Novel compounds for use in the treatment and / or prevention of a disease, disorder or condition associated with 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.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to novel compounds, their use as medicaments useful for treating and / or preventing diseases, disorders and / or conditions associated with the peptide angiotensin II and methods for preparing such compounds. BACKGROUND

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

[0003] The central role of ACE and renin enzymes in the renin-angiotensin system (RAS) has been the starting point for structure-based drug design and led to drugs that inhibit these enzymes. The drug Losartan, which acts as a selective antagonist for the AT1 receptor, was introduced in 1995 and was 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] It has also been suggested that agonists that selectively act on the AT2 receptor can be useful for the treatment of diseases associated with the renin-angiotensin system (RAS) and that activation of the AT2 receptor generally has opposite effects to AT1 receptor-mediated activation. While the AT1 receptor is expressed in most organs in the human body, the AT2 receptor has been found in fetal tissue, with expression significantly decreasing after birth. However, expression of the AT2 receptor is upregulated under pathological conditions such as heart failure, kidney failure, myocardial infarction, brain injury, vascular injury, and wound healing.

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

[0006] WO 02 / 096883 discloses tricyclic compounds useful as selective agonists of the AT2 receptor. The compounds can comprise an imidazole moiety. The compounds can be used in the treatment of gastrointestinal conditions such as dyspepsia, inflammatory bowel disease (IBS) and multiple organ failure (MOF) (see, e.g., International Patent Application WO 99 / 43339), as well as cardiovascular disorders.

[0007] EP 0512675 A1 discloses substituted imidazoles linked via a methylene group to novel substituted phenylthiophene or phenylfuran derivatives are angiotensin II antagonists and are useful in the treatment of hypertension and congestive heart failure.

[0008] DE 10 2012 004 589 A1 discloses new angiotensin II receptor agonists useful in the treatment of neurodegenerative diseases, preferably Alzheimer's dementia, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.

[0009] U.S. Patent Application US 2004 / 0167176 describes the preparation of tricyclic heterocycles useful as angiotensin II receptor agonists.

[0010] A trans-esterification 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 small molecule AT2 receptor agonists. The discovery of the selective small molecule AT2 receptor agonist compound 21C21 is described (see also International Patent Application WO 2002 / 096883). C21 is now in clinical development for the treatment of AT2 receptor related disorders, including IPF (see, e.g., International Patent Application WO 2016 / 139475).

[0012] C21 has also been shown to have potential use, inter alia, in the treatment of stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cardiotoxicity associated with cancer therapy, peripheral neuropathy and systemic sclerosis (see, for example, International Patent Applications WO 2004 / 046141, WO 2016 / 092329, WO 2016 / 107879, WO 2016 / 139475, WO 2017 / 221012, WO 2019 / 008393 and US Patent Application US 2012 / 035232).

[0013] Compound C21 has been reported to inhibit a range of oxidases of the CYP family, and substitution of the imidazole ring of C21 with a methyl or trifluoromethyl group reduces the level of inhibition of CYP 3A4 and 2C9. Further, a minor structural change of C21 transforms it from a selective AT2 receptor agonist to a selective AT2 receptor antagonist C38 / M132.

[0014]

[0015] Cytochrome P450 (CYP) is a family of enzymes found in, for example, mammals, which are important for the clearance of various compounds, such as drugs. It is therefore important to consider the interaction of drugs with various CYPs in order to avoid unwanted side effects. Excessive levels of CYP inhibition can have a potentially negative impact on the usefulness of a compound as a drug.

[0016] Selective AT2 receptor agonists with reduced CYP inhibition are described in Bioorg. Med. Chem. 2010; 18: 4570-4590.

[0017] There remains a need for pharmaceutically active compounds, such as small molecules acting as AT2 receptor agonists, for the treatment and / or prevention of diseases, disorders or conditions associated with angiotensin II. In particular, there is a need for such drugs, wherein the drug exhibits an acceptable level of CYP inhibition towards one or more CYPs. SUMMARY

[0018] The present disclosure provides a drug, such as a small molecule acting as an AT2 receptor agonist, for the treatment and / or prevention of diseases, disorders or conditions associated with angiotensin II. The drug can exhibit an acceptable level of CYP inhibition towards one or more CYPs.

[0019] Further, the present disclosure provides a drug, such as a small molecule acting as a selective AT2 receptor agonist, which exhibits an acceptable level of CYP inhibition towards one or more CYPs.

[0020] In this regard, there is provided a compound of Formula I:

[0021]

[0022] or a pharmaceutically acceptable salt thereof, wherein, in the compound of Formula I,

[0023] R 1 represents

[0024] H;

[0025] C2-C6alkyl substituted with zero, one, or two substituents selected from the group consisting of OR 6 , SR 7 , and NR 8 R 9 , halogen, thiazole, oxazole, and pyrazole;

[0026] C3-C6cycloalkyl substituted with zero, one, or two substituents selected from the group consisting of OR 6 , SR 7 , and NR 8 R 9 ;

[0027] thiazole;

[0028] benzyl, wherein the phenyl portion is substituted with zero, one, or two substituents selected from the group consisting of OR 6 , SR 7 , and NR 8 R 9 ; or

[0029] (CH2) m -R 10 ;

[0030] R 2 represents

[0031] H;

[0032] F;

[0033] Cl;

[0034] C2-C6alkyl substituted with zero, one, or two substituents selected from the group consisting of OR 6 , SR 7 , and NR 8 R 9 , halogen, thiazole, oxazole, and pyrazole;

[0035] C3-C6cycloalkyl substituted with zero, one or two substituents selected from the group consisting of: OR 6 , SR 7 , and NR 8 R 9 ;

[0036] benzyl, wherein the phenyl moiety is substituted with zero, one or two substituents selected from the group consisting of: OR 6 , SR 7 , and NR 8 R 9 ; or

[0037] (CH2) m -R 10 ,

[0038] provided that R 1 and R 2 are not both H;

[0039] R 3 represents

[0040] H;

[0041] halogen; or

[0042] C1-C3alkyl substituted with zero, one, two or three halogens selected from the group consisting of: F and Cl;

[0043] R 4 and R 5 independently represent C1-C6alkyl substituted with zero, one, two or three F;

[0044] X represents CH=CH, CH, N, NH, O or S; and

[0045] Y represents CH=CH, CH, N, NH, O or S,

[0046] provided that:

[0047] (a) X and Y are not the same;

[0048] (b) when X represents CH=CH, then Y can only represent CH; and

[0049] (c) when Y represents CH=CH, then X can only represent CH;

[0050] Z represents a single bond, O or S;

[0051] R6 , R 7 , R 8 and R 9 independently represent

[0052] H or C1-C3 alkyl substituted with 0, 1, 2 or 3 F (i.e. optionally substituted with 1, 2 or 3 fluoro substituents);

[0053] R 10 is selected from the group consisting of phenyl, thiazole, oxazol and pyrazole;

[0054] n is 0, 1, 2, 3 or 4; and

[0055] m is 0 or 1.

[0056] The above compounds disclosed herein, including pharmaceutically acceptable salts thereof, are hereinafter interchangeably referred to as “compounds of the invention”, “compounds of the disclosure”, “compounds as described herein” or “compounds of Formula I”.

[0057] Also provided is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient and / or diluent.

[0058] Further, provided is a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use as a medicament. The medicament can be a medicament for use in the treatment and / or prevention of a disease, disorder and / or condition associated with the peptide angiotensin II.

[0059] Also provided is a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment and / or prevention of a disease, disorder and / or condition selected from the group consisting of an obstructive lung disease, such as chronic obstructive pulmonary disease, an autoimmune disease, such as rheumatoid arthritis, a viral respiratory tract infection, such as pneumonia caused by a respiratory virus infection (viral pneumonia) and more preferably hypertension, heart failure, stroke, chronic kidney disease (including nephropathy), pulmonary fibrosis, such as idiopathic pulmonary fibrosis, a sclerotic condition, such as systemic sclerosis, a sarcoidosis, such as pulmonary sarcoidosis and other conditions, including one or more of the conditions not described herein above but listed herein below and any combination thereof.

[0060] Also provided is the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition as described herein, for the manufacture of a medicament for the treatment and / or prevention of a disease, disorder, and / or condition selected from the group consisting of hypertension, heart failure, stroke, kidney disease, pulmonary fibrosis, such as idiopathic pulmonary fibrosis, sclerotic conditions, such as systemic sclerosis, sarcoidosis, such as pulmonary sarcoidosis, and other conditions, including one or more of the conditions not described herein above but listed herein below, and any combination thereof.

[0061] Also provided is a method for the treatment and / or prevention of a disease, disorder, and / or condition selected from the group consisting of hypertension, heart failure, stroke, kidney disease, pulmonary fibrosis, such as idiopathic pulmonary fibrosis, sclerotic conditions, such as systemic sclerosis, sarcoidosis, such as pulmonary sarcoidosis, and other conditions, including one or more of the conditions not described herein above but listed herein below, and any combination thereof, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutical composition as described herein. DETAILED DESCRIPTION

[0062] The present disclosure provides a compound of Formula I:

[0063]

[0064] or a pharmaceutically acceptable salt thereof, as defined herein above.

[0065] For the avoidance of doubt, the skilled person will understand that reference herein to a compound of a particular aspect of the application, such as any aspect of the application relating to a compound of Formula I, as defined herein above, will include reference to all embodiments and their particular features, which can be combined to form further embodiments and features of the application.

[0066] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this application belongs.

[0067] The term "alkyl" denotes a straight chain or branched saturated or unsaturated alkyl chain. It will be appreciated that when "alkyl" is an unsaturated alkyl chain, i.e. an alkene, it comprises two or more carbon atoms.

[0068] The term "C1-C6alkyl" denotes a straight chain, or, when there is a sufficient number of carbon atoms, i.e. a minimum of two or three, as the case can be, branched and / or cyclic (thus forming a C 3-6 cycloalkyl) saturated or unsaturated alkyl chain, which comprises one to six carbon atoms. When there is a sufficient number of carbon atoms, i.e. a minimum of four, such groups can also be partially cyclic (thus forming a C 4-6 part-cycloalkyl).

[0069] 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, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.

[0070] The term "C2-C6 alkyl" refers to a straight-chain or branched saturated or unsaturated alkyl chain as defined above, comprising two to six carbon atoms. Examples of "C2-C6 alkyl" include, but are not limited to: ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.

[0071] The term "C1-C3 alkyl" refers to a straight-chain or branched saturated or unsaturated alkyl chain as defined above, comprising one to three carbon atoms. Examples of "C1-C3 alkyl" include, but are not limited to, ethyl, propyl, and isopropyl.

[0072] The term "C3-C6 cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic ring as defined above, consisting of three, four, five, or six carbon atoms. Examples of "C3-C6 cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0073] Examples of partially cyclic alkyl groups (which may also be referred to as “partially cyclic alkyl”) include cyclopropylmethyl. Such groups can also be polycyclic (e.g., bicyclic or tricyclic) and / or spirocyclic when a sufficient number of carbon atoms are present.

[0074] The term "halogen" includes fluorine, chlorine, bromine, and iodine.

[0075] It should be understood that when the R described in this article 1 When the substituent represents, for example, a thiazole, it can be combined with the imidazole ring of a compound of formula I as follows:

[0076]

[0077] In compounds of the present invention, where the identity of two or more substituents may be identical, the actual identity of the corresponding substituents does not depend on each other in any way. For example, in the presence of two or more halogen groups, those groups may be the same or different (e.g., two chlorine groups, or one fluorine group and one chlorine group). Similarly, in the presence of two or more alkyl groups, the groups in question may be the same or different in terms of their number of carbon atoms and / or whether they are straight-chain, branched, unsaturated, or otherwise.

[0078] Unless otherwise indicated, substituents can be located at any position on the group to which they are attached. In this regard, alkyl groups that can be substituted with one or more substituents (for example) can also be terminated with such substituents (which means located at the end of the alkyl chain, for example).

[0079] For the avoidance of doubt, where a substituent is itself substituted with 1 or more substituents (for example, C1-C3 alkyl substituted with 1, 2 or 3 halogens), these substituents (for example, halogens) can be located on the same or different atoms, where possible.

[0080] The skilled person will appreciate that the compounds of the application that are the subject of the present application comprise those compounds that are obtainable, i.e. those compounds that can be prepared in a stable form. That is, the compounds of the application comprise compounds that are sufficiently robust to survive isolation, for example, from a reaction mixture to a useful degree of purity.

[0081] The compounds of formula I can be prepared according to techniques well known to those skilled in the art, for example, as described hereinafter.

[0082] In one embodiment, the moiety containing X and Y of the compound of formula I can be a benzene ring, thereby providing a compound of formula la or formula lb:

[0083]

[0084] Alternatively, the moiety containing X and Y of the compound of formula I can be a thiophene, thereby providing a compound of formula Ic.

[0085]

[0086] In another embodiment, the moiety containing X and Y of the compound of formula I can be a thiazole, thereby providing a compound of formula Id.

[0087]

[0088] The compounds of formula I described herein can have the following values for R 1 and R 2 :

[0089] R 1 represents C2-C6 alkyl substituted (i.e. optionally substituted) with 0, 1 or 2 substituents selected from the group consisting of OR 6 , SR 7 , NR 8 R 9 , halogen or thiazole, oxazole or pyrazole; and

[0090] R 2 may represent H.

[0091] For example, R 1 may be selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, and R 2 may represent H.

[0092] In a further example, R 1 may represent ethyl or propyl, optionally substituted with 1 or 2 substituents selected from OR 6 or halogen, and R 2-6 may represent H. 2 may represent H.

[0093] For example, R 1 may represent ethyl or propyl, optionally substituted with a -OH group, for example 2-hydroxyprop-2-yl or 1-ethanol, and R 2 may represent H. R 1 may also represent ethyl or propyl, optionally substituted with F, for example 2-fluoroprop-2-yl, and R 2 may represent H.

[0094] In another example, R 1 may represent C2-C6alkyl, such as isopropyl or cyclopropyl, and R 2 may represent H.

[0095] In yet another example, R 1 may represent thiazole, and R 2 may represent H.

[0096] In a yet further example, R 1 may represent 2-hydroxyprop-2-yl, more preferably, tert-butyl, and R 2 may represent H.

[0097] Other compounds of the application that can be mentioned include those compounds in which:

[0098] R 1 may represent H, and

[0099] R 2 represents C2-C6alkyl substituted with 0, 1 or 2 substituents selected from the group consisting of OR 6 , SR 7 , NR 8 R 9 , halogen or thiazole, oxazole or pyrazole.

[0100] For example, R 1 may represent H, and R 2may be selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.

[0101] In a further example, R 1 may represent H, and R 2 may represent tert-butyl.

[0102] The compounds of formula I described herein can have R 4 substituents selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. For example, R 4 The substituents can be tert-butyl, methyl, ethyl, n-propyl, or n-butyl, such as n-butyl or, in particular, methyl.

[0103] Additionally or alternatively, the compounds of formula I described herein can have R 5 substituents selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. For example, R 5 The substituents can be isopropyl or isobutyl.

[0104] For example, there is provided a compound of formula I described herein, wherein

[0105] R 4 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl, and

[0106] R 5 is selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0107] Further, there is provided a compound of formula I described herein, wherein

[0108] R 4 is methyl, and

[0109] R 5 is isopropyl or isobutyl.

[0110] In a further example, there is provided a compound of formula I described herein, wherein

[0111] R 4 is methyl, and

[0112] R 5 is n-propyl.

[0113] In yet a further example, there is provided a compound of formula I described herein, wherein

[0114] R 4 is n-butyl, and

[0115] R 5 is n-propyl.

[0116] In another example, there is provided a compound of the formula I as described herein, wherein

[0117] R 4 is n-propyl.

[0118] R 5 is n-propyl.

[0119] Preferred compounds of the application include compounds of any one of formulae Ia, Ib, Ic or Id, wherein:

[0120] R 1 represents C 6 alkyl optionally substituted by one or more substituents selected from OR 2-4 alkyl;

[0121] R 2 and R 3 both represent H;

[0122] R 4 represents C 1-2 alkyl;

[0123] R 5 represents isopropyl or isobutyl;

[0124] n represents 0.

[0125] More preferred compounds of the application include compounds of any one of formula Ic or, more preferably, Ia, wherein:

[0126] R 1 represents linear or branched propyl or butyl optionally substituted by OH or fluoro, for example, R 1 represents t-butyl or 2-hydroxyprop-2-yl;

[0127] R 4 represents methyl;

[0128] R 5 represents isopropyl.

[0129] The present disclosure also provides a compound of the formula I as described herein, wherein the phenyl ring bound to the nitrogen atom of the imidazole moiety via a methylene group can be unsubstituted. Thus, the value of "n" can be 0.

[0130] The present disclosure provides a compound that is one or more of:

[0131] Methyl ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2- yl)sulfonyl)carbamate;

[0132] Butyl ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2- yl)sulfonyl)carbamate;

[0133] Methyl ((4-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazol-5- yl)sulfonyl)carbamate;

[0134] Butyl ((4-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazol-5- yl)sulfonyl)carbamate;

[0135] Methyl ((4-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5- yl)sulfonyl)carbamate;

[0136] Butyl ((4-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5- yl)sulfonyl)carbamate;

[0137] Butyl ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'- biphenyl]-2-yl)sulfonyl)carbamate;

[0138] Methyl ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'- biphenyl]-2-yl)sulfonyl)carbamate;

[0139] Butyl ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2- yl)sulfonyl)carbamate;

[0140] Methyl ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2- yl)sulfonyl)carbamate;

[0141] Butyl ((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2- yl)sulfonyl)carbamate;

[0142] Methyl ((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamate;

[0143] Butyl ((4-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- propylthiazol-5-yl)sulfonyl)carbamate;

[0144] Butyl ((4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5- yl)sulfonyl)carbamate;

[0145] Butyl ((2-isobutyl-4-(4-((2-(thiazol-2-yl)-1H-imidazol-1-yl)methyl)phenyl)thiazol- 5-yl)sulfonyl)carbamate;

[0146] Butyl ((4-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- isobutylthiazol-5-yl)sulfonyl)carbamate;

[0147] Butyl ((2-isobutyl-4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)thiazol-5- yl)sulfonyl)carbamate;

[0148] Methyl ((4-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- isobutylthiazol-5-yl)sulfonyl)carbamate;

[0149] Methyl ((2-isobutyl-4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)thiazol-5- yl)sulfonyl)carbamate;

[0150] Butyl ((2-propyl-4-(4-((2-(thiazol-2-yl)-1H-imidazol-1-yl)methyl)phenyl)thiazol-5- yl)sulfonyl)carbamate;

[0151] Butyl ((4-(4-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazol- 5-yl)sulfonyl)carbamate;

[0152] Methyl ((4-(4-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutyl- thiazol-5-yl)sulfonyl)carbamate;

[0153] Butyl ((4-(4-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol- 5-yl)sulfonyl)carbamate;

[0154] ((4-(4-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5- yl)sulfonyl)carbamic acid methyl ester;

[0155] ((4-(4-((2-cyclopropyl-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazol-5- yl)sulfonyl)carbamic acid methyl ester;

[0156] ((4-(4-((2-cyclopropyl-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazol-5- yl)sulfonyl)carbamic acid methyl ester;

[0157] ((4-(4-((2-cyclopropyl-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5- yl)sulfonyl)carbamic acid methyl ester;

[0158] ((4-(4-((2-cyclopropyl-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5- yl)sulfonyl)carbamic acid methyl ester;

[0159] ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'- biphenyl]-2-yl)sulfonyl)carbamic acid methyl ester;

[0160] ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'- biphenyl]-2-yl)sulfonyl)carbamic acid methyl ester;

[0161] ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'- biphenyl]-2-yl)sulfonyl)carbamic acid methyl ester;

[0162] ((5-isobutyl-4'-((2-(thiazol-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2- yl)sulfonyl)carbamic acid methyl ester;

[0163] ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'- biphenyl]-2-yl)sulfonyl)carbamic acid methyl ester;

[0164] ((5-isobutyl-4'-((2-(thiazol-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2- yl)sulfonyl)carbamic acid methyl ester;

[0165] Methyl ((5-isobutyl-4'-((2-(isoprop-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2- yl)sulfonyl)carbamate;

[0166] Butyl ((5-isobutyl-4'-((2-(isoprop-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2- yl)sulfonyl)carbamate;

[0167] Butyl ((5-isobutyl-4'-((2-(cycloprop-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2- yl)sulfonyl)carbamate;

[0168] Methyl ((5-isobutyl-4'-((2-(cycloprop-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2- yl)sulfonyl)carbamate;

[0169] Butyl ((5-isobutyl-3-(4-(2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- yl)sulfonyl)carbamate;

[0170] Methyl ((5-isobutyl-3-(4-(2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- yl)sulfonyl)carbamate;

[0171] Butyl ((5-isobutyl-3-(4-(2-(2-fluoropropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- yl)sulfonyl)carbamate;

[0172] Methyl ((5-isobutyl-3-(4-(2-(2-fluoropropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- yl)sulfonyl)carbamate;

[0173] 2-Methoxyethyl ((5-isobutyl-3-(4-(2-(2-tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2- yl)sulfonyl)carbamate;

[0174] Butyl ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5- yl)sulfonyl)carbamate;

[0175] Methyl ((4-(4-((2-(2-fluoropropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5- yl)sulfonyl)carbamate;

[0176] ((4-(4-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutyl- thiazol-5-yl)sulfonyl)carbamic acid butyl ester;

[0177] ((4-(4-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutyl- thiazol-5-yl)sulfonyl)carbamic acid methyl ester;

[0178] or a pharmaceutically acceptable salt of any of the above compounds.

