TW201738244A - FXR modulators and methods of their use - Google Patents

Abstract

The present disclosure is directed to modulators of farnesoid X receptor. Methods of making and using these modulators is also described.

Description

FXR regulator and its use method

The present invention relates to modulators of the farnesoid X receptor. Methods of making and using such conditioning agents are also described.

The farnesoid X receptor (FXR) system is known to be expressed in the liver, kidney and intestine. Lundquist, IV, JT et al . , J. Med. Chem. 2010, 53, 1774-1787. FXR's natural system is cholic acid, such as chodeoxycholic acid. Id. In rodent models, activation of FXR by FXR agonists results in beneficial metabolic effects such as glucose drop, insulin sensitization, triglyceride decline, and cholesterol drop. Abel, U., et al., Bioorg. & Med. Chem. Lett. 20 (2010) 4911-4917; Richter, HGF et al., Bioorg. & Med. Chem. Lett. 21 (2011) 1134-1140. FXR agonists have also been shown to have hepatoprotective effects by preventing lipid accumulation, reducing fibrosis, and reducing inflammation in the liver. Abel, U., et al. at 4911.

FXR modulators (ie, agonists or partial agonists) have a variety of indications, including, for example, abnormal dyslipidemia, liver disease, diabetes, diabetic nephropathy, vitamin D-related diseases, drug-induced side effects, hepatitis, inflammatory bowel Disease, hypertriglyceridemia, gallstones, nonalcoholic steatohepatitis, atherosclerosis, and primary biliary liver Hardening treatment. Lundquist, IV, J.T., et al., 1774; Richter, H.G.F., et al., 1134; Abel, U., et al., 4911. Therefore, a modulator of FXR is required.

This disclosure relates to compounds of formula I Wherein R ¹ is H, halogen, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, -OC _1-6 alkyl, or -OC _3-6 cycloalkyl; R ² halogen, - CN, C _1-6 alkyl, C _3-6 cycloalkyl, -OC _1-6 alkyl, or -OC _3-6 cycloalkyl; R ³ -C _1-6 alkyl or C _3-6 ring Alkyl; R ⁴ and R ⁵ are each independently H or C _1-6 alkyl; at least one of A, B, D and E is N and the other is CH or CR ⁶ ; R ⁶ halogen, -CN , OH, -OC _1-6 alkyl, or C _1-6 alkyl; Z system O, -NH-, or -N(C _1-6 alkyl)-; G system CH, or N; J system C , CH, or N; and A single or double bond; and a pharmaceutically acceptable salt thereof. Methods of making and using the compounds of formula I are also described.

The disclosure can be more fully understood by reference to the following description, including the <RTIgt; It will be understood that certain features of the disclosed compositions and methods described herein in the context of the various aspects may also be in a single state for the sake of clarity. The combination is provided in the sample. Conversely, various features of the compositions and methods described in the context of a single aspect may be provided separately or in any sub-combination.

The term "alkyl", when used alone or as part of a substituent, means having from 1 to 12 carbon atoms ("C _1-12 "), preferably from 1 to 6 carbon atoms in the chain. A linear or branched alkyl group ("C _1-6 "). Examples of the alkyl group include methyl (Me, C ₁ alkyl), ethyl (Et, C ₂ alkyl), n-propyl (C ₃ alkyl), isopropyl (C ₃ alkyl), butyl ( C ₄ alkyl), isobutyl (C ₄ alkyl), secondary butyl (C ₄ alkyl), tertiary butyl (C ₄ alkyl), pentyl (C ₅ alkyl), isopentyl (C ₅ alkyl), tertiary pentyl (C ₅ alkyl), hexyl (C ₆ alkyl), isohexyl (C ₆ alkyl), and according to those of ordinary skill in the art and as provided herein A group of equivalents of any of the above examples that can be considered by the technology.

The term "cycloalkyl", when used alone or as part of a substituent, refers to an alkyl group having at least one ring. Preferably, the cycloalkyl groups disclosed herein have from 3 to 6 carbon atoms (" _C3-6 "). Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a methyl-cyclopropyl group, a methyl-cyclobutyl group, a methyl-cyclopentyl group, and the like.

When a range of carbon atoms is used herein, for example, C _1-6 , all ranges and individual numbers of carbon atoms are encompassed. For example, "C _1-3 " includes C _1-3 , C _1-2 , C _2-3 , C ₁ , C ₂ and C ₃ .

The term "halogen" means chlorine, fluorine, bromine, or iodine. The term "halo" means a chloro group, a fluoro group, a bromo group, or an iodine group.

As used herein, the term "compound of formula I" includes such "form I" compounds as well as any compounds of the subclass I.

The term "pharmaceutically acceptable" means approved or approved by the competent authority of the United States federal or state government or a country other than the United States, or listed in the US Pharmacopoeia or other generally recognized pharmacopoeia. Used in animals (especially humans).

&quot;Pharmaceutically acceptable salt&quot; refers to a salt of a compound of the present disclosure which is pharmaceutically acceptable and which possesses the desired pharmacological activity of the parent compound. In particular, the salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts formed by inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acid Forming, for example, acetic acid, propionic acid, caproic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3 -(4-hydroxybenzhydryl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, grape heptanoic acid, 3 - phenylpropionic acid, trimethylacetic acid, tertiary butyl acetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; or 2) a salt formed when an acidic proton in a parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion or an aluminum ion; or a salt formed by coordination of the acidic proton with an organic base, such as ethanolamine , diethanolamine, triethanolamine, N-methylglucamine and the like. For illustrative purposes only, the salt may further comprise Sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like; and when the compound contains a basic functionality, a non-toxic salt of an organic or inorganic acid, such as a hydrochloride, a hydrobromide or a tartrate , mesylate, acetate, maleate, oxalate and the like.

&quot;Pharmaceutically acceptable vehicle&quot; means a diluent, adjuvant, excipient, or carrier with which the compound of the present disclosure is administered. "Pharmaceutically acceptable excipient" means a substance that is non-toxic, biologically tolerant or biologically suitable for administration to an individual, for example, added to a pharmaceutical composition or as a vehicle, carrier or diluent to facilitate An inert substance that is administered and compatible with the agent. Examples of the excipient include calcium carbonate, calcium phosphate, various sugars, and various types of starch, cellulose derivatives, gelatin, vegetable oil, and polyethylene glycol.

"Individual" contains people. The terms "human", "patient" and "subject" are used interchangeably herein.

In one embodiment, "treating or treating" any disease or condition refers to amelioration of the disease or condition (ie, preventing or reducing the progression of the disease or at least one of its clinical symptoms). In another embodiment, "treating" refers to ameliorating at least one physical parameter, which may be a parameter that the individual cannot discern. In yet another embodiment, "treating" refers to modulating a disease or condition, whether the disease or condition is physical (eg, identifiable by symptoms), physiological (eg, stabilization of physical parameters), or both diseases Or illness. In yet another embodiment, "treating" refers to delaying the onset of a disease or condition.

"Compound of the present disclosure" and equivalent expression are intended to encompass a compound of formula (I) as described herein, and where the context permits, the expression includes pharmaceutically acceptable salts and solvents. a compound such as a hydrate. Likewise, when the context permits, reference to an intermediate is intended to cover its salts and solvates, whether or not they are claimed.

As used herein, the term "isotopic variant" refers to a compound comprising an unnatural proportion of isotopes at one or more of the atoms that make up the compound. For example, the compound "isotopic variant" may be a radioactive label, i.e. containing one or more non-radioactive isotopes, for example, such as deuterium ⁽² H or D), carbon--13 ⁽¹³ C), nitrogen-15 ⁽¹⁵ N), or the like. It will be appreciated that in compounds where such isotopic substitutions occur, the following atoms may be altered if present, so that, for example, any hydrogen may be ² H/D, any carbon may be ¹³ C, or any nitrogen. It may be ¹⁵ N and the presence and location of such atoms can be determined within the skill of the art. As such, the disclosure may include the preparation of isotopic variations having a radioisotope, such as where the resulting compound is useful in drug and/or matrix distribution studies. The radiolabeled compounds of the present disclosure can be used in diagnostic methods, such as single photon emission computed tomography (SPECT). The radioisotope strontium (ie, ³ H) and carbon-14 (ie, ¹⁴ C) are particularly suitable because they are easy to incorporate and have off-the-shelf detection methods. In addition, compounds substituted with positron-emitting isotopes (eg, ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be prepared and can be used in positron tomography (PET) studies to examine the possession of the receptor.

All isotopic variations of the compounds disclosed herein, whether or not they are radioactive, are encompassed within the scope of the present disclosure.

It should also be understood that compounds having the same molecular formula but differing in the nature or sequence of their atomic bonds or in the arrangement of their atoms in space are referred to as "isomers". (isomer). The isomers in which their atoms are arranged in space are called "stereoisomers", such as non-image isomers and mirror image isomers.

Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, the centerline is bonded to four different groups, it may have a pair of mirror image isomers. Mirror isomers can be characterized by the absolute configuration of their asymmetric centers, which are described by the R and S sequence rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarization to specify right-handed or left-handed rotation. (ie, (+) or (-) isomers, respectively). Palm compounds may be present as individual mirror image isomers or as a mixture thereof. Mixtures containing the same proportion of mirror image isomers are referred to as "racemic mixtures".

"Tautomer" means a compound having a structural form of a specific compound that can be converted to each other, with the difference being the transposition of a hydrogen atom and electrons. Therefore, the two structures are in equilibrium by the movement of π electrons and atoms (usually H). For example, enol and ketone tautomers can be rapidly converted to each other by treatment with an acid or a base.

Another example of tautomerism is the acid and nitro form of phenylnitromethane, which is also formed by treatment with an acid or a base.

Tautomeric forms may be associated with achieving optimal chemical reactivity and biological activity of the desired compound.

The compounds of the present disclosure may have one or more asymmetric centers; such compounds may thus be produced as individual ( R ) or ( S ) stereoisomers or as a mixture thereof.

The description or naming of a particular compound in the specification and claims is intended to include individual singular isomers, and such racemic mixtures or other mixtures, unless otherwise indicated. Within the present disclosure, any open valence of a carbon, oxygen, or nitrogen atom present in any of the structures described herein indicates the presence of a hydrogen atom. When there is a palm center in the structure, but the center does not show a specific stereochemistry, the structure covers two mirror image isomers, either separately or in a mixture. Methods for determining stereochemistry and isolating stereoisomers are well known in the art.

The disclosure relates to a compound of formula I: According to the present disclosure, R ¹ is H, halogen, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, -OC _1-6 alkyl, or -OC _3-6 cycloalkyl. When R ¹ is halogen, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, -OC _1-6 alkyl, or -OC _3-6 cycloalkyl, R ¹ may be attached thereto Attach any position of the benzene ring. In some preferred aspects, R ¹ is H. In other preferred aspects, R ¹ is a halogen, i.e., F, Cl, Br, or I. In such an aspect, wherein R ¹ is halogen, the halogen is preferably F or Cl. In some aspects, R ¹ is -CN. In other aspects, R ¹ is C _1-6 alkyl, such as C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl. In still other aspects, R ¹ is C _3-6 cycloalkyl, such as C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, or C ₆ cycloalkyl. In some aspects, R ¹ is -OC _1-6 alkyl, such as -OC ₁ alkyl, -OC ₂ alkyl, -OC ₃ alkyl, -OC ₄ alkyl, -OC ₅ alkyl, or - OC ₆ alkyl. In other aspects, R ¹ is -OC _3-6 cycloalkyl, such as -OC ₃ cycloalkyl, -OC ₄ cycloalkyl, -OC ₅ cycloalkyl, or -OC ₆ cycloalkyl.

According to the present disclosure, R ² is halogen, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, -OC _1-6 alkyl, or -OC _3-6 cycloalkyl. In a preferred aspect, R ² is a halogen, i.e., F, Cl, Br, or I. In such an aspect, wherein R ² is halogen, the halogen is preferably F or Cl. In some aspects, R ² is -CN. In other aspects, R ² is C _1-6 alkyl, such as C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl. In still other aspects, R ² is C _3-6 cycloalkyl, such as C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, or C ₆ cycloalkyl. In some aspects, R ² is -OC _1-6 alkyl, for example -OC ₁ alkyl, -OC ₂ alkyl, -OC ₃ alkyl, -OC ₄ alkyl, -OC ₅ alkyl, or - OC ₆ alkyl. In other aspects, R ² is -OC _3-6 cycloalkyl, such as -OC ₃ cycloalkyl, -OC ₄ cycloalkyl, -OC ₅ cycloalkyl, or -OC ₆ cycloalkyl.

In a preferred embodiment of the present disclosure, R ¹ is H and R ² is F or Cl. In some preferred embodiments of the present disclosure, R ¹ is H and R ² is F. In other preferred embodiments, R ¹ is H and R ² is Cl. In some preferred embodiments of the present disclosure, R ¹ is F and R ² is F. In other embodiments, R ¹ is Cl and R ² is Cl.

According to the disclosure, R ³ is C _1-6 alkyl or C _3-6 cycloalkyl. In some aspects, R ³ is C _1-6 alkyl, such as C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl. In other aspects, R ³ is C _3-6 cycloalkyl, such as C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, or C ₆ cycloalkyl. In a preferred aspect, R ³ is C ₂ alkyl (ethyl). In other preferred aspects, R ³ is C ₃ alkyl (propyl or isopropyl), wherein the isopropyl group is more preferred.

According to the present disclosure, R ⁴ and R ⁵ are each independently H or C _1-6 alkyl. In some aspects, R ⁴ is H and R ⁵ is C _1-6 alkyl, such as C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl. In other embodiments, R ⁴ is C _1-6 alkyl, such as C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl, and R ⁵ series H. In still other embodiments, R ⁴ and R ⁵ are each independently C _1-6 alkyl, that is, R ⁴ and R ⁵ are each independently C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl. In some embodiments, R ⁴ and R ⁵ are each H. In a preferred embodiment, each of R ⁴ and R ⁵ is a methyl group (C ₁ alkyl group).

According to the disclosure, at least one of A, B, D and E is N and the other independently CH or CR ⁶ , wherein R ⁶ is halogen, -CN, OH, -OC _1-6 alkyl, or C _{1 -6} alkyl. In a preferred embodiment, at least one of A, B, D, and E is N and other systems CH. In other preferred embodiments, at least one of A, B, D, and E is N, and one of the others is CR ⁶ , and the remaining system CH.

In these embodiments employing R ⁶ , R ^{6 is} preferably -OH or -OC _1-6 alkyl, such as -OC _1-6 alkyl, such as -OC ₁ alkyl, -OC ₂ alkyl, - OC ₃ alkyl, -OC ₄ alkyl, -OC ₅ alkyl, or -OC ₆ alkyl. In other aspects, R ⁶ is a halogen, preferably F or Cl. In other aspects, R ⁶ is -CN. In still other aspects, R ⁶ is C _1-6 alkyl, such as C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl.

In some aspects, the A-line N and B, D, and E are independently CH or CR ⁶ . In other aspects, the A system N and B, D, and E are each CH. In some aspects, one of the A lines N, B, D, and E is CR ⁶ and the other is CH. In other aspects, the two of the A series N, B, D, and E are independently CR ⁶ and the other system CH. In still other aspects, each of the A-series N and B, D, and E is independently CR ⁶ . In still other aspects, the A system is N, the B system is CR ⁶ , the D is CH, and the E is CH. In other aspects, A is N, B is CH, D is CR ⁶ , and E is CH. In still other aspects, the A system is N, the B system is CH, the D is CH, and the E is CR ⁶ .

In some aspects, the B line N and A, D, and E are independently CH or CR ⁶ . In other aspects, B is N and each of A, D, and E is CH. In some aspects, one of the B systems N, A, D, and E is CR ⁶ and the other is CH. In other aspects, the B series N, A, D, and E are independently CR ⁶ and other lines CH. In yet other aspects, B is N and the lines A, D and E are each independently of the Department CR ^6. In still other aspects, the B system is N, the A system is CR ⁶ , the D is CH, and the E is CH. In other aspects, B is N, A is CH, D is CR ⁶ , and E is CH. In still other aspects, B is N, A is CH, D is CH, and E is CR ⁶ .

In some aspects, D is N and lines A, B and E are independently CH or based CR ^6. In other aspects, D is N and each of A, B, and E is CH. In some aspects, one of the D systems N, A, B, and E is CR ⁶ and the other is CH. In other aspects, the D system N, A, B, and E are independently CR ⁶ and other systems CH. In still other aspects, each of D system N and A, B, and E is independently CR ⁶ . In still other aspects, D is N, A is CR ⁶ , B is CH, and E is CH. In other aspects, D is N, A is CH, B is CR ⁶ , and E is CH. In still other aspects, D is N, A is CH, B is CH, and E is CR ⁶ .

In some aspects, E is N, and lines A, B and D are independently CH or based CR ^6. In other aspects, E is N and each of A, B, and D is CH. In some aspects, one of the E-systems N, A, B, and D is CR ⁶ and the other is CH. In other aspects, the E series N, A, B, and D are independently CR ⁶ and other lines CH. In still other aspects, each of the E-system N and A, B, and D is independently CR ⁶ . In still other aspects, E is N, A is CR ⁶ , B is CH, and D is CH. In other aspects, E is N, A is CH, B is CR ⁶ , and D is CH. In still other aspects, E is N, A is CH, B is CH, and D is CR ⁶ .

