Novel compounds useful for the treatment and / or prevention of diseases, disorders, or conditions related to angiotensin II

Abstract

The present disclosure relates to compounds of formula I and their utility in treating diseases, disorders and / or conditions associated with the peptide angiotensin II. [Formula 1] JPEG2023518948000091.jpg71165

Description

[Technical Field]

[0001] This disclosure relates to novel compounds, their use as pharmaceuticals useful for the treatment and / or prevention of diseases, disorders and / or conditions related to the peptide angiotensin II, and processes for preparing such compounds. [Background technology]

[0002] The renin-angiotensin system (RAS) is a hormonal system that regulates blood pressure, fluid and electrolyte balance, and systemic vascular resistance. The RAS includes angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and two Ang II receptors, AT1 and AT2. Angiotensinogen is a protein with 452 amino acids that is cleaved by the enzyme renin to produce the peptide angiotensinogen I (Ang I), which is then cleaved by angiotensin-converting enzyme ACE to produce Ang II. Ang II acts as an agonist by activating receptors AT1 and AT2, thereby regulating physiological and pathophysiological states. Importantly, Ang II provides a potent hypertensive effect mediated by the AT1 receptor and regulates many cardiovascular functions.

[0003] The central roles of ACE and renin enzymes in the renin-angiotensin system (RAS) have been a starting point for structure-based drug design, leading to the development of drugs that inhibit these enzymes. Losartan, a drug that acts as a selective antagonist of the AT1 receptor, was introduced to the market in 1995, followed by many other "sartan" drugs such as valsartan, candesartan, and irbesartan. The renin inhibitor aliskiren was approved in the United States in 2007 for the treatment of hypertension.

[0004] Furthermore, it has been suggested that agonists that selectively act on the AT2 receptor may be used to treat disorders related to the renin-angiotensin system (RAS), and that activation of the AT2 receptor often has the opposite effect to that mediated by the AT1 receptor. While the AT1 receptor is expressed in most organs of the human body, the AT2 receptor is found in fetal tissue, and its expression decreases significantly after birth. However, AT2 receptor expression is upregulated in pathological conditions such as heart failure, renal failure, myocardial infarction, brain lesions, vascular injury, and wound healing.

[0005] The AT2 receptor has also been shown to be involved in inhibiting apoptosis and cell proliferation (Pharmacol. Rev. 2000; 52: 415-472).

[0006] WO02 / 096883 discloses a tricyclic compound useful as a selective agonist at the AT2 receptor. The compound may contain an imidazole moiety. The compound may be used in the treatment of gastrointestinal conditions such as indigestion, inflammatory bowel disease (IBS), and multiple organ failure (MOF) (see, for example, International Patent Application No. 99 / 43339), as well as cardiovascular diseases.

[0007] EP0512675 A1 discloses that substituted imidazoles, conjugated via methylene to novel substituted phenylthiophene or phenylfuran derivatives, are angiotensin II antagonists and are useful in the treatment of hypertension and congestive heart failure.

[0008] DE10 2012 004 589 A1 discloses novel angiotensin II receptor agonists useful for the treatment of neurodegenerative diseases, preferably Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.

[0009] U.S. Patent Application No. 2004 / 0167176 describes the preparation of a tricyclic heterocycle useful as an angiotensin II receptor agonist.

[0010] A transesterification method for the synthesis of AT2 receptor ligands with improved stability in human liver microsomes is described in Bioorg.Med.Chem.Lett.2018;28:519-522.

[0011] Med.Res.Rev.2018;38:602-624 discloses a small molecule AT2 receptor agonist. It describes the discovery of the selective small molecule AT2 receptor agonist compound 21 C21 (see also International Patent Application No. 2002 / 096883). C21 is currently in clinical development for the treatment of AT2 receptor-related diseases, including IPF (see, for example, International Patent Application No. 2016 / 139475).

[0012] C21 has also been shown to be potentially useful in the treatment of stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cancer treatment-related cardiotoxicity, peripheral neuropathy, and systemic sclerosis (see, for example, International Patent Applications Nos. 2004 / 046141, 2016 / 092329, 2016 / 107879, 2016 / 139475, 2017 / 221012, 2019 / 008393, and U.S. Patent Application No. 2012 / 035232).

[0013] Compound C21 has been reported to inhibit a series of oxidases from the CYP family, and substitution of the imidazole ring of C21 with a methyl or trifluoromethyl group has been reported to reduce the inhibition levels of CYP3A4 and 2C9. Furthermore, a minor structural modification of C21 converted it from a selective AT2 receptor agonist to a selective AT2 receptor antagonist C38 / M132. [ka]

[0014] Cytochrome P450 (CYP) is a family of enzymes found in mammals that are important for the clearance of various compounds, such as pharmaceuticals. Therefore, it is important to consider drug interactions with various CYPs to avoid undesirable side effects. If the degree of CYP inhibition is too high, it can potentially adversely affect the usefulness of the compound as a pharmaceutical.

[0015] A selective AT2 receptor agonist with reduced CYP inhibition is described in Bioorg.Med.Chem.2010;18:4570-4590.

[0016] There is still a need for pharmaceutically active compounds, such as small molecules, that act as AT2 receptor agonists to treat and / or prevent diseases, disorders, or conditions related to angiotensin II. In particular, there is a need for drugs that exhibit tolerable levels of CYP inhibition of one or more CYP enzymes. [Overview of the project]

[0017] This disclosure provides pharmaceuticals, such as small molecules, that act as AT2 receptor agonists for the treatment and / or prevention of diseases, disorders, or conditions related to angiotensin II. These pharmaceuticals may exhibit tolerable levels of CYP inhibition of one or more CYP enzymes.

[0018] Furthermore, this disclosure provides pharmaceuticals such as small molecules that act as selective AT2 receptor agonists exhibiting tolerable levels of CYP inhibition of one or more CYPs.

[0019] In this regard, Equation I: [ka] A compound of or a pharmaceutically acceptable salt thereof, in which a compound of formula I, R 1 but, H, Ure 6 , SR 7 , NR 8R 9 C2-C6 alkyl optionally substituted with 0, 1 or 2 substituents selected from the group consisting of halogen, thiazole, oxazole and pyrazole (i.e., optionally substituted with 1 or 2 substituents), OR 6 SR 7 and NR 8 R 9 C3-C6 cycloalkyl optionally substituted with 0, 1 or 2 substituents selected from the group consisting of halogen, thiazole, oxazole and pyrazole (i.e., optionally substituted with 1 or 2 substituents), thiazole, where the phenyl moiety is optionally substituted with 0, 1 or 2 substituents selected from the group consisting of OR 6 SR 7 and NR 8 R 9 benzyl, or (CH2) m -R 10 represents, R 2 is H, F, Cl, OR 6 SR 7 NR 8 R 9 C2-C6 alkyl optionally substituted with 0, 1 or 2 substituents selected from the group consisting of halogen, thiazole, oxazole and pyrazole (i.e., optionally substituted with 1 or 2 substituents), OR 6 SR 7 and NR 8 R 9 C3-C6 cycloalkyl optionally substituted with 0, 1 or 2 substituents selected from the group consisting of halogen, thiazole, oxazole and pyrazole (i.e., optionally substituted with 1 or 2 substituents), where the phenyl moiety is optionally substituted with 0, 1 or 2 substituents selected from the group consisting of OR 6 SR 7 and NR 8 R 9Benzyl, which is substituted with 0, 1, or 2 substituents selected from the group consisting of (i.e., optionally substituted with 1 or 2 substituents), (CH2) m -R 10 This represents, However, R 1 and R 2 However, both will never be H. R 3 but, H, Halogen, or This represents a C1-C3 alkyl group substituted with 0, 1, 2, or 3 halogens selected from the group consisting of F and Cl (i.e., optionally substituted with 1, 2, or 3 halogens). R 4 and R 5 However, independently, they represent C1-C6 alkyl groups substituted with 0, 1, 2, or 3 F atoms (i.e., optionally substituted with 1, 2, or 3 fluoro substituents). X represents CH=CH, CH, N, NH, O, or S. Y represents CH=CH, CH, N, NH, O, or S. however, (a) X and Y are not the same, (b) If X represents CH=CH, then Y can only represent CH, (c) If Y represents CH=CH, then X can only represent CH. Z represents a single bond, O, or S. R 6 , R 7 , R 8 and R 9 However, they became independent, This represents a C1-C3 alkyl group substituted with H or 0, 1, 2, or 3 F atoms (i.e., optionally substituted with 1, 2, or 3 fluoro substituents). R 10 However, selected from the group consisting of phenyl, thiazole, oxazole, and pyrazole, n is 0, 1, 2, 3, or 4. A compound or a pharmaceutically acceptable salt thereof is provided, wherein m is 0 or 1.

[0020] The aforementioned compounds disclosed herein (including their pharmaceutically acceptable salts) will hereafter be interchangeably referred to as "compounds of the present invention," "compounds of the disclosure," "compounds described herein," or "compounds of formula I."

[0021] Pharmaceutical compositions are also provided, comprising a therapeutically effective amount of a compound of formula I described herein or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient, and / or diluent.

[0022] Furthermore, compounds of formula I described herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described herein, are provided for use as pharmaceuticals. The pharmaceuticals may be for the treatment and / or prevention of diseases, disorders and / or conditions related to the peptide angiotensin II.

[0023] Also provided are compounds of formula I as described herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as described herein, for use in the treatment and / or prevention of diseases, disorders and / or conditions selected from the group consisting of obstructive pulmonary diseases such as chronic obstructive pulmonary disease, autoimmune diseases such as rheumatoid arthritis, viral respiratory infections such as pneumonia caused by respiratory viral infections (viral pneumonia), and more preferably hypertension, heart failure, stroke, chronic kidney disease (including nephropathy), pulmonary fibrosis such as idiopathic pulmonary fibrosis, sclerosis such as systemic sclerosis, sarcoidosis such as pulmonary sarcoidosis, and other conditions including one or more of those not previously described herein but listed hereafter, and any combination thereof.

[0024] Also provided are compounds of Formula I as described herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as described herein, for manufacturing pharmaceuticals for the treatment and / or prevention of diseases, disorders and / or conditions selected from the group consisting of hypertension, heart failure, stroke, nephropathy, pulmonary fibrosis such as idiopathic pulmonary fibrosis, sclerosis such as systemic sclerosis, sarcoidosis such as pulmonary sarcoidosis, and other conditions including one or more of those not previously described herein but listed hereafter, and any combination thereof.

[0025] Methods for the treatment and / or prevention of diseases, disorders and / or conditions selected from the group consisting of hypertension, heart failure, stroke, nephropathy, pulmonary fibrosis such as idiopathic pulmonary fibrosis, sclerosis such as systemic sclerosis, sarcoidosis such as pulmonary sarcoidosis, and other conditions including one or more of those not previously described herein but listed hereafter, and any combination thereof, comprising the step of administering a therapeutically effective amount of a compound of formula I as described herein or a pharmaceutical composition as described herein to a patient in need thereof. [Modes for carrying out the invention]

[0026] This disclosure is based on Formula I, as previously defined herein: [ka] The present invention provides compounds of the same, or pharmaceutically acceptable salts thereof.

[0027] To avoid any doubt, those skilled in the art will understand that any reference in the specification to a compound of a particular embodiment of the present invention (such as any embodiment of the present invention referring to a compound of formula I as previously defined herein) includes references to all of its embodiments and specific features, and that combinations of such embodiments and specific features may form further embodiments and features of the present invention.

[0028] Unless otherwise indicated, all technical and scientific terms used herein have the general meanings understood by those skilled in the art to which this invention pertains.

[0029] The term "alkyl" refers to saturated or unsaturated linear or branched chains. Hydrocarbons It means a chain. If "alkyl" refers to an unsaturated alkyl chain, i.e., an alkene, it should be understood that it contains two or more carbon atoms.

[0030] The term "C1-C6 alkyl" refers to a linear chain or, if a sufficient number of carbon atoms are present (i.e., at least 2 or 3 as needed), a branched chain and / or cyclic chain containing 1 to 6 carbon atoms (hence C 3~6 Saturated or unsaturated (forming cycloalkyl groups) Hydrocarbons The chain is shown. When there are a sufficient number of carbon atoms (i.e., at least four), such a group may also be subcyclic (and therefore C 4~6 (Forms a partial cycloalkyl group).

[0031] Examples of "C2-C6 alkyl" include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.

[0032] The term "C2-C6 alkyl" refers to a linear or branched saturated or unsaturated alkyl group containing 2 to 6 carbon atoms, as previously defined herein. Hydrocarbons The chain is shown. Examples of "C2-C6 alkyl" include, but are not limited to, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.

[0033] The term "C1-C3 alkyl" refers to a linear or branched saturated or unsaturated alkyl group containing 1 to 3 carbon atoms, as previously defined herein. Hydrocarbons The chain is shown. Examples of "C1-C3 alkyl" include, but are not limited to, ethyl, propyl, and isopropyl.

[0034] The term "C3-C6 cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic ring, as previously defined herein, consisting of 3, 4, 5, or 6 carbon atoms. Examples of "C3-C6 cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0035] An example of a partially cyclic alkyl group (which may also be called a “partially cycloalkyl” group) that can be mentioned is cyclopropylmethyl. If a sufficient number of carbon atoms are present, such a group may be polycyclic (e.g., bicyclic or tricyclic) and / or spirocyclic.

[0036] The term "halogen" includes fluoro, chloro, bromo, and iodine.

[0037] R as described in this specification 1 If the substituent represents, for example, thiazole, it can be understood that it can be bonded to the imidazole ring of the compound of formula I as follows. [ka]

[0038] If two or more substituents in the compound of the present invention may be identical, the actual identity of each substituent is never interdependent. For example, in the presence of two or more halo groups, those groups may be identical or different (e.g., two chloro groups, or a fluoro group and a chloro group). Similarly, in the presence of two or more alkyl groups, the groups in question may be identical or different with respect to the number of carbon atoms they have and / or whether they are linear, branched, unsaturated, or otherwise.

[0039] Unless otherwise specified, substituents can be located at any point on the group to which they can be attached. In this respect, an alkyl group that can be substituted by one or more substituents (for example) can also be terminated by such substituents (i.e., located at the end of an alkyl chain).

[0040] To avoid ambiguity, if a substituent is described as being substituted with one or more substituents (e.g., a C1-C3 alkyl substituted with one, two, or three halogens), these substituents (e.g., halogens) may, where possible, be located on the same or different atoms.

[0041] Those skilled in the art will understand that the compounds of the present invention, which are the subject of this invention, include those that are readily available, i.e., those that can be prepared in a stable form. That is, the compounds of the present invention include compounds that are robust enough to survive isolation, for example, isolation from a reaction mixture to a useful purity.

[0042] Compounds of formula I can be produced, for example, according to techniques well known to those skilled in the art, as described below.

[0043] In one embodiment, the portions of the compound of formula I containing X and Y may be phenyl rings, thereby providing a compound of formula Ia or formula Ib. [ka]

[0044] Alternatively, the X and Y portions of the compound of formula I may be thiophene, thereby providing the compound of formula Ic. [ka]

[0045] In another embodiment, the portions of the compound of formula I containing X and Y may be thiazoles, thereby providing the compound of formula Id. [ka]

[0046] The compounds of formula I described herein are R 1 and R 2 The following values ​​may be available for this: R 1 is OR 6 , SR 7 , NR 8 R 9 C is substituted with 0, 1, or 2 substituents selected from the group consisting of halogens, thiazoles, oxazoles, or pyrazoles (i.e., optionally substituted with 1 or 2 substituents). 2 It can represent ~C6 alkyl groups. R 2 This can represent H.

[0047] For example, R 1 R may be selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, 2 This can represent H.

[0048] In further examples, R 1 is OR 6 Or C, optionally substituted with one or two substituents selected from halogens. 2~6 It can represent alkyl (e.g., ethyl, propyl, or butyl), R 2 This can represent H.

[0049] For example, R 1 R can represent ethyl or propyl, optionally substituted with an -OH group, for example, 2-hydroxypropyl-2-yl or 1-ethanol. 2 This can represent H. 1F can also represent ethyl or propyl, for example, 2-fluoropropyl-2-yl, which is optionally substituted by F, and R 2 This can represent H.

[0050] In another example, R 1 R can represent a C2-C6 alkyl group such as isopropyl or cyclopropyl, 2 This can represent H.

[0051] In yet another example, R 1 This can represent thiazole, and R 2 This can represent H.

[0052] In yet another example, R 1 R can represent 2-hydroxypropyl-2-yl, or more preferably tert-butyl, 2 This can represent H.

[0053] Other compounds of the present invention that may be mentioned include: R 1 However, it can represent H, R 2 However, OR 6 , SR 7 , NR 8 R 9 The compounds include those that can represent C2-C6 alkyl groups substituted with halogens or 0, 1, or 2 substituents selected from the group consisting of thiazoles, oxazoles, or pyrazoles (i.e., optionally substituted with 1 or 2 substituents).

[0054] For example, R 1 H can be represented, R 2 The compound may be selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.

[0055] In further examples, R 1 H can be represented, R 2This can represent tert-butyl.

[0056] The compounds of formula I described herein are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. 4 It may have substituents. For example, R 4 The substituent may be tert-butyl, methyl, ethyl, n-propyl, or n-butyl, for example, n-butyl or especially methyl.

[0057] Additionally or alternatively, the compounds of formula I described herein are selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. 5 It may have substituents. For example, R 5 The substituent may be isopropyl or isobutyl.

[0058] For example, a compound of formula I described herein, in which, R 4 However, it is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, R 5 A compound is provided, selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0059] Furthermore, a compound of formula I described herein, wherein in the formula, R 4 However, it is methyl, R 5 A compound is provided which is isopropyl or isobutyl.

[0060] In further examples, a compound of formula I described herein, wherein, R 4 However, it is methyl, R 5 However, a compound that is n-propyl is provided.

[0061] In a further example, a compound of formula I as described herein, wherein: R 4 is n-butyl, R 5 is isopropyl or isobutyl, is provided.

[0062] In another example, a compound of formula I as described herein, R 4 is n-butyl, R 5 is n-propyl, is provided.

[0063] Preferred compounds of the present invention are compounds of any one of formulae Ia, Ib, Ic or Id, wherein: R 1 is C 6 alkyl optionally substituted by one or more substituents selected from OR 2~4 or halogen, R 2 and R 3 both represent H, R 4 is C 1~2 alkyl, R 5 [[ID=5l]]represents isopropyl or isobutyl, n represents 0, including the compound.

[0064] More preferred compounds of the present invention are compounds of any one of formula Ic, or more preferably Ia, wherein: R 1 represents a straight-chain or branched-chain propyl or butyl group optionally substituted by OH or fluoro, for example, R 1 represents tert-butyl or 2-hydroxyprop-2-yl, R 4 represents methyl,[[ID=6S]] R 5 represents isopropyl, including the compound.

[0065] This disclosure also provides compounds of formula I as described herein, wherein the phenyl ring bonded to the nitrogen atom of the imidazole moiety via a methylene group may be unsubstituted. Thus, the value of "n" may be 0.

[0066] This disclosure is as follows: ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)2-propylthiazole-5-yl)sulfonyl)methyl carbamate, ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)butyl carbamate, ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate butyl, ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate, ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((3-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate butyl, ((3-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)methyl carbamate, ((4-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-isopropyl-1H-imidazole-1-yl)methyl)phenyl)2-propylthiazole-5-yl)sulfonyl)butyl carbamate, ((2-Isobutyl-4-(4-((2-(Thiazol-2-yl)-1H-imidazole-1-yl)methyl)phenyl)thiazol-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)butyl carbamate, ((2-isobutyl-4-(4-((2-isopropyl-1H-imidazole-1-yl)methyl)phenyl)thiazole-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, ((2-Isobutyl-4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)thiazol-5-yl)sulfonyl)methyl carbamate, ((2-Propyl-4-(4-((2-(thiazol-2-yl)-1H-imidazol-1-yl)methyl)phenyl)thiazol-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazol-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5-yl)sulfonyl)methyl carbamate, ((4-(4-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5-yl)sulfonyl)methyl carbamate, ((4-(4-((2-Cyclopropyl-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazol-5-yl)sulfonyl)methyl carbamate,[[ID=?]] ((4-(4-((2-Cyclopropyl-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazol-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-Cyclopropyl-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5-yl)sulfonyl)methyl carbamate, ((4-(4-((2-Cyclopropyl-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5-yl)sulfonyl)butyl carbamate, Note: There seems to be a mistake in the original text where the tag is shown as [[ID=?]] in the provided text. I've translated it as in the output for consistency with the original numbering system. If this was an actual error in the original, it should be corrected before translation for an accurate result.((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate, ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate butyl, ((5-isobutyl-4'-((2-(thiazole-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((5-isobutyl-4'-((2-(thiazole-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate, ((5-isobutyl-4'-((2-(isopropan-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((5-isobutyl-4'-((2-(isopropan-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate, ((5-isobutyl-4'-((2-(cyclopropan-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate, ((5-isobutyl-4'-((2-(cyclopropan-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((5-isobutyl-3-(4-(2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-yl)sulfonyl)carbamate butyl, ((5-isobutyl-3-(4-(2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-yl)sulfonyl)methyl carbamate, ((5-isobutyl-3-(4-(2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-yl)sulfonyl)carbamate butyl, ((5-isobutyl-3-(4-(2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-yl)sulfonyl)methyl carbamate, ((5-isobutyl-3-(4-(2-(2-tertbutyl)-1H-imidazole-1-yl)methyl)phenyl)-2-yl)sulfonyl)carbamate 2-methoxyethyl, ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)methyl carbamate, ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutyl-thiazole-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutyl-thiazole-5-yl)sulfonyl)methyl carbamate The present invention provides a compound which is one or more of the above compounds, or a pharmaceutically acceptable salt of any one of the above compounds.

[0067] Furthermore, the present invention provides the following: ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((3-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate butyl, ((3-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)methyl carbamate, ((4-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-isopropyl-1H-imidazole-1-yl)methyl)phenyl)2-propylthiazole-5-yl)sulfonyl)butyl carbamate, ((2-Isobutyl-4-(4-((2-(Thiazol-2-yl)-1H-imidazole-1-yl)methyl)phenyl)thiazol-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)butyl carbamate, ((2-isobutyl-4-(4-((2-isopropyl-1H-imidazole-1-yl)methyl)phenyl)thiazole-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, ((2-isobutyl-4-(4-((2-isopropyl-1H-imidazole-1-yl)methyl)phenyl)thiazole-5-yl)sulfonyl)methyl carbamate, ((2-propyl-4-(4-((2-(thiazole-2-yl)-1H-imidazole-1-yl)methyl)phenyl)thiazole-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(1-hydroxyethyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(1-hydroxyethyl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)methyl carbamate, ((4-(4-((2-(1-hydroxyethyl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(1-hydroxyethyl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)methyl carbamate, ((4-(4-((2-cyclopropyl-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, ((4-(4-((2-cyclopropyl-1H-imidazole-1-yl)methyl)phenyl)2-isobutylthiazole-5-yl)sulfonyl)carbamate butyl, ((4-(4-((2-cyclopropyl-1H-imidazole-1-yl)methyl)phenyl)2-propylthiazole-5-yl)sulfonyl)methyl carbamate, ((4-(4-((2-cyclopropyl-1H-imidazole-1-yl)methyl)phenyl)2-propylthiazole-5-yl)sulfonyl)butyl carbamate, ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate, ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate butyl, ((5-isobutyl-4'-((2-(thiazole-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((5-isobutyl-4'-((2-(thiazole-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate, ((5-isobutyl-4'-((2-(isopropan-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((5-isobutyl-4'-((2-(isopropan-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate, ((5-isobutyl-4'-((2-(cyclopropan-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate, ((5-Isobutyl-4’-((2-(cyclopropan-2-yl)-1H-imidazol-1-yl)methyl)-[1,1’-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((5-Isobutyl-3-(4-(2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-yl)sulfonyl)butyl carbamate, ((5-Isobutyl-3-(4-(2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-yl)sulfonyl)methyl carbamate, ((5-Isobutyl-3-(4-(2-(2-fluoropropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-yl)sulfonyl)butyl carbamate, ((5-Isobutyl-3-(4-(2-(2-fluoropropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-yl)sulfonyl)methyl carbamate, ((5-Isobutyl-3-(4-(2-(2-tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-yl)sulfonyl)2-methoxyethyl carbamate, ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5-yl)sulfonyl)methyl carbamate, ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazol-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazol-5-yl)sulfonyl)methyl carbamate, ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-3'-fluoro-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate, (4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-3'-fluoro-5-isobutyl-[1,1'-biphenyl]-2-yl)methyl sulfonylcarbamate The present invention provides a compound which is one or more of the above compounds, or a pharmaceutically acceptable salt of any one of the above compounds.