[0179] Further, the present disclosure provides compounds that are one or more of:

[0180] ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2- yl)sulfonyl)carbamic acid methyl ester;

[0181] ((4-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazol-5- yl)sulfonyl)carbamic acid methyl ester;

[0182] ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'- biphenyl]-2-yl)sulfonyl)carbamic acid methyl ester;

[0183] ((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2- yl)sulfonyl)carbamic acid butyl ester;

[0184] ((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2- yl)sulfonyl)carbamic acid methyl ester;

[0185] ((4-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- propylthiazol-5-yl)sulfonyl)carbamic acid butyl ester;

[0186] ((4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5- yl)sulfonyl)carbamic acid butyl ester;

[0187] ((2-isobutyl-4-(4-((2-(thiazol-2-yl)-1H-imidazol-1-yl)methyl)phenyl)thiazol-5- yl)sulfonyl)carbamic acid butyl ester;

[0188] Butyl ((2-isobutyl-4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)thiazol-5- yl)sulfonyl)carbamate;

[0189] Butyl ((2-isobutyl-4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)thiazol-5- yl)sulfonyl)carbamate;

[0190] Butyl ((2-isobutyl-4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)thiazol-5- yl)sulfonyl)carbamate;

[0191] Butyl ((2-isobutyl-4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)thiazol-5- yl)sulfonyl)carbamate;

[0192] Butyl ((2-isobutyl-4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)thiazol-5- yl)sulfonyl)carbamate;

[0193] Butyl ((2-isobutyl-4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)thiazol-5- yl)sulfonyl)carbamate;

[0194] Butyl ((2-isobutyl-4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)thiazol-5- yl)sulfonyl)carbamate;

[0195] Butyl ((2-isobutyl-4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)thiazol-5- yl)sulfonyl)carbamate;

[0196] Butyl ((2-isobutyl-4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)thiazol-5- yl)sulfonyl)carbamate;

[0197] Butyl ((2-isobutyl-4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)thiazol-5- yl)sulfonyl)carbamate;

[0198] Butyl ((2-isobutyl-4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)thiazol-5- yl)sulfonyl)carbamate;

[0199] Butyl ((2-isobutyl-4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)thiazol-5- yl)sulfonyl)carbamate;

[0200] ((4-(4-((2-cyclopropyl-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5- yl)sulfonyl)amino acetic acid;

[0201] ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]- 2-yl)sulfonyl)amino acetic acid;

[0202] ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]- 2-yl)sulfonyl)amino acetic acid;

[0203] ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]- 2-yl)sulfonyl)amino acetic acid;

[0204] ((5-isobutyl-4'-((2-(thiazol-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2- yl)sulfonyl)amino acetic acid;

[0205] ((4'-((2-(2-fluoropropan-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]- 2-yl)sulfonyl)amino acetic acid;

[0206] ((5-isobutyl-4'-((2-(thiazol-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2- yl)sulfonyl)amino acetic acid;

[0207] ((5-isobutyl-4'-((2-(isoprop-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2- yl)sulfonyl)amino acetic acid;

[0208] ((5-isobutyl-4'-((2-(isoprop-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2- yl)sulfonyl)amino acetic acid;

[0209] ((5-isobutyl-4'-((2-(cycloprop-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2- yl)sulfonyl)amino acetic acid;

[0210] ((5-isobutyl-4'-((2-(cycloprop-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2- yl)sulfonyl)amino acetic acid;

[0211] butyl ((5-isobutyl-3-(4-(2-(2-methoxyprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- yl)sulfonyl)carbamate;

[0212] butyl ((5-isobutyl-3-(4-(2-(2-methoxyprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- yl)sulfonyl)carbamate;

[0213] butyl ((5-isobutyl-3-(4-(2-(2-methoxyprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- yl)sulfonyl)carbamate;

[0214] butyl ((5-isobutyl-3-(4-(2-(2-methoxyprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- yl)sulfonyl)carbamate;

[0215] butyl ((5-isobutyl-3-(4-(2-(2-methoxyprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- yl)sulfonyl)carbamate;

[0216] butyl ((5-isobutyl-3-(4-(2-(2-methoxyprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- yl)sulfonyl)carbamate;

[0217] butyl ((5-isobutyl-3-(4-(2-(2-methoxyprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- yl)sulfonyl)carbamate;

[0218] butyl ((5-isobutyl-3-(4-(2-(2-methoxyprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- yl)sulfonyl)carbamate;

[0219] butyl ((5-isobutyl-3-(4-(2-(2-methoxyprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- yl)sulfonyl)carbamate;

[0220] butyl ((5-isobutyl-3-(4-(2-(2-methoxyprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- yl)sulfonyl)carbamate;

[0221] butyl ((5-isobutyl-3-(4-(2-(2-methoxyprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- yl)sulfonyl)carbamate;

[0222] or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0223] In any case, preferred compounds of the present application comprise the compounds of the examples described hereinafter.

[0224] Pharmaceutical formulations and medical uses

[0225] The present 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, and at least one pharmaceutically acceptable carrier, excipient, or diluent.

[0226] The compounds of the present application can be used both for therapeutic, palliative and / or diagnostic treatment, and for prophylactic treatment of any of the above-mentioned conditions (by which we include preventing and / or ameliorating the worsening and / or worsening of the condition).

[0227] The compounds of the present application are generally administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, or by inhalation or pulmonary route, or any combination thereof, in a pharmaceutically acceptable dosage form, solution, suspension, emulsion (including nanosuspension), or liposomal formulation. Additional methods of administration include, but are not limited to, intra-arterial, intramuscular, intraperitoneal, intra-portal vein, intradermal, epidural, intrathecal administration, or any combination thereof.

[0228] The pharmaceutical composition can be in the form of an oral dosage form, such as a tablet, capsule, or syrup.

[0229] In some embodiments, the compounds of the present application can be administered separately (e.g., apart) and / or sequentially and / or concurrently (e.g., concurrently) using different routes of administration, but are preferably administered 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 by inhalation, etc. Preferred administration by inhalation is by use of a nebulizer, thereby delivering the compounds of the present application to the small lung tissue comprising alveoli and bronchioles, preferably without causing irritation or coughing in the subject being treated.

[0230] Administration of a therapeutically effective amount of the compounds of the present application can be performed by a combination of routes of administration, either separately (e.g., about 2 hours or more apart from each other), sequentially (e.g., within about 2 hours of each other), or concurrently (e.g., simultaneously), including by inhalation and orally, thereby achieving an effective dose.

[0231] As used herein, the expression "therapeutically effective amount" means an amount of a compound as described herein, which is sufficient to induce a desired therapeutic effect in a patient to whom the compound is administered. Further, the patient as described herein can be a human.

[0232] Also provided is a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use as a medicament. The medicament can be a medicament for the treatment and / or prevention of a disease, disorder and / or condition associated with the peptide angiotensin II. The medicament can be for the treatment and / or prevention of a disease, disorder and / or condition associated with the peptide angiotensin II, wherein the medicament exhibits an acceptable level of CYP inhibition on one or more CYPs.

[0233] Thus, there is provided a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment and / or prevention of a disease, disorder and / or condition associated with the peptide angiotensin II. The compounds described herein, and pharmaceutically acceptable salts thereof, optionally in the form of a pharmaceutical composition, can thus be used in the treatment and / or prevention of a disease, disorder and / or condition associated with the peptide angiotensin II, wherein the compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition exhibits an acceptable level of CYP inhibition on one or more CYPs.

[0234] Further, there is provided the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for the treatment and / or prevention of a disease, disorder and / or condition associated with the peptide angiotensin II.

[0235] In addition, there is provided a method for the treatment and / or prevention of a disease, disorder and / or condition associated with the peptide angiotensin II, the method comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0236] For the avoidance of doubt, the expression “exhibits an acceptable level of CYP inhibition” means that CYP inhibition is not desired and / or wherein the level of CYP inhibition is for example less than 50%, such as between 40% and 20%, for example less than 20%, such as between 10% and 0%, for example less than 0%, such as -50%.

[0237] For the avoidance of doubt, the expression “disease, disorder and / or condition associated with the peptide angiotensin II” means a disease, disorder and / or condition for which activation of the AT2 receptor is desired or required.

[0238] Thus, in some embodiments, there is provided a method of treating a disease, disorder and / or condition for which activation of the AT2 receptor is desired or required but for which inhibition of CYP is not desired, the method comprising administering to a patient in need of such therapy a therapeutically effective amount of a compound of the application, either alone, sequentially or simultaneously in parallel, preferably by inhalation and orally, to achieve an effective amount or dose.

[0239] Such formulations can be prepared according to standard and / or accepted pharmaceutical practice.

[0240] Suitable subjects for treatment with the formulations of the application include, but are not limited to, mammalian subjects, particularly human subjects.

[0241] It is contemplated that the compounds as described herein, or a pharmaceutically acceptable salt thereof, can be used for those diseases, disorders, and / or conditions in which the AT2 receptor is expressed and stimulation thereof is desired or required. In particular, the compounds as described herein, or a pharmaceutically acceptable salt thereof, can be used to treat diseases, disorders, and / or conditions in which activation of the AT2 receptor is desired or required, but inhibition of CYP is not desired.

[0242] In relation to "diseases, disorders, and / or conditions associated with angiotensin II", this includes diseases, disorders, and / or conditions known to be treatable by activation of the AT2 receptor, such as those mentioned below, but wherein existing treatments for such conditions can include administration of other therapeutic agents which are metabolised by CYP. Thus, such diseases, disorders, and / or conditions can include conditions in which inhibition of at least one CYP enzyme is not required, is advantageous, and / or is desired, or conditions in which such inhibition would be detrimental or would be detrimental to the patient.

[0243] As described herein, the compounds of the application are useful because they have pharmacological activity, and / or are metabolised in vivo following oral or parenteral administration to form compounds having pharmacological activity.

[0244] In particular, the compounds of the application are agonists of the Ang II receptor. Thus, it is contemplated that the compounds of the application can be used for those diseases, disorders, and / or conditions in which endogenous production of Ang II is insufficient and / or in which increased activity of the Ang II receptor is desired or required.

[0245] More particularly, the compounds of the application are agonists of the AT2 receptor, and especially selective (relative to the AT1 receptor) agonists of the sub-receptor, for example as can be demonstrated in the assays described below.

[0246] AT2 receptor agonists include agonists which fully and partially activate the AT2 receptor. Thus, the compounds of the application selectively bind to the AT2 receptor and exhibit agonist activity at the AT2 receptor. For a compound to "selectively bind" to the AT2 receptor, this includes compounds in which the affinity ratio of the relevant compounds (AT2:AT1) at a given concentration is at least 50:1, such as at least 100:1, preferably at least 1000:1.

[0247] In this regard, the compounds of the application are useful in the treatment of conditions characterised by vasoconstriction, fibrosis, increased cell growth and / or differentiation, increased cardiac contractility, increased cardiovascular hypertrophy, and / or increased fluid and electrolyte retention, as well as skin disorders and musculoskeletal disorders.

[0248] The compounds of the present application can also exhibit thromboxane receptor activity. In this regard, the compounds of the present application can have an inhibitory effect on platelet activation and / or aggregation (and thus have an anti-thrombotic effect), and / or can reduce vasoconstriction and / or bronchoconstriction in a therapeutic manner.

[0249] The compounds of the present application are further useful in the treatment of stress-related disorders, and / or in the improvement of microcirculation and / or mucosal protective mechanisms.

[0250] Thus, it is contemplated that the compounds of the present application are useful in the treatment of disorders characterized as described above, and which are, for example, in the gastrointestinal tract, the cardiovascular system, the respiratory tract, the kidney, the eye, the female reproductive (ovulation) system, and the central nervous system (CNS).

[0251] Gastrointestinal disorders that can be mentioned include esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, dyspepsia (including non-ulcer dyspepsia), gastroesophageal reflux, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pancreatitis, liver disease (e.g., hepatitis), gallbladder disease, multiple organ failure (MOF), and sepsis. Other gastrointestinal disorders that can be mentioned include dry mouth, gastritis, gastroparesis, gastric hyperacidity, biliary tract disorders, coelom disease, Crohn's disease, ulcerative colitis, diarrhea, constipation, colic, dysphagia, emesis, nausea, indigestion, and Sjogren's syndrome.

[0252] Respiratory tract diseases that can be mentioned include inflammatory disorders such as asthma, obstructive lung diseases (e.g., chronic obstructive pulmonary disease), pneumonia, pulmonary hypertension, and adult respiratory distress syndrome.

[0253] Kidney disorders that can be mentioned include renal failure, nephritis, and renal hypertension.

[0254] Eye disorders that can be mentioned include diabetic retinopathy, premature retinopathy, and retinal microvascularization.

[0255] Disorders of the female reproductive system that can be mentioned include ovulation dysfunction.

[0256] Cardiovascular disorders that can be mentioned include hypertension, cardiac hypertrophy, heart failure (including heart failure with preserved ejection fraction), atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial damage, post-balloon dilation stenosis, angiogenesis, diabetic complications, microvascular dysfunction, angina pectoris, arrhythmia, intermittent claudication, preeclampsia, myocardial infarction, reinfarction, ischemic injury, erectile dysfunction, and neointimal hyperplasia.

[0257] CNS disorders that can be mentioned include cognitive dysfunction, food intake dysfunction (hunger / satiety) and thirst, stroke, cerebral haemorrhage, cerebral embolism and cerebral infarction, multiple sclerosis (MS), Alzheimer's disease and Parkinson's disease.

[0258] The compounds of the application can also be used to modulate growth metabolism and proliferation, for example, for the treatment of aging, hypertrophic disorders, prostate hyperplasia, autoimmune diseases (e.g., arthritis, such as rheumatoid arthritis or systemic lupus erythematosus), psoriasis, obesity, neuronal regeneration, ulcer healing, inhibition of adipose tissue proliferation, stem cell differentiation and proliferation, fibrotic disorders, cancer (e.g., in the gastrointestinal tract (including the esophagus or stomach), prostate, breast, liver, kidney, and lymphatic, lung, ovarian, pancreatic, hematological malignancies, etc.), apoptosis, tumors (in general) and hypertrophy, diabetes, neuronal damage and organ rejection.

[0259] The compounds of the application can also be used to treat stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cancer treatment-related cardiotoxicity, peripheral neuropathy, in particular systemic sclerosis.

[0260] The diseases, disorders and / or conditions described herein related to the peptide angiotensin II can be selected from the group consisting of hypertension, heart failure, stroke, kidney disease, pulmonary fibrosis, such as idiopathic pulmonary fibrosis, hardening, such as systemic sclerosis, sarcoidosis, such as pulmonary sarcoidosis, and any combination thereof.

[0261] Particular diseases, disorders and / or conditions for which activation of the AT2 receptor is desired or needed but for which inhibition of CYP enzymes is not desired are 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 disease (e.g., diabetic nephropathy), pulmonary hypertension, pulmonary arterial hypertension and / or infarction (e.g., myocardial infarction and stroke). Thus, the compounds of the application are particularly suitable for use in the treatment of interstitial lung diseases such as IPF; autoimmune diseases such as rheumatoid arthritis; chronic kidney diseases such as diabetic nephropathy; pulmonary arterial hypertension including pulmonary arterial hypertension; and / or infarction such as myocardial infarction.

[0262] The compounds of the application are particularly suitable for use in the treatment and / or prevention of ILD, such as sarcoidosis or fibrosis, more particularly pulmonary fibrosis, and in particular IPF, and conditions that can trigger ILD, such as systemic sclerosis, rheumatoid arthritis, myositis or systemic lupus erythematosus, or conditions that are otherwise associated with ILD, such as pulmonary arterial hypertension and / or pulmonary arterial hypertension.

[0263] The compounds of the application are particularly suitable for use in the treatment of pulmonary fibrosis, in particular IPF.

[0264] According to another aspect of the application, there is provided a method of treating pulmonary fibrosis, in particular IPF, comprising administering to a person suffering from such condition a therapeutically effective amount of a compound of the application.

[0265] In the treatment of pulmonary fibrosis, including IPF, the compounds of the application can have an anti-fibrotic effect, reducing fibrosis and preventing further deposition of extracellular matrix. The compounds of the application can reduce lung scarring / wound healing and also have an anti-apoptotic effect, preventing alveolar epithelial cell apoptosis, which is an initiating factor in the development of pulmonary fibrosis. The compounds of the application can also have an anti-proliferative effect, reducing the cancer-like proliferation of fibroblasts and myofibroblasts in pulmonary fibrosis. The compounds of the application can also improve vascular remodelling in pulmonary fibrosis, reducing secondary pulmonary arterial hypertension.

[0266] The compounds of the application can further exhibit anti-inflammatory, anti-growth factor (e.g. transforming growth factor beta) and / or anti-cytokine effects.

[0267] In addition, the compounds of the application can also be used to treat or prevent any fibrotic condition of one or more internal organs characterised by excessive accumulation of fibrous connective tissue, and / or to treat or prevent fibrogenesis and the morbidity and mortality that can be associated therewith. Such fibrosis can be associated with acute inflammatory conditions, such as acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS) and multi-organ inflammation, damage and / or failure, which can be caused by internal or external trauma (e.g. injury) or by infection.

[0268] Thus, such conditions can be caused by sepsis or septic shock caused by viral, bacterial or fungal infection. Furthermore, acute lung injury, ARDS, and in particular SARS can be caused by viruses, such as coronaviruses, including novel SARS coronavirus 2 (SARS-CoV-2), which can cause internal tissue damage, associated internal (e.g. mucosal) tissue (such as respiratory epithelium) dysfunction, and thereby viral-induced pneumonia, impaired lung function, respiratory dysfunction, distress and / or failure. Such tissue damage can also lead to severe fibrosis. For example, the SARS disease caused by the novel coronavirus SARS-CoV-2 (coronavirus disease 2019 or COVID-19) is known to cause fibrosis in many cases.

[0269] The compounds of the application have the advantage that they are more effective than metabolic hydrolysis and / or are more stable to metabolic hydrolysis and / or have an acceptable level of CYP enzyme inhibition, as mentioned above.

[0270] The compounds of the present invention can also have the advantage that they can be more efficacious, less toxic, longer acting, more potent, produce fewer side effects, be more easily absorbed, and / or have better pharmacokinetic profiles (e.g., higher oral bioavailability and / or lower clearance) and / or have other useful pharmacological, physical, or chemical properties than compounds known in the art, whether or not used or otherwise used in the treatment of any of the disease states described above (such as IPF). Such effects can be assessed clinically, objectively, and / or subjectively by a health care professional, treating subject, or observer.