According to the disclosure, Z is O, -NH-, or -N(C _1-6 alkyl)-. In some preferred aspects, the Z system is O. In other aspects, the Z system is -NH-. In still other aspects, Z-N(C _1-6 alkyl)-, such as -N(C ₁ alkyl)-, -N(C ₂ alkyl)-, -N(C ₃ alkyl) -, -N(C ₄ alkyl)-, -N(C ₅ alkyl)-, or -N(C ₆ alkyl)-.

According to the disclosure, G is CH or N. In some aspects, G is CH. In other aspects, G is N.

According to the disclosure, One or two keys. In some aspects, One button. In other aspects, Double key.

According to the disclosure, J is C, CH, or N. In some aspects, J is C. In other aspects, J is CH. In still other aspects, J is N. In the embodiments in which the J series CH or N, One button. In the embodiments of the J system C, Double key.

In a preferred embodiment of the present disclosure, the compound of formula I is a compound of formula IA:

In other preferred embodiments of the present disclosure, the compound of formula I is a compound of formula IB:

In still other preferred embodiments of the present disclosure, the compound of formula I is a compound of formula IC:

In some preferred embodiments of the present disclosure, the compound of formula I is a compound of formula ID:

The disclosure also relates to methods of using the compounds described herein to treat an individual diagnosed with or having a disease, disorder, or condition mediated by the farnesoid X receptor (FXR). The compounds disclosed herein are FXR agonists or partial agonists. The disclosed methods are achieved by administering to a subject a compound sufficient to modulate the amount of FXR.

The disclosure also relates to methods of using the compounds described herein to treat an individual diagnosed with or having a disease, disorder, or condition mediated by the farnesoid X receptor (FXR). The compounds disclosed herein are FXR agonists or FXR partial agonists. The disclosed methods are achieved by administering to a subject a compound sufficient to modulate the amount of FXR.

In some aspects, the compounds described herein are useful for treating chronic biliary stagnation conditions, such as primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). Rizzo et al., Curr. Drug Targets Immune Endocr. Metabol. Disord. 2005, 5(3), 289-303; Zollner, Mol. Pharm. 2006, 3(3), 231-51; Cai et al., Expert Opin. Ther. Targets 2006, 10(3) 409-421. The compounds described herein are also useful for the treatment of progressive familial intrahepatic cholestasis (PFIC), alcohol-induced cirrhosis and associated bile stasis, and liver fibrosis. The compounds disclosed herein are useful in the treatment of hepatic steatosis and related syndromes such as nonalcoholic steatohepatitis (NASH). this The disclosed compounds are useful for the treatment of bile stasis and/or fibrosis associated with cirrhosis (alcoholic cirrhosis) or viral hepatitis.

In other aspects, the compounds described herein are useful in the treatment of gallstones, such as preventing the formation of cholesterol gallstones or preventing the re-formation of gallstones after surgical resection or lithotripsy. Doggrell, S. Curr. Opin. Investig. Drugs 2006, 7(4), 344-348.

In still other aspects, the compounds described herein are useful for reducing serum triglycerides and/or reducing total serum cholesterol. Kast et al., Mol. Endocrinol. 2001, 15(10), 1720-1728; Urizar et al., Science 2002, 296 (5573), 1703-1706; Lambert et al., J. Biol. Chem. 2003, 278, 2563 -2570; Watanabe et al., J. Clin. Invest. 2004, 113(10), 1408-1418; Figge et al., J. Biol. Chem. 2004, 279(4), 2790-2799; Bilz et al. .J. Physiol. Endocrinol. Metab. 2006, 290(4), E716-22. That is, the compounds described herein can be used to reduce total cholesterol, reduce LDL cholesterol water, reduce VLDL cholesterol, increase HDL cholesterol, and/or reduce triglyceride levels. The compounds described herein can also be used to treat abnormal dyslipidemia.

The compounds disclosed herein are useful in the treatment of lipid and lipoprotein disorders such as hypercholesterolemia, hypertriglyceridemia, and artherosclerosis. Hanniman et al., J. Lipid Res. 2005, 46(12), 2595-2604. In some aspects, the compounds disclosed herein are useful for treating cardiovascular conditions, such as acute myocardial infarction, acute stroke, or thrombosis.

In other aspects, the compounds described herein are useful for improving insulin sensitivity and glucose tolerance. The compounds described herein are also useful for the treatment of metabolic disorders such as Type II diabetes and diabetic complications (eg, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, peripheral arterial occlusive disease). Stayrook et al., Endocrinology 2005, 146(3), 984-91; Zhang et al., Proc. Natl. Acad. Sci. USA 2006, 103(4), 1006-1011; Cariou et al., J. Biol. Chem. 2006, 281, 11039-11049; Ma et al., J. Clin. Invest. 2006. 116(4). 1102-1109; Duran-Sandoval et al., Biochimie 2005, 87(1), 93-98, Holt et al. Genes Dev. 2003, 17(13), 1581-1591. The compounds described herein are useful for treating obesity.

The compounds disclosed herein are useful for treating cancer, such as breast cancer, colorectal cancer, or prostate cancer. Niesor et al., Curr. Pharm. Des. 2001, 7(4), 231-259; Silva, J. Lipid Res. 2006, 47(4), 724-733; De Gottardi et al., Dig. Dis. Sci. 2004, 49(6), 982-989.

In still other aspects, the compounds described herein are useful for treating gastrointestinal conditions associated with reduced intake of dietary fats and fat-soluble dietary vitamins (eg, vitamin D), which can be overcome by increasing the quality of the intestinal bile acids and phospholipids. .

In other aspects, the compounds disclosed herein are useful for treating inflammatory bowel disease, such as, for example, Crohn&apos;s disease or ulcerative colitis. Inagaki et al., Proc. Natl. Acad. Sci. USA. 2006, 103(10), 3920-3905.

In other aspects, the compounds disclosed herein are useful for the treatment of hepatitis B virus (HBV). See for example WO 2015/036442.

In a method of treatment according to the present disclosure, an effective amount of an agent according to the present disclosure is administered to an individual having or diagnosed with the disease, disorder, or condition. By "effective amount" is meant an amount or dose sufficient to generally achieve the desired therapeutic benefit in a patient in need of treatment for the specified disease, disorder, or condition. An effective amount or dose of a compound of the present disclosure can be by conventional methods (e.g., model experiments, dose escalation studies, or clinical trials), as well as by consideration of conventional factors (e.g., mode or route of administration or drug delivery, compound pharmacokinetics). Confirmation of the severity and course of the disease, condition, or condition, the prior or ongoing treatment of the individual, the health of the individual and the response to the drug, and the judgment of the attending physician. Dosage examples are in the range of from about 0.001 to about 200 mg of compound per kilogram of body weight per day, preferably from about 0.05 to 100 mg/kg/day, or from about 1 to 35 mg/kg/day; in single dose units or Fractional dosage units (eg BID, TID, QID). For a 70 kg person, an exemplary range of suitable dosages is from about 0.05 to about 7 g/day, or from about 0.2 to about 2.5 g/day.

In addition, the compounds of the present disclosure can be used in combination with additional active ingredients to treat the above conditions. The additional active ingredient can be co-administered separately from the compounds of the present disclosure, or the agent can be included in a pharmaceutical composition according to the present disclosure. In an exemplary embodiment, the additional active ingredients are those that are known or found to be effective in treating any of the diseases or conditions described herein. The combination can be used to increase the therapeutic effect (e.g., by including in the combination a compound that enhances the potency or effectiveness of the active agent according to the present disclosure), reducing one or more side effects, or reducing the desired dose of the active agent according to the present disclosure.

The compounds of the present disclosure are used alone or in combination with one or more other active ingredients to formulate the pharmaceutical compositions of the present disclosure. The pharmaceutical composition of the present disclosure comprises: (a) an effective amount of at least one compound according to the present disclosure; and (b) a pharmaceutically acceptable excipient.

The delivery form of the pharmaceutical composition containing the active agent in one or more dosage units can be prepared using suitable pharmaceutical excipients and compounding techniques which are known or available to those of ordinary skill in the art. In the methods of the invention, the composition can be administered by a suitable route of administration, for example, orally, parenterally, rectally, topically, or via the eye, or by inhalation.

The preparation may be in the form of a tablet, a capsule, a sachet, a dragee, a powder, a granule, a lozenge, a powder for reconstitution, a liquid preparation, or a suppository. Preferably, the composition is formulated for intravenous infusion, topical administration, or oral administration.

For oral administration, the compounds of the present disclosure may be provided in the form of a tablet or capsule, or in the form of a solution, emulsion, or suspension. To prepare an oral composition, the compound can be formulated to yield a dosage of, for example, from about 0.05 to about 100 mg/kg per day, or from about 0.05 to about 35 mg/kg per day, or from about 0.1 to about 10 mg/kg per day. For example, a total daily dose of about 5 mg to 5 g per day can be accomplished by administering once, twice, three times, or four times a day.