[0068] In any case, preferred compounds of the present invention include the compounds of the examples described below.

[0069] Pharmaceutical preparations and medical uses The disclosure also provides a pharmaceutical composition comprising a therapeutically acceptable amount of a compound of formula I as described herein or a therapeutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient, or diluent.

[0070] The compounds of the present invention are manifested in both therapeutic, symptomatic, and / or diagnostic treatments, as well as prophylactic treatments (including the prevention and / or suppression of the deterioration and / or worsening of any of the above conditions).

[0071] The compounds of the present invention are typically administered orally, intravenously, subcutaneously, buccally, rectally, cutaneously, intranasally, intratracheally, intrabronchally, by other parenteral routes, or by inhalation, pulmonary routes, or any combination thereof, in pharmaceutically acceptable dosage forms, in solutions, suspensions, emulsions (including nanosuspensions), or liposomal formulations. Additional methods of administration include, but are not limited to, intra-arterial, intramuscular, intraperitoneal, intra-portal, intradermal, epidural, intrathecal administration, or any combination thereof.

[0072] The pharmaceutical composition may be in the form of an oral dosage form such as a lozenge, capsule, or syrup.

[0073] In some embodiments, the compounds of the present invention may be administered alone (e.g., separately), and / or sequentially, and / or simultaneously and concurrently (e.g., synchronously), using different routes of administration, but preferably by known pharmaceutical formulations (including tablets, capsules, or elixirs for oral administration, suppositories for rectal administration, sterile solutions, suspensions, or emulsions for parenteral or intramuscular administration or inhalation). Inhalation administration is preferably performed using a nebulizer to deliver, for example, the compounds of the present invention to small lung tissues, including alveoli and bronchioles, preferably without causing irritation or coughing to the target of treatment.

[0074] The administration of a therapeutically effective dose of the compound of the present invention may be carried out by inhalation and orally, depending on the combination of administration routes, separately (e.g., about 2 hours or more apart from each other), consecutively (e.g., within about 2 hours of each other), or simultaneously and in parallel (e.g., concurrently).

[0075] As used herein, the term "therapeutic dose" means an amount of the compound described herein that is sufficient to induce the desired therapeutic effect in a patient to whom the compound is administered. Furthermore, the patient described herein may be a human being.

[0076] Compounds or pharmaceutically acceptable salts thereof as described herein, or pharmaceutical compositions as described herein, are also provided for use as pharmaceuticals. A pharmaceutical may be a pharmaceutical for the treatment and / or prevention of diseases, disorders and / or conditions related to peptide angiotensin II. A pharmaceutical may be used in the treatment and / or prevention of diseases, disorders and / or conditions related to peptide angiotensin II, and such pharmaceutical exhibits an acceptable level of CYP inhibition of one or more CYPs.

[0077] Accordingly, compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as described herein, are provided for use in the treatment and / or prevention of diseases, disorders and / or conditions related to peptide angiotensin II. Accordingly, compounds and pharmaceutically acceptable salts thereof, optionally in the form of pharmaceutical compositions, can be used for the treatment and / or prevention of diseases, disorders and / or conditions related to peptide angiotensin II, and the compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions exhibit acceptable levels of CYP inhibition of one or more CYPs.

[0078] Furthermore, compounds described herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described herein, are provided for use in the manufacture of pharmaceuticals for the treatment and / or prevention of diseases, disorders and / or conditions related to peptide angiotensin II.

[0079] Furthermore, there is a method for treating and / or preventing diseases, disorders and / or conditions related to peptide angiotensin II, comprising the step of administering to a patient in need of such treatment and / or prevention a therapeutically effective amount of a compound of formula I as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition as described herein.

[0080] To avoid ambiguity, the expression "shows an acceptable level of CYP inhibition" means that CYP inhibition is undesirable, and / or that the level of CYP inhibition is, for example, less than 50%, for example between 40% and 20%, for example less than 20%, for example between 10% and 0%, for example less than 0%, for example -50%.

[0081] To avoid ambiguity, the phrase "diseases, disorders and / or conditions related to peptide angiotensin II" means diseases, disorders and / or conditions in which activation of the AT2 receptor is desired or required.

[0082] Accordingly, the present invention provides a method for treating a disease, disorder and / or condition in which activation of the AT2 receptor is desired or required, but inhibition of CYP is undesirable, comprising administering a therapeutically effective amount of the compound of the present invention to a patient requiring such treatment, either separately, sequentially, or simultaneously in parallel, preferably by inhalation and orally, in order to achieve a therapeutically effective dose or dosage.

[0083] Such formulations may be prepared in accordance with standard and / or acceptable pharmaceutical regulations.

[0084] Subjects suitable for treatment with the formulations of the present invention include, but are not limited to, mammalian subjects, particularly human subjects.

[0085] The compounds described herein or their pharmaceutically acceptable salts are expected to be useful in diseases, disorders and / or conditions in which AT2 receptors are expressed and their stimulation is desired or required. In particular, the compounds described herein or their pharmaceutically acceptable salts are useful in the treatment of diseases, disorders and / or conditions in which AT2 receptor activation is desired or required, but CYP inhibition is undesirable.

[0086] The term "Angiotensin II-related diseases, disorders, and / or conditions" includes diseases, disorders, or conditions known to be treatable by AT2 receptor activation, as described below, but existing treatments for such conditions may include the administration of other therapeutic agents metabolized by CYP enzymes. Thus, such diseases, disorders, or conditions may include advantageous and / or desired conditions where inhibition of at least one CYP enzyme is not required, or conditions where such inhibition is or is harmful to the patient.

[0087] As described herein, the compounds of the present invention are useful because they have pharmacological activity and / or are metabolized in the body after oral or parenteral administration to form compounds that have pharmacological activity.

[0088] In particular, the compounds of the present invention are agonists of the Ang II receptor. Therefore, the compounds of the present invention are expected to be useful in diseases, disorders and / or conditions in which endogenous production of Ang II is insufficient and / or in which an increase in the activity of the Ang II receptor is desired or required.

[0089] More specifically, the compounds of the present invention are agonists of the AT2 receptor, and in particular, selective agonists of its subreceptors (vs. AT1 receptor), as can be demonstrated, for example, in the tests described below.

[0090] AT2 receptor agonists include those that completely activate the AT2 receptor and those that partially activate it. Therefore, the compounds of the present invention can selectively bind to the AT2 receptor and exhibit agonist activity at the AT2 receptor. A compound that "selectively binds" to the AT2 receptor includes having an affinity ratio (AT2:AT1) of the related compound at a given concentration of at least 50:1, for example, at least 100:1, preferably at least 1000:1.

[0091] In this regard, the compounds of the present invention are shown to be effective in treating conditions characterized by vasoconstriction, fibrosis, increased cell proliferation and / or differentiation, increased cardiac contractility, increased cardiovascular hypertrophy, and / or increased fluid and electrolyte retention, as well as skin diseases and musculoskeletal disorders.

[0092] The compounds of the present invention may also exhibit thromboxane receptor activity. In this regard, the compounds of the present invention may have inhibitory effects on platelet activation and / or aggregation (and therefore, for example, antithrombotic effects), and / or may reduce vasoconstriction and / or bronchoconstriction in a therapeutic manner.

[0093] The compounds of the present invention are further demonstrated in the treatment of stress-related diseases and / or in the improvement of microcirculation and / or mucosal protective mechanisms.

[0094] Therefore, the compounds of the present invention are expected to be useful in the treatment of disorders characterized as described above, such as disorders of the gastrointestinal tract, cardiovascular system, airway, kidneys, eyes, female reproductive (ovulation) system, and central nervous system (CNS).

[0095] Gastrointestinal disorders that may be mentioned include esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, indigestion (including non-ulcerative indigestion), gastroesophageal reflux, irritant bowel syndrome (IBS), inflammatory bowel disease (IBD), liver disorders (such as hepatitis), gallbladder disease, multiple organ failure (MOF), and sepsis. Other gastrointestinal disorders that may be mentioned include xerostomia, gastritis, gastroparesis, hyperacidity, biliary tract disorders, coelicia, Crohn's disease, ulcerative colitis, diarrhea, constipation, colitis, loss of appetite, vomiting, nausea, dyspepsia, and Sjögren's syndrome.

[0096] Airway disorders that may be mentioned include inflammatory diseases such as asthma, obstructive pulmonary diseases (such as chronic obstructive pulmonary disease), non-infectious pneumonia, pulmonary hypertension, and adult dyspnea syndrome.

[0097] Kidney diseases that may be mentioned include renal failure, nephritis, and renal hypertension.

[0098] Eye conditions that may be mentioned include diabetic retinopathy, retinopathy of prematurity, and retinal microangiopathy.

[0099] Disorders of the female reproductive system that may be mentioned include ovulation disorders.

[0100] Cardiovascular diseases that may be mentioned include hypertension, cardiac hypertrophy, heart failure (including heart failure with maintained ejection fraction), atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial lesions, post-balloon stenosis, neovascularization, diabetic complications, microvascular dysfunction, angina, cardiac arrhythmias, intermittent claudication, preeclampsia, myocardial infarction, reinfarction, ischemic lesions, erectile dysfunction, and neoendimal hyperplasia.

[0101] Disorders of the CNS that may be mentioned include cognitive impairment, impaired food intake (hunger / satiety) and thirst, stroke, cerebral hemorrhage, cerebral embolism and cerebral infarction, multiple sclerosis (MS), Alzheimer's disease, and Parkinson's disease.

[0102] The compounds of the present invention may also be useful in regulating growth metabolism and proliferation, for example, in the treatment of aging, hypertrophic diseases, benign prostatic hyperplasia, autoimmune diseases (e.g., arthritis such as rheumatoid arthritis, or systemic lupus erythematosus), psoriasis, obesity, nerve cell regeneration, ulcer healing, inhibition of adipose tissue hyperplasia, stem cell differentiation and proliferation, fibrous diseases, cancer (e.g., cancers of the gastrointestinal tract (including the esophagus or stomach), cancers of the prostate, breast, liver, kidney, and lymph nodes, lung cancer, ovarian cancer, pancreatic cancer, hematological malignancies, etc.), apoptosis, tumors (in general) and hypertrophy, diabetes, neurological lesions, and organ rejection.

[0103] The compounds of the present invention are also useful in the treatment of stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cancer treatment-related cardiotoxicity, peripheral neuropathy, and especially systemic sclerosis.

[0104] The diseases, disorders, and / or conditions related to the peptide angiotensin II described herein may be selected from the group consisting of hypertension, heart failure, stroke, nephropathy, pulmonary fibrosis such as idiopathic pulmonary fibrosis, sclerosis such as systemic sclerosis, sarcoidosis such as pulmonary sarcoidosis, and any combination thereof.

[0105] Certain diseases, disorders, and / or conditions in which AT2 receptor activation is desired or required, but inhibition of CYP enzymes is undesirable, include interstitial lung diseases (e.g., pulmonary fibrosis, IPF, systemic sclerosis, and sarcoidosis), autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, and inflammatory bowel disease), chronic kidney diseases (e.g., diabetic nephropathy), pulmonary hypertension, pulmonary arterial hypertension, and / or infarctions (e.g., myocardial infarction and stroke). Therefore, the compounds of the present invention are particularly useful in the treatment of interstitial lung diseases such as IPF, autoimmune diseases such as rheumatoid arthritis, chronic kidney diseases such as diabetic nephropathy, pulmonary hypertension including pulmonary arterial hypertension, and / or infarctions such as myocardial infarction.

[0106] The compounds of the present invention are particularly suitable for the treatment and / or prevention of sarcoidosis or fibrosis, more specifically pulmonary fibrosis, in particular ILDs such as IPF, as well as conditions that can induce ILDs, such as systemic sclerosis, rheumatoid arthritis, myositis, or systemic lupus erythematosus, or conditions associated with ILDs, such as pulmonary hypertension and / or pulmonary arterial hypertension.

[0107] The compounds of the present invention are particularly useful in the treatment of pulmonary fibrosis, especially IPF.

[0108] A further aspect of the present invention provides a method for treating pulmonary fibrosis, in particular IPF, which comprises administering a therapeutically effective amount of the compound of the present invention to a person suffering from such a condition.

[0109] In the treatment of pulmonary fibrosis, including IPF, the compounds of the present invention may have an anti-fibrotic effect, accompanied by a reduction in fibrosis and prevention of further deposition of extracellular matrix. The compounds of the present invention may reduce lung scarring / wound healing and have an anti-apoptotic effect, thereby preventing apoptosis of alveolar endothelial cells, which are initiating factors in the development of pulmonary fibrosis. The compounds of the present invention may also have an antiproliferative effect, and therefore may reduce cancer-like proliferation of fibroblasts and myofibroblasts in pulmonary fibrosis. The compounds of the present invention may also improve vascular remodeling in pulmonary fibrosis, thereby alleviating secondary pulmonary hypertension.

[0110] The compounds of the present invention may further exhibit anti-inflammatory, anti-growth factor (e.g., transforming growth factor beta), and / or anti-cytokine effects.

[0111] Furthermore, the compounds of the present invention may also be useful in the treatment or prevention of fibrous conditions of one or more viscera characterized by excessive accumulation of fibrous connective tissue, and / or in the treatment or prevention of fibrosis and the morbidity and mortality that may be associated therewith. Such fibrosis may be associated with acute inflammatory conditions such as acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), multi-organ inflammation, and injuries and / or dysfunctions that may be caused by internal or external trauma (e.g., injury) or infection.

[0112] Therefore, such conditions can result from sepsis or septic shock caused by viral, bacterial, or fungal infections. Furthermore, acute lung injury, ARDS, and especially SARS, which can be caused by viruses such as coronaviruses, including the novel SARS coronavirus 2 (SARS-CoV-2), can cause damage to internal tissues, dysfunction of associated internal tissues (e.g., mucous membranes) such as the respiratory epithelium, resulting in virus-induced pneumonia, pulmonary dysfunction, respiratory dysfunction, pain, and / or failure. Such tissue damage can also lead to severe fibrosis. For example, SARS disease, caused by the novel coronavirus SARS-CoV-2 (coronavirus disease 2019 or COVID-19), is known to often cause fibrosis.

[0113] The compounds of the present invention have the advantage of being potent against metabolic hydrolysis and / or stable against metabolic hydrolysis, and / or having the acceptable levels of CYP enzyme inhibition previously mentioned herein.

[0114] The compounds described herein, whether or not they are intended for use in the treatment of any of the disease conditions described above (such as IPF) or other conditions, may have advantages over compounds known in the prior art, such as being more potent, less toxic, longer-acting, more potent, having fewer side effects, being more readily absorbed, and / or having a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance), and / or having other useful pharmacological, physical, or chemical properties. Such effects may be evaluated clinically, objectively, and / or subjectively by healthcare professionals, the patient, or observers.

[0115] combination The compounds of this disclosure, or pharmaceutically acceptable salts thereof, may be used in combination with one or more further pharmaceuticals in combination therapies for the treatment of a variety of conditions, including those previously mentioned herein. Since the compounds of the present invention exhibit minimal CYP enzyme inhibition, such combinations are particularly advantageous when the other therapeutic agents used for use in the relevant conditions are themselves metabolized by CYP enzymes.

[0116] Therefore, the compounds of the present invention can be administered in combination with other AT2 agonists known in the art, such as C21, and in combination with AT1 receptor antagonists known in the art, and / or in combination with angiotensin-converting enzyme (ACE) inhibitors.

[0117] Non-limiting but exemplary examples of AT1 receptor antagonists that may be used according to the embodiment include azilsartan, candesartan, eprosartan, fimasartan, irbesartan, losartan, milfasartan, olmesartan, pomisartan, platosartan, lipiasartan, suprisartan, tasosartan, telmisartan, valsartan and / or combinations thereof. Non-limiting but exemplary examples of ACE inhibitors that may be used according to the embodiment include captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, fosinopril, moexipril, cilazapril, spirapril, temocapril, seronapril, derepril, muberticril and / or combinations thereof.

[0118] Other active ingredients that can be administered in combination with the compounds of the present invention include disodium cromoglycate; endothelin receptor antagonists such as bosentan, ambrisentan, cytaxentan, and macitentan; PDE5 inhibitors such as sildenafil and tadalafil; prostacyclins (epoprostenol) and their analogues such as iloprost and treprostinil; other biological agents including interferon-gamma-1b, etanercept, infliximab, and adalimumab; and methotrexate. Further active ingredients under development that can be administered co-administered with the compounds of the present invention include pamrebulumab (anti-CTGF, Fibrogen), GLPG1690 (autotaxin inhibitor, Galapagos), TD139 (galectin-3 inhibitor, Galecto), PRM-151 (recombinant pentraxin-2, Promedior), BBT-877 (autotaxin inhibitor, Boehringer / Bridge), CC-90001 (JNK inhibitor, Celgene), PBI-4050 (dual GPR40 agonist / GPR84 antagonist, Prometic), BMS-986020 (lysophosphatidic acid receptor antagonist, BMS), RVT-1601 (mast cell stabilizer, Respivant), SMO4646 (wnt-signaling inhibitor, United Therapeutics), and KD25 (Rho-related kinase inhibitor, Kadmon). This includes BG00011 (integrin antagonist, Biogen), PLN-74809 (integrin antagonist, Pilant Therapeutics), salakatinib (src kinase inhibitor, AstraZeneca), PAT-1251 (lysyl oxidase inhibitor 2, Pharmakea), ABM-125 (IL-25MAB, Abeome), and TA5-115 (multikinase inhibitor, Otsuka).

[0119] When the condition being treated is an interstitial lung disease such as IPF, systemic sclerosis, or fibrous diseases known in the art, the compounds of the present invention are preferably administered in combination with established therapies for such treatment, including but not limited to galectin-3 inhibitors, lysophosphatidic acid receptor 1 (LPA1) antagonists, autotaxin (ATX) inhibitors, recombinant human pentraxin-2 protein, or pirfenidone and / or nintedanib. Preferably, the combination of the compounds of the present invention is with pirfenidone or a pharmaceutically acceptable salt thereof, which is known to be metabolized by CYP enzymes such as CYP1A.

[0120] Furthermore, if the condition being treated is a chronic kidney-related disease, the compounds of the present invention are preferably administered in combination with one or more other drugs also used in such treatments, such as irbesartan and / or torsemide, which are metabolized by CYP enzymes such as CYP2C9.

[0121] When the condition being treated is pulmonary hypertension, the compounds of the present invention are preferably administered in combination with one or more drugs also used for such treatment, such as selexipag and / or sildenafil, which are compounds known to be metabolized by CYP enzymes such as CYP3A4.

[0122] When the condition being treated or prevented is myocardial infarction and / or stroke-related disease, the compounds of the present invention are preferably administered in combination with one or more other drugs also used in such treatment, such as propranolol, warfarin, clopidogrel, atorvastatin, cilostazol, lidocaine and / or simvastatin, or pharmaceutically acceptable salts thereof, which are compounds known to be metabolized by CYP enzymes such as CYP1A, CYP2CP and / or CYP3A4.

[0123] When the condition being treated is an autoimmune disease such as rheumatoid arthritis, multiple sclerosis, or psoriasis, the compounds of the present invention are preferably administered in combination with one or more other drugs also used in such treatments, including but not limited to drugs such as tizanidine, cyclophosphamide, cyclosporine, deflazacort, and / or hydrocortisone, riluzole, or pharmaceutically acceptable salts thereof.

[0124] Therefore, the compounds of the present invention are particularly useful in the treatment of diseases, disorders and / or conditions that can be administered to treat diseases including those previously mentioned herein, in combination with one or more other therapeutic agents previously mentioned herein, including pirfenidone, naproxen, propranolol, riluzole, tizanidine, warfarin, celecoxib, clopidogrel, irbesartan, meloxicam, pirfenidone, torsemide, cyclophosphamide, indomethacin, atorvastatin, cilostazol, cyclosporine, deflazacort, hydrocortisone, lidocaine, selexipag, sildenafil and / or simvastatin, which are useful or may be useful, but for which activation of the AT2 receptor is desired or required, but inhibition of CYP enzymes is undesirable and therefore metabolized via the CYP enzyme pathway. Most preferably, the compounds of the present invention are administered in combination with pirfenidone to treat interstitial lung diseases such as IPF.

[0125] Therapeutic agents that can be used in combination with the compounds of the present invention include a wide range of standard therapies applied to various viral infections, including: antibody therapies (e.g., LY-CoV555 / LY-CoV016 (bamuranivimab and etesevimab), LY-CoV555 (bamuranivimab, Eli Lilly), REGN-COV2 (casiribimab and imdevimab), REGN3048-3051, TZLS-501, SNG001 (Synairgen), eculizumab (Soliris; Alexion Pharmaceuticals), ravulizumab (Ultomiris; Alexion Pharmaceuticals), renzilumab, leronlimab, tocilizumab (Actemra; Roche), sarilumab (Kevzara; Regeneron) Pharma, and Octapharma), antiviral drugs (e.g., oseltamivir, remdesivir, faviravir, mornupiravir, simeprevir, daclatasvir, sofosbuvir, ribavirin, umifenovir, lopinavir, ritonavir, lopinavir / ritonavir (Kaletra; AbbVie Deutschland GmbH Co.)KG), teicoplanin, baricitinib (Olumiant; Eli Lilly), ruxolitinib (Jakavi; Novartis), tofacitinib (Xeljanz; Pfizer), TMPRSS2 inhibitor camostat or camostat mesylate, actenbra (Roche), AT-100 (rhSP-D), MK-7110 (CD24Fc; Merck), OYA1 (OyaGen9), BPI-002 (BeyondSpring), NP-120 (Ifenprodil; Algernon Pharmaceuticals), galidesivir (Biocryst Pharmacy, anti-inflammatory drugs (e.g., NSAIDs, ibuprofen, ketrolac, naproxen, etc.), chloroquine, hydroxychloroquine, interferons (e.g., interferon-beta (interferon-beta-1a), tocilizumab (Actemra), lenalidomide, pomalidomide, and thalidomide), analgesics (e.g., paracetamol or opioids), antifungal agents (e.g., dextromethorphan), vaccines (e.g., INO-4800 from Inovio Pharmaceuticals and Beijing Advaccine Biotechnology (if available)), passive antibody therapy with COVID-19 convalescent plasma (CCP) and / or antibodies derived from the blood of people who have recovered from SARS-CoV or SARS-CoV-2 infection.