[0271] Compositions

[0272] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can be used in combination with one or more additional drugs in combination therapy to treat a variety of conditions, including those mentioned above. Such combinations are particularly advantageous when the other therapeutic agent used in the related condition is itself metabolized by CYP enzymes, as the compounds of the present invention exhibit minimal CYP enzyme inhibition.

[0273] Thus, the compounds of the present invention can be administered in combination with other AT2 agonists known in the art, such as C21, and can also be administered in combination with AT1 receptor antagonists known in the art, and / or with inhibitors of angiotensin converting enzyme (ACE).

[0274] Non-limiting but illustrative examples of AT1 receptor antagonists that can be used in accordance with embodiments include azilsartan, candesartan, eprosartan, fimasartan, irbesartan, losartan, milfasartan, olmesartan, pomisartan, pratosartan, ripiasartan, saprisartan, tasosartan, telmisartan, valsartan, and / or combinations thereof. Non-limiting but illustrative examples of ACE inhibitors that can be used in accordance with embodiments include captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, fosinopril, moexipril, cilazapril, spirapril, temocapril, alacepril, ceronapril, delepril, moveltipril, and / or combinations thereof.

[0275] Other active ingredients that can be administered in combination with the compounds of the application include sodium cromoglycate; endothelin receptor antagonists such as bosentan, ambrisentan, sitaxentan and macitentan; PDE5 inhibitors such as sildenafil and tadalafil; prostacyclins (epoprostenol) and analogues thereof such as iloprost and treprostinil; other biologies including interferon gamma-1 b, etanercept, infliximab and adalimumab; and methotrexate. Other active ingredients under development that can be co-administered with the compounds of the application include pamrevlumab (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 protein signaling inhibitor, United Therapeutics), KD25 (Rho-associated kinase inhibitor, Kadmon Holdings), BG00011 (integrin antagonist, Biogen), PLN-74809 (integrin antagonist, Pilant Therapeutics), Saracatinib (src kinase inhibitor, AstraZeneca), PAT-1251 (lysyl oxidase inhibitor 2, PharmAkea), ABM-125 (IL-25 MAB, Abeome), and TA5-115 (multi-kinase inhibitor, Otsuka).

[0276] When the condition to be treated is an interstitial lung disease such as IPF, systemic sclerosis or a fibrotic disease known in the art, the compounds of the present application are preferably administered in combination with a galectin-3 inhibitor, a lysophosphatidic acid receptor 1 (LPA1 ) antagonist, a autotoxin (ATX) inhibitor, a recombinant human pentraxin-2 protein or an established therapy for such treatment, including but not limited to pirfenidone and / or nintedanib. Preferably, the combination of the compounds of the present application with pirfenidone or a pharmaceutically acceptable salt thereof, which is known to be metabolized by CYP enzymes such as CYP1 A.

[0277] Further, when the condition to be treated is a chronic kidney related disease, the compounds of the present application are preferably administered in combination with one or more other drugs also used for such treatment, such as irbesartan and / or torsemide, which are known to be metabolized by CYP enzymes such as CYP2C9.

[0278] When the condition to be treated is pulmonary arterial hypertension, the compounds of the present application are preferably administered in combination with one or more other drugs also used for such treatment, such as selexipag and / or sildenafil, which are known to be metabolized by CYP enzymes such as CYP3A4.

[0279] When the condition to be treated or prevented is a myocardial infarction and / or stroke related disease, the compounds of the present application are preferably administered in combination with one or more other drugs also used for such treatment, such as propranolol, warfarin, clopidogrel, atorvastatin, cilostazol, lidocaine and / or simvastatin or a pharmaceutically acceptable salt thereof, which are known to be metabolized by CYP enzymes such as CYP1 A, CYP2CP and / or CYP3A4.

[0280] When the condition to be treated is an autoimmune disease, such as rheumatoid arthritis, multiple sclerosis or psoriasis, the compounds of the application are preferably administered in combination with one or more other drugs also used for such treatment, including but not limited to non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen, celecoxib, meloxicam or analogs thereof (e.g., piroxicam) or indomethacin; or drugs such as tizanidine, cyclophosphamide, cyclosporine, deflazacort and / or hydrocortisone, riluzole or a pharmaceutically acceptable salt thereof, which are known to be metabolized by CYP enzymes such as CYP1A, CYP2CP, CYP2C19 and / or CYP3A4.

[0281] Thus, the compounds of the application are particularly useful for the treatment of diseases, disorders and / or conditions for which activation of the AT2 receptor is desired or required but for which inhibition of CYP enzymes is not desired, and thus can be administered in combination with one or more of the above-mentioned other therapeutic agents that are metabolized by the CYP enzyme pathway, including those mentioned above, including pirfenidone, naproxen, propranolol, riluzole, tizanidine, warfarin, celecoxib, clopidogrel, irbesartan, meloxicam, piroxicam, torsemide, cyclophosphamide, indomethacin, atorvastatin, cilostazol, cyclosporine, deflazacort, hydrocortisone, lidocaine, seliprog, sildenafil and / or simvastatin, are or can be useful, including pirfenidone. Most preferably, the compounds of the application are administered in combination with pirfenidone for the treatment of interstitial lung diseases such as IPF.

[0282] Therapeutic agents that can be used in conjunction with the compounds of the present application include standard treatments variously applied for viral infections, including antibody therapies (e.g., LY-CoV555 / LY-CoV016 (bamlanivimab and etesevimab), LY-CoV555 (bamlanivimab by Eli Lilly), REGN-COV2 (asirivimab and imdevimab), REGN3048-3051, TZLS-501, SNG001 (Synairgen), eculizumab (Soliris; Alexion Pharmaceuticals), ravulizumab (Ultomiris; Alexion Pharmaceuticals), lenzilumab, leronlimab, tocilizumab (Actemra; Roche), Sarilumab (Kevzara; Regeneron Pharma), and Octagam (Octapharma), including antiviral drugs (e.g., oseltamivir, remdesivir, favilavir, molnupiravir, simeprevir, daclatasvir, sofosbuvir, ribavirin, umifenovir, lopinavir, ritonavir, lopinavir / ritonavir (Kaletra; AbbVie Deutschland GmbH Co.baricitinib (Olumiant; Eli Lilly), ruxolitinib (Jakavi; Novartis), tofacitinib (Xeljanz; Pfizer), TMPRSS2 inhibitor camostat or camostat mesylate, tocilizumab (Actemra) (Roche), AT-100 (rhSP-D), MK-7110 (CD24Fc; Merck), OYA1 (OyaGen9), BPI-002 (BeyondSpring), NP-120 (Ifenprodil; Algernon Pharmaceuticals), and Galidesivir (Biocryst Pharma), anti-inflammatory agents (e.g. NSAIDs such as ibuprofen, ketorolac, naproxen, etc.), chloroquine, hydroxychloroquine), interferons (e.g. interferon beta (interferon beta-1a)), tocilizumab (Actemra), lenalidomide, pomalidomide, and thalidomide, analgesics (e.g. paracetamol or opioids), antitussive agents (e.g. dextromethorphan), vaccination (e.g. INO-4800 by Inovio Pharmaceuticals and Beijing Advaccine Biotechnology, if available), COVID-19 convalescent plasma (CCP) and / or passive antibody therapy with antibodies extracted from the blood of people infected with SARS-CoV or SARS-CoV-2.

[0283] Further therapeutic agents that can be mentioned include anti-fibrotic agents (e.g. nintedanib, in particular pirfenidone), vitamins (e.g. vitamins B, C and D) and mucolytic agents such as acetylcysteine and ambroxol.

[0284] According to the present invention, other therapeutic agents that can be used in combination with the compounds of the present invention or their pharmaceutically acceptable salts include corticosteroids. Corticosteroids include naturally occurring corticosteroids and synthetic corticosteroids.

[0285] Naturally occurring corticosteroids that may be mentioned include cortisol (hydrocortisone), aldosterone, corticosterone, corticosterone, pregnenolone, progesterone, as well as natural precursors and intermediates in the biosynthesis of corticosteroids, and other naturally occurring derivatives of corticosteroids, such as 11-deoxycortisol, 21-deoxycortisol, 11-dehydrocorticosterone, 11-deoxycorticosterone, 18-hydroxy-11-deoxycorticosterone, 18-hydroxycorticosterone, 21-deoxycorticosterone, 11β-hydroxypregnenolone, 11β,17α,21-trihydroxypregnenolone, 17α,21-dihydroxypregnenolone, 17α-hydroxypregnenolone, 21-hydroxypregnenolone, 11-ketoprogesterone, 11β-hydroxyprogesterone, 17α-hydroxyprogesterone, and 18-hydroxyprogesterone.

[0286] Synthetic corticosteroids that can be mentioned include hydrocortisone-type synthetic corticosteroids (Group A), such as cortisone acetate, hydrocortisone propyl ester, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, tixocortol and tixocortol neovalerate, prednisolone, methylprednisolone, prednisone, chloroprednisone, cloprednol, difluprednate, fludrocortisone, fluocinolone, and fluperolone.

[0287] Fluprednisolone, Loteprednol, Prednicarbate and Triamcinolone; Acetone compounds and related substances (Group B) such as Amcinonide, Budesonide, Desonide, Fluocinolone cetonide, Fluocinonide, Halcinonide, Triamcinolone acetonide, Ciclesonide, Deflazacort, Formocortal, Fludroxycortide, Flunisolide and Fluocinolone acetonide;(b) synthetic corticosteroids of the Methylprednisolone type (Group C), such as beclomethasone, betamethasone, betamethasone dipropionate and betamethasone valerate, dexamethasone, fluocortolone, halometasone, mometasone and mometasone furoate, alclometasone and alclometasone dipropionate, clobetasol and clobetasol propionate, clobetasone and clobetasone butyrate, clocortolone, desoximetasone, diflorasone, difluocortolone, fluclorolone, flumetasone, fluocortin, fluprednidene and fluprednidene acetate, fluticasone, fluticasone furoate and fluticasone propionate, meprednisone, paramethasone, prednylidene, rimexolone and ulobetasol; synthetic corticosteroids of the Progesterone type, such as flugestone, fluorometholone, medrysone and prebediolone acetate;and progestin derivatives such as chlormadinone acetate, cyproterone acetate, medrogestone, medroxyprogesterone acetate, megestrol acetate, and segesterone acetate; and other corticosteroids such as cortivazol and 6-methyl-l lbeta, 17beta-dihydroxy- 17alpha-(l-propynyl)androst- 1,4,6-trien-3-one.

[0288] Preferred corticosteroids include cortisone, prednisone, prednisolone, methylprednisolone, and especially dexamethasone.

[0289] Further, therapeutic agents that can be used in conjunction with the compounds of the application or pharmaceutically acceptable salts thereof include H2 receptor blockers, anticoagulants, antiplatelet drugs, and statins, antibacterial agents, and anti-allergy / anti-asthma drugs.

[0290] H2 receptor blockers that can be mentioned include famotidine. Anticoagulants that can be mentioned include heparin and low molecular weight heparins (e.g. bemiparin, nadroparin, reviparin, enoxaparin, parnaparin, certoparin, dalteparin, tinzaparin); direct oral anticoagulants (e.g. dabigatran, argatroban, rivaroxaban, apixaban, edoxaban, betrixaban, darexaban, otamixaban, letaxaban, eribaxaban, hirudin, lepirudin and bivalirudin); coumarin-type vitamin K antagonists (e.g. coumarin, acenocoumarol, phenprocoumon, atromentin and phenindione) and synthetic pentasaccharide inhibitors of factor Xa (e.g. fondaparinux, idraparinux and idrabiotaparinux). Antiplatelet drugs that can be mentioned include irreversible cyclooxygenase inhibitors (e.g. aspirin and triflusal); adenosine diphosphate receptor inhibitors (e.g. cangrelor, clopidogrel, prasugrel, ticagrelor and ticlopidine); phosphodiesterase inhibitors (e.g. cilostazol); proteinase-activated receptor-1 antagonists (e.g. vorapaxar); glycoprotein IIB / IIIA inhibitors (e.g. abciximab, eptifibatide and tirofiban); adenosine reuptake inhibitors (e.g. dipyridamole); and thromboxane inhibitors (e.g. terutroban, ramatroban, seratrodast and picotamide).Statins that can be mentioned include atorvastatin, simvastatin and rosuvastatin. Anti-microbial agents that can be mentioned include azithromycin, ceftriaxone, cefuroxime, doxycycline, fluconazole, piperacillin, tazobactam and teicoplanin. Anti-allergy / anti-asthma drugs that can be mentioned include chlorphenamine, levocetirizine and montelukast.

[0291] Thus, the subject can also (and / or can have) be receiving one or more of any of the other therapeutic agents described above, which means one or more of those other therapeutic agents in a prescribed dose prior to, in addition to and / or after treatment with the compound of the application, or a pharmaceutically acceptable salt thereof.

[0292] When the compound of the application is "combined" with another therapeutic agent mentioned above, the active ingredients can be administered together in the same formulation, or separately (simultaneously or sequentially) in different formulations.

[0293] Such combination products provide for the conjoint administration of the compound of the application and the other therapeutic agent, and can exist in the form of separate formulations which are packaged together (e.g. in a single kit), or as a single formulation.

[0294] The compositions can be provided as a kit of parts optionally comprising instructions for use. Alternatively, the compositions can be provided as a single composition or formulation, wherein at least one of these compositions or formulations comprises the compound of the application, and at least one comprises the other therapeutic agent, or as (i.e. formulated as) a combination preparation (i.e. as a single composition or formulation comprising the compound of the application and the other therapeutic agent).

[0295] Thus, further provided are:

[0296] (1) a pharmaceutical composition or formulation comprising the compound of the application; a therapeutic agent known to be metabolised by a CYP enzyme, such as any of those mentioned above; and a pharmaceutically acceptable excipient (e.g. adjuvant, diluent or carrier), said composition or formulation being hereinafter referred to as a "combination preparation"; and

[0297] (2) a kit-of-parts comprising components:

[0298] (A) a pharmaceutical composition or formulation comprising a compound of the application, said pharmaceutical formulation being in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and

[0299] (B) a pharmaceutical composition or formulation comprising a therapeutic agent known to be metabolised by CYP enzymes, such as any of the pharmaceutical compositions or formulations mentioned hereinbefore, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, said components (A) and (B) each being provided in a form suitable for administration in conjunction with the other component.

[0300] In another aspect of the application, there is provided a method of preparing a combination preparation as defined hereinbefore, said method comprising associating a compound of the application, another therapeutic agent and at least one (e.g. pharmaceutically acceptable) excipient.

[0301] In another aspect of the application, there is provided a method of preparing a kit-of-parts as defined hereinbefore, said method comprising associating components (A) and (B). As used herein, reference to associating will mean adapting the two components to be used in conjunction with each other.

[0302] Thus, in relation to a method for preparing a kit-of-parts as defined hereinbefore by associating two components with each other, the two components comprising the kit-of-parts can:

[0303] (i) be provided in the form of separate compositions or formulations (i.e. independently of each other), which are subsequently combined together for use in conjunction with each other in a combination therapy; or

[0304] (ii) be packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in a combination therapy.

[0305] Thus, there is further provided a kit-of-parts comprising:

[0306] (I) one of components (A) and (B) as defined herein; together with

[0307] (II) instructions for using said components in conjunction with the other of the two components.

[0308] The compounds of the application can be administered at different dosages depending on the patient to be treated and the route of administration. While the dosage varies with the patient, a suitable daily dose for each patient is in the range of about 0.1 mg to about 1000 mg (e.g., 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, etc., or any range or value therein) administered in single or multiple doses. A more preferred daily dose range is about 0.1 mg to about 250 mg per patient (e.g., 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, etc., or any range or value therein). A particularly preferred daily dose range is about 0.3 mg to about 100 mg per patient.

[0309] An individual dose of a compound of the application can be in the range of about 0.1 mg to about 100 mg (e.g., 0.3 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100, etc., or any range or value therein).

[0310] The term "about" (or similar terms, such as "approximately"), when used in this context in relation to a specific value (such as a quantity), will be understood to indicate that variation of such value can be up to 10% of the defined value (in particular, up to 5%, such as up to 1%). It is contemplated that in each case such term can be replaced with the symbol "+10%", or the like (or by indicating the variance of a specific amount calculated based on the relevant value). It is also contemplated that in each case such term can be deleted.

[0311] In any case, the physician or technician will be able to determine the actual dose most appropriate for an individual patient, which can vary with the condition to be treated, and the species, age, body weight, sex and response of the particular patient to be treated. The above-mentioned dosages are in general exemplary; of course, greater or lesser dosage ranges can be needed in individual cases, and such dosage ranges are all within the scope of the application.

[0312] The benefit of using the compounds of the application, for example, by a combination of routes of administration, individually and / or sequentially, and / or simultaneously in parallel, is to provide a tailored treatment for the patient in need of treatment, with the possibility of preventing and / or reducing side effects, and also adjusting the correct dosage level of the therapeutically effective amount of the compounds of the application.

[0313] To provide repeated dosing, the multi-part kits described herein can include more than one composition or formulation comprising an appropriate amount / dose of a compound of the application, and / or more than one composition or formulation comprising an appropriate amount / dose of another therapeutic agent. If there is more than one composition or formulation (including any one active compound), such compositions or formulations can be identical, or can differ in the dosage, chemical composition, and / or physical form of any one compound.

[0314] Thus, in terms of the combination product according to the application, the term "combined administration" includes administration of both components of the combination product (the compound of the application and the other therapeutic agent) together (optionally repeatedly), or sufficiently close in time to enable a greater beneficial effect on the patient during the course of treatment of the relevant condition than if the composition or formulation comprising the compound of the application, or the composition or formulation comprising the other agent, were administered alone (optionally repeatedly) during the same course of treatment in the absence of the other component. Determining whether a combination provides a greater beneficial effect in terms of a particular condition, and during the course of treatment of the particular condition, will depend on the condition to be treated or prevented, but can be routinely achieved by the skilled person.

[0315] Further, in the context of a kit-of-parts according to the application, the term "in combination with" encompasses that one of the two compositions or formulations can be administered before, after and / or simultaneously (optionally repeatedly) with the other. The terms "simultaneously administered" and "simultaneously administering" when used in this context encompass that the individual doses of the relevant compound of the application and the other therapeutic agent are administered within 48 hours (e.g. 24 hours) of each other.

[0316] In a further aspect of the application, there is provided a method for the preparation of a combination product or a kit-of-parts as defined hereinbefore, which method comprises bringing into association certain compounds of the application as defined hereinbefore with the other therapeutic agent useful in the treatment of the relevant disease, disorder and / or condition and at least one pharmaceutically acceptable excipient.

[0317] Pharmaceutically acceptable salts

[0318] The compounds of the present disclosure and / or the present application can be provided in the form of a pharmaceutically acceptable salt. For example, the pharmaceutically acceptable salt can be an acid addition salt or a base addition salt. The acid addition salt can be formed from a compound of Formula I and an acid, such as an organic acid. The organic acid can be trifluoroacetic acid, formic acid, acetic acid, benzoic acid, oxalic acid, fumaric acid, maleic acid, preferably trifluoroacetic acid. The organic acid can also be a sulfonic acid, such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and the like. The acid can also be an inorganic acid, such as hydrochloric acid, hydrobromic acid, and the like. Examples of acid addition salts include salts of cations including a compound of Formula I and a conjugate base of an acid, such as CF3C(O)O - The base addition salt can be formed from a compound of Formula I and a base, such as an organic base. Base addition salts that can be mentioned include salts with alkali metals, such as Li salts, Na salts, and K salts; with alkaline earth metals, such as Mg salts and Ca salts; with other metals, such as Al salts and Zn salts; or with amine bases, such as ammonia, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, and tromethamine. Examples of base addition salts include salts of anions including a compound of Formula I and a cation, such as Na + or K + .