Oral lozenges may include a compound according to the present disclosure in admixture with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binders, lubricants, sweeteners, flavoring agents, coloring agents and preservatives. . Suitable inert fillers include sodium carbonate, calcium carbonate, sodium phosphate, calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral vehicles include B Alcohol, glycerin, water and the like. Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose and alginic acid are suitable disintegrants. The binder may include starch and gelatin. The lubricant, if present, can be magnesium stearate, stearic acid, or talc. If desired, the tablet may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract or may be coated by enteric coating.

Capsules for oral administration include hard gelatin capsules and soft gelatin capsules. For the preparation of hard gelatin capsules, the compounds of the present disclosure may be combined with a solid, semi-solid, or liquid diluent. Soft gelatin capsules can be prepared by mixing the disclosed compounds with water, oil (such as peanut oil or olive oil), liquid paraffin, a mixture of monoglycerides and diglycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol. preparation.

The liquid for oral administration can be in the form of a suspension, solution, emulsion, or syrup, or can be lyophilized or presented as a dried product for reconstitution with water or other suitable vehicle before use. The liquid compositions may optionally contain: pharmaceutically acceptable excipients such as suspending agents (for example, sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose) , aluminum stearate gel and the like); non-aqueous vehicles such as oils (eg almond oil, or fractionated coconut oil), propylene glycol, ethanol, or water; preservatives (eg, methylparaben, pair a propyl hydroxybenzoate, or sorbic acid; a wetting agent, such as lecithin; and, if desired, a flavoring agent, or a coloring agent.

The active agents of the present disclosure may also be administered by a non-oral route. For example, the composition can be formulated as a suppository for rectal administration. For parenteral use (including intravenous, intramuscular, intraperitoneal, or subcutaneous routes), the compounds of the present disclosure may be provided in sterile aqueous solutions or suspensions buffered to the appropriate pH and isotonicity, or Provided in a parenteral Acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms will be presented in unit dosage form (e.g., ampoules or disposable injection devices), in multi-dose forms (e.g., vials from which appropriate dosages may be taken), or in solid or pre-concentrated form for injectable formulations. Exemplary infusion doses of the compound can range from about 1 to 1000. mu.g/kg/minute and are mixed with the pharmaceutical carrier over a period of minutes to days.

For topical administration, the compound can be combined with the pharmaceutical carrier to a concentration of from about 0.1% to about 10% drug to vehicle. Another mode of administration of the compounds of the present disclosure may utilize patch formulations to achieve transdermal delivery.

Alternatively, in the methods of the present disclosure, the compounds of the present disclosure may be administered by inhalation via the nasal or oral route, for example, in a spray formulation that also contains a suitable carrier.

Exemplary compounds that can be used in the methods of the present disclosure will now be described with reference to the following generally prepared illustrative synthetic schemes and the following specific examples. Those skilled in the art will be able to appreciate that in order to obtain the various compounds herein, the starting materials can be suitably selected such that the permeation reaction scheme will carry the final desired substituent (with or without appropriate protection) to produce The desired product. Alternatively, a suitable group may be required or desired at the position of the final desired substituent, which may be carried throughout the reaction scheme and, where appropriate, substituted with the desired substituent. Unless otherwise indicated, this variable refers to the definition of formula (I) above. The reaction can be carried out between the melting point and the reflux temperature of the solvent, preferably between 0 ° C and the reflux temperature of the solvent. The reaction may be heated by conventional heating or microwave heating. The reaction can also be carried out in a sealed pressure vessel at a normal reflux temperature above the solvent.

The compounds disclosed herein can be prepared by reference to Scheme 1.

Certain compounds of formula I can be prepared by reference to Schemes 2.1 to 2.3.

Certain compounds of formula I can be prepared by reference to Schemes 3.1 to 3.3.

Option 3.1

Certain compounds of formula I can be prepared by reference to Scheme 4.

Certain compounds of formula I can be prepared by reference to Schemes 5.1 to 5.3.

Instance

Intermediate 1. Isopropyl 3-bromo-2-oxopropionate.

For the preparation of isopropyl 3-bromo-2-oxopropionate, see US20050054634A1.

Intermediate 2: isopropyl 2-(benzyloxy)-5,5-dimethyl-5,6,7,10-tetrahydropyrido[3',2':4,5]pyrrolo[2 , 3-d] azine-9-carboxylate.

Step 1. N,N-Dimethyl-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)methylamine. Dimethylformiminium chloride (25.74 g, 275.09 mmol) was added to 1H-pyrrolo[2,3-b]pyridine (25 g, 211.61 mmol) at MeCN at 20 ° C under N ₂ . (500 mL) in solution. The mixture was stirred at 80 ° C for 3 hours. The reaction mixture was cooled to EtOAc (EtOAc m.

Step 2. 2-(1H-Pyrolo[2,3-b]pyridin-3-yl)acetonitrile. Me ₂ SO ₄ (45.85 g, 363.52 mmol) was added to the compound N,N-dimethyl-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)methylamine (35 g, 199.74 mmol ) in a solution of THF (180 mL) and MeOH (180 mL). The mixture was stirred at 20 ° C for 30 minutes. The mixture was concentrated under reduced pressure to give a residue, which was washed three times with PE (50mL*3). In H ₂ O (150mL) and NaCN (27.9g, 569.26mmol, 2.85eq) was treated residue, and the solution was stirred at 100 ℃ 24 hours. The reaction mixture was cooled to 20 _&lt;0&gt_; C and diluted with H20 (EtOAc) The combined organic layers were (50mL * 2) and washed with brine, dried over anhydrous Na ₂ SO _4, filtered, and concentrated under reduced pressure. By column chromatography _{(SiO 2, DCM / MeOH =} 10/1) to obtain the residue was purified as a yellow solid of the title compound (8g, 25.48%). ¹ H-NMR (400 MHz, CDCl ₃ ), δ = 10.27-10.06 (m, 1 H), 8.49 - 8.31 (m, 1 H), 7.78 (dd, J = 0.8, 7.6 Hz, 1 H), 7.38 ( s, 1 H), 7.17 (dd, J = 4.8, 7.6 Hz, 1 H), 3.85 (s, 2 H).

Step 3. 2-(1-((2-(Trimethyldecyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile. Add NaH (3.05 g, 76.35 mmol, 60% purity) to 2-(1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile (8 g, 50.9 mmol) in THF (100 mL) ) in the solution. After 30 minutes, SEM-Cl (12.73 g, 76.35 mmol) was added in one portion and the mixture was warmed to 20 ° C and stirred for 2 hours. The mixture was poured into ice water (500 mL), and the aqueous phase was extracted with ethyl acetate (200mL*3). The combined organic phases (200mL * 2) and washed with brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc (EtOAc/EtOAc) ¹ H-NMR (400 MHz, CDCl ₃ ), δ = 8.42 - 8.37 (m, 1 H), 7.98-7.90 (m, 1 H), 7.39 (s, 1 H), 7.16 (dd, J = 4.8, 7.6 Hz, 1 H), 5.67 (s, 2 H), 3.84 (s, 2 H), 3.60-3.50 (m, 2 H), 0.95-0.89 (m, 2 H), 0 (s, 9 H).

Step 4. 2-Methyl-2-(1-((2-(trimethylmethyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)propan Nitrile. At -78 deg.] C and N _2, a LiHMDS (1M, 97.4mL) was added dropwise 2- (1 - ((2- (trimethyl silicon based) ethoxy) methyl) lH-pyrrolo [ A solution of 2,3-b]pyridin-3-yl)acetonitrile (7 g, 24.35 mmol) in THF (50 mL). The mixture was stirred at -78 °C for 60 minutes, and MeI (14.52 g, 102.27 mmol) was added to the resulting mixture and stirred for 30 minutes at -78 °C. The temperature was raised to 20 ° C and stirred for 1 hour. The mixture was poured into ice water (200 mL) and extracted with ethyl acetate (300mL*3). The combined organic phases (100mL * 2) and washed with brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc ¹ H-NMR (400 MHz, CDCl ₃ ), δ=8.47-8.41 (m, 1 H), 8.24-8.17 (m, 1 H), 7.35-7.31 (m, 1 H), 7.26-7.19 (m, 1 H), 5.72 (s, 2 H), 3.67-3.58 (m, 2 H), 1.90 (s, 6 H), 1.70 (s, 2 H), 1.02-0.94 (m, 2 H), 0 (s) , 9 H).