[0126] Further therapeutic agents that may be mentioned include antifibrotic agents (egnintedanib, particularly pirfenidone), vitamins (e.g., vitamins B, C, and D), and mucolytic agents such as acetylcysteine ​​and ambroxol.

[0127] Other therapeutic agents that may be used in combination with the compounds of the present invention or pharmaceutically acceptable salts thereof, according to the present invention, include corticosteroids. Corticosteroids include both natural and synthetic corticosteroids.

[0128] Naturally occurring corticosteroids that may be mentioned include cortisol (hydrocortisone), aldosterone, corticosterone, cortisone, pregnenolone, progesterone, as well as naturally occurring precursors and intermediates in corticosteroid biosynthesis, and 11-deoxycortisol, 21-deoxycortisol, 11-dehydrocorticosterone, 11-deoxycorticosterone, 18-hydroxy-11-deoxycorticosterone, 18-hydroxy This includes other naturally occurring corticosteroid derivatives such as corticosterone, 21-deoxycortisone, 11β-hydroxypregnenolone, 11β,17α,21-trihydroxypregnenolone, 17α,21-dihydroxypregnenolone, 17α-hydroxypregnenolone, 21-hydroxypregnenolone, 11-ketoprogesterone, 11β-hydroxyprogesterone, 17α-hydroxyprogesterone, and 18-hydroxyprogesterone.

[0129] Synthetic corticosteroids that may be mentioned include cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate, hydrocortisone valveate, thixocortol and thixocortol pivalate, prednisolone, methylprednisolone, prednisone, chloroprednisone, cloprednol, difluprednate, fludrocortisone, fluocinolone, fluperolone, fluprednisolone, loteprednol, prednicarbate and triamcinolone Hydrocortisone-type substances (Group A), such as amcinonides, budesonides, desonides, fluocinolone cetonides, fluocinonides, halcinonides, triamcinolone acetonides, ciclesonides, deflazacort, formocortal, fludroxycortide, flunisolide, and fluocinolone acetonides (Group B); beclomethasone, betamethasone, betamethasone dipropionate, and betamethasone valerate, dexamethasone, flucortone, halomethasone, mometasone, and mometasone furoate. (β)methasone type (Group C) such as alclomethasone and alclomethasone dipropionate, clobetasol and clobetasol propionate, clobetasol and clobetasol butyrate, crocoltrone, desoxymethasone, diflorasone, difluocortrone, fluchlorolone, flumethasone, fluocortin, flupredniden and flupredniden acetate, fluticasone, fluticasone furoate and fluticasone propionate, meprednisone, paramethasone, prednilidene, rimexolone and urobetasol. This includes: progesterone-type substances such as flugestone, fluorometholone, medrizone, and prevediolone acetate; and progesterone derivatives (progestins) such as chlormadinone acetate, cyproterone acetate, medroguestone, medroxyprogesterone acetate, megestrol acetate, and segesterone acetate; as well as other corticosteroids such as cortibazole and 6-methyl-11β,17β-dihydroxy-17α-(1-propynyl)androsta-1,4,6-trien-3-one.

[0130] Preferred corticosteroids include cortisone, prednisone, prednisolone, methylprednisolone, and especially dexamethasone.

[0131] Furthermore, therapeutic agents that may be used in combination with the compound of the present invention or a pharmaceutically acceptable salt thereof include H2 receptor blockers, anticoagulants, antiplatelet agents, as well as statins, antibacterial agents, and anti-allergic / anti-asthmatic agents.

[0132] H2 receptor blockers that may be mentioned include famotidine. Anticoagulants that may be mentioned include heparin and low molecular weight heparins (e.g., bemiparin, nadroparin, reviparin, enoxaparin, parnaparin, sertoparin, dalteparin, tinzaparin), direct-acting oral anticoagulants (e.g., dabigatran, argatroban, rivaroxaban, apixaban, edoxaban, betrixaban, dalexaban, otamichaban, retaxaban, eribaxaban, hirudin, repirudine, and bivalirudine), coumarin vitamin K antagonists (e.g., coumarin, asenocoumarol, fenprocumone, atromentin, and phenindione), and factor Xa synthesis pentasaccharide inhibitors (e.g., fondaparinux, hydraparinux, and hydrabiotaparinux). Antiplatelet agents that may be mentioned include irreversible cyclooxygenase inhibitors (e.g., spirin and triflusal), adenosine diphosphate receptor inhibitors (e.g., cangrelor, clopidogrel, prasugrel, ticagrelor and ticlopidine), phosphodiesterase inhibitors (e.g., cilostazol), protease-activated receptor 1 antagonists (e.g., borapaxal), glycoprotein IIB / IIIA inhibitors (e.g., absiximab, eptifivatide and tirofiban), adenosine reuptake inhibitors (e.g., dipyridamole), and thromboxane inhibitors (e.g., tertroban, ramatroban, seratrodast and picotamide). Statins that may be mentioned include atorvastatin, simvastatin and rosuvastatin. Antimicrobial agents that may be mentioned include azithromycin, ceftriaxone, cefuroxime, doxycycline, fluconazole, piperacillin, tazobactam, and teicoplanin. Antiallergic / antiasthmatic drugs that may be mentioned include chlorpheniramine, levocetirizine, and montelukast.

[0133] Therefore, the subjects may also (and / or already) be administered one or more of the other therapeutic agents described above, meaning that they are administered one or more of these other therapeutic agents in prescribed doses prior to, in addition to, and / or after, treatment with the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0134] When the compounds of the present invention are “combined” with other therapeutic agents as previously mentioned in the specification, the active ingredients may be administered together in the same formulation or separately (simultaneously or sequentially) in different formulations.

[0135] Such combination products provide an administration of the compound of the present invention in combination with other therapeutic agents and may therefore be presented as separate formulations (at least one of which contains the compound of the present invention and at least one of which contains the other therapeutic agent) or as a combination formulation (i.e., formulated) (i.e., presented as a single formulation containing the compound of the present invention and the other therapeutic agent).

[0136] The combinations may optionally be provided as a parts kit including instructions for use. Alternatively, the combinations may be provided as single compositions or formulations, at least one of which comprises the compound of the present invention and at least one comprises another therapeutic agent, or may be presented (i.e., formulated) as a combined preparation (i.e., presented as a single composition or formulation comprising the compound of the present invention and another therapeutic agent).

[0137] therefore, (1) A pharmaceutical composition or preparation comprising a compound of the present invention, a therapeutic agent known to be metabolized by a CYP enzyme (such as any of those previously mentioned herein), and a pharmaceutically acceptable excipient (e.g., an adjuvant, diluent, or carrier), which is hereinafter referred to as a "combination preparation," and (2) The following ingredients: (A) A pharmaceutical composition or formulation comprising the compound of the present invention, mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier, (B) A parts kit is further provided, comprising a pharmaceutical composition or formulation containing a therapeutic agent (e.g., any of those previously mentioned herein) that is known to be metabolized by a CYP enzyme when mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier, wherein components (A) and (B) are each provided in a form suitable for administration in combination with the other.

[0138] In a further aspect of the present invention, a process for preparing combination formulations as previously defined herein is provided, comprising associating a compound of the present invention, another anti-inflammatory agent, or therapeutic agent with at least one (e.g., pharmaceutically acceptable) excipient.

[0139] In a further aspect of the present invention, a process is provided for preparing a parts kit as previously defined in the specification, the process comprising associating components (A) and (B). As used herein, reference to associating means that the two components are suitable for combined administration with each other.

[0140] Therefore, with respect to the process for preparing a parts kit as previously defined in the specification, by "associating" the two components with respect to each other, the inventors have made the two components of the parts kit such that (i) They may be provided as separate compositions or formulations (i.e., independently of each other) and then combined for use in combination therapy, or (ii) which may be packaged and presented together as separate components of a “combination pack” for use in combination therapy with each other.

[0141] therefore, (I) one of components (A) and (B) as defined herein, (II) A parts kit is further provided, which includes instructions for using the component together with the other of the two components.

[0142] Depending on the patient being treated and the route of administration, the compounds of the present invention may be administered in various doses. While the dose will vary from patient to patient, an appropriate daily dose is in the range of approximately 0.1 to approximately 1000 mg per patient (e.g., 0.1, 0.5, 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 mg, or any range or value within that range), and will be administered as a single or multiple dose. A more preferable daily dose is in the range of approximately 0.1 to approximately 250 mg per patient (for example, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250 mg, or any range or value within that range). The particularly preferred daily dose is in the range of approximately 0.3 to 100 mg per patient.

[0143] The individual doses of the compounds of the present invention may range from about 0.1 to about 100 mg (for example, 0.3, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg, or any range or value within that range).

[0144] When used herein in relation to a specific value (such as a quantity), the term “about” (or similar terms such as “approximately”) is understood to indicate that such a value may vary by up to 10% (in particular, up to 5%, e.g., up to 1%) of the defined value. In each case, such a term may be replaced by notation such as “±10%” (or by indicating the variation of a particular quantity calculated based on the relevant value). In each case, such a term may be deleted.

[0145] In any case, a physician or a person skilled in the art can determine the most appropriate actual dosage for each individual patient, which is likely to vary depending on the route of administration, the type and severity of the condition being treated, and the species, age, weight, sex, renal function, hepatic function, and response of the specific patient being treated. The above dosages are examples of average cases, and naturally, there may be individual cases where higher or lower dosage ranges are appropriate, and such cases are within the scope of the present invention.

[0146] The advantage of using the compounds of the present invention separately and / or sequentially and / or simultaneously in parallel, for example, through a combination of administration routes, is to produce a treatment tailored for patients who need it, which may prevent and / or reduce side effects, and to adjust the correct dosage level of the therapeutically effective amount of the compounds of the present invention.

[0147] The parts kit described herein may include two or more compositions or formulations containing an appropriate amount / dose of the compound of the present invention, and / or two or more compositions or formulations containing an appropriate amount / dose of another therapeutic agent, in order to provide repeated doses. If two or more compositions or formulations (containing any of the active compounds) exist, such compositions or formulations may be the same or different in terms of the dosage, chemical composition, and / or physical form of any of the compounds.

[0148] Accordingly, with respect to the combination products of the present invention, the term "administered in combination with ~" means that, over the course of treatment of the relevant condition, the two components of the combination product (the compound of the present invention and the other therapeutic agent) are administered together or in sufficiently close time intervals (optionally repeated) over the same course of treatment, enabling a greater beneficial effect to the patient than if either the composition or formulation containing the compound of the present invention or the composition or formulation containing the other agent were administered alone or without the other component (optionally repeated). The determination of whether the combination provides a greater beneficial effect with respect to the treatment of a particular condition and over the course of treatment will depend on the condition being treated or prevented, but can be conventionally achieved by those skilled in the art.

[0149] Furthermore, in the context of the parts kit according to the present invention, the term “in combination with ~” includes the fact that one or the other of the two compositions or formulations may be administered before, after, and / or simultaneously with (optionally and repeatedly) the administration of the components of the other. As used in this context, the terms “simultaneously administered” and “administered at the same time as ~” include the fact that individual doses of the relevant compounds of the present invention and other therapeutic agents are administered within 48 hours (e.g., 24 hours) of each other.

[0150] In a further embodiment of the present invention, a process is provided for preparing a combination product or parts kit as previously defined in the specification, comprising combining a compound of the present invention as previously defined in the specification with another therapeutic agent useful in the treatment of a related disease, disorder, or condition, and at least one pharmaceutically acceptable excipient.

[0151] Pharmaceutically acceptable salts The compounds disclosed and / or the present invention may be provided in the form of pharmaceutically acceptable salts. For example, pharmaceutically acceptable salts may be acid addition salts or base addition salts. Acid addition salts may be formed from the compound of formula I and an acid such as an organic acid. The organic acid is trifluoroacetic acid, formic acid, acetic acid, benzoic acid, oxalic acid, fumaric acid, maleic acid, and preferably trifluoroacetic acid. The organic acid may also be a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, or toluenesulfonic acid. The acid may also be an inorganic acid such as hydrochloric acid or hydrobromic acid. An example of an acid addition salt is the cation of the compound of formula I and CF3C(O)O - Examples include salts containing the conjugate base of acids such as . Base addition salts can be formed from compounds of formula I and bases such as organic bases. Specific base addition salts that may be mentioned include salts formed with alkali metals (such as Li, Na, and K salts), alkaline earth metals (such as Mg and Ca salts), or other metals (such as Al and Zn salts), or amine bases (such as ammonia, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, and tromethamine). Examples of base addition salts include anions of compounds of formula I and Na + or K + Examples of cation-containing salts include those mentioned above.

[0152] solvate It should be understood that the compounds of this disclosure may exist in solvated forms, such as solvates of free compounds or solvates of pharmaceutically acceptable salts of the compounds. The term “solvate” is used herein to describe a molecular complex comprising the compounds of this disclosure or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term “hydrate” is used when the solvent is water. Thus, solvated forms may include monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and so on.

[0153] Prodrug The compounds of this disclosure may also be in the form of prodrugs. Prodrugs are compounds that themselves have little or no pharmacological activity, but when such compounds are administered into or onto a patient's body, they are converted into pharmacologically active compounds.

[0154] polymorph The compounds of this disclosure may exist in a continuous solid state ranging from completely amorphous to completely crystalline. The compounds of this disclosure may also exist as oils. Where the compounds of formula I exist in crystalline and partially crystalline forms, such forms may include solvates that fall within the scope of the present invention. It should be understood that all polymorphs, such as mixtures of polymorphs, fall within the scope of the claimed compounds.

[0155] The compounds of the present invention may also exist in solution (i.e., in solution in a suitable solvent). For example, the compound of formula I may exist in aqueous solution, in which case the compound of the present invention may exist in the form of its hydrate.

[0156] The compounds of the present invention may contain double bonds, and therefore, unless otherwise specified, they may exist as E (entgegen) and Z (zusammen) geometric isomers for each individual double bond. Unless otherwise specified, all such isomers and mixtures thereof are included within the scope of the present invention.

[0157] The compounds of the present invention may also exhibit tautomerism. All tautomer forms and mixtures thereof are included within the scope of the present invention (in particular those that are sufficiently stable to allow their isolation).

[0158] The compounds of the present invention may also contain one or more chiral carbon atoms and therefore may exhibit optical isomerism and / or diastereoisomerism (i.e., exist in enantiomer or diastereomer forms). Diastereomers may be separated using conventional techniques, such as chromatography or fractional crystallization. Various stereoisomers (i.e., enantiomers) may be isolated by separating racemic or other mixtures of the compound using conventional techniques, such as fractional crystallization or HPLC. Alternatively, the desired enantiomer or diastereomer may be obtained by derivatization (i.e., decomposition including dynamic decomposition, e.g., treatment with a homochiral acid followed by separation of the diastereomer derivative by conventional means such as chromatography) from a starting material with suitable optical activity under conditions that do not cause racemization or epimerization (i.e., the "chiral pool" method), by reaction of a suitable starting material with a "chiral auxiliary" which can then be removed in a suitable step, or by reaction with a suitable chiral reagent or chiral catalyst, all of which can be carried out under conditions known to those skilled in the art. Unless otherwise specified, all stereoisomers and mixtures thereof are included within the scope of the present invention.

[0159] isotope labeled compounds The compounds of this disclosure may be used in labeled or unlabeled forms. The compounds of this disclosure can be isotoped by substituting one or more of their atoms with one or more of the following isotopes: 2H (deuterium), 3H (tritium), 11C, 13C, 14C, 18O, 17O, 19F, 18F.

[0160] Therefore, the compounds of the present invention may have one of their atoms replaced with an atom having an atomic mass or mass number different from that commonly found in nature (or the most abundant one in nature). All isotopes of any specific atom or element designated herein are intended to be within the range of the compounds of the present invention.

[0161] Preparation method The compounds of Formula I described herein may be prepared using methods known in the art and / or methods described herein.

[0162] Those skilled in the art will understand that in the processes described above and below, it may be necessary to protect the functional groups of the intermediate compound with protecting groups.

[0163] Functional groups that are desirable to protect include sulfonamides, amides, aminos, and aldehydes. Suitable protecting groups for sulfonamides, amides, and aminos include tert-butyloxycarbonyl, benzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl (Teoc), or tert-butyl. Suitable protecting groups for aldehydes include alcohols such as methanol or ethanol, and diols such as 1,3-propanediol or preferably 1,2-ethanediol (which thus form cyclic acetals). Protection and deprotection of functional groups may be carried out before or after the reactions outlined in Scheme 1 below.

[0164] Protecting groups are well known to those skilled in the art and can be applied and removed according to techniques such as those described below. For example, the protected compounds / intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques. The type of chemistry involved will determine the need and type of protecting group and the sequence for achieving the synthesis. The use of protecting groups is well described in “Protective Groups in Organic Synthesis”, 3rd edition, TW Greene & PGMWutz, Wiley-Interscience (1999), the contents of which are incorporated herein by reference.

[0165] For example, the compound of formula I can be synthesized as outlined in Scheme 1 below. [ka]

[0166] In scheme 1, dibromide 1 reacts with heterocyclic compound 2 under reaction condition a) to provide compound 3. Dibromide 1 may be substituted with 0, 1, 2, 3, or 4 F atoms, i.e., n may be 0, 1, 2, 3, or 4. Heterocyclic compound 2 has substituent R 1 , R 2 and R 3 The compounds are substituted with and may have the values ​​shown for the compounds of formula I described herein. Therefore, heterocyclic compound 2 may be a substituted imidazole. Compound 3 is then subjected to reaction conditions b) to obtain protected sulfonamide 4. The values ​​X, Y and R of protected sulfonamide 4 are 5 This may relate to the compound of formula I described herein, where PG is a protecting group such as tert-butyl. The X and Y portions of the compound of formula I may be a phenyl ring, a thiophene ring, or a thiazole ring. Reaction condition b) may include Suzuki cross-coupling conditions. Subsequently, the protecting group is removed, and the resulting sulfonamide 5 is converted to the compound of formula I using reaction condition d).

[0167] The reaction conditions used in a), b), and c) may vary depending on the final chemical structure synthesized.

[0168] For example, it contains imidazole, and the X and Y-containing portions are phenyl rings, and R 5 -Z represents isobutyl, R 4 However, compounds of formula I representing C1-C6 alkyl groups substituted with 0, 1, 2, or 3 F atoms can be prepared using the following reaction conditions: a) React with NaH, N,N'-dimethylformamide at 0°C to room temperature overnight; b) 2-(N-tert-butyl)sulfamoyl)-5-isobutylphenyl)boronic acid, Pd(PPh3)4, K2CO3, toluene, ethanol, water, microwave irradiation at 120°C for 1 hour; c) Trifluoroacetic acid, room temperature, overnight; and d) Triethylamine, appropriate alkyl chloroformate, dichloromethane, room temperature, 2 hours.

[0169] It will be understood that the boronic acid in step b) can be prepared as reported in Bioorg.Med.Chem.Lett.2018,28(3),519-522. Alternatively, the synthesis may include boronic acid esters such as MIDA derivatives or pinacol esters.

[0170] R 1 , R 2 , R 3 , R 4 , R 5 It is understood that the values ​​of X, Y, and Z may be as described for the compounds disclosed in this document, such as the compound of formula I.

[0171] This disclosure also provides compounds of formula 4 or 5 as described herein. Compounds of formula 4 or 5 may function as intermediates in the preparation of compounds of formula I as described herein. [Examples]

[0172] The following abbreviations are used throughout this document. Abbreviation ACN Acetonitrile DAST Diethylaminosulfur Trifluoride DCM Dichloromethane DMA N,N'-dimethylacetamide DMF (N,N'-dimethylformamide) Dppf 1,1'-ferrocenediyl-bis(diphenylphosphine) EA ethyl acetate FCC Flash Column Chromatography h time HFBA (Heptafluorobutyrate) HLM (Human Liver Microsomes) HPLC (High-Performance Liquid Chromatography) HRMS (ESI) High-Resolution Mass Spectrometry (Electrospray Ionization) Hz (Hertz) μM micromoles MHz (megahertz) LCM Liquid Chromatography LCMS (Liquid Chromatography Mass Spectrometry) MIDA (methyliminodiacetic acid) min MLM mouse liver microsomes NMR nuclear magnetic resonance PA Propionic Acid PBS (phosphate-buffered saline) RLM rat liver microsomes TFA (Trifluoroacetic Acid) Xantphos 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene

[0173] Compound nomenclature in this document was performed using ChemDraw Professional 15.0 or ChemDraw Professional 16.0. In this document, if the chemical name and chemical structure do not match, the chemical structure should be assumed to be correct.

[0174] general All chemicals and solvents were purchased from Sigma Aldrich, Fisher Scientific, FluoroChem, and Enamine and used without further purification. Microwave heating was performed in a Biotage single-mode microwave reactor that generated controlled irradiation at 2450 MHz with a power of 0–400 W. The reaction temperature was measured and controlled using a built-in online IR sensor. Microwave reactions were performed in septum-sealed vials designed for reaction volumes of 0.5–2.0 mL, 2.0–5.0 mL, or 10–20 mL. Commercially available Isolute HM-N (diatomaceous earth) pre-packed columns were used to remove trace amounts of moisture. Automated flash column chromatography was performed on Biotage Isolera or Grace Reveleris instruments using commercially available silica cartridges. Manual flash chromatography was performed on silica gel 60 (40–63 μm). Preparative reverse-phase HPLC was performed using a C18 column (Macherey-Nagel VP 125 / 21 Nucleodur C18 HTec 5μm) with UV (254nm) detection, and a mobile phase of acetonitrile in 0.05% formic acid aqueous solution or acetonitrile in 0.1% trifluoroacetic acid aqueous solution.

[0175] Analytical HPLC / ESI-MS was performed using electrospray ionization (ESI) and a C18 column (50 × 3.0 mm, particle size: 2.6 μm, pore size: 100 Å) with a gradient of acetonitrile in 0.05% formic acid aqueous solution as the mobile phase, at a flow rate of 1.5 ml / min. High-resolution molecular mass (HRMS) was measured using a mass spectrometer equipped with an ESI source and a 7-T hybrid linear ion trap (LTQ). Nuclear magnetic resonance (NMR) spectra were obtained. 1 For H, 400MHz and 500MHz, 13 For C, 101MHz and 126MHz, 19 F was recorded at 376 MHz using a Varian instrument. The chemical shift (δ) is reported in ppm, with the residual solvent peak as the internal standard. 1H: 7.26 ppm chloroform-d, 2.50 ppm DMSO-d6, 2.05 ppm acetone-d6, 3.31 ppm methanol-d4; 13 C: 77.2 ppm chloroform-d, 39.5 ppm DMSO-d6; 19 F: 0.00 ppm FCCl3 capillary). The binding constant (J) is reported in Hertz (Hz). Unless otherwise specified, all final compounds were measured for purity of 95% or higher by analytical HPLC and / or NMR.