[0319] Solvate

[0320] It is understood that the compounds of the present disclosure can exist in solvated forms, such as solvates of the free compounds or solvates of the pharmaceutically acceptable salts of the compounds. The term "solvate" is used herein to describe a molecular complex comprising the compound of the present disclosure or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used. Thus, solvate forms can include monohydrates, dihydrates, hemi-hydrates, trihydrates, tetrahydrates, and the like.

[0321] Prodrug

[0322] The compounds of the present disclosure can be in the form of a prodrug. A prodrug is a compound that can have little or no pharmacological activity itself, but which is converted in the body or on the body into a compound having pharmacological activity.

[0323] Polymorphs

[0324] The compounds of the present disclosure can exist in a continuum of solid states ranging from completely amorphous to completely crystalline. The compounds of the present disclosure can also exist as oils. When the compounds of Formula I exist in crystalline and partially crystalline forms, such forms can include solvates, which are included within the scope of the present invention. It is understood that all polymorphs, such as mixtures of polymorphs, are included within the scope of the compounds claimed.

[0325] The compounds of the present invention can also exist in solution (i.e., in solution in a suitable solvent). For example, the compounds of Formula I can exist in aqueous solution, in which case the compounds of the present invention can exist in a hydrate form.

[0326] The compounds of the present invention can contain double bonds (unless otherwise indicated) and can thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. Unless otherwise specified, all such isomers and mixtures thereof are included within the scope of the present invention.

[0327] The compounds of the present invention can also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the present invention (particularly those of sufficient stability to isolate).

[0328] The compounds of the present invention can also contain one or more asymmetric carbon atoms and can thus exhibit optical and / or diastereomeric phenomena (i.e., exist in enantiomeric or diastereomeric forms). The diastereomeric forms can be separated using conventional techniques (e.g., chromatography or fractional crystallization). The various stereoisomers (i.e., enantiomers) can be isolated by separation of a racemic or other mixture of compounds using conventional (e.g., fractional crystallization or HPLC) techniques. Alternatively, the desired enantiomer or diastereomer can be obtained by reacting the appropriate optically active starting material with a “chiral auxiliary” under conditions that will cause the desired enantiomer or diastereomer to be obtained (i.e., the “chiral pool” method), which can then be removed at an appropriate stage by derivatization (i.e., resolution, including dynamic resolution; e.g., with a pure chiral acid, followed by separation of the diastereomeric derivatives by conventional methods such as chromatography), or by reaction with an appropriate chiral reagent or chiral catalyst, all of which methods and processes can be performed under conditions known to the skilled artisan. Unless otherwise stated, all stereoisomers and mixtures thereof are included within the scope of the present invention.

[0329] Isotopically labeled compounds

[0330] The compounds of the present disclosure can be used in their labeled or unlabeled form. The compounds of the present disclosure can be isotopically-labeled by substituting one or more atoms of the compounds by one or more of the isotopes of hydrogen, deuterium, tritium, 11C, 13C, 14C, 18O, 17O, 19F, 18F.

[0331] Thus, the compounds of the present invention can have one of their atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant atomic mass number found in nature). All isotopes of any particular atom or element as described herein are contemplated within the scope of the compounds of the present invention.

[0332] Methods of preparation

[0333] The compounds of Formula I described herein can be prepared using methods known in the art and / or as described in this document.

[0334] It will be appreciated by persons skilled in the art that in the methods described above and below, the functional groups of intermediate compounds can need to be protected by protecting groups.

[0335] Functional groups desirably protected include sulfonamide groups, amide groups, amino groups, and aldehydes. Suitable protecting groups for sulfonamide groups, amide groups, and amino groups include tert-butoxycarbonyl, 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 (thus forming a cyclic acetal). Protection and deprotection of functional groups can be carried out before or after the reactions outlined in Scheme 1 below.

[0336] Protecting groups can be applied and removed in accordance with techniques well known to those skilled in the art and as described below. For example, standard deprotection techniques can be used to chemically transform a protected compound / intermediate described herein into an unprotected compound. The chemistry involved will dictate the need for and type of protecting group, as well as the sequence used to accomplish the synthesis. The use of protecting groups is fully described in “Protective Groups in Organic Synthesis”, 3rdedition, T.W. Greene and P.G.M. Wutz, Wiley-Interscience (1999), the contents of which are incorporated herein by reference.

[0337] For example, compounds of Formula I can be synthesized as described in Scheme 1 below.

[0338]

[0339] In Scheme 1, dibromide 1 is reacted with heterocycle 2 under reaction conditions a) to provide compound 3. Dibromide 1 can be substituted with 0, 1, 2, 3, or 4 F, i.e., n can be 0, 1, 2, 3, or 4. Heterocycle 2 is substituted with substituents R 1 , R 2 , and R 3 , which can have the values indicated for compounds of Formula I described herein. Thus, heterocycle 2 can be a substituted imidazole. Compound 3 is then subjected to reaction conditions b) to provide protected sulfonamide 4. Values X, Y, and R 5 of protected sulfonamide 4 can be the same as values X, Y, and R 5 of compounds of Formula I described herein, and PG is a protecting group, such as t-butyl. The portion of compounds of Formula I containing X and Y can be a benzene ring, a thiophene ring, or a thiazole ring. Reaction conditions b) can involve Suzuki cross coupling conditions. The protecting group is then removed, and the resulting sulfonamide 5 is converted to a compound of Formula I using reaction conditions d).

[0340] The reaction conditions used in a), b), and c) can vary depending on the final chemical structure to be synthesized.

[0341] For example, the following reaction conditions can be used to prepare compounds of Formula I containing an imidazole and wherein the portion containing X and Y is a benzene ring, R 5 - Z represents isobutyl and R 4 represents C1-C6 alkyl substituted with 0, 1, 2, or 3 F:

[0342] a) NaH, N,N'-dimethylformamide, 0 °C to room temperature, reaction overnight;

[0343] b) ((2-(N-tert-butyl)sulfamoyl)-5-isobutylphenyl)boronic acid, Pd(PPh3)4, K2CO3, toluene, ethanol, water, 120 °C microwave irradiation, 1 hour;

[0344] c) trifluoroacetic acid, room temperature, overnight; and

[0345] d) triethylamine, appropriate alkyl chloroformate, dichloromethane, room temperature, 2 hours.

[0346] It will be appreciated that the boronic acid of step b) can be prepared as reported in Bioorganic & Medicinal Chemistry Letters 2018, 28(3), 519-522. Alternatively, the synthesis can involve boronic esters such as MIDA derivatives or pinacol esters.

[0347] It will be appreciated that R 1 , R 2 , R 3 , R 4 , R 5 , X, Y and Z can be as described for compounds as disclosed in this document, such as compounds of formula I.

[0348] The present disclosure also provides compounds of formula 4 or 5 as described herein. Compounds of formula 4 or 5 can serve as intermediates in the preparation of compounds of formula I as described herein.

[0349] Examples

[0350] The following abbreviations are used throughout this document.

[0351] Abbreviations

[0352] ACN acetonitrile

[0353] DAST diethylaminosulfur trifluoride

[0354] DCM dichloromethane

[0355] DMA N,N'-dimethylacetamide

[0356] DMF N,N'-dimethylformamide

[0357] Dppf 1,1'-bis(diphenylphosphino)ferrocene

[0358] EA ethyl acetate

[0359] FCC flash column chromatography

[0360] h hour(s)

[0361] HFBA heptafluorobutyric acid

[0362] HLM human liver microsomes

[0363] HPLC high performance liquid chromatography

[0364] HRMS(ESI) high resolution mass spectrometry (electrospray ionization)

[0365] Hz hertz

[0366] pM picomolar

[0367] MHz megahertz

[0368] LCM liquid chromatography

[0369] LCMS liquid chromatography mass spectrometry

[0370] MIDA methyl-iminodiacetic acid

[0371] min minute

[0372] MLM mouse liver microsomes

[0373] NMR nuclear magnetic resonance

[0374] PA propionic acid

[0375] PBS phosphate buffered saline

[0376] RLM rat liver microsomes

[0377] TFA trifluoroacetic acid

[0378] Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0379] In this document, the naming of compounds is carried out using ChemDraw Professional 15.0 or ChemDraw Professional 16.0. In this document, if the chemical name is not consistent with the chemical structure, the chemical structure shall be considered correct.

[0380] SUMMARY

[0381] All chemicals and solvents were purchased from Sigma Aldrich, Fisher Scientific, FluoroChem, and Enamine and were ready for use without further purification. Microwave heating was carried out in a Biotage single-mode microwave reactor, generating controlled radiation at 2450 MHz with a power range of 0-400 W. The reaction temperature was determined and controlled using a built-in online IR sensor. The microwave-mediated reaction was carried out in diaphragm-sealed vials designed for reaction volumes of 0.5-2.0 mL, 2.0-5.0 mL, or 10-20 mL. A commercially available Isolute HM-N (diatomaceous earth) pre-packed column was used for trace water removal. Automated rapid column chromatography was performed using commercial silica gel columns on Biotage Isolera or Grace Reveleris instruments. Manual rapid chromatography was also performed on silica gel 60 (40-63 μm). Preparative reversed-phase HPLC was performed using a C18 column (Macherey-Nagel VP 125 / 21 Nucleodur C18 HTec 5 μm) and a UV (254 nm) detector and a mobile phase of 0.05% aqueous formic acid containing acetonitrile or 0.1% aqueous trifluoroacetic acid containing acetonitrile.

[0382] Electroinjection ionization (ESI) and a C18 column (50 x 3.0 mm, 2.6 μm particle size) were used. Analytical HPLC / ESI-MS was performed using a 0.05% aqueous formic acid gradient containing acetonitrile as the mobile phase at a flow rate of 1.5 mL / min. High-resolution molecular weight (HRMS) was determined on a mass spectrometer equipped with an ESI source and a 7-T hybrid linear ion trap (LTQ). Nuclear magnetic resonance (NMR) spectra were recorded on a Varian instrument, targeting [specific parameters missing]. 1 H is for 400MHz and 500MHz, targeting 13 C is 101MHz and 126MHz, and is targeted at 19 F is 376 MHz. Chemical shift (δ) is reported in ppm, with the residual solvent peak used as an internal standard. 1 H: Chloroform-d is 7.26 ppm, DMSO-d6 is 2.50 ppm, acetone-d6 is 2.05 ppm, and methanol-d4 is 3.31 ppm; 13 C: Chloroform-d is 77.2 ppm, DMSO-d6 is 39.5 ppm; 19 F: FCCl3 capillary concentration is 0.00 ppm. Coupling constants (J) are reported in Hertz (Hz). Unless otherwise specified, all final compounds are ≥95% pure, as determined by analytical HPLC and / or NMR.

[0383] The present application is illustrated by the following examples with reference to the accompanying drawings, which must in no way be considered as limiting thereof, in which: Figures 1 to 4 Col1a1 (Col1a1) levels secreted in PCLus culture supernatant at 48, 96 and 144 hours are shown for C21, Example 1A, Example 12A and Example 3. Figures 5 to 8 TGF-β1 levels secreted in PCLus culture supernatant at 48, 96 and 144 hours are shown for C21, Example 1A, Example 12A and Example 3. Figure 9 and 10 Selected gene transcript levels of Col1a1 and TGF-β1 (normalized to β-actin) at 144 hours for PCLus treated with C21, Example 1A, Example 12A and Example 3 are shown.

[0384] Preparation of starting materials for Examples 1-2

[0385] 2-tert-Butyl-1H-imidazole was purchased from Fluorochem.

[0386] N-alkylation of heterocycles

[0387] 1-[(4-Bromophenyl)methyl]-2-tert-butyl-imidazole

[0388] NaH (0.184 g, 8.0 mmol, 2 eq) was added to a stirred solution of 2-tert-butyl-1H- imidazole (0.497 g, 4.0 mmol, 1 eq) in DMF (0.27 M) at 0 °C. After 20 min, 1-bromo-4- (bromomethyl)benzene (1.05 g, 4.2 mmol, 1.05 eq) was added. The resulting mixture was allowed to warm to ambient temperature and stirred overnight, then quenched with water (15 mL). The product was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgS04, and concentrated in vacuo. The crude product was obtained without trituration (1.16 g, 0.396 mmol) in 99% yield.

[0389] Suzuki cross-coupling of MIDA boronates and N-alkylated heterocycles

[0390] N-tert-Butyl-2-[4-[(2-tert-butylimidazol-1-yl)methyl]phenyl]-4-isobutyl- benzenesulfonamide

[0391] N-(tert-butyl)-4-isobutyl-2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborinan-2-yl)benzenesulfonamide (0.441 g, 1.04 mmol, 1.04 mmol), potassium carbonate (0.083 g, 0.6 mmol, 1.5 eq) and tetrakis(triphenylphosphine)palladium(0) (0.231 g, 0.02 mmol, 0.05 eq) were suspended in toluene (0.18 M). To this mixture was added 1 -[(4-bromophenyl)methyl]-2-tert-butyl-imidazole (0.293 g, 1.0 mmol, 1 eq) in ethanol (0.5 M). Water (0.25 mL). 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 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous MgS04and concentrated. The crude product was purified by FCC (15-30% EA / Isohexane) to give the title compound as a solid in 36% yield (0.171 g, 0.355 mmol).

[0392] Deprotection of sulfonamides

[0393] 2-[4-[(2-tert-Butylimidazol-1 -yl)methyl]phenyl]-4-isobutyl-benzenesulfonamide

[0394] N-tert-Butyl-2-[4-[(2-tert-butylimidazol-1 -yl)methyl]phenyl]-4-isobutyl- benzenesulfonamide (0.135 g, 0.28 mmol) was stirred in trifluoroacetic acid (4.6 mL) at ambient temperature overnight. The reaction was diluted with water (10 mL) and the product was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous MgS04and concentrated in vacuo. The crude product sulfonamide was purified by FCC (5% MeOH / DCM) to give the product as a white amorphous solid in 86% yield (0.102 g, 0.24 mmol).

[0395] Preparation of starting materials for Examples 3-6

[0396] General procedure for the synthesis of thiazole sulfonamides

[0397] a) 2-Alkylation of 2,4-dibromothiazoles

[0398] Pd(OAc)2(0.03 mmol, 0.03 equiv) was mixed with xantphos (0.05 mmol, 0.05 equiv) in dry THF under a nitrogen atmosphere. After stirring for 5 minutes, this solution was transferred to a separate vessel containing 2,4-dibromothiazole (1.03 mmol, 1 equiv) and alkyl zinc bromide (0.5 M in THF, 1.08 mmol, 1.05 equiv) under nitrogen. The sealed vessel was heated at 80 °C for 16 hours. After cooling to room temperature, the insoluble solids were removed by filtration through a pad of celite (eluted with CH2Cl2). The filtrate was diluted with H2O (50 mL) and extracted with CH2Cl2(3 x 50 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, and concentrated in vacuo to give the crude product. The crude product was purified by FCC (0-10% ethyl acetate / isohexane) to give the corresponding product in 55-65% yield.

[0399] b) Synthesis of sulfonic acid derivatives of thiazoles

[0400] The 4-bromo-2-alkylated thiazole (1 mmol, 1 equiv) was dissolved in DMF (2 mL) and cooled to 5 °C. Chlorosulfonic acid (5 mmol, 5 equiv) was added slowly at this temperature. After this time, the mixture was stirred at 120 °C for 16 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the crude product material was purified by column chromatography (10% MeOH / DCM) to give the corresponding product.

[0401] c) Synthesis of sulfonyl chlorides from sulfonic acids

[0402] The 4-bromo-2-alkylated thiazole-5-sulfonic acid (1 mmol, 1 equiv) was dissolved in 10 mL of DCM and PCl5 (2 mmol, 2 equiv) was added slowly and the reaction mixture was stirred at 60 °C overnight. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (30 mL), brine (25 mL) and dried over anhydrous MgSO4and concentrated in vacuo. The crude product was purified by FCC (0-25% ethyl acetate / isohexane) to give the chloride intermediate in 80-95% yield.

[0403] d) Synthesis of 4-bromo-N-(tert-butyl)-2-alkylated thiazole-sulfonamides

[0404] The chloride intermediate (1 mmol, 1 eq) was dissolved in DCM (2 mL) and tert-butylamine (1.1 mmol, 1.1 eq) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then extracted with DCM (2 x 50 mL). The combined organic layers were washed with water (30 mL), brine (25 mL), and dried over anhydrous MgS04and concentrated in vacuo. The crude product was purified by FCC (0-30% ethyl acetate / isohexane) to give the corresponding sulfonamide in 90-95% yield.

[0405] N-alkylation of 2-tert-butylimidazole

[0406] 2-tert-Butylimidazole (6.0 mol, 1 eq), benzylbromide (6 mol, 1 eq), and base NaH (6 mol, 1 eq) in acetonitrile (10 mL) were stirred at room temperature overnight. The reaction was quenched with water (50 mL), extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (30 mL), brine (25 mL), and dried over anhydrous MgS04and concentrated in vacuo. The crude product was purified by FCC (50-100% ethyl acetate / isohexane) to give the N-alkylated heterocycle in 80-95% yield.

[0407] Synthesis of pinacol boronate

[0408] Pd(dppf)Cl2(0.03 mmol, 0.03 eq) was added to a mixture of 2-tert-butylimidazole (1.0 mmol, 1 eq), KOAc (3.0 mmol, 3 eq), and B2pin2(3.5 mmol, 3.5 eq) in DMF (5 mL). The mixture was stirred at 80 °C under N2for 16 h. Insoluble solids were removed by filtration through a pad of celite (eluted with CH2Cl2). The filtrate was diluted with H2O (50 mL) and extracted with CH2Cl2(3 x 50 mL). The combined organic extracts were washed with brine (30 mL), dried over MgS04and concentrated in vacuo to give the crude product. The crude product was purified by FCC (50-100% ethyl acetate / isohexane) to give the corresponding product in 80-95% yield.

[0409] General procedure for Suzuki cross-coupling of thiazole sulfonamides with boronates of N-alkylated heterocycles

[0410] Thiazole sulfonamide (1 mmol, 1 equiv), N-alkylated product (1 mmol, 1 equiv), potassium carbonate (4 mmol, 4 equiv), and Pd(dppf)Cl2(0.05 mmol, 0.05 equiv) were suspended in 1,2-dimethoxyethane (3 mL) and water (0.6 mL). The vial was sealed and the resulting reaction mixture was stirred under microwave irradiation at 120 °C for 60 min. The mixture was allowed to cool to ambient temperature and then extracted with chloroform (3 x 2 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous MgS04and concentrated. The crude product was separated by manual FCC (0-10% MeOH / DCM) to give the product in 70-85% yield.

[0411] General procedure for deprotection of sulfonamide products

[0412] The Suzuki coupling product (0.15 mmol) was stirred in trifluoroacetic acid (2.5 mL) at 50 °C overnight. The reaction was diluted with water (10 mL) and the product was extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous MgS04and concentrated. The sulfonamide was purified by a small plug of silica gel (0-5% MeOH / acetonitrile) and used in the subsequent carbamate formation reaction without further purification.

[0413] Example 1A

[0414] ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamic acid methyl ester ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)(methoxycarbonyl)amide potassium

[0415]

[0416] Methyl ((4'-((2-(tert-butyl)-lH-imidazol-l-yl)methyl)-5-isobutyl-[l,l'-biphenyl]-2- yl)sulfonyl)carbamate was synthesized as described. The crude sulfonamide (55.3 mg, 0.13 mmol, 1 equiv) was dissolved in DCM (0.05 M). Triethylamine (90 μL, 0.65 mmol, 5 equiv) and methyl chloroformate (11 μL, 0.14 mmol, 1.1 equiv) were added. The reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate (10 mL), extracted with ethyl acetate (3 x 5 mL), washed with brine (3 mL), dried over MgS04and concentrated. The crude product was purified by HPLC (30-70% ACN / water with 0.05% formic acid). The product was obtained as a white amorphous solid after lyophilization (17 mg, 27% yield). 1H NMR (500 MHz, Acetone-d6) δ 8.11 (d, J = 8.2 Hz, 1H), 7.43 (dd, J = 8.3, 1.8 Hz, 1H), 7.41 - 7.36 (m, 2H), 7.18 - 7.09 (m, 3H), 6.91 (d, J = 1.3 Hz, 1H), 6.83 (d, J = 1.3 Hz, 1H), 5.48 (s, 2H), 3.54 (s, 2H), 2.62 (d, J = 7.2 Hz, 2H), 2.02 - 1.91 (m, 1H), 1.41 (s, 9H), 0.94 (d, J = 6.6 Hz, 6H). 13 C NMR (126 MHz, 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) calculated for C 26 H 34 N3O4S + [M+H] + 484.2270, found: 484.2269.