Step 5. 2-Methyl-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanenitrile. TFA (18.8 g, 164.8 mmol) was added in one portion to 2-methyl-2-(1-((2-(trimethylmethyl)ethoxy)methyl)) at 20 ° C under N ₂ 1H-Pyrolo[2,3-b]pyridin-3-yl)propanenitrile (5.2 g, 16.5 mmol) in DCM (15 mL). The mixture was stirred at 40 ° C for 3 hours. The mixture was cooled to 20 ° C and concentrated under reduced pressure at 20 ° C. The residue was dissolved in MeOH (15mL), and the _{CH 3 ONa (4.45g, 82.41mmol,} 5eq) was added thereto. The mixture was stirred at 20 ° C for 8 hours. The mixture was concentrated under reduced pressure at 20 °C. The residue was poured into ice water (w/w = 1/1) (100 mL) and stirred for 2 min. The aqueous phase was extracted with DCM (30 mL * 3). The combined organic phases (100mL * 2) and washed with brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAcjjjjjjj +ESI-MS : m/z 185.8 [M+H] ⁺ .

Step 6. 3-(2-Cyanopropan-2-yl)-1H-pyrrolo[2,3-b]pyridine 7-oxide. 2-Methyl-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanenitrile (2.3 g, 12.4 mmol) and m- CPBA (6.3 g, 85% purity) in ethyl acetate The mixture in the ester (20 mL) was stirred at 20 ° C for 12 h. K ₂ CO ₃ (2M, 12.5 mL) was added to the resulting mixture and then stirred at 20 ° C for 3 h. By addition of H ₂ O (50mL) and the reaction mixture was quenched. The mixture was extracted with EtOAc (30 mL*3). The combined organic layers were (25mL * 2) and washed with brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj +ESI-MS : m/z 201.8 [M+H] ⁺ .

Step 7. 2-(6-(Benzyloxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylpropanenitrile. Me ₂ SO ₄ (1.52 g, 12 mmol) was added in one portion to 3-(2-cyanopropan-2-yl)-1H-pyrrolo[2,3-b]pyridine 7 at 25 ° C under N ₂ - Oxide (2.2 g, 10.9 mmol) in a solution of MeCN (30 mL). The mixture was stirred at 65 ° C for 3 hours. The mixture was concentrated to give a residue (yield in BnOH (10 mL)) then BnONa (2M, 21.8 mL, 4 eq). The mixture was heated to 80 ° C for 5 hours under N ₂ . The mixture was cooled to 25 ° C and poured into ice water (250 mL). Ethyl acetate (300mL * 3) The aqueous phase was extracted, washed with brine the combined organic phases were (200mL * 2), dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc) ¹ H-NMR (400 MHz, CDCl 3 ), δ = 8.77 - 8.69 (m, 1 H), 8.07 - 8.01 (m, 1 H), 7.51 - 7.44 (m, 2 H), 7.38 (br.s., 1 H), 7.34-7.28 (m, 2 H), 6.95 (d, J = 2.4 Hz, 1 H), 6.72 (d, J = 8.8 Hz, 1 H), 5.39 (s, 2 H), 4.70 (s) , 2 H), 1.80 (s, 6 H).

Step 8. 2-(6-(Benzyloxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylpropan-1-amine. LAH (625 mg, 16.5 mmol) was added in one portion to 2-(6-(benzyloxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2 at 20 ° C under N ₂ Methylpropionitrile (800 mg, 2.7 mmol) in THF (15 mL). The mixture was stirred at 60 ° C for 3 hours. The mixture was cooled to 0 ° C and water (625 μL) was added, then NaOH (aqueous solution, 10%, 625 μL) was added and stirred for 30 minutes. The mixture was dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc +ESI-MS : m/z 296.3 [M+H] ⁺ .

Step 9. Isopropyl 2-(benzyloxy)-8-(bromomethyl)-5,5-dimethyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3- b: 5,4-c']bipyridine-8-carboxylate. At 20 ° C and N ₂ , HCl / II Alkane (4M, 405 μL) was added in one portion to 2-(6-(benzyloxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylpropan-1-amine (400 mg , 1.35 mmol) in a solution of propan-2-ol (10 mL). The mixture was stirred at 20 ° C for 30 minutes, and isopropyl 3-bromo-2-oxopropanoate (intermediate 1, 2 M, 1.01 mL) was added and heated to 80 ° C and stirred for 12 hours. The mixture was cooled to 20 ° C and then the mixture was evaporated.

Step 10. Isopropyl 2-(benzyloxy)-5,5-dimethyl-5,6,7,10-tetrahydropyrido[3',2':4,5]pyrrolo[2, 3-d]azepine-9-carboxylate. Isopropyl 2-(benzyloxy)-8-(bromomethyl)-5,5-dimethyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b: A solution of 5,4-c']dipyridin-8-carboxylate (700 mg, crude) in pyridine (10 mL). The mixture was concentrated under reduced pressure at 20 °C. The residue was poured into ice water (w/w = 1/1) (50 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (30 mL * 2). The combined organic phases of (60mL * 2) and washed with brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: +ESI-MS :m/z 406.1[M+H] ⁺

Intermediate 3: isopropyl 5,5-dimethyl-4a,5,6,7,10,10a-hexahydropyrido[3',2':4,5]pyrrolo[ hydrochloride] 2,3-d]azepine-9-carboxylate.

Step 1. 7-(Tributyl) 9-isopropyl 2-(benzyloxy)-5,5-dimethyl-5,10-dihydropyrido[3',2':4,5 Pyrrolo[2,3-d]azepine-7,9(6H)-dicarboxylate. Et ₃ N (139 mg, 1.38 mmol) and Boc ₂ O (113 mg, 517 umol) were added in one portion to isopropyl 2-(benzyloxy)-5,5-dimethyl- at 25 ° C under N ₂ . 5,6,7,10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-9-carboxylate (intermediate 2, 140 mg, 345 μmol) DCM (4 mL) in solution. The mixture was stirred at 25 ° C for 16 hours. The residue was poured into ice water (w/w = 1/1) (20 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (25 mL * 2). The combined organic phases of (15mL * 2) and washed with brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc (EtOAc: +ESI-MS : m/z 506.2 [M+H] ⁺ .

Step 2. 7-(Tributyl) 9-isopropyl 5,5-dimethyl-2-oxo-2,5,6,10-tetrahydropyrido[3',2':4 , 5] pyrrolo[2,3-d]azepine-7,9(1H)-dicarboxylate. Pd(OH) ₂ (47 mg, 20% purity) was added to 7-(tert-butyl) 9-isopropyl 2-(benzyloxy)-5,5-dimethyl-5 under H ₂ , 10-dihydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-7,9(6H)-dicarboxylate (170 mg, 336.23 μmol) in EtOAc ( 3 mL) in solution. Under vacuum and the suspension was degassed several times to purge H _2. The mixture was stirred at H ₂ (15 psi) and 25 ° C for 1.5 hours. The reaction mixture was filtered with EtOAcqqqqqqqq The crude product was used in the next step without further purification. +ESI-MS : m/z 416.1 [M+H] ⁺ .

Step 3. Isopropyl 5,5,7-trimethyl-2-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,10-tetrahydropyrido[3', 2': 4,5]pyrrolo[2,3-d]azepine-9-carboxylate. Tf ₂ O (187 mg, 664 μmol, 109 μL) was added dropwise at 7 ° C and N ₂ to 7-(tert-butyl) 9-isopropyl 5,5-dimethyl-2-oxo- 2,5,6,10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-7,9(1H)-dicarboxylate (138 mg, 332.15 Molmol) and pyridine (500 μL) in a solution of DCM (5 mL). The mixture was stirred at 0 ° C for 1 h. The residue was poured into ice water (w/w = 1/1) (20 mL) and stirred for 2 min. The aqueous phase was extracted with DCM (25 mL * 3). The combined organic phases of (20mL * 2) and washed with brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. By silica gel chromatography (SiO _2, petroleum ether / ethyl acetate = 5/1) to afford to give the title compound as a yellow solids (175mg, 92%). +ESI-MS : m/z 548.1 [M+H] ⁺ .

Step 4. 7-(Tributyl) 9-isopropyl 5,5-dimethyl-5,10-dihydropyrido[3',2':4,5]pyrrolo[2,3- d] azepine-7,9(6H)-dicarboxylate. Pd(dppf)Cl ₂ (34 mg, 46 μmol) was added in one portion to isopropyl 5,5,7-trimethyl-2-((trifluoromethyl)sulfonyl group at 25 ° C under N ₂ )oxy)-5,6,7,10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-9-carboxylate (170 mg, 309 μmol) and Et ₃ SiH (251mg, 2.1mmol) in DMF (5mL) solution. The mixture was stirred at 70 ° C for 6 hours. The residue was poured into ice water (w/w = 1/1) (25 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (35 mL * 3). The combined organic phases of (20mL * 2) and washed with brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAcjjjjjj ¹ H-NMR (400 MHz, CDCl ₃ ), δ = 11.11-10.97 (m, 1 H), 8.44 - 8.29 (m, 1 H), 8.27-8.14 (m, 1 H), 8.09-7.95 (m, 1 H), 7.06-6.91 (m, 1 H), 5.29-5.18 (m, 1 H), 3.84-3.67 (m, 2 H), 1.56 (d, J = 3.2 Hz, 7 H), 1.51 (br. s., 5 H), 1.35 (dd, J = 3.2, 6.2 Hz, 6 H); +ESI-MS : m/z 400.1 [M+H] ⁺ .