[0176] The present invention will be described by the following embodiments with reference to the accompanying drawings, but will not be limited thereto. Figures 1-4 show the secreted Col1a1 (Col1a1) levels in the PCLus culture supernatant at 48, 96, and 144 hours for C21, Example 1A, Example 12A, and Example 3. Figures 5-8 show the secreted TGF-β1 levels in the PCLus culture supernatant at 48, 96, and 144 hours for C21, Example 1A, Example 12A, and Example 3. Figures 9 and 10 show the selected gene transcription levels in PCLus for Col1a1 and TGF-β1 (normalized to β-actin) after treatment with C21, Example 1A, Example 12A, and Example 3 at 144 hours.

[0177] Preparation of starting materials for Examples 1 and 2 2-tert-butyl-1H-imidazole was purchased from Fluorochem.

[0178] N-alkylation of heterocycles 1-[(4-bromophenyl)methyl]-2-tert-butylimidazole NaH (0.184 g, 8.0 mmol, 2 equivalents) was added at 0°C to a stirred solution of 2-tert-butyl-1H-imidazole (0.497 g, 4.0 mmol, 1 equivalent) in DMF (0.27 M). After 20 minutes, 1-bromo-4-(bromomethyl)benzene (1.05 g, 4.2 mmol, 1.05 equivalents) was added. The resulting mixture was heated to ambient temperature, stirred overnight, and then quenched with water (15 mL). The product was extracted with ethyl acetate (3 × 25 ml). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO4, and concentrated under vacuum. Crude product was obtained in 99% yield (1.16 g, 0.396 mmol) without the need for grinding.

[0179] Suzuki cross-coupling of boronic acid MIDA and N-alkylated heterocycle N-tert-butyl-2-[4-[(2-tert-butylimidazole-1-yl)methyl]phenyl]-4-isobutylbenzenesulfonamide N-(tert-butyl)-4-isobutyl-2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzenesulfonamide (0.441 g, 1.04 mmol, 1.04 mmol), potassium carbonate (0.083 g, 0.6 mmol, 1.5 equivalents), and tetrakis(triphenylphosphine)palladium (0) (0.231 g, 0.02 mmol, 0.05 equivalents) were suspended in toluene (0.18 M). To this mixture, 1-[(4-bromophenyl)methyl]-2-tert-butylimidazole (0.293 g, 1.0 mmol, 1 equivalent) in ethanol (0.5 M) was added. 0.25 mL of water. The resulting reaction mixture was stirred under microwave irradiation at 120°C for 60 minutes, allowed to cool to ambient temperature, water (10 mL) was added, and the reaction mixture was extracted with ethyl acetate (2 × 25 mL). The combined organic layer was washed with brine (25 mL), dried over anhydrous MgSO4, and concentrated. The crude product was purified by FCC (15-30% EA in isohexane) to obtain the title compound as a solid in 36% yield (0.171 g, 0.355 mmol).

[0180] Deprotection of sulfonamides 2-[4-[(2-tert-butylimidazole-1-yl)methyl]phenyl]-4-isobutylbenzenesulfonamide N-tert-butyl-2-[4-[(2-tert-butylimidazole-1-yl)methyl]phenyl]-4-isobutylbenzenesulfonamide (0.135 g, 0.28 mmol) was stirred overnight at ambient temperature in trifluoroacetic acid (4.6 mL). The reaction mixture was diluted with water (10 mL), and the product was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous MgSO4, and concentrated under vacuum. The crude sulfonamide was purified by FCC (5% MeOH in DCM) to obtain the product as a white amorphous solid in 86% yield (0.102 g, 0.24 mmol).

[0181] Preparation of starting materials for Examples 3-6 General procedure for the synthesis of thiazole sulfonamides a) 2-alkylation of 2,4-dibromothiazole Under a nitrogen atmosphere, Pd(OAc)2 (0.03 mmol, 0.03 equivalents) was combined with xanthophos (0.05 mmol, 0.05 equivalents) in dry THF. After stirring for 5 minutes, this solution was transferred to another container containing 2,4-dibromothiazole (1.03 mmol, 1 equivalent) and alkylzinc bromide (0.5 M, 1.08 mmol, 1.05 equivalents in THF) under nitrogen. The sealed container was heated at 80°C for 16 hours. After cooling to room temperature, the insoluble solid was removed by filtration through a Celite pad (eluted with CH2Cl2). The filtrate was diluted with H2O (50 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined organic extract was washed with brine (30 mL), dried over MgSO4, and concentrated under vacuum to obtain the crude product. The crude product was purified by FCC (0-10% ethyl acetate in isohexane) to obtain the corresponding product in a yield of 55-65%.

[0182] b) Synthesis of thiazole sulfonic acid derivatives 4-bromo-2-alkylated thiazole (1 mmol, 1 equivalent) was dissolved in DMF (2 mL), cooled to 5°C, and then chlorosulfonic acid (5 mmol, 5 equivalents) was slowly added in this manner. The mixture was then stirred at 120°C for 16 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (10% MeOH in DCM) to obtain the corresponding product.

[0183] c) Synthesis of sulfonyl chloride from sulfonic acid 4-bromo-2-alkylated thiazole-5-sulfonic acid (1 mmol, 1 equivalent) was dissolved in 10 mL of DCM, and PCl5 (2 mmol, 2 equivalents) was slowly added. The reaction mixture was stirred overnight at 60°C. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layer was washed with water (30 mL) and brine (25 mL), dried over anhydrous MgSO4, and concentrated under vacuum. The crude product was purified by FCC (0-25% ethyl acetate in isohexane) to obtain a chloride intermediate in 80-95% yield.

[0184] d) Synthesis of 4-bromo-N-(tert-butyl)-2-alkylated thiazole sulfonamide A chloride intermediate (1 mmol, 1 equivalent) was dissolved in DCM (2 mL), tert-butylamine (1.1 mmol, 1.1 equivalents) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then extracted with DCM (2 × 50 mL). The combined organic layer was washed with water (30 mL) and brine (25 mL), dried over anhydrous MgSO4, and concentrated under vacuum. The crude product was purified by FCC (0-30% ethyl acetate in isohexane) to obtain the corresponding sulfonamide in 90-95% yield.

[0185] N-alkylation of 2-tert-butylimidazole 2-tert-butylimidazole (6.0 mol, 1 equivalent), bromobenzyl bromide (6 mol, 1 equivalent), and base NaH (6 mol, 1 equivalent) were stirred overnight at room temperature in acetonitrile (10 mL). The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layer was washed with water (30 mL) and brine (25 mL), dried over anhydrous MgSO4, and concentrated under vacuum. The crude product was purified by FCC (50-100% ethyl acetate in isohexane) to obtain the N-alkylated heterocycle in 80-95% yield.

[0186] Synthesis of pinacolatoboronic acid esters Pd(dppf)Cl2 (0.03 mmol, 0.03 equivalents) was added to a mixture of 2-tert-butylimidazole (1.0 mmol, 1 equivalent), KOAc (3.0 mmol, 3 equivalents), and B2pin2 (3.5 mmol, 3.5 equivalents) in DMF (5 mL). The mixture was stirred under N2 at 80°C for 16 hours. Insoluble solids were removed by filtration through a Celite pad (eluted with CH2Cl2). The filtrate was diluted with H2O (50 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, and concentrated under vacuum to obtain the crude product. The crude product was purified by FCC (50-100% ethyl acetate in isohexane) to obtain the corresponding product in 80-95% yield.

[0187] General procedure for Suzuki cross-coupling of thiazole sulfonamide and N-alkylated heterocyclic boronic acid esters Thiazole sulfonamide (1 mmol, 1 equivalent), N-alkylation product (1 mmol, 1 equivalent), potassium carbonate (4 mmol, 4 equivalents), and Pd(dppf)Cl2 (0.05 mmol, 0.05 equivalents) were suspended in 1,2-dimethoxyethane (3 mL) and water (0.6 mL). The vial was sealed, and the resulting reaction mixture was stirred at 120°C for 60 minutes under microwave irradiation. The mixture was allowed to cool to ambient temperature and then extracted with chloroform (3 × 2 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous MgSO4, and concentrated. The crude product was isolated by manual FCC (0-10% MeOH in DCM) to obtain the product in 70-85% yield.

[0188] General procedure for deprotection of sulfonamide products The Suzuki coupling product (0.15 mmol) was stirred overnight in trifluoroacetic acid (2.5 mL) at 50°C. The reaction mixture was diluted with water (10 mL), and the product was extracted with dichloromethane (2 × 20 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous MgSO4, and concentrated. The sulfonamide was purified by passing it through a small silica plug (0-5% MeOH in acetonitrile) and used in the subsequent carbamate ester formation reaction without further purification.

[0189] Example 1A ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate [ka] ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate methyl was synthesized as described. Crude sulfonamide (55.3 mg, 0.13 mmol, 1 equivalent) was dissolved in DCM (0.05 M). Triethylamine (90 μL, 0.65 mmol, 5 equivalents) and methyl chloroformate (11 μL, 0.14 mmol, 1.1 equivalents) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (10 mL), extracted with ethyl acetate (3 × 5 mL), washed with brine (3 mL), dried over MgSO4, and concentrated. The crude product was purified by HPLC (30-70% ACN in water containing 0.05% formic acid). After freeze-drying, the product was obtained as a white amorphous solid (17 mg, 27% yield). 1 H NMR(500MHz,acetone-d6)δ 8.11(d,J=8.2Hz,1H),7.43(dd,J=8.3,1.8Hz,1H),7.41-7.36(m,2H),7.18-7.09(m,3H),6.91(d,J=1.3Hz,1H),6.83(d ,J=1.3Hz,1H),5.48(s,2H),3.54(s,2H),2.62(d,J=7.2Hz,2H),2.02-1.91(m,1H),1.41(s,9H),0.94(d,J=6.6Hz,6H). 13 ¹³C NMR (126MHz, acetone-d6) δ 154.6, 152.7, 148.1, 141.5, 139.7, 138.6, 136.7, 134.0, 131.1, 130.3, 129.1, 126.8, 126.7, 122.8, 53.1, 51.2, 45.3, 34.1, 30.8, 30.4, 22.6. HRMS (ESI) C 26 H 34 N3O4S + [M+H] + The calculated value is 484.2270, and the measured value is 484.2269.

[0190] Example 1B Potassium ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)(methoxycarbonyl)amide [ka] Potassium ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)(methoxycarbonyl)amide was prepared as described. To a stirred solution of ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate methyl (45.9 mg, 95 μmol, 1 equivalent) in chloroform (95 μM), KOH (11.1 mg, 0.198 mmol, 2 equivalents) in MeOH (0.59 M) was added. The resulting solution was stirred at room temperature for 4 hours, during which time a white solid precipitate was observed. The crude product was partially evaporated and triturated with pentane (50 mL) from chloroform. The obtained solid was filtered and then dissolved in water (5 mL). The solution was filtered to ensure complete removal of organic residue. After freeze-drying, the product was obtained as a white amorphous solid in 93% yield (46.1 mg, 88 μmol). 1 H NMR(400MHz,DMSO-d6)δ 7.86(d,J=8.0Hz,1H),7.53-7.28(m,2H),7.13(dd,J=8.1,1.9Hz,1H),7.02-6.90(m,3H),6.86(d,J=1.8Hz,1H),6.76(d,J=1 .2Hz,1H),5.38(s,2H),3.15(s,3H),2.46(d,J=7.1Hz,2H),1.84(dt,J=13.6,6.8Hz,1H),1.34(s,9H),0.87(d,J=6.6Hz,6H). LCMS C 26 H 34 N3O4S + [M+H] + The calculated value is 484.2, and the measured value is 484.1.

[0191] Example 2A ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate [ka] ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate butyl was synthesized using crude sulfonamide (21.3 mg, 50 μmol) instead of butyl chloroformate (8.8 μL, 69.2 μmol), as described for ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate butyl. The crude product was purified by FCC (5% MeOH in DCM), followed by mini-preparative TLC (10% MeOH in DCM), and triturated with isohexane from DCM to obtain the product as a white amorphous solid (5 mg, 21% yield). 1 H NMR(400MHz,acetone-d6)δ 8.11(d,J=8.2Hz,1H),7.44(dd,J=8.2,1.9Hz,1H),7.37(d,J=8.2Hz,2H), 7.24-7.00(m,3H),6.88(d,J=1.3Hz,1H),6.80(d,J=1.3Hz,1H),5.47(s,2H) ),3.96(t,J=6.5Hz,2H),2.62(d,J=7.2Hz,2H),2.03-1.86(m,1H),1.51-1. 39(m,2H),1.28-1.16(m,2H),0.93(d,J=6.6Hz,6H),0.85(t,J=7.4Hz,3H). 13 ¹³C NMR (101 MHz, acetone-d6) δ 154.6, 151.6, 148.3, 141.6, 139.5, 138.8, 136.5, 134.1, 131.1, 130.3, 129.2, 126.9, 126.9, 122.8, 66.5, 51.2, 45.3, 34.1, 31.3, 30.8, 30.4, 22.5, 19.5, 13.9. HRMS (ESI) C 29 H 40 N3O4S+ [M+H] + The calculated value is 526.2740, and the measured value is 526.2731.

[0192] Example 2B Potassium ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)(butoxycarbonyl)amide [ka] The title compound was synthesized as described in Example 1B using ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)-butyl carbamate (20.4 mg, 38.5 μmol, 1.0 equivalent) and KOH in MeOH (0.59 M) (2.33 mg, 41.6 μmol, 1.08 equivalent). The product was obtained as a white amorphous solid (16.5 mg, 76% yield). 1 H NMR(400MHz,DMSO-d6)δ7.85(d,J=8.1Hz,1H),7.45-7.35(m,2H),7.12(dd,J=8.1,1.8 Hz,1H),6.94(dd,J=4.7,3.4Hz,3H),6.84(d,J=1.8Hz,1H),6.76(d,J=1.2Hz,1H),5.37 (s,2H),3.54(t,J=6.5Hz,2H),2.45(d,J=7.1Hz,2H),1.91-1.74(m,1H),1.34(s,9H), 1.30(d,J=6.8Hz,2H),1.27-1.13(m,2H),0.87(d,J=6.6Hz,6H),0.83(t,J=7.3Hz,3H). LCMS C 29 H 40 N3O4S + [M+H] + The calculated value is 526.2734, and the measured value is 526.2.

[0193] Example 3 ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate [ka] To a mixture of the corresponding sulfonamide (0.12 mmol, 1 equivalent) and triethylamine (0.58 mmol, 5 equivalents) in DCM (2 mL), methyl chloroformate (0.17 mmol, 1.5 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was quenched with water, diluted in DCM (25 mL), and then sequentially extracted with 10% citric acid (aqueous solution, 20 mL), water (3 × 30 mL), and brine (20 mL). The combined organic layer was dried over MgSO4 and concentrated. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (40 mg, 71% yield). 1 H NMR(400MHz,acetone-d6)δ 8.26(d,J=8.4Hz,2H),7.13(d,J=8.4Hz,2H),7.09(d,J=1.5Hz,1H),7.03(d,J=1.5Hz,1H),5.56( s,2H),3.40(s,3H),2.83(d,J=7.1Hz,2H),2.19-2.09(m,1H),1.45(s,9H),1.02(d,J=6.7Hz,6H). 13 ¹³C NMR (101 MHz, acetone-d6) δ 168.5, 160.3, 153.5, 150.7, 137.7, 137.4, 133.9, 130.4, 125.6, 124.0, 122.7, 51.5, 50.8, 41.6, 33.4, 29.3, 29.1, 21.7. HRMS (ESI) C 23 H 31 N4O4S2 + [M+H] + The calculated value is 491.1781, and the measured value is 491.1795.

[0194] Example 4 ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)carbamate butyl [ka] To a mixture of the corresponding sulfonamide (0.12 mmol, 1 equivalent) and triethylamine (0.58 mmol, 5 equivalents) in DCM (2 mL), butyl chloroformate (0.17 mmol, 1.5 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was quenched with water, diluted in DCM (25 mL), and then sequentially extracted with 10% citric acid (aqueous solution, 20 mL), water (3 × 30 mL), and brine (20 mL). The combined organic layer was dried over MgSO4 and concentrated. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (39 mg, 63% yield). 1 H NMR(400MHz,chloroform-d)δ 7.98(d,J=8.1Hz,2H),7.03(d,J=8.1Hz,2H),6.92(d,J=1.5Hz,1H),6.80(d,J=1.5Hz,1H),5.30(s,2H),3.81(t,J=6.8Hz,2H), 2.77(d,J=7.1Hz,2H),2.15-2.04(m,1H),1.44-1.40(m,11H),1.23-1.14(m,2H),0.97(d,J=6.6Hz,6H),0.80(t,J=7.3Hz,3H). 13 ¹³C NMR (101 MHz, chloroform-d) δ 170.5, 160.3, 153.9, 152.5, 137.0, 135.1, 133.7, 130.3, 126.1, 124.4, 122.5, 66.0, 51.0, 42.2, 33.5, 30.9, 29.6, 29.6, 22.3, 19.0, 13.8. HRMS (ESI) C 26 H 37 N4O4S2 + [M+H] + The calculated value is 533.2251, and the measured value is 533.2241.

[0195] Example 5 ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)methyl carbamate [ka] A mixture of sulfonamide (0.12 mmol, 1 equivalent) and triethylamine (0.60 mmol, 5 equivalents) in DCM (2 mL) was added dropwise with methyl chloroformate (0.14 mmol, 1.2 equivalents) over approximately 2 hours, and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was quenched with water, diluted with DCM (25 mL), and then sequentially extracted with 10% citric acid (aqueous solution, 20 mL), water (3 × 30 mL), and brine (20 mL). The combined organic layer was dried over MgSO4 and concentrated. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (28 mg, 49% yield). 1 H NMR(400MHz,acetone-d6)δ 8.12(d,J=8.4Hz,2H),7.03(d,J=3.7Hz,2H),7.01-6.96(m,2H),5.47(s,2H),5.23(s,1H), 3.27(s,3H),2.79(t,J=7.2Hz,2H),1.77-1.60(m,2H),1.34(s,9H),0.89(t,J=7.4Hz,3H). 13 ¹³C NMR (101 MHz, acetone-d6) δ 169.7, 160.4, 153.4, 150.7, 137.5, 137.0, 134.0, 130.4, 125.7, 123.1, 123.0, 51.6, 51.0, 34.7, 33.5, 28.9, 22.8, 13.1. HRMS (ESI) C 22 H 29 N4O4S2 + [M+H] + The calculated value is 477.1625, and the measured value is 477.1631.

[0196] Example 6 ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)butyl carbamate [ka] To a mixture of the corresponding sulfonamide (0.12 mmol, 1 equivalent) and triethylamine (0.60 mmol, 5 equivalents) in DCM (2 mL), butyl chloroformate (0.14 mmol, 1.2 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was quenched with water, diluted in DCM (25 mL), and then sequentially extracted with 10% citric acid (aqueous solution, 20 mL), water (3 × 30 mL), and brine (20 mL). The combined organic layer was dried over MgSO4 and concentrated. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (43 mg, 69% yield). 1 H NMR(400MHz,acetone-d6)δ 8.26(d,J=8.5Hz,2H),7.10(d,J=8.5Hz,2H),7.05(d,J=1.5Hz,1H),6.97(d,J=1.5Hz,1H),5.86(s,1H),5.54(s,2H),3.84(t,J=6.6H z,2H),2.92(t,J=7.6Hz,2H),1.88-1.76(m,2H),1.48-1.43(m,11H),1.32-1.23(m,2H),1.03(t,J=7.4Hz,3H),0.86(t,J=7.4Hz,3H). 13 ¹³C NMR (101 MHz, acetone-d6) δ 169.5, 160.0, 153.5, 150.6, 137.7, 137.6, 133.9, 130.4, 125.6, 124.4, 122.6, 64.4, 50.7, 34.7, 33.4, 31.1, 29.2, 22.8, 19.0, 13.3, 13.1. HRMS (ESI) C 25 H 35 N4O4S2 + [M+H] + The calculated value is 519.2094, and the measured value is 519.2096.

[0197] Example 7A ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate butyl [ka] To a stirred solution of the corresponding sulfonamide (74.3 mg, 0.156 mmol) and triethylamine (108.6 μL, 0.78 mmol, 5 equivalents) in DCM (1.0 mL), butyl chloroformate (27.5 μL, 0.216 mmol) was added at room temperature. After 20 minutes, the reaction was quenched with water (2 mL). The crude product was extracted with DCM (3 × 5 mL), washed with brine (5 mL), dried over anhydrous MgSO4, and concentrated. The crude product was purified by FCC (5% MeOH in DCM) to obtain the product as a white amorphous solid in 47% yield (39 mg, 73.5 μmol). 1 H NMR(400MHz,acetone-d6)δ 8.11(d,J=8.2Hz,1H),7.43(dd,J=8.2,1.8Hz,1H),7.38-7.29(m,2H),7.29-7.23( m,2H),7.14(d,J=1.8Hz,1H),6.89(d,J=1.3Hz,1H),6.77(d,J=1.3Hz,1H),5.65(s, 2H),3.96(t,J=6.5Hz,2H),2.62(d,J=7.2Hz,2H),2.01-1.88(m,1H),1.63(s,6H), 1.51-1.39(m,2H),1.32-1.15(m,2H),0.93(d,J=6.6Hz,6H),0.85(t,J=7.4Hz,3H). 13 ¹³C NMR (101MHz, acetone-d6) δ 153.0, 151.8, 148.1, 141.6, 139.5, 138.7, 136.6, 134.1, 131.1, 130.2, 129.1, 127.7, 126.7, 122.1, 71.1, 66.4, 50.9, 45.3, 31.3, 31.0, 30.8, 22.5, 19.5, 13.9. HRMS (ESI) C 28 H 38 N3O5S + [M+H] +The calculated value is 528.2532, and the measured value is 528.2526.

[0198] Example 7B Potassium (butoxycarbonyl)((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide [ka] To a stirred solution of ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate butyl (39 mg, 73.9 μmol) in chloroform, KOH (4.47 mg, 79.8 μmol) in MeOH was added. The resulting solution was stirred at room temperature for 4 hours, during which time a white solid precipitate was observed. The crude product was partially evaporated and triturated with pentane (50 mL) from chloroform. The resulting solid was filtered and then dissolved in water (5 mL). The solution was filtered to ensure the removal of organic residue. The product was obtained as a white amorphous solid in 99% yield (41.5 mg, 73.4 μmol). 1 1H NMR (400MHz, DMSO-d6)δ 7.86(d,J=8.1Hz,1H),7.40(d,J=8.1Hz,2H),7.11(t,J=8.1Hz,3H),6.93(d,J=1 .3Hz,1H),6.85(d,J=1.8Hz,1H),6.74(d,J=1.2Hz,1H),5.53(s,2H),5.42(s,1H) ),3.54(t,J=6.5Hz,2H),2.49-2.42(m,2H),1.90-1.73(m,1H),1.52(s,6H),1.3 9-1.26(m,2H),1.27-1.13(m,2H),0.87(d,J=6.6Hz,6H),0.83(t,J=7.3Hz,3H).