[0417] Example 1B

[0418] ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamic acid butyl ester ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)(butoxycarbonyl)amide

[0419]

[0420] Potassium ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)(methoxycarbonyl)amide was prepared as described. To a stirred solution of methyl ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate (45.9 mg, 95 μmol, 1 equiv) in chloroform (95 μM) was added KOH (11.1 mg, 0.198 mmol, 2 equiv) in MeOH (0.59 M). The resulting solution was stirred at room temperature for 4 hours, during which time a white solid was observed to precipitate. The crude product was partially evaporated and triturated from chloroform with pentane (50 mL). The resulting solid was filtered and then dissolved in water (5 mL). The solution was filtered to ensure removal of organic residue. The product was obtained as a white amorphous solid after lyophilization in 93% yield (46.1 mg, 88 μmol). 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.0 Hz, 1H), 7.53 - 7.28 (m, 2H), 7.13 (dd, J = 8.1, 1.9 Hz, 1H), 7.02 - 6.90 (m, 3H), 6.86 (d, J = 1.8 Hz, 1H), 6.76 (d, J = 1.2 Hz, 1H), 5.38 (s, 2H), 3.15 (s, 3H), 2.46 (d, J = 7.1 Hz, 2H), 1.84 (dt, J = 13.6, 6.8 Hz, 1H), 1.34 (s, 9H), 0.87 (d, J = 6.6 Hz, 6H). LCMS calculated for C 26 H 34 N3O4S + [M+H] + 484.2, found: 484.1.

[0421] Example 2A

[0422] ((4-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazol-5-yl)sulfonyl)carbamic acid methyl ester ((4-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazol-5-yl)sulfonyl)carbamic acid butyl ester

[0423]

[0424] As described for methyl ((4'-((2-(tert-butyl)-lH-imidazol-l-yl)methyl)-5- isobutyl-[l,r-biphenyl]-2-yl)sulfonyl)carbamate, except using crude sulfonamide (21.3 mg, 50 μmol) and butyl chloroformate (8.8 μL, 69.2 μmol), synthesize butyl ((4'-((2-(tert-butyl)-lH-imidazol-l-yl)methyl)-5-isobutyl-[l,r- biphenyl]-2-yl)sulfonyl)carbamate. Purify the crude product by FCC (5% MeOH / DCM) and a small amount of preparative TLC (10% MeOH / DCM) to give the product as a white amorphous solid (5 mg, 21% yield) after trituration with isohexane from DCM. 1H NMR (400 MHz, Acetone-d6) δ 8.11 (d, J = 8.2 Hz, 1H), 7.44 (dd, J = 8.2, 1.9 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H), 7.24 - 7.00 (m, 3H), 6.88 (d, J = 1.3 Hz, 1H), 6.80 (d, J = 1.3 Hz, 1H), 5.47 (s, 2H), 3.96 (t, J = 6.5 Hz, 2H), 2.62 (d, J = 7.2 Hz, 2H), 2.03 - 1.86 (m, 1H), 1.51 - 1.39 (m, 2H), 1.28 - 1.16 (m, 2H), 0.93 (d, J = 6.6 Hz, 6H), 0.85 (t, J = 7.4 Hz, 3H). 13 C 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) calculated for C 29 H 40 N3O4S + [M+H] + 526.2740, found: 526.2731.

[0425] Example 2B

[0426] ((4-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5-yl)sulfonyl)carbamic acid methyl ester ((4-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazol-5-yl)sulfonyl)carbamic acid butyl ester Potassium

[0427]

[0428] The title compound was synthesized as described for Example IB using ((4'-((2-(tert-butyl)-lH-imidazol-l-yl)methyl)-5-isobutyl-[l,r-biphenyl]-2-yl)sulfonyl)- carbamic acid butyl ester (20.4 mg, 38.5 μmol, 1.0 equiv) and KOH in MeOH (0.59 M) (2.33 mg, 41.6 μmol, 1.08 equiv). The product was obtained as a white amorphous solid (16.5 mg, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 8.1 Hz, 1H), 7.45 - 7.35 (m, 2H), 7.12 (dd, J = 8.1, 1.8 Hz, 1H), 6.94 (dd, J = 4.7, 3.4 Hz, 3H), 6.84 (d, J = 1.8 Hz, 1H), 6.76 (d, J = 1.2 Hz, 1H), 5.37 (s, 2H), 3.54 (t, J = 6.5 Hz, 2H), 2.45 (d, J = 7.1 Hz, 2H), 1.91 - 1.74 (m, 1H), 1.34 (s, 9H), 1.30 (d, J = 6.8 Hz, 2H), 1.27 - 1.13 (m, 2H), 0.87 (d, J = 6.6 Hz, 6H), 0.83 (t, J = 7.3 Hz, 3H). LCMS calculated for C 29 H 40 N3O4S + [M+H] + 526.2734, found: 526.2.

[0429] Example 3

[0430] ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamic acid butyl ester ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)(butoxycarbonyl)amide potassium

[0431]

[0432] To a mixture of the corresponding sulfonamide (0.12 mmol, 1 equiv) and triethylamine (0.58 mmol, 5 equiv) in DCM (2 mL) was added methyl chloroformate (0.17 mmol, 1.5 equiv) dropwise over approximately 2 minutes and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was quenched with water and diluted with DCM (25 mL) and then extracted with 10% citric acid (aqueous, 20 mL), water (3 x 30 mL), and brine (20 mL) sequentially. The combined organic layers were dried over MgS04and concentrated. The crude product was purified by manual FCC (0-5% MeOH / acetonitrile) and the product was obtained as a white amorphous solid (40 mg, 71% yield). 1 H NMR (400 MHz, Acetone-d6) δ 8.26 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 1.5 Hz, 1H), 7.03 (d, J = 1.5 Hz, 1H), 5.56 (s, 2H), 3.40 (s, 3H), 2.83 (d, J = 7.1 Hz, 2H), 2.19 - 2.09 (m, 1H), 1.45 (s, 9H), 1.02 (d, J = 6.7 Hz, 6H). 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): calc. for C 23 H 31 N4O4S2 + [M+H] + 491.1781; Found: 491.1795.

[0433] Example 4

[0434] ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamic acid methyl ester ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)(methoxycarbonyl)amide potassium

[0435]

[0436] To a mixture of the corresponding sulfonamide (0.12 mmol, 1 equiv) and triethylamine (0.58 mmol, 5 equiv) in DCM (2 mL) was added dropwise butyl chloroformate (0.17 mmol, 1.5 equiv) over approximately 2 minutes and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was quenched with water and diluted with DCM (25 mL) and then extracted with 10% citric acid (aqueous, 20 mL), water (3 x 30 mL), and brine (20 mL) sequentially. The combined organic layers were dried over MgS04and concentrated. The crude product was purified by manual FCC (0-5% MeOH / acetonitrile) and the product was obtained as a white amorphous solid (39 mg, 63% yield). 1 HNMR (400 MHz, Chloroform-d) δ 7.98 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 1.5 Hz, 1H), 6.80 (d, J = 1.5 Hz, 1H), 5.30 (s, 2H), 3.81 (t, J = 6.8 Hz, 2H), 2.77 (d, J = 7.1 Hz, 2H), 2.15 - 2.04 (m, 1H), 1.44 - 1.40 (m, 11H), 1.23 - 1.14 (m, 2H), 0.97 (d, J = 6.6 Hz, 6H), 0.80 (t, J = 7.3 Hz, 3H). 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): calc. for C 26 H 37 N4O4S2 + [M+H] + 533.2251; found: 533.2241.

[0437] Example 5

[0438] ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamic acid butyl ester ​

[0439]

[0440] To a mixture of sulfonamide (0.12 mmol, 1 equiv) and triethylamine (0.60 mmol, 5 equiv) in DCM (2 mL) was added methyl chloroformate (0.14 mmol, 1.2 equiv) dropwise over approximately 2 minutes and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was quenched with water and diluted with DCM (25 mL) and then extracted with 10% citric acid (aqueous, 20 mL), water (3 x 30 mL), and brine (20 mL) sequentially. The combined organic layers were dried over MgS04and concentrated. The crude product was purified by manual FCC (0-5% MeOH / acetonitrile) and the product was obtained as a white amorphous solid (28 mg, 49% yield). 1 H NMR (400 MHz, Acetone-d6) δ 8.12 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 3.7 Hz, 2H), 7.01 - 6.96 (m, 2H), 5.47 (s, 2H), 5.23 (s, 1H), 3.27 (s, 3H), 2.79 (t, J = 7.2 Hz, 2H), 1.77 - 1.60 (m, 2H), 1.34 (s, 9H), 0.89 (t, J = 7.4 Hz, 3H). 13 C 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): calc. for C 22 H 29 N4O4S2+ [M+H] + 477.1625; Found: 477.1631.

[0441] Example 6

[0442] ​ ​

[0443]

[0444] To a mixture of the corresponding sulfonamide (0.12 mmol, 1 equiv) and triethylamine (0.60 mmol, 5 equiv) in DCM (2 mL) was added butyl chloroformate (0.14 mmol, 1.2 equiv) dropwise over approximately 2 minutes and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was quenched with water and diluted with DCM (25 mL) and then extracted with 10% citric acid (aqueous, 20 mL), water (3 x 30 mL), and brine (20 mL) sequentially. The combined organic layers were dried over MgS04and concentrated. The crude product was purified by manual FCC (0-5% MeOH / acetonitrile) and the product was obtained as a white amorphous solid (43 mg, 69% yield). 1 HNMR (400 MHz, Acetone-d6) δ 8.26 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 1.5 Hz, 1H), 6.97 (d, J = 1.5 Hz, 1H), 5.86 (s, 1H), 5.54 (s, 2H), 3.84 (t, J = 6.6 Hz, 2H), 2.92 (t, J = 7.6 Hz, 2H), 1.88 - 1.76 (m, 2H), 1.48 - 1.43 (m, 11H), 1.32 - 1.23 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H). 13 C 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): calc. for C 25 H 35 N4O4S2 + [M+H] + 519.2094; Found: 519.2096.

[0445] Example 7A

[0446] ​ ​

[0447]

[0448] To a stirred solution of the corresponding sulfonamide (74.3 mg, 0.156 mmol) and triethylamine (108.6 μL, 0.78 mmol, 5 equiv) in DCM (1.0 mL) was added butyl chloroformate (27.5 μL, 0.216 mmol) at room temperature. After 20 min, the reaction was quenched with water (2 mL). The crude product was extracted with DCM (3 x 5 mL), washed with brine (5 mL), dried over anhydrous MgS04and concentrated. The crude product was purified by FCC (5% MeOH / DCM) to give the product as a white amorphous solid in 47% yield (39 mg, 73.5 μmol). 1 H NMR (400 MHz, Acetone-d6) δ 8.11 (d, J = 8.2 Hz, 1H), 7.43 (dd, J = 8.2, 1.8 Hz, 1H), 7.38 - 7.29 (m, 2H), 7.29 - 7.23 (m, 2H), 7.14 (d, J = 1.8 Hz, 1H), 6.89 (d, J = 1.3 Hz, 1H), 6.77 (d, J = 1.3 Hz, 1H), 5.65 (s, 2H), 3.96 (t, J = 6.5 Hz, 2H), 2.62 (d, J = 7.2 Hz, 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 = 6.6 Hz, 6H), 0.85 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, 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) calculated for C 28 H 38 N3O5S + [M+H] + 528.2532, found: 528.2526.

[0449] Example 7B

[0450] ​ ​

[0451]

[0452] To a stirred solution of butyl ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)-5- isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate (39 mg, 73.9 pmol) in chloroform was added KOH (4.47 mg, 79.8 pmol) in MeOH. The resulting solution was stirred at room temperature for 4 hours, during which time a white solid was observed to precipitate. The crude product was partially evaporated and triturated from chloroform with pentane (50 mL). The resulting solid was filtered and then dissolved in water (5 mL). The solution was filtered to ensure removal of organic residues. The product was obtained as a white amorphous solid in 99% yield (41.5 mg, 73.4 pmol). 1 H NMR (400 MHz, DMSO-d6) d 7.86 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.11 (t, J = 8.1 Hz, 3H), 6.93 (d, J = 1.3 Hz, 1H), 6.85 (d, J = 1.8 Hz, 1H), 6.74 (d, J = 1.2 Hz, 1H), 5.53 (s, 2H), 5.42 (s, 1H), 3.54 (t, J = 6.5 Hz, 2H), 2.49 - 2.42 (m, 2H), 1.90 - 1.73 (m, 1H), 1.52 (s, 6H), 1.39 - 1.26 (m, 2H), 1.27 - 1.13 (m, 2H), 0.87 (d, J = 6.6 Hz, 6H), 0.83 (t, J = 7.3 Hz, 3H).

[0453] Example 8A

[0454] ​ ​

[0455]

[0456] Butyl ((4'-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'- biphenyl]-2-yl)sulfonyl)carbamate (16.2 mg, 30.7 pmol) was stirred under MW irradiation in MeOH (1 mL) at 120 degrees (7 bar pressure) for 20 minutes. The crude product was purified by FCC (2-4% MeOH / DCM) to give the product as a white amorphous solid (14.7 mg, 99% yield). 1H NMR (400 MHz, Acetone-d6) δ 8.12 (d, J = 8.2 Hz, 1H), 7.42 (dd, J = 8.2, 1.8 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.25 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 1.8 Hz, 1H), 6.90 (d, J = 1.3 Hz, 1H), 6.77 (d, J = 1.3 Hz, 1H), 5.89 (s, 1H), 5.65 (s, 2H), 3.54 (s, 3H), 2.61 (d, J = 7.2 Hz, 2H), 2.02 - 1.84 (m, 1H), 1.63 (s, 6H), 0.92 (d, J = 6.6 Hz, 6H). 13 C NMR (101 MHz, 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 + ) calcd. for C 25 H 32 N3O5S + [M+H] + 486.2063, found 486.2060.

[0457] Example 8B

[0458] ​ ​

[0459]

[0460] The title compound was synthesized as described for ((4'-((2-(2- hydroxypropan-2-yl)-lH-imidazol-l-yl)methyl)-5-isobutyl-[l,l'-biphenyl]-2- yl)sulfonyl)amino)methyl dihydrogen phosphate using ((4'-((2-(2- hydroxypropan-2-yl)-lH-imidazol-l-yl)methyl)-5-isobutyl-[l,l'-biphenyl]-2- yl)sulfonyl)amino)methyl dihydrogen phosphate (15.7 mg, 30.2 μmol) and KOH (1.83 mg, 32.7 μmol). The product was obtained as a white amorphous solid (15.7 mg, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.16 - 7.06 (m, 3H), 6.94 (d, J = 1.3 Hz, 1H), 6.86 (d, J = 1.8 Hz, 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 = 7.1 Hz, 2H), 2.02 - 1.74 (m, 1H), 1.52 (s, 6H), 0.87 (d, J = 6.6 Hz, 6H).

[0461] Example 9A

[0462] ​ ​

[0463]

[0464] The title compound was synthesized as described for ((4'-((2-(2-hydroxypropan-2-yl)-lH- imidazol-l-yl)methyl)-5-isobutyl-[l,l'-biphenyl]-2-yl)sulfonyl)carbamic acid butyl ester using the corresponding sulfonamide (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 (400 MHz, Acetone-d6) δ 8.14 (d, J = 8.2 Hz, 1H), 7.46 (dd, J = 8.2, 1.9 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.26 - 7.11 (m, 3H), 6.92 (d, J = 1.4 Hz, 1H), 6.83 (d, J = 1.4 Hz, 1H), 5.50 (s, 2H), 3.97 (t, J = 6.5 Hz, 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 = 7.3 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, 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+ )Calcd: C 28 H 38 N3O4S + [M+H] + : 512.2583; Found: 512.2577.

[0465] Example 9B

[0466] (butoxycarbonyl)((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl] [2-yl)sulfonyl)amide potassium

[0467]

[0468] The title compound was synthesized as described for ((butoxycarbonyl)((4'-((2-(2- hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)amino)methyl dihydrogen phosphate potassium salt using ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5- propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamic acid butyl ester (18.8 mg, 36.4 μmol) and KOH (2.20 mg, 39.3 μmol). 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 7.16 (dd, J = 8.1, 1.8 Hz, 1H), 6.96 - 6.92 (m, 3H), 6.88 (d, J = 1.8 Hz, 1H), 6.76 (d, J = 1.3 Hz, 1H), 5.37 (s, 2H), 3.54 (t, J = 6.5 Hz, 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 = 7.3 Hz, 3H), 0.83 (t, J = 7.3 Hz, 3H).

[0469] Example 10A

[0470] ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl Methyl carbamate

[0471]

[0472] The title compound was synthesized as described for ((4'-((2-(2- hydroxypropan-2-yl)-lH-imidazol-l-yl)methyl)-5-isobutyl-[l,l'-biphenyl]-2-yl)sulfonyl)carbamic acid methyl ester using ((4'-((2-(tert-butyl)-lH-imidazol-l-yl)methyl)-5- propyl-[l,l'-biphenyl]-2-yl)sulfonyl)carbamic acid butyl ester (18.8 mg, 33.3 μmol). The crude product was concentrated and purified by FCC (4-6% MeOH / CH2Cl2) to give the product as a white amorphous solid (41.5 mg, 86% yield). 1 H NMR (400 MHz, Acetone-d6) δ 8.12 (d, J = 8.2 Hz, 1H), 7.49 (s, br., 1H), 7.44 (dd, J = 8.2, 1.9 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.21 - 7.04 (m, 3H), 6.91 (d, J = 1.4 Hz, 1H), 6.83 (d, J = 1.4 Hz, 1H), 5.49 (s, 2H), 3.53 (s, 3H), 2.71 (dd, J = 8.6, 6.7 Hz, 2H), 1.81 - 1.60 (m, 2H), 1.42 (s, 9H), 0.95 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, 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 + ) calcd for C 25 H 32 N3O4S + [M+H] + : 470.2114; found: 470.2115.

[0473] Example 10B

[0474] ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl Potassium (methoxycarbonyl)amide

[0475]

[0476] The title compound was synthesized as described for (butoxy carbonyl)((4'-((2-(2- hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide potassium using ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'- biphenyl]-2-yl)sulfonyl)carbamic acid methyl ester (42.4 mg, 89.4 μmol) and KOH (5.41 mg, 96.5 μmol). The product was obtained as a white amorphous solid (42.2 mg, 93% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.16 (dd, J = 8.1, 1.9 Hz, 1H), 7.05 - 6.91 (m, 3H), 6.89 (d, J = 1.8 Hz, 1H), 6.77 (d, J = 1.2 Hz, 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 = 7.3 Hz, 3H).

[0477] Example 11A

[0478] ((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl) Butyl carbamate

[0479]

[0480] The title compound was synthesized as described for (butoxy carbonyl)((4'-((2-(2- hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide potassium using ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'- biphenyl]-2-yl)sulfonyl)carbamic acid methyl ester (42.4 mg, 89.4 μmol) and KOH (5.41 mg, 96.5 μmol). The product was obtained as a white amorphous solid (42.2 mg, 93% yield). 1H NMR (400 MHz, Acetone-d6) δ 7.79 - 7.66 (m, 2H), 7.12 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 1.5 Hz, 1H), 6.95 - 6.79 (m, 2H), 5.54 (s, 2H), 2.72 (d, J = 7.1 Hz, 2H), 2.00 - 1.87 (m, 6.7 Hz, 1H), 1.54 - 1.44 (m, 2H), 1.43 (s, 9H), 1.32 - 1.18 (m, 4H), 0.99 (d, J = 6.6 Hz, 6H), 0.86 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, 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 + ) calcd. for C 27 H 38 N3O4S2 + [M+H] + 532.2304, found 532.2300.