Step 5. Isopropyl 5,5-dimethyl-4a,5,6,7,10,10a-hexahydropyrido[3',2':4,5]pyrrolo[2,3-d] Nitrogen-9-carboxylate. At 25 ° C and N ₂ , with HCl / two Alkane (4.0 M, 2 mL) was treated with isopropyl 7-((l1-methyl)(l1-oxyalkyl)boranyl)-5,5-dimethyl-4a,5,6 in a beaker. 7,10,10a-Hexidopyrido[3',2':4,5]pyrrolo[2,3-d]azepine-9-carboxylate (55 mg, 137.68 μmol). The mixture was stirred at 25 ° C for 6 hours. The reaction mixture was concentrated in vacuo to give crystall +ESI-MS: m/z 300.0 [M+H] ⁺ .

Intermediate 4: isopropyl 2-(benzyloxy)-10,10-dimethyl-5,8,9,10-tetrahydropyrido[2',3':4,5]pyrrolo[2 , 3-d]azepine-6-carboxylate.

The title compound was prepared in a similar manner to the intermediate 2 in the step 1 using 4-azindole instead of 1H-pyrrolo[2,3-b]pyridine.

Intermediate 5. Isopropyl 10,10-dimethyl-5,8,9,10-tetrahydropyrido[2',3':4,5]pyrrolo[2,3-d]azepine- 6-carboxylate.

The title compound is used in the same manner as the intermediate 4, using isopropyl 10,10-dimethyl-5,8,9,10-tetrahydropyrido[2',3':4,5 in the step 1. Pyrrolo[2,3-d]azepine-6-carboxylate (intermediate 5) substituted for isopropyl 2-(benzyloxy)-5,5-dimethyl-5,6,7,10 - Tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-9-carboxylate (Intermediate 2).

Intermediate 6. Ethyl 2-methoxy-5,5-dimethyl-5,6,7,10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3- d] Azaindole-9-carboxylate.

Step 1. 2-(6-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylpropanenitrile. 3-(2-Cyanopropan-2-yl)-1H-pyrrolo[2,3-b]pyridine 7-oxide (Intermediate 2, product from Step 6, 320 mg, 1.6 mmol) and Me ₂ SO ₄ (160.4mg, 1.3mmol) in MeCN (5mL) was 80 deg.] C with stirring at reflux for 12 hours. After cooling to 20 °C, NaOMe (103 mg, 1.91 mmol) in MeOH (5 mL) was added to this mixture. The mixture was stirred at 80 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj ¹ H-NMR: (400MHz, CDCl ₃ ), δ 8.18-7.83 (m, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.65 (d, J = 8.8 Hz, 1H), 3.97 (s, 3H), 1.82 (s, 6H).

Step 2. 2-(6-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylpropan-1-amine. Addition of Raney nickel (88.3 mg, 1.0 mmol) to 2-(6-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylpropanol at 20 °C A solution of the nitrile (111 mg, 515.6 [mu]mol) in MeOH (10 mL). Under vacuum and the suspension was degassed several times to purge H _2. The mixture was stirred for 1 hour at H ₂ (50 psi) and 20 °C. The reaction mixture was filtered, and the filtrate was evaporated. +ESI-MS: m/z 202.9 [M-NH ₂ ] ⁺ .

Step 3. Ethyl 2-methoxy-5,5-dimethyl-5,6,7,10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d Azin-9-carboxylate. The title compound is substituted in the same manner as the intermediate 2, steps 9 to 10, in step 9, using ethyl 3-bromo-2-oxopropionate in place of isopropyl 3-bromo-2-oxopropionate, and Substituting 2-(6-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylpropan-1-amine for 2-(6-(benzyloxy)-1H -Pyrolo[2,3-b]pyridin-3-yl)-2-methylpropan-1-amine was prepared.

Intermediate 7: 2-(1H-pyrrolo[3,2-c]pyridin-3-yl)acetonitrile.

The title compound was prepared in a similar manner to the intermediate 2, steps 1 to 2, using 1H-pyrrolo[3,2-c]pyridine in 1 to 1H-pyrrolo[2,3-b]pyridine.

Intermediate 8: ethyl 2-benzyl-10,10-dimethyl-2,8,9,10-tetrahydropyrido[3',4':4,5]pyrrolo[2,3-d Azinium-6-carboxylate.

Step 1. Tert-butyl butyl 3-(cyanomethyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate. Add Et ₃ N (457.1 mg, 4.5 mmol) and DMAP (55.2 mg, 452 umol) to 2-(1H-pyrrolo[3,2-c]pyridin-3-yl)acetonitrile (intermediate 7,710 mg, 4.5 Methyl acetate and dibutyl succinate (1.28 g, 5.9 mmol) in DCM (30 mL). The mixture was stirred at 20 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjj + ESI-MS: m/z 257.8 [M+H] ⁺ .

Step 2. Tert-butyl 3-(2-cyanopropan-2-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate. Add LiHMDS (1M, 11.18 mL) and CH ₃ I (2.98 g, 21 mmol) to tris-butyl 3-(cyanomethyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid The ester (1.2 g, 4.7 mmol) was taken in THF (5 mL). The mixture was stirred at -78 °C for 10 minutes. By addition of H ₂ O (10mL) and the reaction mixture was quenched. The reaction in EtOAc (20mL * 2) The mixture was extracted, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc

Step 3. 2-(5-Benzyl-3a,4,5,6,7,7a-hexahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-2-methylpropanenitrile . Tri-tert-butyl 3-(2-cyanopropan-2-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (1 g, 3.5 mmol) and (bromomethyl)benzene A solution of (1.8 g, 10.6 mmol) in PhMe (10 mL) was stirred at 110 ° C for 8 h. The solution was cooled to 20 ° C and most of the THF was poured to give a gummy intermediate which was washed several times with PE (20 mL * 2). The residue was dissolved in THF (5mL) in deg.] C and at 20 is the NaBH ₄ (133.9mg, 3.54mmol) was added and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

Step 4. 2-(5-Benzyl-3a,4,5,6,7,7a-hexahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-2-methylpropene- 1-amine. Add LiAlH ₄ (475.4 mg, 12.5 mmol) to 2-(5-benzyl-3a,4,5,6,7,7a-hexahydro-1H-pyrrolo[3,2-c]pyridine-3- A solution of 2-methylpropionitrile (700 mg, 2.51 mmol) in THF (5 mL). The mixture was stirred at 70 ° C for 1 hour. The reaction mixture was cooled to 0 ° C and carefully quenched with wet THF (containing 10% H ₂ O) until gas evolution ceased. The resulting mixture through Celite ^® was filtered and the filtrate was concentrated to afford the title compound (610mg) under reduced pressure, which was used without further purification in the next step. ¹ H-NMR (400 MHz, CD ₃ OD), δ 7.62-7.61 (m, 2H), 7.52-7.51 (m, 3H), 6.65 (d, J = 2.4 Hz, 1H), 4.57 (d, J =13.2) Hz, 1H), 4.51-4.44 (m, 2H), 4.32 (d, J = 14.0 Hz, 1H), 3.72-3.68 (m, 1H), 3.41-3.38 (m, 1H), 3.01-2.93 (m, 4H), 1.31 (s, 6H)

Step 5. Ethyl 2-benzyl-10,10-dimethyl-2,8,9,10-tetrahydropyrido[3',4':4,5]pyrrolo[2,3-d] Azepine-6-carboxylate. 2-(5-Benzyl-3a,4,5,6,7,7a-hexahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-2-methylpropan-1- Amine (570 mg, 2 mmol), 3-bromo-2-oxo-propionic acid ethyl ester (627.5 mg, 2.4 mmol), and HCl/II Mixture (10 mL) dioxane (4M, 0.5mL) in EtOH was stirred under an atmosphere of 90 deg.] C and N ₂ 30 hours. Pyridine (3 mL) was added and the mixture was stirred at 90 ° C for an additional 15 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjj

Intermediate 9. Ethyl 2-benzyl-8-(3,4-difluorobenzyl)-10,10-dimethyl-2,8,9,10-tetrahydropyrido[3',4 ':4,5]pyrrolo[2,3-d]azepine-6-carboxylate.