[0199] Example 8A ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate [ka] ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate butyl (16.2 mg, 30.7 μmol) was stirred in MeOH (1 mL) at 120°C (pressure 7 bar) for 20 minutes under MW irradiation. The crude product was purified by FCC (2-4% MeOH in DCM) to obtain the product as a white amorphous solid (14.7 mg, 99% yield). 1 H NMR(400MHz,acetone-d6)δ 8.12(d,J=8.2Hz,1H),7.42(dd,J=8.2,1.8Hz,1H),7.39-7.30(m,2H),7.25(d,J=8.2Hz,2H),7.13(d,J=1.8Hz,1H),6.90(d,J=1.3Hz,1H), 6.77(d,J=1.3Hz,1H),5.89(s,1H),5.65(s,2H),3.54(s,3H),2.61(d,J=7.2Hz,2H),2.02-1.84(m,1H),1.63(s,6H),0.92(d,J=6.6Hz,6H). 13 ¹³C NMR (101MHz, acetone-d6) δ 153.0, 152.6, 148.0, 141.6, 139.6, 138.6, 136.6, 134.0, 131.2, 130.2, 129.0, 127.7, 126.5, 122.2, 71.1, 53.1, 50.9, 45.3, 30.9, 30.7, 22.5. HRMS (ESI + )C 25 H 32 N3O5S + [M+H] + The calculated value is 486.2063, and the measured value is 486.2060.

[0200] Example 8B Potassium ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)(methoxycarbonyl)amide [ka] The title compound was synthesized using potassium (butoxycarbonyl)((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide, as described for potassium (butoxycarbonyl)((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide, with as described for potassium (butoxycarbonyl)((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)amide. The product was obtained as a white amorphous solid (15.7 mg, 99% yield). 1 H NMR(400MHz,DMSO-d6)δ 7.86(d,J=8.0Hz,1H),7.42(d,J=8.2Hz,2H),7.16-7.06(m,3H),6.94(d,J=1.3Hz,1H),6.86(d,J=1.8Hz,1H),6.74(d,J=1.3 Hz,1H),5.53(s,2H),5.43(s,1H),3.15(s,3H),2.46(d,J=7.1Hz,2H),2.02-1.74(m,1H),1.52(s,6H),0.87(d,J=6.6Hz,6H).

[0201] Example 9A ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized using the corresponding sulfonamide (107 mg, 0.261 mmol) and butyl chloroformate (45.8 μL, 0.360 mmol) as described for butyl ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate. The product was obtained as a white amorphous solid (48 mg, 36%). 1 1H NMR (400MHz, acetone-d6)δ 8.14(d,J=8.2Hz,1H),7.46(dd,J=8.2,1.9Hz,1H),7.44-7.36(m,2H),7.26- 7.11(m,3H),6.92(d,J=1.4Hz,1H),6.83(d,J=1.4Hz,1H),5.50(s,2H),3.97 (t,J=6.5Hz,2H),2.80-2.64(m,2H),1.80-1.66(m,2H),1.53-1.44(m,2H),1 .44(s,9H),1.30-1.18(m,2H),0.97(t,J=7.3Hz,3H),0.87(t,J=7.4Hz,3H). 13 ¹³C NMR (101MHz, acetone-d6) δ 154.5, 152.2, 148.9, 141.5, 139.8, 138.2, 136.8, 133.4, 131.2, 130.3, 128.4, 126.9, 126.2, 122.8, 66.2, 51.3, 38.0, 34.1, 31.3, 30.3, 24.9, 19.5, 14.0, 13.9. HRMS (ESI + )C 28 H 38 N3O4S + [M+H] + The calculated value is 512.2583, and the measured value is 512.2577.

[0202] Example 9B Potassium (butoxycarbonyl)((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide [ka] The title compound was synthesized using potassium (butoxycarbonyl)((4'-((2-(2-hydroxypropan-2-yl)-1Himidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide, as described for potassium (butoxycarbonyl)((4'-((2-(2-hydroxypropan-2-yl)-1Himidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide, with butyl ((4'-((2-(2-hydroxypropan-2-yl)-1Himidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide, using potassium (butoxycarbonyl)((4'-((2-(2-hydroxypropan-2-yl)-1Himidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide, as described for 1 1H NMR (400MHz, DMSO-d6)δ 7.85(d,J=8.1Hz,1H),7.41(d,J=8.2Hz,2H),7.16(dd,J=8.1,1.8Hz,1H),6. 96-6.92(m,3H),6.88(d,J=1.8Hz,1H),6.76(d,J=1.3Hz,1H),5.37(s,2H),3. 54(t,J=6.5Hz,2H),2.60-2.52(m,2H),1.73-1.49(m,2H),1.36-1.30(m,2H), 1.34(s,9H),1.25-1.11(m,2H),0.89(t,J=7.3Hz,3H),0.83(t,J=7.3Hz,3H).

[0203] Example 10A ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate [ka] The title compound was synthesized using ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-)2-yl)sulfonyl)butyl carbamate (18.8 mg, 33.3 μmol) as described for ((4'-((2-(2-hydroxypropane-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl)]-2-yl)sulfonyl)methyl carbamate. The crude product was concentrated and purified by FCC (4-6% MeOH in CH2Cl2) to obtain the product as a white amorphous solid (41.5 mg, 86% yield). 1 H NMR(400MHz,acetone-d6)δ 8.12(d,J=8.2Hz,1H),7.49(s,br.,1H),7.44(dd,J=8.2,1.9Hz,1H),7.42-7.36(m,2H),7.21-7.04(m,3H),6.91(d,J=1.4Hz,1H),6 .83(d,J=1.4Hz,1H),5.49(s,2H),3.53(s,3H),2.71(dd,J=8.6,6.7Hz,2H),1.81-1.60(m,2H),1.42(s,9H),0.95(t,J=7.3Hz,3H). 13 ¹³C NMR (101MHz, acetone-d6) δ 154.5, 152.9, 148.9, 141.5, 139.9, 138.1, 136.8, 133.3, 131.3, 130.3, 128.4, 126.9, 126.1, 122.9, 53.0, 51.3, 38.1, 34.1, 30.2, 24.9, 14.0. HRMS (ESI + )C 25 H 32 N3O4S + [M+H] + The calculated value is 470.2114, and the measured value is 470.2115.

[0204] Example 10B Potassium ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)(methoxycarbonyl)amide [ka] The title compound was synthesized using potassium (butoxycarbonyl)((4'-((2-(2-hydroxypropan-2-yl)-1Himidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide, as described for potassium (butoxycarbonyl)((4'-((2-(2-hydroxypropan-2-yl)-1Himidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide, with potassium (butoxycarbonyl)((4'-((2-(2-hydroxypropan-2-yl)-1Himidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide, with potassium (butoxycarbonyl)((4'-((2-(2-hydroxypropan-2-yl)-1Himidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide, as described for 1 H NMR(400MHz,DMSO-d6)δ 7.86(d,J=8.1Hz,1H),7.43(d,J=8.2Hz,2H),7.16(dd,J=8.1,1.9Hz,1H),7.05-6.91(m,3H),6.89(d,J=1.8Hz,1H),6.7 7(d,J=1.2Hz,1H),5.38(s,2H),3.15(s,3H),2.58-2.52(m,2H),1.66-1.52(m,2H),1.34(s,9H),0.90(t,J=7.3Hz,3H).

[0205] Example 11A ((3-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate butyl [ka] The title compound was synthesized using the corresponding sulfonamide (168 mg, 0.389 mmol) and butyl chloroformate (68.3 μL, 0.537 mmol) as described for butyl ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate. The crude product was purified by FCC (5% MeOH in DCM) to obtain the product as a white amorphous solid (179 mg, 87%). 1 H NMR(400MHz,acetone-d6)δ 7.79-7.66(m,2H),7.12(d,J=8.1Hz,2H),7.03(d,J=1.5Hz,1H),6.95-6.79(m,2H),5.54(s,2H),2.72(d,J=7.1Hz,2H),2 .00-1.87(m,6.7Hz,1H),1.54-1.44(m,2H),1.43(s,9H),1.32-1.18(m,4H),0.99(d,J=6.6Hz,6H),0.86(t,J=7.4Hz,3H). 13 ¹³C NMR (101MHz, acetone-d6) δ 154.3, 154.1, 149.4, 144.0, 137.8, 136.0, 135.3, 130.5, 130.0, 127.1, 124.5, 123.4, 65.8, 51.6, 39.5, 34.3, 31.5, 31.2, 29.9, 22.5, 19.6, 14.0. HRMS (ESI + )C 27 H 38 N3O4S2 + [M+H] + The calculated value is 532.2304, and the measured value is 532.2300.

[0206] Example 11B Potassium (butoxycarbonyl)((3-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)amide [ka] The title compound was synthesized using potassium (butoxycarbonyl)((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophene-2-)yl)sulfonyl)carbamate butyl ((3-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide as described. The product was obtained as a white amorphous solid (29.7 mg, 87% yield). 1 H NMR(400MHz,DMSO-d6)δ 7.77(d,J=8.3Hz,2H),7.03-6.89(m,3H),6.86-6.69(m,2H),5.37(s,2H),3.23(s, 3H), 2.60(d,J=6.9Hz,6H),1.91-1.70(m,1H),1.31(s,9H),0.93(d,J=6.6Hz,6H).

[0207] Example 12A ((3-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)methyl carbamate [ka] ((3-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)butyl carbamate (45.8 mg, 86.1 μmol) was stirred in MeOH (1 mL) at 120 °C (pressure 7 bar) for 20 minutes under MWI. The crude product was concentrated and purified by FCC (5% MeOH in DCM) to obtain the product as a white amorphous solid (35.7 mg, 85% yield). 1H NMR(400MHz, methanol-d4)δ 7.65(d,J=8.3Hz,2H),7.21-7.03(m,4H),6.74(s,1H),5.51(s,2H),3.47(s,3 H),2.73-2.61(m,2H),1.97-1.83(m,1H),1.50(s,9H),0.97(d,J=6.6Hz,6H). 13 ¹³C NMR (101 MHz, methanol-d4) δ 158.5, 154.0, 148.5, 143.1, 136.9, 136.3, 135.2, 130.8, 129.5, 127.2, 124.3, 121.2, 52.7, 52.4, 39.7, 34.3, 31.2, 29.2, 22.5. HRMS (ESI + )C 24 H 33 N3O4S2 + [M+H] + The calculated value is 490.1834, and the measured value is 490.1838.

[0208] Example 12B Potassium ((3-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)(methoxycarbonyl)amide [ka] The title compound was synthesized using potassium (butoxycarbonyl)((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophene-2-)yl)sulfonyl)amide as described for potassium (butoxycarbonyl)((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide, with methyl ((3-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide, with KOH (4.06 mg, 72.3 μmol, 1.08 equivalents) in MeOH (0.59 M). The product was obtained as a white amorphous solid (29.7 mg, 87% yield). 1H NMR(400MHz,DMSO-d6)δ 7.77(d,J=8.3Hz,2H),7.03-6.89(m,3H),6.86-6.69(m,2H),5.37(s,2H),3.23(s, 3H), 2.60(d,J=6.9Hz,6H),1.91-1.70(m,1H),1.31(s,9H),0.93(d,J=6.6Hz,6H).

[0209] Example 13 Sodium ((3-(4-((1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)(butoxycarbonyl)amide [ka] A solution of ((3-(4-((1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)butyl carbamate (100 g, 0.210 mol) in dichloromethane (380 mL) was filtered through Celite beads. A 3.3% NaOH solution in methanol (198 g) was added to the filtrate at 25-30°C and maintained at the same temperature with stirring for 1 hour. The above solution was concentrated to approximately 200 mL, the residue was cooled to 25-30°C, and 1.46 L of isopropyl was added. The resulting solution was concentrated to obtain approximately 400 mL of oily syrup. Heptane (1.18 L) was slowly added to the oily syrup with stirring. The resulting solid was filtered and washed with heptane (200 mL). The solid salt was dried at a temperature below 50°C for 8 hours to obtain sodium ((3-(4-((1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)(butoxycarbonyl)amide (C21) as a white solid with HPLC purity >98% in yield of 85% (89 g, 0.178 mol).

[0210] Example 14 ((4-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized as described for ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, except that the mixture was kept on dry ice and butyl chloroformate (0.2 mmol, 1.2 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (48 mg, 55% yield). 1 H NMR(400MHz, methanol-d4)δ 7.81(d,J=8.4Hz,2H),7.27-7.16(m,4H),5.63(s,2H),3.78(t,J=6.5Hz,2H),2.89(dd,J=8.0,7.2Hz,2H),1.80 -1.71(m,2H),1.58(s,6H),1.41-1.32(m,2H),1.20-1.14(m,2H),0.95(t,J=7.4Hz,3H),0.77(t,J=7.4Hz,3H). 13 ¹³C NMR (101 MHz, methanol-d4) δ 173.1, 157.2, 152.9, 151.7, 136.3, 133.5, 135.0, 130.1, 126.9, 123.3, 120.1, 69.3, 64.8, 51.2, 34.6, 30.7, 28.4, 22.9, 18.7, 12.7, 12.5. HRMS (ESI) C 24 H 33 N4O5S2 + [M+H] + The calculated value is 521.1887, and the measured value is 521.1879.

[0211] Example 15 ((4-(4-((2-isopropyl-1H-imidazole-1-yl)methyl)phenyl)2-propylthiazole-5-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized as described for ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, except that the mixture was kept on dry ice and butyl chloroformate (0.2 mmol, 1.2 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (51 mg, 58% yield). 1 H NMR(400MHz,acetone-d6)δ 8.32-8.19(m,2H),7.8-7.16(m,3H),7.01(d,J=1.5Hz,1H),5.34(s,2H),3.83(t,J=6.7Hz,2H),3.26-3.18(m,1H),2.97-2. 85(m,2H),1.80(dt,J=15.3,7.6Hz,2H),1.56-1.38(m,2H),1.37-1.17(m,8H),1.02(t,J=7.4Hz,3H),0.86(t,J=7.4Hz,3H). 13 ¹³C NMR (101 MHz, acetone-d6) δ 169.4, 160.2, 152.6, 150.5, 137.9, 137.1, 134.1, 130.4, 126.0, 125.1, 120.1, 64.3, 48.9, 34.7, 31.1, 25.6, 22.8, 21.1, 19.0, 13.3, 13.1. HRMS (ESI) C 24 H 33 N4O4S2 + [M+H] + The calculated value is 505.1938, and the measured value is 505.1930.

[0212] Example 16 ((2-Isobutyl-4-(4-((2-(Thiazol-2-yl)-1H-imidazole-1-yl)methyl)phenyl)thiazol-5-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized as described for ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, except that the mixture was kept on dry ice and butyl chloroformate (0.13 mmol, 1.2 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (31 mg, 51% yield). 1 1H NMR (400MHz, acetone-d6)δ 7.97(d,J=8.4Hz,2H),7.89(d,J=3.3Hz,1H),7.62(d,J=3.3Hz,1H),7.37(d, J=1.2Hz,1H),7.35(d,J=8.7Hz,2H),7.11(d,J=1.2Hz,1H),6.02(s,2H),3.97 (t,J=6.5Hz,2H),2.92(d,J=7.1Hz,2H),2.16(dt,J=13.5,6.8Hz,1H),1.52- 1.42(m,2H),1.30-1.19(m,2H),1.03(d,J=6.6Hz,6H),0.86(t,J=7.4Hz,3H). 13 ¹³C NMR (101 MHz, acetone-d6) δ 172.3, 160.1, 154.5, 153.0, 143.3, 140.2, 138.9, 132.8, 132.3, 130.1, 129.5, 127.0, 123.7, 120.0, 65.7, 49.9, 41.7, 30.5, 29.4, 21.6, 18.7, 13.1. HRMS (ESI) C 25 H 30 N5O4S3 + [M+H] +The calculated value is 560.1454, and the measured value is 560.1453.

[0213] Example 17 ((4-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized as described for ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, except that the mixture was kept on dry ice and butyl chloroformate (0.22 mmol, 1.2 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (51 mg, 52% yield). 1 H NMR(400MHz, methanol-d4)δ 7.94(d,J=8.4Hz,2H),7.37-7.28(m,4H),5.75(s,2H),3.90(t,J=6.5Hz,2H),2.90(d,J=7.2Hz,2H),2.18-2 .11(m,1H),1.70(s,6H),1.55-1.44(m,2H),1.34-1.23(m,2H),1.05(d,J=6.7Hz,6H),0.89(t,J=7.4Hz,3H). 13 ¹³C NMR (101 MHz, methanol-d4) δ 172.0, 157.3, 152.8, 151.6, 136.3, 135.3, 133.5, 130.1, 126.9, 123.3, 120.1, 69.4, 64.8, 51.2, 41.5, 30.7, 29.6, 28.4, 21.2, 18.7, 12.7. HRMS (ESI) C 19 H 22 N4O4S2[M+H] +Calculated value: 435.1155, measured value: 435.1174. HRMS(ESI)C 25 H 35 N4O5S2 + [M+H] + The calculated value is 535.2043, and the measured value is 535.2035.

[0214] Example 18 ((2-Isobutyl-4-(4-((2-Isopropyl-1H-imidazole-1-yl)methyl)phenyl)thiazole-5-yl)sulfonyl)carbamate butyl [ka] The title compound was synthesized using the corresponding sulfonamide (80.0 mg, 0.191 mmol) and butyl chloroformate (29.6 μL, 0.232 mmol) as described for ((4-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)carbamate butyl. The crude product was purified by FCC (0-5% MeOH in MeCN) to obtain the product as a white amorphous solid (51 mg, 51% yield). 1 H NMR(400MHz,acetone-d6)δ 8.26(d,J=8.4Hz,2H),7.20-7.19(m,3H),7.05(d,J=1.4Hz,1H),5.36(s,2H),3.83(t,J=6.7Hz,2H),3.30-3.18(m,1H),2. 83(d,J=7.1Hz,2H),2.20-2.08(m,1H),1.49-1.40(m,2H),1.33-1.21(m,8H),1.02(d,J=6.6Hz,6H),0.86(t,J=7.4Hz,3H). 13 ¹³C NMR (101MHz, acetone-d6) δ 168.4, 160.01, 152.5, 150.5, 138.0, 136.9, 134.1, 130.6, 126.1, 124.8, 120.2, 64.3, 49.0, 41.6, 31.1, 29.4, 25.6, 21.7, 21.0, 18.9, 13.2. HRMS (ESI + ):C 25H 35 N4O4S2 + [M+H] + The calculated value is 519.2094, and the measured value is 519.2084.

[0215] Example 19 ((4-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate [ka] The title compound was synthesized as described for ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)carbamate methyl, except that the mixture was kept on dry ice and methyl chloroformate (0.16 mmol, 1.2 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (41 mg, 60% yield). 1 H NMR(400MHz, methanol-d4)δ 7.81(d,J=8.4Hz,2H),7.28(d,J=2.0Hz,1H),7.27(d,J=2.0Hz,1H),7.23(d,J=8.4Hz,2H),5.64( s,2H),3.37(s,3H),2.79(d,J=7.2Hz,2H),2.08-1.97(m,1H),1.58(s,6H),0.93(d,J=6.6Hz,6H). 13 ¹³C NMR (101 MHz, methanol-d4) δ 172.2, 157.7, 152.9, 151.5, 135.9, 135.0, 133.7, 130.2, 126.9, 123.6, 119.3, 69.3, 51.5, 51.4, 41.4, 29.6, 28.2, 21.2. HRMS (ESI) C 22 H 29 N4O5S2+ [M+H] + The calculated value is 493.1574, and the measured value is 493.1566.

[0216] Example 20 ((2-Isobutyl-4-(4-((2-Isopropyl-1H-imidazole-1-yl)methyl)phenyl)thiazole-5-yl)sulfonyl)methyl carbamate [ka] The title compound was synthesized as described for ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, except that the mixture was kept on dry ice and methyl chloroformate (0.2 mmol, 1.2 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (41 mg, 51% yield). 1 H NMR(400MHz, methanol-d4)δ 7.85(d,J=8.4Hz,2H),7.09(d,J=8.6Hz,2H),7.05(d,J=1.6Hz,1H),6.95(d,J=1.6Hz,1H),5.20(s,2H),3.32(s,3H), 3.14-3.05(m,1H),2.76(d,J=7.2Hz,2H),2.01(dt,J=13.5,6.8Hz,1H),1.13(d,J=6.9Hz,6H),0.92(d,J=6.6Hz,6H). 13 ¹³C NMR (101 MHz, methanol-d4) δ 171.0, 160.5, 153.1, 151.8, 136.8, 136.5, 133.5, 130.2, 126.0, 124.0, 120.4, 51.1, 49.0, 41.4, 29.6, 25.5, 21.2, 20.4. HRMS (ESI) C 22 H 29 N4O4S2 +[M+H] + The calculated value is 477.1625, and the measured value is 477.1618.

[0217] Example 21 ((2-Propyl-4-(4-((2-(Thiazol-2-yl)-1H-imidazole-1-yl)methyl)phenyl)thiazol-5-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized as described for ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, except that the mixture was kept on dry ice and butyl chloroformate (0.14 mmol, 1.2 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (37 mg, 60% yield). 1 H NMR(400MHz,acetone-d6)δ 7.95(d,J=8.3Hz,2H),7.89(d,J=3.3Hz,1H),7.63(d,J=3.3Hz,1H),7.38(d ,J=1.2Hz,1H),7.35(d,J=8.7Hz,2H),7.12(d,J=1.2Hz,1H),6.03(s,2H),3 .97(t,J=6.5Hz,2H),3.02(t,J=7.5Hz,2H),1.86(h,J=7.4Hz,2H),1.52-1. 41(m,2H),1.29-1.19(m,2H),1.04(t,J=7.4Hz,3H),0.86(t,J=7.4Hz,3H). 13¹³C NMR (101MHz, acetone-d6) δ 170.6, 160.2, 157.68, 151.9, 143.3, 140.2, 138.1, 135.8, 133.5, 130.2, 129.4, 126.8, 123.7, 119.9, 64.8, 50.0, 34.7, 30.9, 22.8, 18.8, 13.2, 13.0. HRMS (ESI) C 24 H 28 N5O4S3 + [M+H] + The calculated value is 546.1298, and the measured value is 546.1295.

[0218] Example 22 ((4-(4-((2-(1-hydroxyethyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized as described for ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, except that the mixture was kept on dry ice and butyl chloroformate (0.16 mmol, 1.2 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (44 mg, 64% yield). 1H NMR(400MHz,acetonitrile-d3)δ 8.04(d,J=8.0Hz,2H),7.19(d,J=7.9Hz,2H),7.06(s,1H),6.99(s,1H),5.42-5.24(m,2H),5.00-4.96(m,1H),3.83(t,J=6.6Hz,2 H),2.85(s,2H),2.11(dt,J=13.5,6.7Hz,1H),1.55-1.39(m,5H),1.32-1.20(m,2H),1.02(d,J=6.7Hz,6H),0.88(t,J=7.4Hz,3H). 13 ¹³C NMR (101 MHz, acetonitrile-d3) δ 170.2, 159.8, 151.5, 138.1, 137.3, 134.6, 130.7, 127.1, 125.2, 121.9, 121.7, 64.9, 62.4, 49.9, 42.1, 31.5, 30.0, 22.3, 22.1, 19.5, 13.7. HRMS (ESI) C 24 H 33 N4O5S2 + [M+H] + The calculated value is 521.1887, and the measured value is 521.1891.