[0481] Example 11B

[0482] (butoxycarbonyl)((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene- 2-yl)sulfonyl)amide potassium

[0483]

[0484] The title compound was synthesized as described for ((4'-((2-(2- hydroxypropan-2-yl)-lH-imidazol-l-yl)methyl)-5-isobutyl-[l,l'-biphenyl]-2- yl)sulfonyl)amino)methyl dihydrogen phosphate, using ((3-(4-((2-(tert-butyl)-lH- imidazol-l-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid butyl ester (33.1 mg, 67 μmol, 1.0 equiv) and KOH (4.06 mg, 72.3 μmol, 1.08 equiv) in MeOH (0.59 M). The product was obtained as a white amorphous solid (29.7 mg, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 8.3 Hz, 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 = 6.9 Hz, 6H), 1.91 - 1.70 (m, 1H), 1.31 (s, 9H), 0.93 (d, J = 6.6 Hz, 6H).

[0485] Example 12A

[0486] ((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl) Methyl carbamate

[0487]

[0488] Butyl ((3-(4-((2-(tert-butyl)-lH-imidazol-l-yl)methyl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamate (45.8 mg, 86.1 μmol) was stirred in MWI at 120 °C (7 bar pressure) in MeOH (1 mL) for 20 min. The crude product was concentrated and purified by FCC (5% MeOH / DCM) to give the product as a white amorphous solid (35.7 mg, 85% yield). 1 H NMR (400 MHz, Methanol-d4) δ 7.65 (d, J = 8.3 Hz, 2H), 7.21 - 7.03 (m, 4H), 6.74 (s, 1H), 5.51 (s, 2H), 3.47 (s, 3H), 2.73 - 2.61 (m, 2H), 1.97 - 1.83 (m, 1H), 1.50 (s, 9H), 0.97 (d, J = 6.6 Hz, 6H). 13 C 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 + ) calcd for C 24 H 33 N3O4S2 + [M+H] + 490.1834, found 490.1838.

[0489] Example 12B

[0490] ((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl) (methoxycarbonyl)amide potassium

[0491]

[0492] The title compound was synthesized as described for ((3-(4-((2-(tert-butyl)-1H- imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid methyl ester using ((3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)-5- isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)oxy)acetic acid (33.1 mg, 67 μmol, 1.0 eq) and KOH in MeOH (0.59 M) (4.06 mg, 72.3 μmol, 1.08 eq). The product was obtained as a white amorphous solid (29.7 mg, 87% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 8.3 Hz, 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 = 6.9 Hz, 6H), 1.91 - 1.70 (m, 1H), 1.31 (s, 9H), 0.93 (d, J = 6.6 Hz, 6H).

[0493] Example 13

[0494] ((3-(4-((1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)(butoxycarbonyl) sodium amide

[0495]

[0496] A solution of butyl ((3-(4-((1H-imidazol-1-yl)methyl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamate (100 g, 0.210 mol) in dichloromethane (380 mL) was filtered through celite beads. To the filtrate was added a solution of 3.3% NaOH in methanol (198 g) at 25-30 °C and stirred at the same temperature for 1 hour. The above solution was concentrated to get approximately 200 mL and the residue was cooled to 25-30 °C and added 1.46 L of isopropyl. The resulting solution was concentrated to get approximately 400 mL of an oily syrup. Heptane (1.18 L) was added slowly to the oily syrup with stirring. The obtained solid was filtered and washed with heptane (200 mL). The solid salt was dried below 50 °C for 8 hours to get 85% yield (89 g, 0.178 mol) of sodium ((3-(4-((1H-imidazol-1-yl)methyl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)(butyloxy carbonyl)amide (C21) as a white solid with HPLC purity >98%.

[0497] Example 14

[0498] ((4-(4-((2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazolyl-5-yl)sulfonyl Acyl) butyl carbamate

[0499]

[0500] The title compound was synthesized as described for methyl ((4-(4-((2-(tert-butyl)-lH- imidazol-l-yl)methyl)phenyl)-2-isobutylthiazol-5-yl)sulfonyl)carbamate, using the corresponding sulfonamide (0.16 mmol, 1 equiv) and triethylamine (0.8 mmol, 5 equiv), except that the mixture was kept on dry ice, where butyl chloroformate (0.2 mmol, 1.2 equiv) was added dropwise over approximately 2 minutes, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% MeOH / acetonitrile) and the product was obtained as a white amorphous solid (48 mg, 55% yield). 1 H NMR (400 MHz, Methanol-d4) δ 7.81 (d, J = 8.4 Hz, 2H), 7.27 - 7.16 (m, 4H), 5.63 (s, 2H), 3.78 (t, J = 6.5 Hz, 2H), 2.89 (dd, J = 8.0, 7.2 Hz, 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 = 7.4 Hz, 3H), 0.77 (t, J = 7.4 Hz, 3H). 13 C 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): calc. for C 24 H 33 N4O5S2 + [M+H] + 521.1887; found: 521.1879.

[0501] Example 15

[0502] ((4-(4-(((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazolyl-5-yl)sulfonyl)amino Butyl formate

[0503]

[0504] The title compound was synthesized as described for methyl ((4-(4-((2-(tert-butyl)-lH- imidazol-l-yl)methyl)phenyl)-2-isobutylthiazol-5-yl)sulfonyl)carbamate, using the corresponding sulfonamide (0.17 mmol, 1 equiv) and triethylamine (0.86 mmol, 5 equiv), except that the mixture was kept on dry ice, where butyl chloroformate (0.2 mmol, 1.2 equiv) was added dropwise over approximately 2 minutes, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% MeOH / acetonitrile) and the product was obtained as a white amorphous solid (51 mg, 58% yield). 1 H NMR (400 MHz, Acetone-d6) δ 8.32 - 8.19 (m, 2H), 7.8 - 7.16 (m, 3H), 7.01 (d, J = 1.5 Hz, 1H), 5.34 (s, 2H), 3.83 (t, J = 6.7 Hz, 2H), 3.26 - 3.18 (m, 1H), 2.97 - 2.85 (m, 2H), 1.80 (dt, J = 15.3, 7.6 Hz, 2H), 1.56 - 1.38 (m, 2H), 1.37 - 1.17 (m, 8H), 1.02 (t, J = 7.4 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H). 13 C 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): calc. for C 24 H 33 N4O4S2 + [M+H] + 505.1938; Found: 505.1930.

[0505] Example 16

[0506] ((2-Isobutyl-4-(4-((2-(thiazo-2-yl)-1H-imidazol-1-yl)methyl)phenyl)thiazo-5-yl)sulfonyl (B-) butyl carbamate

[0507]

[0508] The title compound was synthesized as described for methyl ((4-(4-((2-(tert-butyl)-lH- imidazol-l-yl)methyl)phenyl)-2-isobutylthiazol-5-yl)sulfonyl)carbamate, using the corresponding sulfonamide (0.11 mmol, 1 equiv) and triethylamine (0.54 mmol, 5 equiv), except that the mixture was kept on dry ice, where butyl chloroformate (0.13 mmol, 1.2 equiv) was added dropwise over approximately 2 minutes, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% MeOH / acetonitrile) and the product was obtained as a white amorphous solid (31 mg, 51% yield). 1 H NMR (400 MHz, Acetone-d6) δ 7.97 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 3.3 Hz, 1H), 7.62 (d, J = 3.3 Hz, 1H), 7.37 (d, J = 1.2 Hz, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.11 (d, J = 1.2 Hz, 1H), 6.02 (s, 2H), 3.97 (t, J = 6.5 Hz, 2H), 2.92 (d, J = 7.1 Hz, 2H), 2.16 (dt, J = 13.5, 6.8 Hz, 1H), 1.52 - 1.42 (m, 2H), 1.30 - 1.19 (m, 2H), 1.03 (d, J = 6.6 Hz, 6H), 0.86 (t, J = 7.4 Hz, 3H). 13 C 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): calc. for C 25 H 30 N5O4S3 + [M+H] + 560.1454; found: 560.1453.

[0509] Example 17

[0510] ((4-(4-((2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl) sulfonyl)carbamate butyl ester

[0511]

[0512] The title compound was synthesized as described for methyl ((4-(4-((2-(tert-butyl)-lH- imidazol-l-yl)methyl)phenyl)-2-isobutylthiazol-5-yl)sulfonyl)carbamate, using the corresponding sulfonamide (0.18 mmol, 1 equiv) and triethylamine (0.9 mmol, 5 equiv), except that the mixture was kept on dry ice, where butyl chloroformate (0.22 mmol, 1.2 equiv) was added dropwise over approximately 2 minutes, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified by manual FCC (0-5% MeOH / acetonitrile) and the product was obtained as a white amorphous solid (51 mg, 52% yield). 1 H NMR (400 MHz, Methanol-d4) δ 7.94 (d, J = 8.4 Hz, 2H), 7.37 - 7.28 (m, 4H), 5.75 (s, 2H), 3.90 (t, J = 6.5 Hz, 2H), 2.90 (d, J = 7.2 Hz, 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 = 6.7 Hz, 6H), 0.89 (t, J = 7.4 Hz, 3H). 13 C 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): calc. for C 19 H 22 N4O4S2[M+H] + 435.1155; found: 435.1174. HRMS (ESI): calc. for C 25 H 35 N4O5S2 + [M+H] + 535.2043; found: 535.2035.

[0513] Example 18

[0514] ((2-Isobutyl-4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)thiazolyl-5-yl)sulfonyl)amino Butyl carbamate

[0515]

[0516] As described for butyl carbamate ((4-(4-(((2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazolyl-5-yl)sulfonyl)carbamate), the title compound was synthesized using the corresponding sulfonamide (80.0 mg, 0.191 mmol) and butyl chloroformate (29.6 μL, 0.232 mmol). The crude product was purified by FCC (0-5% MeOH / MeCN) to give the product as a white amorphous solid (51 mg, 51% yield). 1 ¹H NMR (400MHz, acetone-d6) δ 8.26 (d, J = 8.4 Hz, 2H), 7.20–7.19 (m, 3H), 7.05 (d, J = 1.4 Hz, 1H), 5.36 (s, 2H), 3.83 (t, J = 6.7 Hz, 2H), 3.30–3.18 (m, 1H), 2.83 (d, J = 7.1 Hz, 2H), 2.20–2.08 (m, 1H), 1.49–1.40 (m, 2H), 1.33–1.21 (m, 8H), 1.02 (d, J = 6.6 Hz, 6H), 0.86 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, 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) + ): Calculated value: C 25 H 35 N4O4S2 + [M+H] + 519.2094; Measured value: 519.2084.

[0517] Example 19

[0518] ((4-(4-((2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl) methyl sulfonyl carbamate

[0519]

[0520] As described for methyl ((4-(4-(((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding sulfonamide (0.13 mmol, 1 equivalent) and triethylamine (0.69 mmol, 5 equivalent), except that the mixture was kept on dry ice, with methyl chloroformate (0.16 mmol, 1.2 equivalent) added dropwise over approximately 2 minutes, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified manually by FCC (0–5%, MeOH / acetonitrile) to give a product as a white amorphous solid (41 mg, 60% yield). 1 H NMR (400MHz, methanol-d4) δ7.81(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 C NMR (101MHz, 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): Calculated values: C 22 H 29 N4O5S2 + [M+H] + 493.1574; Measured value: 493.1566.

[0521] Example 20

[0522] ((2-Isobutyl-4-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)thiazolyl-5-yl)sulfonyl)amino Methyl carbamate

[0523]

[0524] As described for methyl ((4-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding sulfonamide (0.16 mmol, 1 equivalent) and triethylamine (0.83 mmol, 5 equivalent), except that the mixture was held on dry ice, with methyl chloroformate (0.2 mmol, 1.2 equivalent) added dropwise over approximately 2 minutes, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified manually by FCC (0–5%, MeOH / acetonitrile) to give a product as a white amorphous solid (41 mg, 51% yield). 1 H NMR (400MHz, methanol-d4) δ7.85(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 C NMR (101MHz, 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): Calculated values: C 22 H 29 N4O4S2 + [M+H] + 477.1625; Measured value: 477.1618.

[0525] Example 21

[0526] ((2-propyl-4-(4-((2-(thiazo-2-yl)-1H-imidazol-1-yl)methyl)phenyl)thiazo-5-yl)sulfonyl (B-) butyl carbamate

[0527]

[0528] As described for methyl ((4-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding sulfonamide (0.11 mmol, 1 equivalent) and triethylamine (0.56 mmol, 5 equivalent), except that the mixture was kept on dry ice, with butyl chloroformate (0.14 mmol, 1.2 equivalent) added dropwise over approximately 2 minutes, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified manually by FCC (0-5% MeOH / acetonitrile) to give a product as a white amorphous solid (37 mg, 60% yield). 1 H NMR (400MHz, acetone-d6) δ7.95 (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),6.0 3(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). 13 C NMR (101 MHz, 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): Calculated values: C 24 H 28 N5O4S3 + [M+H] + 546.1298; Measured value: 546.1295.

[0529] Example 22

[0530] ((4-(4-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl (B-) butyl carbamate

[0531]

[0532] As described for methyl ((4-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding sulfonamide (0.13 mmol, 1 equivalent) and triethylamine (0.68 mmol, 5 equivalent), except that the mixture was held on dry ice, with butyl chloroformate (0.16 mmol, 1.2 equivalent) added dropwise over approximately 2 minutes, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified manually by FCC (0–5%, MeOH / acetonitrile) to give a product as a white amorphous solid (44 mg, 64% yield). 1 H NMR (400MHz, acetonitrile-d3) δ8.04(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,2H),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 C 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): Calculated values: C 24 H 33 N4O5S2 + [M+H] + 521.1887; Measured value: 521.1891.

[0533] Example 23

[0534] ((4-(4-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl Methyl carbamate

[0535]

[0536] As described for methyl ((4-(4-(((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding sulfonamide (0.13 mmol, 1 equivalent) and triethylamine (0.65 mmol, 5 equivalent), except that the mixture was held on dry ice, with methyl chloroformate (0.16 mmol, 1.2 equivalent) added dropwise over approximately 2 minutes, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified manually by FCC (0–5%, MeOH / acetonitrile) to give a product as a white amorphous solid (31 mg, 49% yield). 1 H NMR (400MHz, acetone-d6) δ8.06(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 C 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): Calculated values: C 21 H 27 N4O5S2 + [M+H] + 479.1417; Measured value: 479.1418.

[0537] Example 24

[0538] ((4-(4-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazolyl-5-yl)sulfonyl) Butyl carbamate

[0539]

[0540] As described for methyl ((4-(4-(((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding sulfonamide (0.14 mmol, 1 equivalent) and triethylamine (0.68 mmol, 5 equivalent), except that the mixture was held on dry ice, with butyl chloroformate (0.16 mmol, 1.2 equivalent) added dropwise over approximately 2 minutes, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified manually by FCC (0–5%, MeOH / acetonitrile) to give a product as a white amorphous solid (38 mg, 55% yield). 1 H NMR(400MHz, methanol-d4)δ7.95(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 C NMR (101MHz, 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): Calculated values: C 23 H 31 N4O5S2 + [M+H] + 507.1730; Measured value: 507.1735.

[0541] Example 25

[0542] ((4-(4-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazolyl-5-yl)sulfonyl) Methyl carbamate

[0543]

[0544] As described for methyl ((4-(4-(((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding sulfonamide (0.13 mmol, 1 equivalent) and triethylamine (0.68 mmol, 5 equivalent), except that the mixture was kept on dry ice, with methyl chloroformate (0.16 mmol, 1.2 equivalent) added dropwise over approximately 2 minutes, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified manually by FCC (0–5%, MeOH / acetonitrile) to give a product as a white amorphous solid (31 mg, 49% yield). 1 H NMR (400MHz, DMSO-d6) δ8.13(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): Calculated values: C 20 H 25 N4O5S2 + [M+H] + 465.1261; Measured value: 465.1267.

[0545] Example 26

[0546] ((4-(4-((2-Cyclopropyl-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)amino Methyl carbamate

[0547]

[0548] As described for methyl ((4-(4-(((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding sulfonamide (0.12 mmol, 1 equivalent) and triethylamine (0.60 mmol, 5 equivalent), except that the mixture was kept on dry ice, with methyl chloroformate (0.14 mmol, 1.2 equivalent) added dropwise over approximately 2 minutes, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified manually by FCC (0–5%, MeOH / acetonitrile) to give a product as a white amorphous solid (31 mg, 54% yield). 1 H NMR (400MHz, methanol-d4) δ7.98(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,1 H),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 C NMR (101MHz, 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): Calculated values: C 22 H 27 N4O4S2 + [M+H] + 475.1468; Measured value: 475.1457.

[0549] Example 27

[0550] ((4-(4-((2-Cyclopropyl-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)amino Butyl carbamate

[0551]

[0552] As described for methyl ((4-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding sulfonamide (0.12 mmol, 1 equivalent) and triethylamine (0.60 mmol, 5 equivalent), except that the mixture was held on dry ice, with methyl chloroformate (0.15 mmol, 1.2 equivalent) added dropwise over approximately 2 minutes, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified manually by FCC (0–5%, MeOH / acetonitrile) to give a product as a white amorphous solid (38 mg, 61% yield). 1 H NMR (400MHz, methanol-d4) δ7.97(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): Calculated values: C 25 H 33 N4O4S2 + [M+H] + 517.1938; Measured value: 517.1950.

[0553] Example 28

[0554] ((4-(4-((2-Cyclopropyl-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazolyl-5-yl)sulfonyl)amino Methyl formate

[0555]

[0556] As described for methyl ((4-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding sulfonamide (0.15 mmol, 1 equivalent) and triethylamine (0.73 mmol, 5 equivalent), except that the mixture was kept on dry ice, with methyl chloroformate (0.15 mmol, 1.2 equivalent) added dropwise over approximately 2 minutes, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified manually by FCC (0–5%, MeOH / acetonitrile) to give a product as a white amorphous solid (41 mg, 60% yield). 1 H NMR (400MHz, methanol-d4) δ7.97(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 C NMR (101MHz, 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): Calculated values: C 21 H 25 N4O4S2 + [M+H] + 461.1312; Measured value: 461.1309.

[0557] Example 29

[0558] ((4-(4-((2-Cyclopropyl-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazolyl-5-yl)sulfonyl)amino Butyl formate

[0559]

[0560] As described for methyl ((4-(4-(((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding sulfonamide (0.15 mmol, 1 equivalent) and triethylamine (0.74 mmol, 5 equivalent), except that the mixture was held on dry ice, with methyl chloroformate (0.15 mmol, 1.2 equivalent) added dropwise over approximately 2 minutes, and the reaction mixture was stirred on dry ice for 10 minutes. The crude product was purified manually by FCC (0–5%, MeOH / acetonitrile) to give a product as a white amorphous solid (44 mg, 59% yield). 1 H NMR (400MHz, methanol-d4) δ7.97(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 C NMR (101MHz, 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): Calculated values: C 24 H 31 N4O4S2 + [M+H] + 503.1781; Measured value: 503.1778.

[0561] Example 30A

[0562] ((4'-((2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2- methyl carbamate (sulpho)

[0563]

[0564] As described for methyl ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding butyl carbamate (17.7 mg, 34.6 μmol), and the title compound was purified by FCC (2-4% MeOH / CH2Cl2) to give the product (15.6 mg, 96%) as a white amorphous solid. 1 H NMR (400MHz, methanol-d4) δ8.05(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 C 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) + Calculated value: C 27 H 36 N3O5S + [M+H] + 472.1901; Measured value: 472.1897.

[0565] Example 30B

[0566] (methoxycarbonyl)((4'-((2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'- [Biphenyl]-2-yl)sulfonyl)amide potassium

[0567]

[0568] As described for potassium butoxycarbonyl)((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide, the title compound was synthesized using the corresponding methyl carbamate (13.3 mg, 28 μmol) and KOH (1.70 mg, 30.2 μmol). The product was given as a white amorphous solid (14.3 mg, >99% yield). 1HNMR(400MHz,DMSO-d6)δ7.86(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),6.8 9(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).