3,4-Difluorobenzylhydrazine chloride (76.8 mg, 434.8 μmol) was added to ethyl 2-benzyl-8-(3,4-difluorobenzylidene)-10,10- at 20 °C. Dimethyl-2,8,9,10-tetrahydropyrido[3',4':4,5]pyrrolo[2,3-d]azepine-6-carboxylate (intermediate 8,150 mg) _{, 395.3μmol), Et 3 N (} 79.9mg, 790.5μmol) in DCM (3mL) was added and stirred under an atmosphere of N ₂ 0.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjj +ESI-MS: m/z 516.3 [M+H] ⁺ .

Intermediate 10. Isopropyl 2-benzyl-8-(3,4-difluorobenzyl)-10,10-dimethyl-2,8,9,10-tetrahydropyrido[3', 4': 4,5]pyrrolo[2,3-d]azepine-6-carboxylate.

Step 1. Isopropyl 2-benzyl-10,10-dimethyl-2,8,9,10-tetrahydropyrido[3',4':4,5]pyrrolo[2,3-d Azinium-6-carboxylate. K ₂ CO ₃ (9 mg, 698 μmol) was added to ethyl 2-benzyl-8-(3,4-difluorobenzylidene)-10,10-dimethyl-2,8,9,10-tetra a solution of hydropyrido[3',4':4,5]pyrrolo[2,3-d]azepine-6-carboxylate (intermediate 9,120 mg, 232.8 μmol) in i-PrOH (2 mL) Medium and stirred at 80 ° C for 4 hours. The reaction mixture was cooled to EtOAc (EtOAc m.

Step 2. Isopropyl 2-benzyl-8-(3,4-difluorobenzyl)-10,10-dimethyl-2,8,9,10-tetrahydropyrido[3',4 ':4,5]pyrrolo[2,3-d]azepine-6-carboxylate. Add 3,4-difluorobenzylhydrazine chloride (44.9 mg, 254.2 μmol) to isopropyl 2-benzyl-10,10-dimethyl-2,8,9,10-tetra at 20 °C Hydropyrido[3',4':4,5]pyrrolo[2,3-d]azepine-6-carboxylate (90 mg, 231.1 μmol), Et ₃ N (46.7 mg, 462.1 μmol) in DCM (3 mL) in a solution and stirred under N ₂ atmosphere for 0.5 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc

Intermediate 11. 2-(1H-Pyrolo[2,3-c]pyridin-3-yl)acetonitrile.

The title compound was prepared in a similar manner to the intermediate 2, steps 1 to 2, using 1H-pyrrolo[2,3-c]pyridine in 1 to 1H-pyrrolo[2,3-b]pyridine.

Intermediate 12. 2-(6-Benzyl-3a,4,5,6,7,7a-hexahydro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-methylpropane -1-amine.

The title compound is substituted in step 1 with 2-(1H-pyrrolo[2,3-c]pyridin-3-yl)acetonitrile (intermediate 11) in a similar manner to intermediate 8, step 1 to 4. -(1H-Pyrolo[3,2-c]pyridin-3-yl)acetonitrile (Intermediate 7) was prepared.

Intermediate 13. Isopropyl 5,5-dimethyl-5,6,7,10-tetrahydropyrido[4',3':4,5]pyrrolo[2,3-d]azepine- 9-carboxylate.

Step 1. Isopropyl 2-benzyl-5,5-dimethyl-1,2,4a,5,6,7,10,10a-octahydropyrido[4',3':4,5] Pyrrolo[2,3-d]azepine-9-carboxylate. 2-(6-Benzyl-3a,4,5,6,7,7a-hexahydro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-methylpropan-1- The amine (Intermediate 12, 1.8 g, 6.35 mmol) was added to a solution of &lt;RTI ID=0.0&gt;&gt; The mixture was heated to 80 ° C for 5 hours. The mixture was concentrated, and the residue was crystalljjjjjjjjjj The mixture was concentrated under reduced pressure. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc

Step 2. 7-(Tributyl) 9-isopropyl 2-benzyl-5,5-dimethyl-2,4a,5,6,10,10a-hexahydropyridyl[4',3 ':4,5]pyrrolo[2,3-d]azepine-7,9(1H)-dicarboxylate. Add DMAP (60.5 mg, 495.2 μmol) and TEA (751.72 mg, 7.43 mmol) to isopropyl 2-benzyl-5,5-dimethyl-1,2,4a,5,6,7,10, 10a-octahydropyrido[4',3':4,5]pyrrolo[2,3-d]azepine-9-carboxylate (900 mg, 2.48 mmol) and Boc ₂ O (1.1 g, 4.9 mmol) ) in a solution of DCM (5 mL). The mixture was stirred at 20 ° C for 1 hour. The reaction was concentrated, the residue was purified mjjjjjjjjjjj ESI-MS: m/z 492.1 [M+H] ⁺ .

Step 3. 7-(Tributyl) 9-isopropyl 5,5-dimethyl-2,3,4,4a,5,6,10,10a-octahydropyrido[4',3' : 4,5]pyrrolo[2,3-d]azepine-7,9(1H)-dicarboxylate. Add Pd(OH) ₂ (68.7 mg, 20%) to 7-(tertiary butyl) 9-isopropyl 2-benzyl-5,5-dimethyl-2,4a,5,6,10 , 10a-hexahydropyrido[4',3':4,5]pyrrolo[2,3-d]azepine-7,9(1H)-dicarboxylate (810.5 mg, 1.6 mmol) in i -PrOH (30 mL) in solution. Under vacuum and the suspension was degassed several times to purge H _2, and stirred at 25 deg.] C and H ₂ (45psi) 10 hours. The reaction mixture was filtered and EtOAcqqqqqm

Step 4. Isopropyl 5,5-dimethyl-5,6,7,10-tetrahydropyrido[4',3':4,5]pyrrolo[2,3-d]azepine-9 - a carboxylic acid ester. Add Pd/C (327.9 mg, 10%) to 7-(tertiary butyl) 9-isopropyl 5,5-dimethyl-2,3,4,4a,5,6,10,10a- Arhydropyrido[4',3':4,5]pyrrolo[2,3-d]azepine-7,9(1H)-dicarboxylate (210.7 mg, 496.6 μmol) in xylene (10 mL) In the solution, and stirred at 140 ° C for 10 hours. The reaction mixture was filtered and EtOAcqqqqqm

Intermediate 14: N-isopropyl-N,10,10-trimethyl-5,8,9,10-tetrahydropyrido[3',4':4,5]pyrrolo[2,3- d] Nitrogen-6-carbamamine.

Step 1. 8-(Tributyl) 6-ethyl 2-benzyl-10,10-dimethyl-9,10-dihydropyrido[3',4':4,5]pyrrolo[ 2,3-d]azepine-6,8(2H)-dicarboxylate. Et ₃ N (161.7 mg, 1.6 mmol), and (Boc) ₂ O (959.1 mg, 4.4 mmol) were added to ethyl 2-benzyl-10,10-dimethyl-2,8,9,10- Tetrahydropyrido[3',4':4,5]pyrrolo[2,3-d]azepine-6-carboxylate (Intermediate 8, 1.1 g, 2.9 mmol, 1 eq) in DCM (20 mL) The solution was stirred at 25 ° C for 3 hours. The solvent was removed under reduced pressure and the residue was purified eluted elut elut elut elut elut elut elut . +ESI-MS: m/z 476.2 [M+H] ⁺

Step 2. 8-(Tributyl) 6-ethyl 10,10-dimethyl-9,10-dihydropyrido[3',4':4,5]pyrrolo[2,3-d Azepine-6,8(5H)-dicarboxylate. Add Pd(OH) ₂ (707.8 mg, 20%) to 8-(tertiary butyl) 6-ethyl 2-benzyl-10,10-dimethyl-9,10-dihydropyridyl[3 ',4':4,5]A solution of pyrrolo[2,3-d]azepine-6,8(2H)-dicarboxylate (1.2 g, 2.52 mmol) in EtOAc (25 mL). The mixture was degassed, and purged several times to H _2, and stirred at 25 deg.] C and H ₂ (15Psi) 1 hour. The mixture was filtered and the solution was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjj +ESI-MS: m/z 386.1 [M+H] ⁺ .

Step 3. 8-(tertiary butoxycarbonyl)-10,10-dimethyl-5,8,9,10-tetrahydropyrido[3',4':4,5]pyrrolo[2, 3-d]azepine-6-carboxylic acid. KOH (319.2 mg, 5.69 mmol) was added to 8-(tert-butyl) 6-ethyl 10,10-dimethyl-9,10-dihydropyridine [3' at N ₂ and 25 °C. , 4':4,5]pyrrolo[2,3-d]azepine-6,8(5H)-dicarboxylate (731 mg, 1.9 mmol) in H ₂ O (6 mL) and EtOH (20 mL) In solution. The resulting solution was heated to 40 ° C and stirred for 1 hour. The solution was poured into ice water (40 mL) and the pH was adjusted to 5 with citric acid (1.32 g) and ethyl acetate (35mL*3). The combined organic phases were washed with brine (50mL * 2), dried over anhydrous Na ₂ SO _4, filtered and concentrated to afford the title compound as a yellow oil (491mg, crude product) under reduced pressure. +ESI-MS: m/z 358.0 [M+H] ⁺ .