[0219] Example 23 ((4-(4-((2-(1-hydroxyethyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate [ka] The title compound was synthesized as described for ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)carbamate methyl, except that the mixture was kept on dry ice and methyl chloroformate (0.16 mmol, 1.2 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (31 mg, 49% yield). 1 H NMR(400MHz,acetone-d6)δ 8.06(d,J=8.4Hz,2H),7.35(d,J=1.7Hz,1H),7.26(d,J=8.1Hz,2H),7.21(d,J=1.7Hz,1H),5.63(s,2H),5.31(q,J =6.7Hz,1H),3.51(s,3H),2.92(d,J=7.1Hz,2H),2.21-2.14(m,1H),1.56(d,J=6.7Hz,3H),1.05(d,J=6.7Hz,6H). 13 ¹³C NMR (101 MHz, acetone-d6) δ 171.2, 156.0, 152.7, 150.2, 142.6, 136.2, 134.0, 130.3, 126.6, 122.2, 121.8, 61.8, 51.7, 50.0, 41.7, 29.4, 21.7, 21.6. HRMS (ESI) C 21 H 27 N4O5S2 + [M+H] + The calculated value is 479.1417, and the measured value is 479.1418.

[0220] Example 24 ((4-(4-((2-(1-hydroxyethyl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized as described for ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, except that the mixture was kept on dry ice and butyl chloroformate (0.16 mmol, 1.2 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (38 mg, 55% yield). 1 H NMR(400MHz, methanol-d4)δ 7.95(d,J=8.3Hz,2H),7.41(d,J=1.8Hz,1H),7.39-7.29(m,3H),5.50(d,J=2.2Hz,2H),5.13(q,J=6.6Hz,1H),3.88(t,J=6.5Hz,2H),3.13- 2.92(m,2H),1.97-1.79(m,2H),1.56(d,J=6.6Hz,3H),1.50-1.44(m,2H),1.33-1.26(m,2H),1.07(t,J=7.4Hz,3H),0.89(t,J=7.4Hz,3H). 13 ¹³C NMR (101 MHz, methanol-d4) δ 172.7, 158.2, 152.3, 150.0, 135.8, 135.5, 133.8, 130.2, 126.4, 122.4, 120.5, 64.6, 61.1, 50.1, 34.6, 30.7, 23.0, 20.5, 18.7, 12.7, 12.5. HRMS (ESI) C 23 H 31 N4O5S2 + [M+H] + The calculated value is 507.1730, and the measured value is 507.1735.

[0221] Example 25 ((4-(4-((2-(1-hydroxyethyl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)methyl carbamate [ka] The title compound was synthesized as described for ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, except that the mixture was kept on dry ice and methyl chloroformate (0.16 mmol, 1.2 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (31 mg, 49% yield). 1 H NMR(400MHz,DMSO-d6)δ 8.13(d,J=8.1Hz,2H),7.63(d,J=1.8Hz,1H),7.52(d,J=1.8Hz,1H),7.30(d,J=8.1Hz,2H),6.21(s,1H),5.48(s,2H),5.16 (q,J=6.6Hz,1H),3.31(s,3H),2.90(t,J=7.5Hz,2H),1.75(q,J=7.4Hz,2H),1.44(d,J=6.5Hz,3H),0.98(t,J=7.3Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ 170.1,163.5,158.7,150.1,149.8,135.5,134.3,130.6,127.3,123.0,121.0,60.7,51.7,50.1,34.8,23.0,22.2,13.9. HRMS(ESI)C 20 H 25 N4O5S2 + [M+H] + The calculated value is 465.1261, and the measured value is 465.1267.

[0222] Example 26 ((4-(4-((2-cyclopropyl-1H-imidazole-1-yl)methyl)phenyl)2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate [ka] The title compound was synthesized as described for ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)carbamate methyl, except that the mixture was kept on dry ice and methyl chloroformate (0.14 mmol, 1.2 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (31 mg, 54% yield). 1 H NMR(400MHz, methanol-d4)δ 7.98(d,J=8.3Hz,2H),7.48(d,J=2.0Hz,1H),7.35(d,J=8.2Hz,2H),7.31(d,J=2.0Hz,1H),5.51(s ,2H),3.46(s,3H),2.89(d,J=7.2Hz,2H),2.25-2.07(m,2H),1.26-1.17(m,2H),1.07-1.04(m,8H). 13 ¹³C NMR (101 MHz, methanol-d4) δ 171.4, 159.5, 152.0, 148.8, 136.3, 134.9, 134.1, 130.3, 126.9, 122.2, 118.9, 51.2, 50.3, 41.4, 29.6, 21.2, 6.8, 5.5. HRMS (ESI) C 22 H 27 N4O4S2 + [M+H] + The calculated value is 475.1468, and the measured value is 475.1457.

[0223] Example 27 ((4-(4-((2-cyclopropyl-1H-imidazole-1-yl)methyl)phenyl)2-isobutylthiazole-5-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized as described for methyl ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)carbamate, except that the mixture was kept on dry ice and methyl chloroformate (0.15 mmol, 1.2 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (38 mg, 61% yield). 1 H NMR(400MHz, methanol-d4)δ 7.97(d,J=8.1Hz,2H),7.48(d,J=2.0Hz,1H),7.36(d,J=8.0Hz,2H),7.31(d,J=2.0Hz,1H),5.52(s,2H),3.87(t,J=6.5Hz,2H),2.90(d,J=7 .2Hz,2H),2.27-2.08(m,2H),1.48(dq,J=8.5,6.6Hz,2H),1.37-1.26(m,2H),1.26-1.19(m,2H),1.06-1.05(m,8H),0.89(t,J=7.4Hz,3H). 13 C NMR(126MHz, methanol-d4)δ 171.6,158.5,152.1,136.2,148.9,135.0,134.0,130.3,126.9,122.1,119.1,64.5,50.3,41.4,30.8,29.6,21.2,18.7,12.7,6.8,5.5. HRMS(ESI)C 25 H 33 N4O4S2 + [M+H] + The calculated value is 517.1938, and the measured value is 517.1950.

[0224] Example 28 ((4-(4-((2-cyclopropyl-1H-imidazole-1-yl)methyl)phenyl)2-propylthiazole-5-yl)sulfonyl)methyl carbamate [ka] The title compound was synthesized as described for ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, except that the mixture was kept on dry ice and methyl chloroformate (0.15 mmol, 1.2 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (41 mg, 60% yield). 1 H NMR(400MHz, methanol-d4)δ 7.97(d,J=8.3Hz,2H),7.50(d,J=2.1Hz,1H),7.36(d,J=8.1Hz,2H),7.34(d,J=2.0Hz,1H),5.52(s,2H),3.47(s,3H) ),3.00(t,J=7.6Hz,2H),2.26-2.17(m,1H),1.86(q,J=7.4Hz,2H),1.23(dd,J=8.4,2.5Hz,2H),1.07-1.05(m,5H). 13 ¹³C NMR (101 MHz, methanol-d4) δ 172.6, 159.3, 152.1, 148.8, 136.0, 134.8, 134.1, 130.3, 127.0, 122.2, 118.6, 51.3, 50.4, 34.6, 23.0, 12.5, 6.9, 5.5. HRMS (ESI) C 21 H 25 N4O4S2 + [M+H] + The calculated value is 461.1312, and the measured value is 461.1309.

[0225] Example 29 ((4-(4-((2-cyclopropyl-1H-imidazole-1-yl)methyl)phenyl)2-propylthiazole-5-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized as described for ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, except that the mixture was kept on dry ice and methyl chloroformate (0.15 mmol, 1.2 equivalents) was added dropwise over approximately 2 hours, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% with MeOH in acetonitrile) to obtain the product as a white amorphous solid (44 mg, 59% yield). 1 H NMR(400MHz, methanol-d4)δ 7.97(d,J=7.9Hz,2H),7.49(d,J=2.2Hz,1H),7.37(d,J=8.0Hz,2H),7.32(s,1H),5.51(s,2H),3.89(t,J=6.5Hz,2H),2.99(t,J=7.6Hz, 2H),2.26-2.13(m,1H),1.85(q,J=7.4Hz,2H),1.47(dd,J=8.5,6.2Hz,2H),1.34-1.16(m,4H),1.08-1.04(m,5H),0.88(t,J=7.4Hz,3H). 13 ¹³C NMR (101 MHz, methanol-d4) δ 172.9, 157.7, 152.5, 148.7, 135.5, 134.9, 133.9, 130.3, 127.1, 122.3, 118.4, 64.7, 50.4, 34.6, 30.7, 23.0, 18.7, 12.7, 12.6, 7.1, 5.5. HRMS (ESI) C 24 H 31 N4O4S2 + [M+H] + The calculated value is 503.1781, and the measured value is 503.1778.

[0226] Example 30A ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate [ka] The title compound was synthesized using the corresponding butyl carbamate (17.7 mg, 34.6 μmol) as described for ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate methyl, and purified by FCC (2-4% MeOH in CH2Cl2) to obtain the product as a white amorphous solid (15.6 mg, 96%). 1 H NMR(400MHz, methanol-d4)δ 8.05(d,J=8.2Hz,1H),7.45-7.32(m,3H),7.25(d,J=7.9Hz,2H),7.12(d,J=1.6Hz,1H),7.08(d,J=1.8Hz,1H),7.03(d, J=1.6Hz,1H),5.67(s,2H),3.49(s,3H),2.67(t,J=7.7Hz,2H),1.74-1.60(m,2H),1.66(s,6H),0.96(t,J=7.4Hz,3H). 13 ¹³C NMR (101 MHz, methanol-d4) δ 155.8, 153.3, 149.0, 141.9, 140.9, 137.7, 137.5, 133.5, 131.1, 130.8, 128.6, 127.9, 124.5, 123.8, 71.1, 53.1, 52.0, 38.6, 30.3, 25.3, 14.1. HRMS (ESI + )C 27 H 36 N3O5S + [M+H] + The calculated value is 472.1901, and the measured value is 472.1897.

[0227] Example 30B Potassium (methoxycarbonyl)((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl))sulfonyl)amide [ka] The title compound was synthesized using the corresponding methyl carbamate (13.3 mg, 28 μmol) and KOH (1.70 mg, 30.2 μmol) as described for potassium (butoxycarbonyl)((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide. The product was obtained as a white amorphous solid (14.3 mg, >99% yield). 1 H NMR(400MHz,DMSO-d6)δ 7.86(d,J=8.0Hz,1H),7.40(d,J=7.9Hz,2H),7.21-7.14(m,1H),7.10(d,J=8.0Hz,2H),6.94(s,1H),6.89(s,1H),6. 75(s,1H),5.53(s,2H),3.15(s,3H),2.55(t,J=7.9Hz,4H),),1.67-1.52(m,2H),1.51(s,6H),0.89(t,J=7.2Hz,3H).

[0228] Example 31A ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized using the corresponding sulfonamide (74.3 mg, 0.156 mmol) and butyl chloroformate (27.5 μL, 0.216 mmol) as described for ((4-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate. The crude product was purified by FCC (5% MeOH in DCM) to obtain the product as a white amorphous solid (39 mg, 47% yield). 1 1H NMR (400MHz, acetone-d6)δ 8.10(d,J=8.2Hz,1H),7.45(dd,J=8.2,1.8Hz,1H),7.34(d,J=7.9Hz,2H),7.26( d,J=7.9Hz,2H),7.16(d,J=1.8Hz,1H),6.92(2,1H),6.81(s,1H),5.65(s,2H),3. 95(t,J=6.5Hz,2H),2.71(t,J=7.6Hz,2H),1.70(p,J=7.5Hz,2H),1.63(s,6H),1. 51-1.38(m,2H),1.30-1.14(m,2H),0.95(t,J=7.3Hz,3H),0.85(t,J=7.4Hz,3H). 13 ¹³C NMR (101MHz, acetone-d6) δ 153.0, 151.8, 149.1, 141.7, 139.5, 138.7, 136.6, 133.4, 131.2, 130.2, 128.4, 127.7, 126.5, 122.2, 71.1, 66.4, 50.9, 38.1, 31.3, 30.9, 24.9, 19.4, 14.0, 13.9. HRMS (ESI + )C 27 H 36 N3O5S + [M+H] + The calculated value is 514.2370, and the measured value is 514.2371.

[0229] Example 31B Potassium (butoxycarbonyl)((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl))sulfonyl)amide [ka] The title compound was synthesized using the corresponding butyl carbamate (15.0 mg, 29.0 μmol) and KOH (1.76 mg, 31.3 μmol) in MeOH (1.0 mL), as described for potassium (butoxycarbonyl)((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide. The product was obtained as a white amorphous solid (15.7 mg, 99% yield). 1 H NMR(400MHz,DMSO-d6)δ 7.86(d,J=8.1Hz,1H),7.53-7.34(m,2H),7.15(dd,J=8.1,1.9Hz,1H),7.10(d,J=8.1H z,2H),6.93(d,J=1.3Hz,1H),6.88(d,J=1.8Hz,1H),6.74(d,J=1.3Hz,1H),5.53(s,2H) ),5.43(s,1H),3.54(t,J=6.5Hz,2H),2.60-2.49(m,2H),1.68-1.54(m,2H),1.52(s,6 H),1.45-1.26(m,2H),1.26-1.14(m,2H),0.89(t,J=7.3Hz,3H),0.83(t,J=7.3Hz,3H).

[0230] Example 32 ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate [ka] The corresponding butyl carbamate (19.0 mg, 36.1 μmol, 1 equivalent) was dissolved in CH2Cl2 (1 mL). The solution was cooled to -40°C. DAST (6.7 μL, 50.5 μmol, 1.4 equivalents) was added dropwise. The reaction mixture was stirred for 2 hours while maintaining the temperature below -20°C. The reaction was quenched with water, extracted with CH2Cl2 (3 × 5 mL), washed with brine (5 mL), dried over Na2SO4, and concentrated. The crude product was purified by preparative HPLC (30-70% MeCN in water with 0.05% formic acid additive) to obtain the product as a white amorphous solid (6.20 mg, 36%). 1 1H NMR (400 MHz, methanol-d4) δ 8.06(d,J=8.2Hz,1H),7.42-7.25(m,3H),7.25-7.14(m,2H),),7.10-7.06(m ,1H),7.03(d,J=1.6Hz,1H),6.94(d,J=1.4Hz,1H),5.44(s,2H),4.09-3.81(m ,2H),2.56(d,J=7.2Hz,2H),1.99-1.87(m,1H),1.79(d,J=21.7Hz,6H),1.55- 1.36(m,2H),1.30-1.14(m,2H),0.91(d,J=6.6Hz,6H),0.85(t,J=7.4Hz,3H). 13 ¹¹C NMR (101 MHz, methanol-d4) δ 152.4, 149.3 (d, 2 J C-F= 24.6Hz),148.5,141.5,139.7,137.4,135.7,134.1,130.9,130.4,129.2,127.4,127.0,123.4,94.5(d, 1 J C-F =165.5Hz),66.9,51.3(d, 4 J C-F= 8.9Hz), 45.6, 31.2, 30.8, 28.1(d, 2 J C-F= 24.5Hz), 22.6, 19.5, 13.9. 19 F NMR (376 MHz, methanol-d4) δ-140.02 (hept, J=21.7 Hz). HRMS (ESI + ):C 28 H 37 N3O4S+ [M+H] + The calculated value is 530.2489, and the measured value is 530.2482.

[0231] Example 33A ((5-isobutyl-4'-((2-(thiazole-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate [ka] The title compound was synthesized using the corresponding butyl carbamate (18.8 mg, 34.0 μmol) as described for ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate methyl. The crude product was concentrated and purified by FCC (4-6% MeOH in CH2Cl2) to obtain the product as a white amorphous solid (17.3 mg, 90% yield). 1 1H NMR a (400MHz,methanol-d4)δ 8.06(d,J=8.2Hz,1H),7.85(d,J=3.2Hz,1H),7.48(t,J=3.3Hz,1H),7.36-7.24(m,5H),7.21-7.16(m,1H),7.10(d,J=1.3 Hz,1H),7.03(d,J=1.8Hz,1H),5.91(s,2H),3.55(s,3H),2.52(d,J=7.2Hz,2H),1.97-1.80(m,1H),0.88(d,J=6.6Hz,6H). 13 C NMR a (101MHz, methanol-d4)δ 159.6,152.7,148.5,144.1,141.5,141.0,139.6,137.3,135.3,134.0,130.9,130.3,129.5,129.1,127.7,124.3,121.0,53.4,51.2,45.6,30.7,22.6. HRMS(ESI + )C 25 H 27 N4O4S2 + [M+H] +The calculated value is 511.1471, and the measured value is 511.1480.

[0232] [a] Spectra recorded with a mixture of MeOD and CDCl3. Example 33B Potassium (methoxycarbonyl)((5-isobutyl-4'-((2-(thiazole-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)amide [ka] The title compound was synthesized using potassium ((3-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)(methoxycarbonyl)amide as described for potassium ((5-isobutyl-4'-((2-(thiazole-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)(methoxycarbonyl)amide, with ((5-isobutyl-4'-((2-(tert-butylthiazole-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)(methoxycarbonyl)amide, with ((5-isobutyl-4'-((2-(thiazole-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)methyl chloroformate (107 mg, 0.261 mmol) and butyl chloroformate (45.8 μL, 0.360 mmol). The product was obtained as a white amorphous solid (48 mg, 36%). 1 H NMR(400MHz,DMSO-d6)δ 7.96(d,J=3.3Hz,1H),7.85(d,J=8.0Hz,1H),7.77(d,J=3.3Hz,1H),7.50(d,J=1.2Hz,1H),7.38(d,J=8.0Hz,2H),7.23 -7.03(m,4H),6.83(s,1H),5.89(s,2H),3.10(s,3H),2.43(d,J=7.0Hz,2H),1.94-1.74(m,1H),0.85(d,J=6.6Hz,6H).

[0233] Example 34 ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate [ka] The title compound was synthesized using the corresponding methyl carbamate (18.2 mg, 35.6 μmol) as described for ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl)]-2-yl)sulfonyl)butyl carbamate, and purified by HPLC (30-70% MeCN in water with 0.05% formic acid additive) to obtain the product as a white amorphous solid (6.20 mg, 36%). 1 H NMR(400MHz, methanol-d4)δ 8.06(d,J=8.2Hz,1H),7.52-7.23(m,6H),7.20(s,1H),7.09(s,1H),5.54(s,2H),3.56(s, 3H),2.58(d,J=7.2Hz,2H),2.01-1.90(m,1H1.84(d,J=21.9Hz,6H),0.92(d,J=6.6Hz,6H). 13 ¹¹C NMR (101 MHz, methanol-d4) δ 153.3, 149.1 (d, 2 J C-F =19.4Hz),149.1,141.9,140.7,137.0,136.2,134.4,131.3,130.8,129.6,128.1,124.9,124.6,94.4(d, 1 J C-F =168.1Hz),53.5,52.2(d, 4 J C-F =8.4Hz),45.8,31.2,27.7(d, 2 J C-F =24.5Hz), 22.6Hz. 19 F NMR (376 MHz, methanol-d4) δ-140.67 (hept, J=21.6 Hz). HRMS (ESI + )C 25 H 31 N3O4S + [M+H] + Calculated value: 488.2019, measured value: 488.2019.

[0234] Example 35A ((5-isobutyl-4'-((2-(thiazole-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized using the corresponding sulfonamide (92.7 mg, 0.205 mmol) and butyl chloroformate (36.0 μL, 0.238 μmol) as described for butyl ((4'-((2(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate. The product was obtained as a white amorphous solid (40.7 mg, 36%). 1 H NMR(400MHz, methanol-d4)δ 8.05(d,J=8.2Hz,1H),7.86(d,J=3.3Hz,1H),7.58(d,J=3.3Hz,1H),7.39 -7.17(m,6H),7.10(d,J=1.3Hz,1H),6.99(d,J=1.8Hz,1H),5.93(s,2H),3 .91(t,J=6.4Hz,2H),2.50(d,J=7.2Hz,2H),1.93-1.75(m,1H),1.48-1.3 5(m,2H),1.25-1.13(m,2H),0.87(d,J=6.6Hz,6H),0.83(t,J=7.4Hz,3H). 13 ¹³C NMR (101 MHz, methanol-d4) δ 160.0, 152.7, 148.9, 144.6, 142.0, 141.4, 140.1, 138.1, 136.3, 134.4, 131.3, 130.6, 129.9, 129.4, 128.2, 125.1, 121.6, 67.0, 51.4, 45.7, 31.6, 31.1, 22.6, 19.8, 13.9. HRMS (APCI) + )C 28 H 33 N4O4S2 + [M+H] + The calculated value is 553.1938, and the measured value is 553.1935.

[0235] Example 35B Potassium (butoxycarbonyl)((5-isobutyl-4'-((2-(thiazole-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)amide [ka] The title compound was synthesized using potassium ((3-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)(methoxycarbonyl)amide as described for potassium ((5-isobutyl-4'-((2-(thiazole-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)(methoxycarbonyl)amide, withtert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)(methoxycarbonyl)amide, with ((5-isobutyl-4'-((2-(thiazole-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)(methoxycarbonyl) as described for potassium ((3-(4-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)(methoxycarbonyl)amide. The product was obtained as a white amorphous solid (48 mg, 36%). 1 1H NMR (400MHz, DMSO-d6)δ 7.96(d,J=3.3Hz,1H),7.84(d,J=8.1Hz,1H),7.77(d,J=3.3Hz,1H),7.49(d,J =1.2Hz,1H),7.39-7.33(m,2H),7.20-7.07(m,4H),6.82(d,J=1.8Hz,1H),5.89 (s,2H),3.51(t,J=6.5Hz,2H),2.43(d,J=7.0Hz,2H),1.91-1.72(m,1H),1.39 -1.25(m,2H),1.25-1.09(m,2H),0.85(d,J=6.6Hz,6H),0.81(t,J=7.3Hz,3H).

[0236] Example 36 ((5-isobutyl-4'-((2-(isopropan-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate [ka] The title compound was synthesized using the corresponding butyl carbamate (48.0 mg, 93.8 μmol) in MeOH (1 mL) as described for ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate. The crude product was concentrated and purified by FCC (5-7% MeOH in CH2Cl2) to obtain the product as a white amorphous solid (41.9 mg, 95% yield). 1 H NMR(400MHz, methanol-d4)δ 8.24-7.83(m,1H),7.39-7.28(m,2H),7.27-7.16(m,2H),7.17-7.05(m,3H),6.90(d,J=1.9Hz,1H),5.27(s,2) H),3.32-3.12(m,1H),2.43(d,J=7.2Hz,2H),1.88-1.65(m,1H),1.21(d,J=7.0Hz,6H),0.81(d,J=6.6Hz,6H). 13 ¹³C NMR (101 MHz, methanol-d4) δ 158.6, 153.8, 146.9, 142.1, 141.3, 139.3, 135.5, 133.9, 131.2, 130.6, 129.1, 127.7, 122.7, 122.5, 52.8, 51.1, 45.8, 31.2, 26.7, 22.7, 21.3. HRMS (ESI + )C 25 H 32 N3O4S + [M+H] + The calculated value is 470.2114, and the measured value is 470.2107.