[0569] Example 31A

[0570] ((4'-((2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2- butyl carbamate (sulfonyl)

[0571]

[0572] As described for methyl ((4-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding sulfonamide (74.3 mg, 0.156 mmol) and butyl chloroformate (27.5 μL, 0.216 mmol). The crude product was purified by FCC (5% MeOH / DCM) to give the product as a white amorphous solid (39 mg, 47% yield). 1 H NMR (400MHz, acetone-d6) δ8.10(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,6 H),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). 13C NMR (101 MHz, 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) + Calculated value: C 27 H 36 N3O5S + [M+H] + 514.2370; Measured value: 514.2371.

[0573] Example 31B

[0574] (butoxycarbonyl)((4'-((2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'- [Biphenyl]-2-yl)sulfonyl)amide potassium

[0575]

[0576] As described for potassium butoxycarbonyl)((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide, the title compound was synthesized using the corresponding butyl carbamate (15.0 mg, 29.0 μmol) and MeOH (1.0 mL) containing KOH (1.76 mg, 31.3 μmol). The product (15.7 mg, 99% yield) was obtained as a white amorphous solid. 1 H NMR(400MHz,DMSO-d6)δ7.86(d,J=8.1Hz,1H),7.53–7.34(m,2H),7.15(dd,J=8.1,1.9Hz,1H ),7.10(d,J=8.1Hz,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),1.5 2(s,6H),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).

[0577] Example 32

[0578] ((4'-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2- butyl carbamate (sulfonyl)

[0579]

[0580] 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 equivalent) was added dropwise. The reaction mixture was stirred for 2 hours while maintaining a temperature below -20 °C. The reaction was quenched with water, extracted with CH₂Cl₂ (3 x 5 mL), washed with brine (5 mL), dried over Na₂SO₄, and concentrated. The crude product was purified by preparative HPLC (30–70% MeCN / water, with 0.05% formic acid additive) to give a product as a white amorphous solid (6.20 mg, 36%). 1 ¹H NMR (400MHz, methanol-d⁴) δ 8.06 (d, J = 8.2 Hz, 1H), 7.42–7.25 (m, 3H), 7.25–7.14 (m, 2H), 7.10–7.06 (m, 1H), 7.03 (d, J = 1.6 Hz, 1H), 6.94 (d, J = 1.4 Hz, 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 C 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) + ): Calculated value: C 28 H 37N3O4S + [M+H] + 530.2489; Measured value: 530.2482.

[0581] Example 33A

[0582] ((5-Isobutyl-4'-((2-(thiazo-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-yl) methyl sulfonyl carbamate

[0583]

[0584] As described for methyl ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding butyl carbamate (18.8 mg, 34.0 μmol). The crude product was concentrated and purified by FCC (4-6% MeOH / CH2Cl2) to give the product as a white amorphous solid (17.3 mg, 90% yield). 1 H NMR a (400MHz, methanol-d4) δ8.06(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=1.3Hz,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)δ159.6,152.7,148.5,144.1,141.5,141.0,139.6,137.3,135.3,134.0,130.9,130.3,129.5,129.1,127.7,124.3,121.0,53.4,51.2,45.6,30.7,22.6.HRMS(ESI) + Calculated value: C 25 H 27 N4O4S2 + [M+H] + 511.1471; Measured value: 511.1480.

[0585] [a] Spectrum recorded in a mixture of MeOD and CDCl3.

[0586] Example 33B

[0587] (methoxycarbonyl)((5-isobutyl-4'-((2-(thiazo-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-bin [Phenyl]-2-yl)sulfonyl)amide potassium

[0588]

[0589] As described for potassium ((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)(methoxycarbonyl)amide, the title compound was synthesized using methyl ((5-isobutyl-4'-((2-(thiazol-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate (107 mg, 0.261 mmol) and butyl chloroformate (45.8 μL, 0.360 mmol). The product (48 mg, 36%) was obtained as a white amorphous solid. 1 HNMR (400MHz, DMSO-d6) δ7.96(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=8.0 Hz,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).

[0590] Example 34

[0591] ((4'-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2- methyl carbamate (sulpho)

[0592]

[0593] As described for ((4'-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding methyl carbamate (18.2 mg, 35.6 μmol), and the title compound was purified by HPLC (30-70% MeCN / water, with 0.05% formic acid additive) to give the product (6.20 mg, 36%) as a white amorphous solid. 1H NMR (400MHz, methanol-d4) δ8.06 (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 C 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), 22.6. 19 F NMR (376 MHz, methanol-d4) δ -140.67 (hept, J = 21.6 Hz). HRMS (ESI) + Calculated value: C 25 H 31 N3O4S + [M+H] + 488.2019; Measured value: 488.2019.

[0594] Example 35A

[0595] ((5-Isobutyl-4'-((2-(thiazo-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-yl) sulfonyl)carbamate butyl ester

[0596]

[0597] As described for butyl ((4'-((2(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding sulfonamide (92.7 mg, 0.205 mmol) and butyl chloroformate (36.0 μL, 0.238 μmol). The product (40.7 mg, 36%) was obtained as a white amorphous solid. 1HNMR (400MHz, methanol-d4) δ8.05(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),1.4 8–1.35(m,2H),1.25–1.13(m,2H),0.87(d,J=6.6Hz,6H),0.83(t,J=7.4Hz,3H). 13 C 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) + Calculated value: C 28 H 33 N4O4S2 + [M+H] + 553.1938; Measured value: 553.1935.

[0598] Example 35B

[0599] (butoxycarbonyl)((5-isobutyl-4'-((2-(thiazo-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-bin [Phenyl]-2-yl)sulfonyl)amide potassium

[0600]

[0601] As described for potassium ((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)(methoxycarbonyl)amide, the title compound was synthesized using butyl ((5-isobutyl-4'-((2-(thiazol-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate (107 mg, 0.261 mmol) and butyl chloroformate (45.8 μL, 0.360 mmol). The product (48 mg, 36%) was obtained as a white amorphous solid. 1HNMR (400MHz, DMSO-d6) δ7.96 (d, J = 3.3 Hz, 1H), 7.84 (d, J = 8.1 Hz, 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=1.8 Hz,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).

[0602] Example 36

[0603] ((5-Isobutyl-4'-((2-(isopropyl-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-yl) methyl sulfonyl carbamate

[0604]

[0605] As described for methyl ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, the title compound was synthesized using MeOH (1 mL) containing the corresponding butyl carbamate (48.0 mg, 93.8 μmol). The crude product was concentrated and purified by FCC (5-7% MeOH / CH2Cl2) to give the product as a white amorphous solid (41.9 mg, 95% yield). 1 H NMR (400MHz, methanol-d4) δ8.24–7.83(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,2H),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 C 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) + Calculated value: C25 H 32 N3O4S + [M+H] + 470.2114; Measured value: 470.2107.

[0606] Example 37A

[0607] ((5-Isobutyl-4'-((2-(isopropyl-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-yl) sulfonyl)carbamate butyl ester

[0608]

[0609] As described for butyl ((4'-((2(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding sulfonamide (97.6 mg, 0.237 mmol) and butyl chloroformate (41.8 μL, 0.327 mmol). The crude product was purified by FCC (3-5% MeOH / CH2Cl2) to give a product as a white amorphous solid (72 mg, 59% yield). 1 ¹H NMR (400 MHz, acetone-d6) δ 8.13 (d, J = 8.2 Hz, 1H), 7.60–7.35 (m, 3H), 7.29–7.13 (m, 2H), 7.10 (d, J = 1.8 Hz, 1H), 7.00 (d, J = 1.4 Hz, 1H), 6.83 (d, J = 1.4 Hz, 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 C NMR (101 MHz, 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) + Calculated value: C 28 H 38 N3O4S + [M+H] +512.2583; Measured value: 512.2579.

[0610] Example 37B

[0611] (butoxycarbonyl)((5-isobutyl-4'-((2-(isopropyl-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-bin [Phenyl]-2-yl)sulfonyl)amide potassium

[0612]

[0613] As described for potassium butoxycarbonyl)((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide, the title compound was synthesized using the corresponding butyl carbamate (13.7 mg, 26.6 μmol) and MeOH (0.59 M) containing KOH (1.61 mg, 28.7 μmol). The product (8.5 mg, 58% yield) was given as a white amorphous solid. 1 ¹H NMR (400MHz, acetone-d6) δ 8.06 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.8 Hz, 2H), 7.25–7.13 (m, 1H), 7.12–7.04 (m, 2H), 6.99 (d, J = 1.2 Hz, 1H), 6.96 (s, 1H), 6.84 (d, J = 1.3 Hz, 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).

[0614] Example 38A

[0615] ((5-Isobutyl-4'-((2-(cyclopropyl-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-yl) sulfonyl)carbamate butyl ester

[0616]

[0617] As described for butyl ((4'-((2(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding sulfonamide (77.4 mg, 0.189 mmol) and butyl chloroformate (33.3 μL, 0.261 mmol). The crude product was purified by FCC (3-5% MeOH / CH2Cl2) to give a product as a white amorphous solid (41 mg, 38% yield). 1H NMR a (400MHz, methanol-d4)δ8.05(d,J=8.2Hz,1H),7.44–7.32(m,2H),7.29(dd,J=8.2,1.8Hz,1H),7 .19(d,J=8.1Hz,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,2H),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)δ154.8,150.0,147.4,141.1,140.6,137.1,135.8,133.7,130.6,130.5,128.9,127.2,124.2,121.6,66.3,50.4,45.6,31.3,30.7,22.6,19.5,13.9,7.6,7.2.HRMS(ESI) + Calculated value: C 28 H 36 N3O4S + [M+H] + 512.2583, measured value: 512.2579.

[0618] [a] Recorded in a mixture of MeOD and CDCl3.

[0619] Example 38B

[0620] (butoxycarbonyl)((5-isobutyl-4'-((2-(cyclopropyl-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-bin [Phenyl]-2-yl)sulfonyl)amide potassium

[0621]

[0622] As described for potassium butoxycarbonyl)((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide, the title compound was synthesized using the corresponding butyl carbamate (13.5 mg, 26.2 μmol) and MeOH (0.59 M) containing KOH (1.59 mg, 28.3 μmol). The product (4.4 mg, 31% yield) was obtained as a white amorphous solid. 1¹H NMR (400 MHz, acetone-d6) δ 8.06 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.14 (t, J = 7.8 Hz, 3H), 7.02 (d, J = 1.3 Hz, 1H), 6.94 (d, J = 1.9 Hz, 1H), 6.75 (d, J = 1.3 Hz, 1H), 5.31 (s, 2H) H),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,2 H),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).

[0623] Example 39A

[0624] ((5-Isobutyl-4'-((2-(cyclopropyl-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-yl) methyl sulfonyl carbamate

[0625]

[0626] As described for methyl ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, the title compound was synthesized using MeOH (1 mL) containing the corresponding butyl carbamate (27.4 mg, 53.8 μmol). The crude product was concentrated and purified by FCC (5-7% MeOH / CH2Cl2) to give the product as a white amorphous solid (21.6 mg, 86% yield). 1 H NMR (400MHz, methanol-d4) δ8.05(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). 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) + Calculated value: C 25 H 30 N3O4S + [M+H] + 468.1957; Measured value: 468.1947.

[0627] Example 39B

[0628] (methoxycarbonyl)((5-isobutyl-4'-((2-(cyclopropyl-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-bin [Phenyl]-2-yl)sulfonyl)amide potassium

[0629]

[0630] As described for potassium butoxycarbonyl)((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)amide, the title compound was synthesized using the corresponding methyl carbamate (21.6 mg, 45.7 μmol) and MeOH (0.59 M) containing KOH (2.77 mg, 49.3 μmol). The product was obtained as a white amorphous solid (20.3 mg, 88% yield). 1 H NMR (400MHz, acetone-d6) δ8.06(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).

[0631] Example 40

[0632] ((5-Isobutyl-3-(4-(2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-yl)sulfonyl (B-) butyl carbamate

[0633]

[0634] As described for butyl ((4'-((2(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding sulfonamide (19.9 mg, 46.0 μmol) and butyl chloroformate (8.7 μL, 63.5 μmol). The crude product was purified by HPLC (30–50% water / MeCN, containing 0.05% formic acid) and lyophilized to give a product as a white amorphous solid (10.3 mg, 42% yield). 1 H NMR (400MHz, methanol-d4) δ7.67–7.54(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),1.57–1.4 0(m,2H),1.37–1.18(m,2H),1.00(d,J=6.6Hz,6H),0.88(t,J=7.4Hz,3H). 13 C 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) + Calculated value: C 26 H 36 N3O5S2 + [M+H] + 534.2096; Measured value: 534.2097.

[0635] Example 41

[0636] ((5-Isobutyl-3-(4-(2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-yl)sulfonyl Methyl carbamate

[0637]

[0638] As described for methyl ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, the title compound was synthesized using MeOH (1 mL) containing the corresponding butyl carbamate (10.0 mg, 18.7 μmol). The crude product was concentrated and purified by FCC (3-6% MeOH / CH2Cl2) to give the product as a white amorphous solid (6.0 mg, 65% yield). 1 H NMR (400MHz, methanol-d4) δ7.58(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 + Calculated value: C 23 H 30 N3O5S2 + [M+H] + 492.1627; Measured value: 492.1628.

[0639] Example 42

[0640] ((5-Isobutyl-3-(4-(2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-yl)sulfonyl) Butyl carbamate

[0641]

[0642] As described for ((4'-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding butyl carbamate (21.6 mg, 38.4 μmol) and DAST (5.1 μL, 38.4 μmol), and the title compound was purified by HPLC (30-70% water / MeCN, containing 0.05% formic acid), and lyophilized to give the product as a white amorphous solid (5.7 mg, 28% yield). 1H NMR (400MHz, methanol-d4) δ7.59–7.46(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=7.1Hz,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 C 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 (376MHz, methanol-d4) δ -140.66 (hept, J = 21.5Hz). HRMS (ESI) + Calculated value: C 26 H 36 FN3O4S2 + [M+H] + 536.2053; Measured value: 536.2051.

[0643] Example 43

[0644] ((5-Isobutyl-3-(4-(2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-yl)sulfonyl) Methyl carbamate

[0645]

[0646] As described for ((4'-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding methyl carbamate (18.9 mg, 38.5 μmol), and the title compound was purified by HPLC (30-70% water / MeCN, containing 0.05% formic acid), and lyophilized to give the product as a white amorphous solid (6.5 mg, 34% yield). 1 H NMR (400MHz, methanol-d4) δ7.53–7.35(m,2H),7.21–7.10(m,3H),7.05(d,J=1.6Hz,1H),6.77(s,1H),5.41(s,2 H),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 C 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), 22.5. 19 F NMR (376MHz, methanol-d4) δ -140.93 (hept, J = 21.8Hz). HRMS (ESI) + Calculated value: C 23 H 29 FN3O4S2 + [M+H] + 494.1584; Measured value: 494.1588.

[0647] Example 44

[0648] ((5-Isobutyl-3-(4-(2-(2-tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-2-yl)sulfonyl)amino 2-Methoxyethyl carbamate

[0649]

[0650] As described for butyl ((4-(4-(((2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazolyl-5-yl)sulfonyl)carbamate, 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). The crude product was purified by FCC (0-5% MeOH / MeCN) to give the product as a white amorphous solid (36 mg, 58% yield). 1 H NMR (400MHz, acetone-d6) δ7.65(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 C NMR (101 MHz, 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) + ): Calculated value: C 26 H 36 N3O5S2 + [M+H] + 534.2091; Measured value: 534.2092.

[0651] Example 45

[0652] ((4-(4-(((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazolyl-5-yl)sulfonyl (B-) butyl carbamate

[0653]

[0654] As described for ((4'-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding butyl carbamate (40.0 mg, 0.073 mmol) and DAST (13.5 μL, 0.102 mmol). The crude product was purified by preparative HPLC (15-80% water / acetonitrile) and lyophilized to give a product as a white amorphous solid (19.0 mg, 45% yield). 1 H NMR (400MHz, acetone-d6) δ7.91(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 C NMR (101 MHz, 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. 19 F NMR (376 MHz, acetone-d6) δ -139.3 (hept, J = 21.5 Hz). HRMS (ESI) + ): Calculated value: C 24 H 32 FN4O4S2 + [M+H] + 523.1844; Measured value: 523.1835.

[0655] Example 46

[0656] ((4-(4-(((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazolyl-5-yl)sulfonyl Methyl carbamate

[0657]

[0658] As described for ((4'-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding methyl carbamate (40 mg, 0.0794 mmol) and DAST (0.015 mL, 0.111 mmol). The crude product was purified by preparative HPLC (15-80% water / acetonitrile) and lyophilized to give a product as a white amorphous solid (17 mg, 40% yield). 1 H NMR (400MHz, acetone-d6) δ7.75(d,J=8.2Hz,2H),7.12(d,J=8.0Hz,2H),7.01(bs,1H),6.83(bs,1H),5.38(s,2 H), 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 C 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) + ): Calculated value: C 21 H 26 FN4O4S2[M+H] + 481.1374; Measured value: 481.1378.

[0659] Example 47

[0660] ((4-(4-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl Acyl) butyl carbamate

[0661]

[0662] As described for ((4'-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding butyl carbamate (40 mg, 0.071 mmol) and DAST (13.0 μL, 0.100 mmol). The crude product was purified by preparative HPLC (15–80% water / MeCN) and lyophilized to give a product as a white amorphous solid (20 mg, 47% yield). 1 H NMR (400MHz, acetone-d6) δ7.91(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,2 H),2.20(dt,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 C NMR (101 MHz, 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) + ): Calculated value: C 25 H 34 FN4O4S2 + [M+H] + 537.2000; Measured value: 537.1992.

[0663] Example 48

[0664] ((4-(4-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- isobutylthiazol-5-yl)sulfonyl)amino methyl carbonate ((4-(4-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- isobutylthiazol-5-yl)sulfonyl)amino methyl carbonate

[0665]

[0666] As described for ((4'-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, the title compound was synthesized using the corresponding butyl carbamate (40.0 mg, 0.077 mmol) and DAST (14.0 μL, 0.108 mmol). The crude product was purified by preparative HPLC (15-80% water / acetonitrile) and lyophilized to give a product as a white amorphous solid (21 mg, 50% yield). 1 H NMR (400MHz, acetone-d6) δ7.90(d,J=8.2Hz,2H),7.27(d,J=8.0Hz,2H),7.17(bs,1H),7.00(bs,1H),5.54(s,2 H), 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 C NMR (101 MHz, 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) + ): Calculated value: C 22 H 28 FN4O4S2 + [M+H] + 495.1531; Measured value: 495.1532.

[0667] Example 49

[0668] ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3'-fluoro-5-isobutyl-[1,1'-biphenyl]-2- yl)sulfonyl)amino methyl carbonate ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3'-fluoro-5-isobutyl-[1,1'-biphenyl]-2- yl)sulfonyl)amino methyl carbonate

[0669]

[0670] The title compound was synthesized as described for ((4'-((2(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, 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 / CH2Cl2) to give the product as a white amorphous solid (58.8 mg, 39% yield). 1 H NMR (400MHz, methanol-d4) δ8.05(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=7.2Hz,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 C 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 FNMR (376 MHz, methanol-d4) δ -113.55–-127.68 (m).

[0671] Example 50

[0672] ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3'-fluoro-5-isobutyl-[1,1'-biphenyl]-2- yl)sulfonyl)amino methyl carbonate Results

[0673]

[0674] As described for methyl ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate, the title compound was synthesized using MeOH (1 mL) containing the corresponding butyl carbamate (33.0 mg, 60.7 μmol). The crude product was concentrated and purified by FCC (5% MeOH / CH2Cl2) to give the product as a white amorphous solid (17.5 mg, 58% yield). 1 H NMR (400MHz, methanol-d4) δ8.05(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)δ160.6(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).

