-Me-azetidine-3-yl),-CH ２ -Azetidine-3-yl, -CH ２ CH ２ -(3-F-pyrrolidine-1-yl),-CH ２ CH ２ OCH ３ ien-CH ２ C(O)N(Me) ２ ien-CH ２ CH ２ N(Me) ２ ien-CH ２ CH ２ CH ２ N(Me) ２ -CH ２ CH ２ N(Me)CH ２ CF ３ ien-CH ２ CH ２ N(Me)cyclopropyl, 4-F-phenyl and -S(O) ２ Substituted by 0, 1, or 2 substituents independently selected from Me, A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21.

23. 0, one or two substituents, including: -F, -Cl, oxo, -Me, -N(Me) ２ -C(O)Me,3-F-azetidine-1-yl,oxetane-3-yl,-CH ２ Cyclopropyl, -CH ２ -CH ２ -Azeditin-1-yl and -CH ２ CH ２ N(Me) ２ A compound according to claim 21 or 22, independently selected from the above.

24. R １ However, the following: -C(O)-CH ３ , -S(O) ２ Me 【Chemistry 8-1】 【Chemistry 8-2】 A compound or a pharmaceutically acceptable salt thereof, selected from any one of claims 1 to 23.

25. R １ However, the following: 【Chemistry 9-1】 【Chemistry 9-2】 A compound or a pharmaceutically acceptable salt thereof, selected from any one of claims 1 to 24.

26. R ２ -Br, -CF ３ 【Chemistry 10】 A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of the above.

27. R ３ However, -F, -CF ３ and -CH ３ A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of the above.

28. below Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

29. below Table 2 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

30. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound selected from any one of claims 1 to 29 or any pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

31. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29 in the manufacture of a pharmaceutical product.

32. A compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

33. In the subject, α ４ β ７ A method for inhibiting the interaction between an integrin and the MAdCAM-1 protein, comprising administering a pharmaceutically effective amount of a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof to a subject requiring such inhibition.

34. A method for treating inflammatory bowel disease in a person in need thereof, comprising administering to the person a pharmaceutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29.

35. A compound selected from any one of claims 1 to 29, a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory bowel disease.

36. The method according to claim 33 or 34, wherein the inflammatory bowel disease is ulcerative colitis.

37. The method according to claim 33 or 34, wherein the inflammatory bowel disease is Crohn's disease.

38. A method for treating ulcerative colon disease in a human, comprising administering to a human in need of such treatment a pharmaceutically effective amount of a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

39. A compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, for use in the treatment of ulcerative colon disease.

40. The method according to claim 38, wherein the ulcerative colon disease is ulcerative colitis.

41. The method according to claim 38, wherein the ulcerative colon disease is Crohn's disease.

42. It's a kit, a) One or more compositions, each comprising a pharmaceutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of claims 1 to 29, and a pharmaceutically acceptable carrier or excipient; and b) Instructions for use for administering one or more compositions to a person who needs them. A kit that includes this.

Images