[0237] Example 37A ((5-isobutyl-4'-((2-(isopropan-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized using the corresponding sulfonamide (97.6 mg, 0.237 mmol) and butyl chloroformate (41.8 μL, 0.327 mmol) as described for butyl ((4'-((2(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate. The crude product was purified by FCC (3-5% MeOH in CH2Cl2) to obtain the product as a white amorphous solid (72 mg, 59% yield). 1 H NMR(400MHz,acetone-d6)δ 8.13(d,J=8.2Hz,1H),7.60-7.35(m,3H),7.29-7.13(m,2H),7.10(d,J=1.8Hz,1H),7. 00(d,J=1.4Hz,1H),6.83(d,J=1.4Hz,1H),6.47(bs,1H),5.30(s,2H),3.94(t,J=6.5Hz ,2H),3.44-3.08(m,1H),2.60(d,J=7.2Hz,2H),2.01-1.81(m,1H),1.71-1.38(m,2H), 1.25(d,J=6.9Hz,6H),1.23-1.16(m,2H),0.92(d,J=6.6Hz,6H),0.85(t,J=7.4Hz,3H). 13 ¹³C NMR (101MHz, acetone-d6) δ 154.4, 153.0, 146.8, 141.1, 141.0, 138.5, 136.5, 133.7, 131.0, 130.6, 128.7, 127.4, 125.1, 120.7, 65.6, 50.0, 45.3, 31.5, 30.7, 26.4, 22.6, 21.8, 19.5, 14.0. HRMS (ESI + )C 28 H 38 N3O4S + [M+H] + The calculated value is 512.2583, and the measured value is 512.2579.

[0238] Example 37B Potassium (butoxycarbonyl)((5-isobutyl-4'-((2-(isopropan-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)amide [ka] The title compound was synthesized using the corresponding butyl carbamate (13.7 mg, 26.6 μmol) and KOH in MeOH (0.59 M) (1.61 mg, 28.7 μmol) as described for potassium (butoxycarbonyl)((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide. The product was obtained as a white amorphous solid (8.5 mg, 58% yield). 1 H NMR(400MHz,acetone-d6)δ 8.06(d,J=8.4Hz,1H),7.52(d,J=7.8Hz,2H),7.25-7.13(m,1H),7.12-7.04(m,2H),6. 99(d,J=1.2Hz,1H),6.96(s,1H),6.84(d,J=1.3Hz,1H),5.24(s,2H),3.68(t,J=6.6Hz ,2H),3.20-3.01(m,1H),2.52(d,J=7.1Hz,2H),1.95-1.79(m,1H),1.51-1.34(m,2H), 1.33-1.23(m,2H),1.22(d,J=6.8Hz,6H),0.91(d,J=6.6Hz,6H),0.86(t,J=7.3Hz,3H).

[0239] Example 38A ((5-isobutyl-4'-((2-(cyclopropan-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized using the corresponding sulfonamide (77.4 mg, 0.189 mmol) and butyl chloroformate (33.3 μL, 0.261 mmol) as described for butyl ((4'-((2(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate. The crude product was purified by FCC (3-5% MeOH in CH2Cl2) to obtain the product as a white amorphous solid (41 mg, 38% yield). 1 1H NMR a (400MHz,methanol-d4)δ 8.05(d,J=8.2Hz,1H),7.44-7.32(m,2H),7.29(dd,J=8.2,1.8Hz,1H),7.19(d,J=8.1 Hz,2H),7.08(d,J=1.6Hz,1H),7.03(d,J=1.8Hz,1H),6.92(d,J=1.6Hz,1H),5.33(s,2 H),3.91(t,J=6.5Hz,2H),2.54(d,J=7.2Hz,2H),2.15-1.80(m,2H),1.58-1.37(m,2H) ),1.32-1.12(m,2H),1.06-0.93(m,4H),0.90(d,J=6.6Hz,6H),0.84(t,J=7.4Hz,3H). 13 C NMR a (101MHz, methanol-d4)δ 154.8,150.0,147.4,141.1,140.6,137.1,135.8,133.7,130.6,130.5,128.9,127.2,124.2,121.6,66.3,50.4,45.6,31.3,30.7,22.6,19.5,13.9,7.6,7.2. HRMS(ESI + )C 28 H 36 N3O4S + [M+H] + The calculated value is 512.2583, and the measured value is 512.2579.

[0240] [a] Recorded with a mixture of MeOD and CDCl3. Example 38B Potassium (butoxycarbonyl)((5-isobutyl-4'-((2-(cyclopropan-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)amide [ka] The title compound was synthesized using the corresponding butyl carbamate (13.5 mg, 26.2 μmol) and KOH in MeOH (0.59 M) (1.59 mg, 28.3 μmol) as described for potassium (butoxycarbonyl)((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide. The product was obtained as a white amorphous solid (4.4 mg, 31% yield). 1 1H NMR (400MHz, acetone-d6)δ 8.06(d,J=7.2Hz,1H),7.54(d,J=8.2Hz,2H),7.14(t,J=7.8Hz,3H),7.02(d,J =1.3Hz,1H),6.94(d,J=1.9Hz,1H),6.75(d,J=1.3Hz,1H),5.31(s,2H),3.64(t ,J=6.7Hz,2H),2.51(d,J=7.1Hz,2H),1.99-1.77(m,4H),1.46-1.30(m,2H),1 .31-1.19(m,2H),0.91(d,J=6.6Hz,6H),0.89-0.86(m,3H),0.86-0.83(m,3H).

[0241] Example 39A ((5-isobutyl-4'-((2-(cyclopropan-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate [ka] The title compound was synthesized using the corresponding butyl carbamate (27.4 mg, 53.8 μmol) in MeOH (1 mL) as described for ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate. The crude product was concentrated and purified by FCC (5-7% MeOH in CH2Cl2) to obtain the product as a white amorphous solid (21.6 mg, 86% yield). 1 H NMR(400MHz, methanol-d4)δ 8.05(d,J=8.2Hz,1H),7.42-7.36(m,2H),7.32-7.21(m,4H),7.08(d,J=1.8Hz,1H),7.01(d,J=1.8Hz,1H),5.41(s,2H),3.43(s,3H) ),2.64-2.35(m,3H),2.25-2.02(m,1H),1.97-1.81(m,J=6.7Hz,1H),1.19-1.03(m,2H),1.03-0.97(m,2H),0.91(d,J=6.6Hz,6H). 13 ¹³C NMR (101 MHz, methanol-d4) δ 158.0, 150.4, 147.2, 141.9, 141.4, 138.9, 135.8, 133.9, 131.1, 130.7, 129.2, 127.9, 122.7, 122.6, 52.9, 51.1, 45.8, 31.2, 22.7, 7.9, 7.3. HRMS (ESI + )C 25 H 30 N3O4S + [M+H] + The calculated value is 468.1957, and the measured value is 468.1947.

[0242] Example 39B Potassium (methoxycarbonyl)((5-isobutyl-4'-((2-(cyclopropane-2-yl)-1H-imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)amide [ka] The title compound was synthesized using the corresponding methyl carbamate (21.6 mg, 45.7 μmol) and KOH in MeOH (0.59 M) (2.77 mg, 49.3 μmol) as described for potassium (butoxycarbonyl)((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide. The product was obtained as a white amorphous solid (20.3 mg, 88% yield). 1 H NMR(400MHz,acetone-d6)δ 8.06(d,J=8.1Hz,1H),7.61-7.48(m,2H),7.22-7.08(m,3H),7.03(d,J=1.3Hz,1H),6.95(d,J=1.8Hz,1H),6.75(d,J=1. 3Hz,1H), 5.31(s,2H),3.23(s,3H),2.52(d,J=7.2Hz,2H),1.99-1.83(m,2H),0.91(d,J=6.6Hz,6H),0.89-0.81(m,4H).

[0243] Example 40 ((5-isobutyl-3-(4-(2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized using the corresponding sulfonamide (19.9 mg, 46.0 μmol) and butyl chloroformate (8.7 μL, 63.5 μmol) as described for butyl ((4'-((2(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate. The crude product was purified by HPLC (30-50% water in MeCN containing 0.05% formic acid), and after lyophilization, the product was obtained as a white amorphous solid (10.3 mg, yield 42%). 1H NMR(400MHz, methanol-d4)δ 7.67-7.54(m,2H),7.26(d,J=8.1Hz,2H),7.11(d,J=1.6Hz,1H),7.05(d,J=1.6Hz,1H),6.83(s,1H),5.66(s,2H),3.91(t,J=6.5Hz,2H),2 .73(d,J=7.1Hz,2H),2.01-1.86(m,1H),1.65(s,6H),1.57-1.40(m,2H),1.37-1.18(m,2H),1.00(d,J=6.6Hz,6H),0.88(t,J=7.4Hz,3H). 13 ¹³C NMR (101 MHz, methanol-d4) δ 156.5, 153.1, 150.0, 144.9, 137.7, 136.0, 132.2, 130.8, 130.3, 128.3, 123.9, 123.7, 71.0, 66.5, 52.1, 40.0, 31.9, 31.8, 30.2, 22.6, 20.0, 14.1. HRMS (ESI + )C 26 H 36 N3O5S2 + [M+H] + The calculated value is 534.2096, and the measured value is 534.2097.

[0244] Example 41 ((5-isobutyl-3-(4-(2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-yl)sulfonyl)methyl carbamate [ka] The title compound was synthesized using the corresponding butyl carbamate (10.0 mg, 18.7 μmol) in MeOH (1 mL) as described for ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate. The crude product was concentrated and purified by FCC (3-6% MeOH in CH2Cl2) to obtain the product as a white amorphous solid (6.0 mg, 65% yield). 1H NMR(400MHz, methanol-d4)δ 7.58(d,J=8.3Hz,2H),7.26(d,J=8.2Hz,2H),7.14(d,J=1.7Hz,1H),7.09(d,J=1.6Hz,1H),6.81(s,1H), 5.66(s,2H),3.48(s,3H),2.72(d,J=7.1Hz,2H),2.10-1.85(m,1H),1.65(s,6H),1.00(d,J=6.6Hz,6H). HRMS(ESI + )C 23 H 30 N3O5S2 + [M+H] + The calculated value is 492.1627, and the measured value is 492.1628.

[0245] Example 42 ((5-isobutyl-3-(4-(2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized using the corresponding butyl carbamate (21.6 mg, 38.4 μmol) and DAST (5.1 μL, 38.4 μmol) as described for ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl)]-2-yl)sulfonyl)butyl carbamate. The compound was purified by HPLC (30-70% water in MeCN containing 0.05% formic acid), and after lyophilization, the product was obtained as a white amorphous solid (5.7 mg, 28% yield). 1H NMR(400MHz, methanol-d4)δ 7.59-7.46(m,2H),7.24(d,J=8.0Hz,2H),7.10(s,1H),6.97(s,1H),6.87(s,1H),5.46(s,2H),3.98(t,J=6.4Hz,2H),2.75(d,J=7.1H z,2H),2.02-1.87(m,1H),1.77(d,J=21.6Hz,6H),1.58-1.40(m,2H),1.34-1.15(m,2H),1.00(d,J=6.6Hz,6H),0.88(t,J=7.4Hz,3H). 13 ¹¹C NMR (101 MHz, methanol-d4) δ 151.5, 150.6, 148.4 (d, 2 J C-F= 25.5Hz),145.2,137.4,133.9,131.9,129.4,129.2,126.8,125.7,122.6,93.5(d, 1 J C-F =165.5Hz),65.7,50.2(d, 4 J C-F= 8.9Hz), 38.6, 30.4, 30.3, 26.7(d, 2 J C-F= 24.6Hz), 21.1, 18.5, 12.6. 19 F NMR (376 MHz, methanol-d4) δ-140.66 (hept, J=21.5 Hz). HRMS (ESI + )C 26 H 36 FN3O4S2 + [M+H] + The calculated value is 536.2053, and the measured value is 536.2051.

[0246] Example 43 ((5-isobutyl-3-(4-(2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-yl)sulfonyl)methyl carbamate [ka] The title compound was synthesized using the corresponding butyl carbamate (18.9 mg, 38.5 μmol) as described for ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl)]-2-yl)sulfonyl)methyl carbamate. The compound was purified by HPLC (30-70% water in MeCN containing 0.05% formic acid), and after lyophilization, the product was obtained as a white amorphous solid (6.5 mg, 34% yield). 1 H NMR(400MHz, methanol-d4)δ 7.53-7.35(m,2H),7.21-7.10(m,3H),7.05(d,J=1.6Hz,1H),6.77(s,1H),5.41(s,2H),3.48(s ,3H),2.65(d,J=7.1Hz,2H),1.96-1.78(m,1H),,1.70(d,J=21.9Hz,6H),0.90(d,J=6.6Hz,6H). 13 ¹¹C NMR (101 MHz, methanol-d4) δ 153.3, 152.3, 149.4 (d, 2 J C-F= 24.8Hz),146.9,138.1,135.5,133.0,130.8,128.3,125.6,124.5,121.4,94.8(d, 1 J C-F =168.1Hz),53.6,52.0(d, 4 J C-F= 9.0Hz), 40.0, 31.8, 27.8(d, 2 J C-F= 24.4Hz), 22.5Hz. 19 F NMR (376 MHz, methanol-d4) δ-140.93 (hept, J=21.8 Hz). HRMS (ESI + )C 23 H 29 FN3O4S2 + [M+H] + The calculated value is 494.1584, and the measured value is 494.1588.

[0247] Example 44 ((5-isobutyl-3-(4-(2-(2-tertbutyl)-1H-imidazole-1-yl)methyl)phenyl)-2-yl)sulfonyl)carbamate 2-methoxyethyl [ka] The title compound was synthesized using the corresponding sulfonamide (50.0 mg, 0.116 mmol) and 2-methoxyethyl chloroformate (16.2 μL, 0.139 mmol) as described for ((4-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)butyl carbamate. The crude product was purified by FCC (0-5% MeOH in MeCN) to obtain the product as a white amorphous solid (36 mg, 58% yield). 1 H NMR(400MHz,acetone-d6)δ 7.65(d,J=7.9Hz,2H),7.16(d,J=7.8Hz,2H),7.01(bs,1H),6.96(s,1H),6.92(bs,1H),5.55(s,2H),4.11(t,J=4Hz,2H), 3.46(t,J=4Hz,2H),3.26(s,3H),2.79(d,J=7.0Hz,2H),1.98(dq,J=13.4,6.7Hz,1H),1.44(s,9H),1.01(d,J=6.5Hz,6H). 13 ¹³C NMR (101MHz, acetone-d6) δ 153.6, 151.9, 149.7, 144.4, 137.7, 134.0, 133.3, 129.6, 129.4, 126.3, 124.7, 122.3, 70.0, 64.7, 57.8, 50.6, 38.6, 33.3, 30.4, 29.2, 21.6. HRMS (ESI + ):C 26 H 36 N3O5S2 + [M+H] + The calculated value is 534.2091, and the measured value is 534.2092.

[0248] Example 45 ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized using the corresponding butyl carbamate (40.0 mg, 0.073 mmol) and DAST (13.5 μL, 0.102 mmol) as described for ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl)]-2-yl)sulfonyl)butyl carbamate. The crude product was purified by preparative HPLC (15-80% with water in acetonitrile), and after lyophilization, the product was obtained as a white amorphous solid (19.0 mg, 45% yield). 1 H NMR(400MHz,acetone-d6)δ 7.91(d,J=7.9Hz,2H),7.28(d,J=7.9Hz,2H),7.14(bs,1H),6.98(bs,1H),5.53(s,2H),4.04(t,J=6.5Hz,2H),3.07(t,J=7.5Hz,2H), 1.96-1.85(m,2H),1.77(d,J=21.6Hz,6H),1.50(p,J=6.8Hz,2H),1.26(h,J=7.4Hz,2H),1.07(t,J=7.3Hz,3H),0.88(t,J=7.4Hz,3H). 13 ¹¹C NMR (101MHz, acetone-d6) δ 174.7, 155.7, 150.6, 148.0 (d, 2 J C-F =25.0Hz),139.3,132.4,130.4,130.1,126.7,126.5,122.6,93.9(d, 1 J C-F =164.0Hz). 66.1,50.1(d, 4 J C-F =8.3Hz),35.0,30.4,27.2(d, 2 J C-F =24.6Hz),22.7,18.5,12.9,12.9. 19F NMR (376 MHz, acetone-d6) δ-139.3 (hept, J=21.5 Hz). HRMS (ESI + ):C 24 H 32 FN4O4S2 + [M+H] + The calculated value is 523.1844, and the measured value is 523.1835.

[0249] Example 46 ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)methyl carbamate [ka] The title compound was synthesized using the corresponding methyl carbamate (40 mg, 0.0794 mmol) and DAST (0.015 mL, 0.111 mmol) as described for ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl)]-2-yl)sulfonyl)butyl carbamate. The crude product was purified by preparative HPLC (15-80% with water in acetonitrile), and after lyophilization, the product was obtained as a white amorphous solid (17 mg, 40% yield). 1 H NMR(400MHz,acetone-d6)δ 7.75(d,J=8.2Hz,2H),7.12(d,J=8.0Hz,2H),7.01(bs,1H),6.83(bs,1H),5.38(s,2H),3.49(s ,3H),2.93(t,J=7.6Hz,2H),1.80-1.70(m,2H),1.62(d,J=21.6Hz,6H),0.93(t,J=7.4Hz,3H). 13 ¹¹C NMR (101 MHz, acetone-d6) δ 174.8, 155.8, 151.3, 148.0 (d, 2 J C-F =25.2Hz),139.3,132.4,130.2,130.1,126.6,126.6,122.6,94.0(d, 1 J C-F=163.9Hz), 52.7, 50.1(d, 4 J C-F =8.3Hz),34.9,27.2(d, 2 J C-F =24.6Hz), 22.7, 12.9. 19 F NMR (376 MHz, acetone-d6) δ-139.5 (hept, J=21.4 Hz). HRMS (ESI + ):C 21 H 26 FN4O4S2[M+H] + The calculated value is 481.1374, and the measured value is 481.1378.

[0250] Example 47 ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized using the corresponding butyl carbamate (40 mg, 0.071 mmol) and DAST (13.0 μL, 0.100 mmol) as described for ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl)]-2-yl)sulfonyl)butyl carbamate. The crude product was purified by preparative HPLC (15-80% with water in MeCN), and after lyophilization, the product was obtained as a white amorphous solid (20 mg, 47% yield). 1H NMR(400MHz,acetone-d6)δ 7.91(d,J=8.3Hz,2H),7.27(d,J=8.2Hz,2H),7.11(bs,1H),6.94(bs,1H),5.51(s,2H),4.04(t,J=6.5Hz,2H),2.98(d,J=7.1Hz,2H),2.20(d t,J=13.5,6.8Hz,1H),1.76(d,J=21.5Hz,6H),1.50(dq,J=8.4,6.6Hz,2H),1.35-1.19(m,2H),1.05(d,J=6.7Hz,6H),0.88(t,J=7.4Hz,3H). 13 ¹¹C NMR (101MHz, acetone-d6) δ 173.7, 155.7, 150.7, 148.1 (d, 2 J C-F =24.8Hz),139.4,132.4,130.5,130.1,126.8,126.7,122.5,94.0(d, 1 J C-F =163.5Hz). 66.1,50.0(d, 4 J C-F =8.3Hz),41.7,30.4,29.4,27.3(d, 2 J C-F =24.6Hz), 21.6, 18.6, 13.0. 19 F NMR (376 MHz, acetone-d6) δ-139.3 (hept, J=21.6 Hz). HRMS (ESI + ):C 25 H 34 FN4O4S2 + [M+H] + The calculated value is 537.2000, and the measured value is 537.1992.

[0251] Example 48 ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate [ka] The title compound was synthesized using the corresponding butyl carbamate (40.0 mg, 0.077 mmol) and DAST (14.0 μL, 0.108 mmol) as described for ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl)]-2-yl)sulfonyl)butyl carbamate. The crude product was purified by preparative HPLC (15-80% with water in acetonitrile), and after lyophilization, the product was obtained as a white amorphous solid (21 mg, 50% yield). 1 H NMR(400MHz,acetone-d6)δ 7.90(d,J=8.2Hz,2H),7.27(d,J=8.0Hz,2H),7.17(bs,1H),7.00(bs,1H),5.54(s,2H),3.63(s ,3H),2.98(d,J=7.1Hz,2H),2.25-2.15(m,1H),1.78(d,J=21.7Hz,6H),1.05(d,J=6.6Hz,6H). 13 ¹¹C NMR (101MHz, acetone-d6) δ 173.9, 161.5, 155.9, 151.1, 147.9 (d, 2 J C-F =25.4Hz),139.2,132.4,130.1,126.7,126.3,122.7,93.9(d, 1 J C-F =164.4Hz). 52.76, 50.2(d, 4 J C-F =8.4Hz),41.7,29.4,27.2(d, 2 J C-F =24.4Hz), 21.5. 19 F NMR (376 MHz, acetone-d6) δ-139.6 (hept, J=21.6 Hz). HRMS (ESI + ):C 22 H 28 FN4O4S2 + [M+H] + The calculated value is 495.1531, and the measured value is 495.1532.

[0252] Example 49 ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-3'-fluoro-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate [ka] The title compound was synthesized as described for butyl((4'-((2(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate butyl, except that butyl chloroformate (42.9 μL, 0.336 mmol, 1.2 equivalents) was added to the corresponding sulfonamide (125 mg, 0.280 mmol, 1 equivalent) at 0°C, and the reaction was quenched after 1 hour. The crude product was purified by FCC (5% MeOH in CH2Cl2) to obtain the product as a white amorphous solid (58.8 mg, 39% yield). 1 H NMR(400MHz, methanol-d4)δ 8.05(d,J=8.2Hz,1H),7.34(dd,J=8.2,1.8Hz,1H),7.26-7.01(m,6H),5.57(s,2H),3.86(t,J=6.5Hz,2H),2.56(d,J=7.2H) z,2H),2.06-1.75(m,1H),1.54(s,9H),1.49-1.35(m,2H),1.34-1.16(m,2H),0.92(d,J=6.6Hz,6H),0.85(t,J=7.4Hz,3H). 13 ¹¹C NMR (10¹ MHz, methanol-d4) δ 160.8 (d, 1 J C-F =246.6Hz),156.8,154.9,147.6,144.3(d, 3 J C-F =8.6Hz),140.0,138.8,133.6,130.7,129.9(d, 4 J C-F =4.0Hz),129.7,127.0(d, 3 J C-F =3.3Hz),124.1,123.0(d, 2 J C-F =14.6Hz),122.9,117.9(d,2 J C-F =22.0Hz),66.3,47.3(d, 3 J C-F =4.1Hz),45.8,34.7,32.0,31.2,29.4,22.7,20.0,14.1. 19 F NMR (376 MHz, methanol-d4) δ-113.55--127.68 (m).