[0675] biology

[0676] Table 1:

[0677] K i values, stability in liver microsomes, and kinetic solubility

[0678] K i Assay. In Eurofins, this was achieved by replacing human AT2R from the HEK-293 cell membrane formulation. 125 I][Sar 1 Ile 8 [-Angiotensin II, these compounds were evaluated in a radioactive agonist assay. [Sar] 1 Ile 8 Angiotensin II (Sarile) acts as a non-selective AT2R agonist. 18 Affinity was determined using an eight- or nine-point dose-response curve, with each point repeated. The incubation buffer (final concentration) consisted of 45 mM Tris / HCl, 4.5 mM MgCl2, 0.9 mM EDTA / Tris, and 0.09% BSA (pH 7.4). PD 123,319 was used as a reference compound. Saralasin was also used as a reference compound in the evaluation of compound affinity in HEK-293 cell membranes. 125 I][Sar 1 Ile 8 [-Inhibitory effect of angiotensin II binding to human AT1R.]

[0679] Stability in liver microsomes. The metabolic stability of the compounds was assessed using human, mouse, and rat liver microsomes. Metabolic stability was determined by Eurostar at a concentration of 1 μM of the compound in 100 mM potassium phosphate buffer (pH 7.4) in 0.5 mg / mL human, mouse, or rat liver microsomes, with a total incubation volume of 500 μL. The assay matrix was as follows: human liver microsomes: mixed sex and 50 cells per pool; rat liver microsomes: male, Sprague-Dawley, 100 or more cells per pool; and mouse liver microsomes: male, CD-1, 250 or more cells per pool. The final microsomal protein concentration was 0.1 mg / mL. The test concentration was 0.1 μM, with the default being 0.01% DMSO, 0.25% acetonitrile, and 0.25% methanol. The experimental protocol was as follows: the test compound and the pooled liver microsomes were pre-incubated in phosphate buffer (pH 7.4) at 37°C in a shaking water bath for 5 minutes. The reaction was initiated by adding the 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. Samples were analyzed by HPLC-MS / MS using the selected reaction monitoring system. The HPLC system consisted of a binary LC pump with an autosampler, a C-18 column, and a gradient. Peak areas corresponding to the tested compounds were recorded. Compound residues were calculated by comparing the peak area at each time point to zero time. Assuming first-order kinetics, the half-life was calculated based on the slope of the initial linear range of the logarithmic curve of compound residues (%) versus time. In addition, intrinsic clearance (Clint) was calculated. 19,20

[0680] Kinetic solubility. Dulbecco's PBS buffer (NaCl 137 mM, KCl 2.7 mM, Na₂HPO₄ 8.1 mM, KH₂PO₄ 1.5 mM, pH 7.4) was used. 200 μM of the test compound was prepared from a 10 mM DMSO stock solution in PBS buffer. The final DMSO concentration was 2%. The buffer samples were thoroughly mixed and then incubated at room temperature for 24 hours. At the end of the incubation, the buffer samples were centrifuged, and the supernatant was then injected for HPLC analysis. On the day of HPLC analysis, a calibration standard of the test compound was prepared at 200 μM from a 10 mM DMSO stock solution in methanol / water (3 / 2, v / v). Analysis was performed by HPLC-UV / VIS with photodiode array detection, monitored at wavelengths of 205 nm, 230 nm, 260 nm, and 300 nm. The HPLC system consisted of C18 columns using gradients A and B (A = 12 mM ammonium formate, 6 mM water containing formic acid, pH 4.0; B = 6 mM ammonium formate, 3 mM formate acetonitrile / water (9 / 1, v / v)). Reference compounds used were metoprolol, rifampicin, ketoconazole, phenytoin, haloperidol, simvastatin, diethylstilbestrol, and tamoxifen, ranked from completely 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 main peak in the calibration standard (200 μM) with the peak area of ​​the corresponding peak in each buffer sample. The determination range was approximately 0.5 μM to 200 μM. Chromatographic purity (%) is determined by the peak area of ​​the main peak relative to the total integrated peak area in the HPLC chromatogram of the calibration standard.

[0681] Table 1 below shows the levels of K in human liver microsomes (HLM), mouse liver microsomes (MLM), and rat liver microsomes. i And stability. (RLM) and the kinetic stability of the compounds in PBS for the indicated examples.

[0682] CYP450 inhibition assay

[0683]

[0684]

[0685] Table 2

[0686] The following procedure was designed to evaluate whether the test compound inhibited the activity of each of the common cytochrome P450 (CYP) enzymes in human liver microsomes aggregated in 96-well plates. The compound was tested at a single concentration (10 μM) using 0.1% DMSO. The test compound, substrate, and human liver microsomes (mixed sex, pool of 50 donors, 0.1 mg / mL) were pre-incubated in phosphate buffer (pH 7.4) at 37°C in a shaking water bath for 5 min. The reaction was initiated by adding an NADPH-generating system. The reaction was allowed to continue for 10 min 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 the corresponding metabolites. The activity of human cytochrome P450 (CYP) enzymes was determined by tracking the formation of probe substrate metabolites. The inhibition of the following enzymes was evaluated using the listed reference substrates and reference inhibitors:

[0687] CYP1A - Phenacetin (reference inhibitor furafylline); CYP2B6 - Bupropion (reference inhibitor clopidogrel); CYP2C8 - Amodiaquine (reference inhibitor montelukast); CYP2C9 - Diclofenac (reference inhibitor sulfaphenazole); CYP2C19 - Omeprazole (reference inhibitor oxybutynin); CYP2D6 - Dextromethorphan (reference inhibitor quinidine); CYP3A - Midazolam (reference inhibitor ketoconazole); and CYP3A - Testosterone (reference inhibitor ketoconazole). Reference inhibitors were tested at multiple concentrations in each assay to obtain IC50 values. Peak areas corresponding to the metabolites were recorded. The percentage of control activity was calculated by comparing the peak area in the presence of the test compound with the peak area of ​​a control sample containing the same solvent. The percentage of inhibition was then calculated by subtracting the percentage of control activity from 100. The IC50 value (the concentration that causes half the maximum inhibition of the control) was determined using nonlinear regression analysis of the concentration-response curves of the Hill equation.

[0688] Testing on human IPF precision-cut lung slices (PCLuS)

[0689] CYP 450 inhibition (% at 10 μM) of Example 44 (sodium salt of C21) and other examples

[0690]

[0691]

[0692] *Bioorganic and Medicinal Chemistry, 2010, 18(12), 4570-4590.

[0693]

[0694] Table 3

[0695] The following procedure was performed using FibroFind (Newcastle Fibrosis Research Group, United Kingdom) and was designed to assess whether the test compound attenuated fibrosis in IPF-PCLuS (IPF-precision-cut lung slices). PCLuS were prepared from biopsy-confirmed transplanted IPF human lung tissue collected at the time of lung transplantation. The PCLuS were then left to stand for 48 hours to allow the post-slice stress period to end before the start of the experiment. Additionally, the PCLuS were incubated at two incremental doses (0.1 μM and 1 μM) in the presence of the test compound. All PCLuS were harvested at 144 hours.

[0696] As shown in Table 3 below, nine different groups of PCLuS were studied for n=5 or 8 individuals. PCLuS were prepared from n=1 biopsy-confirmed transplanted human IPF lungs. The carrier was DMSO, diluted 1:1000 in the culture medium.

[0697] Figures 1 to 8

[0698]

[0699]

[0700] PCLuS was incubated for a 48-hour static period. After static incubation, PCLuS was incubated for an additional 96 hours with or without the test compounds outlined above. The PCLuS medium, containing all test compounds, was updated and collected at 24-hour intervals starting from hour 48. All PCLuS samples were collected at 144 hours. Each medium sample was aliquoted into three approximately 150 μL aliquots, with each aliquot used to measure soluble biomarkers. The soluble biomarkers were collagen 1a1 (Col1a1) and transforming growth factor-β1 (TGF-β1).

[0701] PCLuS Collection. Collect cell culture supernatant daily (n = 5 to 12 samples per group) and rapidly freeze to quantify the soluble output listed below. At the time of collection, rapidly freeze n = 5 to 8 PCLuS samples for RNA isolation and qPCR analysis.

[0702] Soluble output analysis. The level of collagen 1a1 in cell culture supernatant was quantified using the R&D Duoset ELISA kit. A single ELISA (MesoScale Discovery) was used. TM (MSD) quantifies the level of TGF-β1 in cell culture supernatant.

[0703] Quantitative real-time PCR (qPCR). MagMAX was used. TM The -96 Total RNA Isolation Kit was used to extract RNA from PCLuS in all samples. RNA was reverse transcribed into cDNA and used for qPCR to measure the transcriptional levels of Col1a1, TGF-β1, and β-actin.

[0704] Soluble output analysis. 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 a single-weighted ELISA MSD kit. Figure 9 ).

[0705] Quantitative real-time PCR. The transcriptional levels of Col1a1 and TGF-β1 in PCLuS were quantified relative to β-actin. Figures 1 to 4 and 10 ).

[0706] Figures 5 to 8 The levels of secreted collagen 1a1 in the culture supernatant of PCLus are shown when treated with C21, Example 1A, Example 12A, and Example 3. Figures are presented from n = 5 to 12 tissue culture media at each condition and time point. Data are presented as mean ± SEM, with individual values ​​for each tissue culture medium.

[0707] Figure 9 The levels of secreted TGF-β1 in PCLus culture supernatant are shown when treated with C21, Example 1A, Example 12A, and Example 3. Figures are presented by tissue culture media n = 5 to 12 at each condition and time point. Data are presented as mean ± SEM, with individual values ​​for each tissue culture medium.

[0708] Table 3 and 10 The transcript levels of selected genes in PCLus are presented as the relative levels (RLTD%) of transcriptional differences in Col1a1 and TGF-β1 (normalized to β-actin) at 144 hours under C21, Example 1A, Example 12A, and Example 3 treatments. Data are presented as percentage changes in gene expression relative to control and mediator.

[0709] At least at one point in the testing, treatment of IPF PCLus with almost all of the tested compounds strongly reduced TGF-β1 gene transcription and protein secretion. These compounds were also very effective in reducing collagen 1a1 gene transcription.

[0710] Other examples

[0711] The following compounds are also provided, which can be prepared according to one or more of the synthetic procedures described above.

[0712] ((4-(4-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- isobutylthiazol-5-yl)sulfonyl)amino methyl carbonate ((4-(4-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2- isobutylthiazol-5-yl)sulfonyl)amino methyl carbonate ((4'-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3'-fluoro-5-isobutyl-[1,1'-biphenyl]-2

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721] Summarize

[0722] In summary, compared with compound C21 or its sodium salt, the compounds or their salts disclosed herein were found to exhibit low inhibition of CYP enzymes.

[0723] References

[0724] 1. Pharmacology Review (Pharmacol.Rev.) 2000; 52:415-472.

[0725] 2.WO 02 / 096883

[0726] 3.WO 99 / 43339

[0727] 4.EP 0512675 A1

[0728] 5.DE10 2012 004 589 A1

[0729] 6.US 2004 / 0167176

[0730] 7. Medical Research Review (Med.Res.Rev.) 2018;38:602-624.

[0731] 8.WO 2002 / 096883

[0732] 9.WO 2016 / 139475

[0733] 10.WO 2004 / 046141

[0734] 11.WO 2016 / 092329

[0735] 12.WO 2016 / 107879

[0736] 13.WO 2016 / 139475

[0737] 14.WO 2017 / 221012

[0738] 15.WO 2019 / 008393

[0739] 16.US 2012 / 035232

[0740] 17. Bioorganic Chemistry and Pharmaceutical Chemistry Letters, 2018, 28(3), 519-522.

[0741] 18. ACS Med. Chem. Lett. 2014, 5, 1129-1132.

[0742] 19. Biochemistry and Pharmacology, 1994, 47, 1469-1479.

[0743] 20. Drug Metabolism and Disposal (DRUG Metab. Dispos.) 1999, 27, 1350-1359.

[0744] 21. Bioorganic and Medicinal Chemistry (Bioorg.Med.Chem.) 2010, 18(12), 4570-4590.

Claims

1. A compound of formula I: Or its pharmaceutically acceptable salt. in R 1 express C2-C6 alkyl groups substituted with -OH groups or F atoms; R 2 express H； F； Cl； C2-C6 alkyl groups substituted with 0, 1, or 2 substituents selected from the group consisting of: OR 6 SR 7 NR 8 R 9 Halogens, thiazoles, oxazoles, and pyrazoles; C3-C6 cycloalkyl groups substituted with 0, 1, or 2 substituents from the group consisting of: OR 6 SR 7 and NR 8 R 9 ; benzyl, wherein the phenyl moiety is substituted by 0, 1, or 2 substituents selected from the group consisting of: OR 6 SR 7 and NR 8 R 9 ;or (CH2) m -R 10 ; R 3 express H； Halogen; or C1-C3 alkyl groups substituted with 0, 1, 2 or 3 halogens selected from F and Cl; R 4 and R 5 Independently represents C1-C6 alkyl groups substituted with 0, 1, 2, or 3 F atoms; X represents CH=CH, CH, N, NH, O, or S; Y represents CH=CH, CH, N, NH, O, or S. The premise is: (a) X and Y are not the same; (b) When X represents CH = CH, then Y can represent only CH; and (c) When Y represents CH=CH, then X can simply represent CH; Z represents a single bond, O, or S; R 6 R 7 R 8 and R 9 Independently represent H; or C1-C3 alkyl groups substituted with 0, 1, 2, or 3 F atoms; R 10 Choose from the following groups: phenyl, thiazole, oxazole, and pyrazole; n is 0, 1, 2, 3 or 4, and m is 0 or 1.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Ia, Ib, Ic, or Id:

3. The compound according to any one of the preceding claims, wherein R 2 and R 3 H can be represented independently.

4. The compound according to claim 1 or 2, wherein R 1 It is 2-hydroxypropyl-2-yl, 1-ethanol, or 2-fluoropropyl-2-yl.

5. The compound according to claim 1 or 2, wherein R 4 Choose from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

6. The compound according to claim 5, wherein R 4 It is methyl or n-butyl.

7. The compound according to claim 1 or 2, wherein R 5 Choose from the group consisting of: ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

8. The compound according to claim 7, wherein R 5 It is isopropyl or isobutyl.

9. The compound according to claim 1 or 2, wherein n is 0.

10. The compound according to claim 1 or 2, wherein Z is a single bond.

11. The compound according to claim 1 or 2, wherein it is one or more of the following: ((4'-((2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate; ((4'-((2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate; ((4-(4-(((2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazolyl-5-yl)sulfonyl)carbamate; ((4-(4-(((2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate; ((4-(4-(((2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate; ((4-(4-(((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate; ((4-(4-(((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate; ((4-(4-(((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazolyl-5-yl)sulfonyl)carbamate; ((4-(4-(((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazolyl-5-yl)sulfonyl)carbamate; ((4'-((2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate; ((4'-((2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)-5-propyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate; ((4'-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate; ((4'-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)-5-isobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate; ((5-Isobutyl-3-(4-(2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-yl)sulfonyl)carbamate; ((5-Isobutyl-3-(4-(2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-yl)sulfonyl)carbamate; ((5-Isobutyl-3-(4-(2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-yl)sulfonyl)carbamate; ((5-Isobutyl-3-(4-(2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-yl)sulfonyl)carbamate; ((4-(4-(((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazolyl-5-yl)sulfonyl)carbamate; ((4-(4-(((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-propylthiazolyl-5-yl)sulfonyl)carbamate; ((4-(4-(((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate or ((4-(4-((2-(2-fluoroprop-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-2-isobutylthiazolyl-5-yl)sulfonyl)carbamate.

12. The compound according to claim 1 or 2, used as a medicine.

13. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 11, and at least one pharmaceutically acceptable carrier and / or excipient.

14. The compound of claim 1 or 2, for the treatment and / or prevention of diseases, conditions or symptoms associated with angiotensin II, wherein the compound exhibits an acceptable level of CYP inhibition against one or more CYPs.

15. The compound of claim 14, for the treatment and / or prevention of diseases, conditions and / or symptoms selected from the group consisting of: hypertension, heart failure, stroke, kidney disease, pulmonary fibrosis, sclerosis, sarcoidosis, obstructive pulmonary disease, autoimmune diseases, viral respiratory infections and pneumonia caused therefrom, and any combination thereof.

16. The compound for use according to claim 15, wherein the kidney disease is chronic kidney disease.

17. The compound for use according to claim 15, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

18. The compound for use according to claim 15, wherein the sclerosis is systemic sclerosis.

19. The compound for use according to claim 15, wherein the sarcoidosis is pulmonary sarcoidosis.

20. The compound for use according to claim 15, wherein the obstructive pulmonary disease is chronic obstructive pulmonary disease.

21. The compound for use according to claim 15, wherein the autoimmune disease is rheumatoid arthritis.

22. Use of the compound according to claim 14 for manufacturing a medicament for treating diseases, conditions and / or symptoms selected from the group consisting of those requiring activation of the AT2 receptor but not desired inhibition of the CYP enzyme: hypertension, heart failure, stroke, kidney disease, pulmonary fibrosis, sclerosis, sarcoidosis, obstructive pulmonary disease, autoimmune diseases, viral respiratory infections and pneumonia caused therefrom, and any combination thereof.

23. The use according to claim 22, wherein the kidney disease is chronic kidney disease.

24. The use according to claim 22, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

25. The use according to claim 22, wherein the sclerosis is systemic sclerosis.

26. The use according to claim 22, wherein the sarcoidosis is pulmonary sarcoidosis.

27. The use according to claim 22, wherein the obstructive pulmonary disease is chronic obstructive pulmonary disease.

28. The use according to claim 22, wherein the autoimmune disease is rheumatoid arthritis.

29. Use of the compound according to claim 14 in the preparation of a medicament for treating interstitial lung disease.

30. Use of the compound according to claim 14 in the preparation of a medicament for treating idiopathic pulmonary fibrosis or sarcoidosis.

31. Use of the compound according to claim 14 in the preparation of a medicament for treating heart failure, chronic kidney disease, rheumatoid arthritis, and virus-induced pneumonia.

32. A pharmaceutical formulation comprising: The compound according to any one of claims 1 to 11; Therapeutic agents, wherein the therapeutic agents are known to be metabolized by CYP enzymes; And pharmaceutically acceptable adjuvants, diluents or carriers.

33. A complete reagent kit, comprising: (A) A pharmaceutical formulation comprising a compound according to any one of claims 1 to 11, wherein the pharmaceutical formulation is mixed with a pharmaceutically acceptable adjuvant, diluent or carrier; as well as (B) A pharmaceutical formulation comprising a therapeutic agent known to be metabolized by a CYP enzyme, said pharmaceutical formulation being mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier. Components (A) and (B) are each provided in a form suitable for application in combination with another component.

34. The formulation according to claim 32 or the kit according to claim 33, wherein the therapeutic agent is selected from the group consisting of: pirfenidone, naproxen, propranolol, riluzole, tizanidine, warfarin, celecoxib, clopidogrel, irbesartan, meloxicam, piroxicam. Am, torasemide, cyclophosphamide, indomethacin, atorvastatin, cilostazol, cyclosporine, deflazacort, hydrocortisone, lidocaine, selexipag, sildenafil, and / or simvastatin.

35. A method for preparing a compound of formula I according to any one of claims 1 to 10 and 12 to 21 by reacting a compound of formula 5 with a compound of formula 6, Where R 1 R 2 R 3 R 5 X, Y, Z and n are as defined in claim 1. R 4 OC(O)X (Equation 6) Where X represents a suitable leaving group, and R 4 As defined in claim 1.

36. The method of claim 35, wherein the suitable leaving group is a halogen group.

37. The method of claim 36, wherein the halogen group is chlorine.

38. The method according to claim 35 or 36, after the deprotection of the compound of formula 4, Where PG represents a protecting group, and R 1 R 2 R 3 R 5 X, Y, Z and n are defined above, with the compound of production formula 5 as an intermediate.

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