[0253] Example 50 (4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-3'-fluoro-5-isobutyl-[1,1'-biphenyl]-2-yl)methyl sulfonylcarbamate [ka] The title compound was synthesized using the corresponding butyl carbamate (33.0 mg, 60.7 μmol) in MeOH (1 mL) as described for ((4'-((2-(tert-butyl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate. The crude product was concentrated and purified by FCC (5% MeOH in CH2Cl2) to obtain the product as a white amorphous solid (17.5 mg, 58% yield). 1 H NMR(400MHz, methanol-d4)δ 8.05(d,J=8.2Hz,1H),7.34(dt,J=8.2,1.7Hz,1H),7.27-7.14(m,4H),7.13-7.03(m,2H),5.58(s,2H) ,3.45(s,3H),2.57(d,J=7.1Hz,2H),2.06-1.77(m,J=6.7Hz,1H),1.55(s,9H),0.93(d,J=6.6Hz,6H). 13 C NMR a (101MHz, methanol-d4)δ 160.6(d, 1 J C-F =246.7Hz),157.5,154.6,147.2,144.2(d, 3 J C-F=8.5Hz),139.7,138.6,133.3,130.5,129.5(d, 4 J C-F =2.3Hz),126.8(d, 3 J C-F =3.3Hz),123.9,122.7,122.5(d, 2 J C-F =14.4Hz),117.8(d, 2 J C-F =22.0Hz),52.8,47.1(d, 3 J C-F =4.0Hz),45.7,34.5,31.0,29.3,22.6. 19 F NMR (376 MHz, methanol-d4) δ-116.33--132.46 (m).

[0254] biology result K i Values, stability and kinetic solubility in liver microsomes K i Measurement. From human AT2R in HEK-293 cell membrane preparation at Eurofins [ 125 I |Sar 1 Ile 8 The compounds were evaluated by a radioactive agonist assay after substituting ]-angiotensin II. [Sar 1 Ile 8 ]-Angiotensin II (Sarile) acts as a non-selective AT2R agonist. 18 Affinity was measured using an 8-point or 9-point dose-response curve, with each point repeated twice. The incubation buffer (final concentration) consisted of 45 mM Tris / HCl, 4.5 mM MgCl2, 0.9 mM EDTA / Tris, and 0.09% BSA at pH 7.4. PD 123,319 was used as the reference compound. Salaracin was used as the reference compound to test for human AT1R in HEK-293 cell membranes with Eurofins. 125 I |Sar 1 Ile 8 The compounds were also evaluated for their inhibition of ]-angiotensin II binding.

[0255] Stability in liver microsomes. The metabolic stability of the compound was evaluated using human, mouse, and rat liver microsomes. Metabolic stability was measured by Eurofins in 0.5 mg / mL human, mouse, or rat liver microsomes at a compound concentration of 1 μM in 100 mM potassium phosphate buffer (pH 7.4) in a total incubation volume of 500 μL. The assay matrix was as follows: Human liver microsomes: mixed male and female and pool of 50; Rat liver microsomes: male, Sprague-Dawley, pool of 100+; Mouse liver microsomes: male, CD-1, pool of 250+. Final microsomal protein concentration: 0.1 mg / mL. The test concentration was 0.1 μM, and the default solutions were 0.01% DMSO, 0.25% acetonitrile, and 0.25% methanol. The experimental protocol was as follows: The test compounds were pre-incubated for 5 minutes in a shaking water bath at 37°C with pooled liver microsomes in phosphate buffer (pH 7.4). The reaction was initiated by adding a NADPH generating system and incubated for 0, 15, 30, 45, and 60 minutes. The reaction was stopped by transferring the incubation mixture to acetonitrile / methanol. The samples were then mixed and centrifuged. Four reference compounds were tested in each assay. Propranolol and imipramine were relatively stable, while verapamil and terfenadine were readily metabolized in human liver microsomes. The samples were analyzed by HPLC-MS / MS using selected reaction monitoring. The HPLC system consisted of a binary LC pump with an autosampler, a C-18 column, and a gradient. The peak area corresponding to the test compound was recorded. The residual compound was calculated by comparing the peak area at each time point to time zero. The half-life was calculated from the slope of the first linear range of the logarithmic curve of compound residual rate (%) versus time, assuming first-order kinetics. Furthermore, the intrinsic clearance (Clint) was calculated. 19,20

[0256] Kinetic solubility. Dulbecco's PBS buffer was used (NaCl 137 mM, KCl 2.7 mM, Na2HPO4 8.1 mM, KH2PO4 1.5 mM, pH 7.4). The test compound was prepared at 200 μM in PBS buffer from a 10 mM DMSO stock solution. The final DMSO concentration was 2%. After thoroughly mixing the buffer sample, it was incubated at room temperature for 24 hours. At the end of incubation, the buffer sample was centrifuged and the supernatant was injected for HPLC analysis. Calibration standards for the test compound were prepared at 200 μM in methanol / water (3 / 2, v / v) from a 10 mM DMSO stock solution on the day of HPLC analysis. Analysis was performed by HPLC-UV / VIS with photodiode array detection, while monitoring at wavelengths of 205, 230, 260, and 300 nm. The HPLC system consisted of a C18 column using A and B gradients (A = 12 mM ammonium formate, 6 mM formic acid in water, pH 4.0; B = 6 mM ammonium formate, 3 mM acetonitrile formate / water (9 / 1, v / v)). The reference compounds used were metoprolol, rifampicin, ketoconazole, phenytoin, haloperidol, simvastatin, diethylstilbestrol, and tamoxifen, ranked from fully soluble (200 μM) to poorly soluble (<1 μM). The water solubility (μM) of the test compounds was determined by comparing the peak area of ​​the major peak in the calibration standard (200 μM) with the peak area of ​​the corresponding peak in each buffer sample. The assay range was approximately 0.5 μM to 200 μM. Chromatographic purity (%) was determined as the peak area of ​​the major peak relative to the total integrated peak area in the HPLC chromatogram of the calibration standard.

[0257] Table 1 below shows the K2 levels in human liver microsomes (HLM), mouse liver microsomes (MLM), and rat liver microsomes (RLM). i and stability, as well as kinetic stability in PBS for the compounds of the examples shown. [Table 1] [Table 2]

[0258] CYP450 Inhibition Assay The following procedure was designed to evaluate whether the test compounds inhibited the activity of each common cytochrome P450 (CYP) enzyme in pooled human liver microsomes in a 96-well plate format. Compounds were tested at a single concentration (10 μM) using 0.1% DMSO. The test compounds were pre-incubated for 5 minutes in a shaking water bath at 37°C with the substrate and human liver microsomes (mixed sexes, pooled from 50 donors, 0.1 mg / mL) in phosphate buffer (pH 7.4). The reaction was initiated by adding a NADPH generating system. The reaction was allowed to stand for 10 minutes and stopped by transferring the reaction mixture to acetonitrile / methanol. The samples were mixed and centrifuged. The supernatant was used for HPLC-MS / MS of each metabolite. The activity of human cytochrome P450 (CYP) enzymes was measured by tracking the formation of metabolites of the probe substrate. The following enzymes were evaluated for inhibition using the listed reference substrates and reference inhibitors: The reference inhibitors were CYP1A-phenacetin (reference inhibitor fluffillin), CYP2B6-bupropion (reference inhibitor clopidogre), CYP2C8-amodiaquine (reference inhibitor montelukast), CYP2C9-diclofenac (reference inhibitor sulfafenazole), CYP2C19-omeprazole (reference inhibitor oxybutynin), CYP2D6-dextromethorphan (reference inhibitor quinidine), CYP3A-midazolam (reference inhibitor ketoconazole), and CYP3A-testosterone (reference inhibitor ketoconazole). In each assay, the reference inhibitors were tested at multiple concentrations, and IC50 values ​​were obtained. The peak area corresponding to the metabolite was recorded. The percentage of control activity was calculated by comparing the peak area in the presence of the test compound with that of a control sample containing the same solvent. The percentage inhibition was then calculated by subtracting the percentage control activity from 100. The IC50 value (the concentration that yields half of the maximum inhibition of the control) was measured by nonlinear regression analysis of the concentration-response curve using the Hill equation. [Table 3] [Table 4]

[0259] Testing using human IPF precision-cut lung slices (PCLuS) The following procedure was performed by FibroFind (Newcastle Fibrosis Research Group, UK) and was designed to evaluate whether the test compound mitigates fibrosis in IPF-PCLuS (IPF precision-cut lung slices). PCLuS were prepared from biopsy-confirmed and explanted IPF human lung tissue collected at the time of lung transplantation. The PCLuS were then rested for 48 hours to allow for a post-slice stress period before the start of the experiment. Furthermore, the PCLuS were cultured in the presence of the test compound at two increasing doses (0.1 μM and 1 μM). All PCLuS were harvested at 144 hours.

[0260] As shown in Table 3 below, nine different groups with n=5 or n=8 human PCLuS were investigated. PCLuS was prepared from n=1 biopsied and explanted human IPF lung. The vehicle was DMSO diluted 1:1000 in culture medium. [Table 5]

[0261] PCLuS was incubated for a 48-hour rest period. After the rest period, PCLuS was incubated for a further 96 hours in the presence or absence of the test compounds outlined above. PCLuS media containing all test compounds was refreshed and harvested at 24-hour intervals starting from 48 hours. All PCLuS was harvested at 144 hours. Each medium sample was divided into three aliquots of approximately 150 μl, and one aliquot was used for the measurement of soluble markers. The soluble markers were collagen 1a1 (Col1a1) and transforming growth factor-β1 (TGF-β1).

[0262] PCLuS harvesting. Cell culture supernatant (5-12 cells per group) was collected daily and snap-frozen to quantify the soluble output listed below. At harvest, n=5-8 PCLuS cells were rapidly frozen. RNA isolation and qPCR analysis were performed.

[0263] Analysis of solubility output. The level of collagen 1a1 in cell culture supernatant was quantified using the R&D Duoset ELISA kit. The level of TGF-β1 in cell culture supernatant was quantified using SinglePlex ELISA (MesoScaleDiscovery® (MSD)).

[0264] Quantitative real-time PCR (qPCR). Total RNA extraction from PCLuS was performed on all samples using the MagMAX®-96 Total RNA Isolation Kit. RNA was reverse transcribed into cDNA and used in qPCR to measure the transcription levels of Col1a1, TGF-β1, and β-actin.

[0265] Analysis of soluble output. Col1a1 levels in cell culture supernatant were quantified at 48, 96, and 144 hours using the R&D Duoset ELISA kit, while soluble TGF-β1 levels were quantified using the SinglePlex ELISA MSD kit (Figures 1-8).

[0266] Quantitative real-time PCR. The transcription levels of Col1a1 and TGF-β1 in PCLuS were quantified compared with β-actin (Figures 9 and 10).

[0267] Figures 1-4 show the secreted collagen 1a1 levels in PCLus culture supernatant after treatment with C21, Example 1A, Example 12A, and Example 3. The graphs represent n=5-12 tissue culture media for each condition and time point. Data are expressed as mean ± SEM, showing individual values ​​per tissue culture medium.

[0268] Figures 5-8 show the secreted TGF-β1 levels in PCLus culture supernatants treated with C21, Example 1A, Example 12A, and Example 3. The graphs represent n=5-12 tissue culture media for each condition and time point. Data are expressed as mean ± SEM, showing individual values ​​per tissue culture medium.

[0269] Figures 9 and 10 show the relative levels (RLTD%) of transcriptional differences for Col1a1 and TGF-β1 (normalized to β-actin) in PCLus after C21, Example 1A, Example 12A, and Example 3 treatments at 144 hours. The data are expressed as percentage changes in gene expression compared to the control and vehicle.

[0270] Treatment of IPF PCLus with virtually all of the compounds tested reliably reduced TGF-β1 gene transcription and protein secretion at at least one time point tested. These compounds were also highly effective in reducing collagen 1a1 gene transcription.

[0271] Further Examples The following compounds are also provided, which can be prepared according to one or more of the synthetic procedures previously described in the specification. [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12]

[0272] conclusion In conclusion, the compounds of this disclosure or their salts were found to exhibit lower inhibition of CYP enzymes compared to compound C21 or its sodium salt.

[0273] References 1.Pharmacol.Rev.2000;52:415-472. 2.WO02 / 096883 3.WO99 / 43339 4.EP0512675 A1 5.DE10 2012 004 589 A1 6.US2004 / 0167176 7.Med.Res.Rev.2018;38:602-624 8.WO2002 / 096883 9.WO2016 / 139475 10.WO2004 / 046141 11.WO2016 / 092329 12.WO2016 / 107879 13.WO2016 / 139475 14.WO2017 / 221012 15.WO2019 / 008393 16.US2012 / 035232 17.Bioorg.Med.Chem.Lett.2018,28(3),519-522. 18.ACS Med.Chem.Lett.2014,5,1129-1132. 19.Biochem.Pharmacol.1994,47,1469-1479. 20.DRUG Metab.Dispos.1999,27,1350-1359. 21.Bioorg.Med.Chem.2010,18(12),4570-4590. [Brief explanation of the drawing]

[0274] [Figure 1] Figure 1 shows the secreted Col1a1 (Col1a1) levels in the PCLus culture supernatant for C21 at 48, 96, and 144 hours. [Figure 2] Figure 2 shows the secreted Col1a1 (Col1a1) levels in the PCLus culture supernatant at 48, 96, and 144 hours for Example 1A. [Figure 3] Figure 3 shows the secreted Col1a1 (Col1a1) levels in the PCLus culture supernatant at 48, 96, and 144 hours for Example 12A. [Figure 4] Figure 4 shows the secreted Col1a1 (Col1a1) levels in the PCLus culture supernatant at 48, 96, and 144 hours for Example 3. [Figure 5] Figure 5 shows the secreted TGF-β1 levels in the PCLus culture supernatant for C21 at 48, 96, and 144 hours. [Figure 6] Figure 6 shows the secreted TGF-β1 levels in the PCLus culture supernatant at 48, 96, and 144 hours for Example 1A. [Figure 7] Figure 7 shows the secreted TGF-β1 levels in the PCLus culture supernatant at 48, 96, and 144 hours for Example 12A. [Figure 8] Figure 8 shows the secreted TGF-β1 levels in the PCLus culture supernatant at 48, 96, and 144 hours for Example 3. [Figure 9] Figure 9 shows the selected gene transcription levels in PCLus for Col1a1 (normalized to β-actin) after treatment with C21, Example 1A, Example 12A, and Example 3 at 144 hours. [Figure 10]Figure 10 shows the selected gene transcription levels in PCLus for TGF-β1 (normalized to β-actin) after treatment with C21, Example 1A, Example 12A, and Example 3 at 144 hours.

Claims

1. Formula I: 【Chemistry 1】 A compound thereof, or a pharmaceutically acceptable salt thereof, During the ceremony, R １ but, C substituted with an OH group or a F atom ２ ~C ６ Represents alkyl, R ２ but, H, F, Cl, OR ６ , SR ７ , NR ８ R ９ , a C substituted with 0, 1 or 2 substituents selected from the group consisting of halogen, thiazole, oxazole and pyrazole ２ -C ６ alkyl OR ６ , SR ７ and NR ８ R ９ C substituted with 0, 1, or 2 substituents selected from the group consisting of ３ ~C ６ Cycloalkyl, The phenyl part is OR ６ , SR ７ and NR ８ R ９ benzyl substituted with 0, 1, or 2 substituents selected from the group consisting of the above. 、 or (CH ２ ) ｍ -R １０ This represents, R ３ but, H, Halogen, or C substituted with 0, 1, 2, or 3 halogens selected from the group consisting of F and Cl. １ ~C ３ Represents alkyl, R ４ and R ５ However, C is independently substituted with 0, 1, 2, or 3 Fs. １ ~C ６ Represents alkyl, X represents CH = CH, CH, N, NH, O, or S, Y represents CH = CH, CH, N, NH, O, or S. however, (a) X and Y are not the same, (b) If X represents CH = CH, then Y can only represent CH. (c) If Y represents CH = CH, then X can only represent CH. Z represents a single bond, O, or S. R ６ , R ７ , R ８ and R ９ However, they became independent, H, or C substituted with 0, 1, 2, or 3 F １ ~C ３ Represents alkyl, R １０ However, selected from the group consisting of phenyl, thiazole, oxazole, and pyrazole, n is 0, 1, 2, 3, or 4. An angiotensin II receptor agonist, which is a compound or a pharmaceutically acceptable salt thereof, in which m is 0 or 1 (wherein "alkyl" means a linear or branched saturated or unsaturated hydrocarbon chain).

2. An angiotensin II receptor agonist according to claim 1, which is a compound of formula Ia, formula Ib, formula Ic, or formula Id. 【Chemistry 2】

3. R １ but, OR ６ , SR ７ , NR ８ R ９ C, substituted with 0, 1, or 2 substituents selected from the group consisting of halogens, thiazoles, oxazoles, and pyrazoles. ２ ~C ６ An angiotensin II receptor agonist according to claim 1 or 2, representing an alkyl group.

4. R ２ and R ３ An angiotensin II receptor agonist according to any one of claims 1 to 3, wherein H is represented independently.

5. R １ The angiotensin II receptor agonist according to claim 3 or 4, wherein the compound is 2-hydroxyprop-2-yl, 1-ethanol, or 2-fluoroprop-2-yl.

6. R ４ An angiotensin II receptor agonist according to any one of claims 1 to 5, wherein the agonist is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

7. R ４ The angiotensin II receptor agonist according to claim 6, wherein the agonist is methyl or n-butyl.

8. R ５ An angiotensin II receptor agonist according to any one of claims 1 to 7, wherein the agonist is selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

9. R ５ The angiotensin II receptor agonist according to claim 8, wherein the agonist is isopropyl or isobutyl.

10. An angiotensin II receptor agonist according to any one of claims 1 to 9, wherein n is 0.

11. An angiotensin II receptor agonist according to any one of claims 1 to 10, wherein Z is a single bond.

12. below: ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate butyl, ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((4-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, ((4-(4-((2-(1-hydroxyethyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)carbamate butyl, ((4-(4-((2-(1-hydroxyethyl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate, ((4-(4-((2-(1-hydroxyethyl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(1-hydroxyethyl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)methyl carbamate, ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)butyl carbamate, ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate butyl, ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)methyl carbamate, ((5-isobutyl-3-(4-(2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-yl)sulfonyl)butyl carbamate, ((5-isobutyl-3-(4-(2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-yl)sulfonyl)methyl carbamate, ((5-isobutyl-3-(4-(2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-yl)sulfonyl)butyl carbamate, ((5-isobutyl-3-(4-(2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-yl)sulfonyl)methyl carbamate, ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)butyl carbamate, ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-propylthiazole-5-yl)sulfonyl)methyl carbamate, ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)carbamate butyl, or ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-2-isobutylthiazole-5-yl)sulfonyl)methyl carbamate An angiotensin II receptor agonist according to any one of claims 1 to 11.

13. An angiotensin II receptor agonist according to any one of claims 1 to 12, for use as a pharmaceutical.

14. A pharmaceutical composition comprising a therapeutically effective amount of an angiotensin II receptor agonist according to any one of claims 1 to 12, together with at least one pharmaceutically acceptable carrier, excipient and / or diluent.

15. An angiotensin II receptor agonist according to any one of claims 1 to 12, for treating and / or preventing diseases, disorders or conditions related to angiotensin II, wherein the angiotensin II receptor agonist exhibits an acceptable level of CYP inhibition of one or more CYPs.

16. An angiotensin II receptor agonist according to claim 15 for use in the treatment and / or prevention of diseases, disorders and / or conditions selected from the group consisting of hypertension, heart failure, stroke, chronic kidney disease, nephropathy, pulmonary fibrosis, sclerosis, sarcoidosis, obstructive pulmonary disease, autoimmune diseases, viral respiratory infections and resulting pneumonia, and any combination thereof.

17. The angiotensin II receptor agonist according to claim 16, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis, the sclerosis is systemic sclerosis, the sarcoidosis is pulmonary sarcoidosis, the obstructive pulmonary disease is chronic obstructive pulmonary disease, and the autoimmune disease is rheumatoid arthritis.

18. Use of an angiotensin II receptor agonist according to any one of claims 1 to 12 for manufacturing a medicament for the treatment of diseases, disorders and / or conditions selected from the group consisting of hypertension, heart failure, stroke, chronic kidney disease, nephropathy, pulmonary fibrosis, sclerosis, sarcoidosis, obstructive pulmonary disease, autoimmune diseases, viral respiratory infections and resulting pneumonia, and any combination thereof.

19. The use of an angiotensin II receptor agonist according to claim 18, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis, the sclerosis is systemic sclerosis, the sarcoidosis is pulmonary sarcoidosis, the obstructive pulmonary disease is chronic obstructive pulmonary disease, and the autoimmune disease is rheumatoid arthritis.

20. The angiotensin II receptor agonist for use according to claim 16, wherein the disease is interstitial lung disease.

21. The angiotensin II receptor agonist for use according to claim 20, wherein the interstitial lung disease is idiopathic pulmonary fibrosis or sarcoidosis.

22. An angiotensin II receptor agonist for use according to claim 16, wherein the disease is heart failure, chronic kidney disease, rheumatoid arthritis, and virus-induced pneumonia.

23. The use according to claim 18, wherein the disease is interstitial lung disease.

24. The use according to claim 23, wherein the interstitial lung disease is idiopathic pulmonary fibrosis or sarcoidosis.

25. The use according to claim 18, wherein the disease is heart failure, chronic kidney disease, rheumatoid arthritis, and virus-induced pneumonia.

26. A pharmaceutical formulation comprising an angiotensin II receptor agonist according to any one of claims 1 to 12, a therapeutic agent known to be metabolized by a CYP enzyme, and a pharmaceutically acceptable adjuvant, diluent, or carrier.

27. It is a parts kit, (A) A pharmaceutical formulation comprising an angiotensin II receptor agonist according to any one of claims 1 to 12, mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier, (B) A pharmaceutical preparation comprising a therapeutic agent known to be metabolized by a CYP enzyme, mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier, A parts kit in which components (A) and (B) are provided in forms suitable for administration in combination with the other.

28. The preparation according to claim 26, wherein the therapeutic agent is selected from the group consisting of pirfenidone, naproxen, propranolol, riluzole, tizanidine, warfarin, celecoxib, clopidogrel, irbesartan, meloxicam, piroxicam, torsemide, cyclophosphamide, indomethacin, atorvastatin, cilostazol, cyclosporine, deflazacort, hydrocortisone, lidocaine, selexipag, sildenafil and / or simvastatin.

29. The parts kit according to claim 27, wherein the therapeutic agent is selected from the group consisting of pirfenidone, naproxen, propranolol, riluzole, tizanidine, warfarin, celecoxib, clopidogrel, irbesartan, meloxicam, piroxicam, torsemide, cyclophosphamide, indomethacin, atorvastatin, cilostazol, cyclosporine, deflazacort, hydrocortisone, lidocaine, selexipag, sildenafil and / or simvastatin.

30. Compound of formula 5: 【Transformation 3】 (In the formula, R １ , R ２ , R ３ , R ５ , where X, Y, Z and n are as defined in claim 1, and the compound of formula 6: R ４ OC(O)X (Formula 6) (In the formula, X represents a leaving group, R ４ However, as defined in claim 1, react with to optionally obtain the compound of formula 4: 【Chemistry 4】 (wherein PG represents a protecting group, and the protecting group includes tert-butyloxycarbonyl, benzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl (Teoc), and R １ , R ２ , R ３ , R ５ A process for preparing an angiotensin II receptor agonist according to any one of claims 1 to 13, 15 to 17, or 20 to 22, comprising deprotecting (where X, Y, Z, and n are as defined above) to obtain a compound of formula 5 as an intermediate.

31. The process according to claim 30, wherein the leaving group is a halogen.

32. The process according to claim 31, wherein the halogen is fluoro, chloro, bromo, or iodine.

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