Step 4. Tert-butyl 6-(isopropyl(methyl)aminemethanyl)-10,10-dimethyl-9,10-dihydropyrido[3',4':4,5] Pyrrolo[2,3-d]azepine-8(5H)-carboxylate. HATU (159.5 mg, 419.7 μmol) and DIPEA (65 mg, 503.6 μmol) were added to 8-(tertiary butoxycarbonyl)-10,10-dimethyl-5,8,9,10-tetrahydropyridine. [3', 4': 4,5] Pyrrolo[2,3-d]azepine-6-carboxylic acid (150 mg, 419.7 μmol) in DMF (6 mL) and stirred for 30 min. N-methylpropan-2-amine (46 mg, 629.5 μmol) was added and the resulting solution was stirred at 25 ° C for 1 hour. The solution was poured into water (50 mL) and extracted with EtOAc EtOAc. The organic phase was dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj +ESI-MS: m/z 413.1 [M+H] ⁺ .

Step 5. N-Isopropyl-N,10,10-trimethyl-5,8,9,10-tetrahydropyrido[3',4':4,5]pyrrolo[2,3-d Nitrogen-6-carbamamine. HCl/two Alkane (4M, 1 mL) was added to the tert-butyl 6-(isopropyl(methyl)aminemethanyl)-10,10-dimethyl-9,10-dihydropyrido[3',4' :4,5]pyrrolo[2,3-d]azepine-8(5H)-carboxylate (130 mg, 315.14 μmol) in two A solution of the alkane (1 mL) was stirred at 25 ° C for 2 hours. The solvent was removed under reduced EtOAcqqqqqqm +ESI-MS: m/z 312.9 [M+H] ⁺ .

Compound 1: isopropyl 7-(3,4-difluorobenzylhydra)-5,5-dimethyl-5,6,7,10-tetrahydropyrido[3',2 as the hydrochloride salt ':4,5]pyrrolo[2,3-d]azepine-9-carboxylate.

Step 1. Isopropyl 7-(3,4-difluorobenzylidene)-5,5-dimethyl-5,6,7,10-tetrahydropyrido[3',2':4,5 Pyrrolo[2,3-d]azepine-9-carboxylate. 3,4-difluorobenzylhydrazine chloride (48.4 mg, 273.9 μmol) in DCM (1 mL) was added to isopropyl 5,5-dimethyl-4a,5 at 0 ° C and N ₂ . 6,7,10,10a-hexahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-9-carboxylate (intermediate 3,41 mg, 136.9 μmol) And DIPEA (70.8 mg, 547.8 [mu]mol, 95 [mu]L) in DCM (3 mL). The mixture was stirred at 0 ° C for 60 minutes. The mixture was poured into ice water (w/w = 1/1) (25 mL) and stirred for 2 min. The aqueous phase was extracted with DCM (30 mL * 3). The combined organic phases of (20mL * 2) and washed with brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography ( petroleum ether / ethyl acetate = 10/1) to yield corresponding product.

Step 2. Isopropyl 7-(3,4-difluorobenzylhydra)-5,5-dimethyl-5,6,7,10-tetrahydropyrido[3',2 as the hydrochloride salt ':4,5]pyrrolo[2,3-d]azepine-9-carboxylate. Isopropyl 7-(3,4-difluorobenzylidene)-5,5-dimethyl-5,6,7,10-tetrahydropyrido[3',2':4,5]pyrrole And [2,3-d]azin-9-carboxylate was dissolved in H ₂ O-MeCN (w/w=1:1) (20 mL) and HCl/II Alkane (0.05 mL) was added in one portion. The mixture was stirred for 10 minutes. The solution was concentrated in EtOAc (EtOAc m.) ¹ H-NMR (400 MHz, CD ₃ OD), δ=8.99-8.94 (m, 1 H), 8.44-8.39 (m, 1 H), 8.28-8.22 (m, 1 H) 7.71-7.64 (m, 1 H), 7.61 - 7.54 (m, 1 H), 7.52 - 7.46 (m, 2 H), 5.24 - 5.16 (m, 1 H), 4.20 - 4.11 (m, 1 H), 1.66 (s, 6 H) , 1.25 (d, J = 6.4 Hz, 6 H). + ESI-MS: m/z 440.1 [M+H] ⁺

Compound 2: isopropyl 7-(3,4-difluorobenzylhydrazone)-5,5-dimethyl-2-oxooxy-1,2,5,6,7,10-hexahydropyridine [3', 2': 4,5] pyrrolo[2,3-d]azepine-9-carboxylate.

Step 1. Isopropyl 2-(benzyloxy)-7-(3,4-difluorobenzylidene)-5,5-dimethyl-5,6,7,10-tetrahydropyrido[3 ', 2': 4,5]pyrrolo[2,3-d]azepine-9-carboxylate. At 3 ° C and N ₂ , Et ₃ N (65.3 mg, 0.98 mmol) was added in one portion to isopropyl 7-((l1-methyl)(l1-oxyalkyl)boranyl)-2-( Benzyloxy)-5,5-dimethyl-5,6,7,10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-9- The carboxylic acid ester (intermediate 2, 100 mg, 246.6 μmol) was taken up in DCM (3 mL). 3,4-Difluorobenzylhydrazine chloride (174.16 mg, 370 μmol) in DCM (1 mL) was added to the mixture at 0 °C. The mixture was stirred at 20 ° C for 2 hours. The reaction mixture was by addition of H ₂ O (10mL) was quenched, extracted with EA (15mL * 3), the combined organic layers were washed with brine (10mL * 2), dried Na ₂ SO _4, and filtered under reduced pressure Concentrated under. The residue was purified by EtOAc EtOAcqqqqqq +ESI-MS : m/z 546.1 [M+H] ⁺ .

Step 2. Isopropyl 7-(3,4-difluorobenzylhydrazone)-5,5-dimethyl-2-oxooxy-1,2,5,6,7,10-hexahydropyridine [3', 2': 4,5] pyrrolo[2,3-d]azepine-9-carboxylate. Isopropyl 2-(benzyloxy)-7-(3,4-difluorobenzyl)-5,5-dimethyl-5,6,7 at H ₂ (15 Psi) and 20 ° C , 10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-9-carboxylate (50 mg, 91.65 μmol) was added to Pd(OH) ₂ /C (40 mg, 10%) in EtOAc (3 mL). The mixture was stirred at 20 ° C for 1.5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAcqqqqqqq ¹ H-NMR (400 MHz, CD ₃ , OD), δ 8.53-8.51 (d, J = 8.0 Hz, 1 H), 7.92 (s, 1 H), 7.67-7.58 (m, 1 H), 7.48-7.42 (m, 2 H), 6.64-6.62 (d, J = 8.0 Hz, 1 H), 5.19-5.12 (m, 1 H), 4.06 (br.s., 1 H), 1.56 (s, 6 H) , 1.21 (d, J = 6.4 Hz, 6 H). + ESI-MS: m/z 465.3 [M+H] ⁺ .

Compound 3: isopropyl 8-(3,4-difluorobenzylidene)-10,10-dimethyl-5,8,9,10-tetrahydropyrido[2',3':4,5 Pyrrolo[2,3-d]azepine-6-carboxylate.

The title compound was used in a similar manner to compound 1, using isopropyl 10,10-dimethyl-5,8,9,10-tetrahydropyrido[2',3':4,5] in step 1. Pyrrolo[2,3-d]azepine-6-carboxylate (intermediate 5) substituted isopropyl 5,5-dimethyl-4a,5,6,7,10,10a-hexahydropyridine [3', 2': 4,5] pyrrolo[2,3-d]azepine-9-carboxylate (Intermediate 3) was prepared. Obtained (17.8 mg, HCl salt) as a yellow solid. ¹ H-NMR (400 MHz, CD ₃ OD), δ = 8.63 - 8.57 (m, 1 H), 8.44 - 8.39 (m, 1 H), 8.34 (s, 1 H), 7.72-7.65 (m, 1 H) ), 7.65-7.60 (m, 1 H), 7.52-7.45 (m, 2 H), 5.21-5.14 (m, 1 H), 4.21-4.12 (m, 2 H), 1.64 (s, 6 H), 1.22 (d, J = 6.4 Hz, 6 H) + ESI-MS: m/z 440.1 [M+H] ⁺ .

Compound 4. Isopropyl 8-(3,4-difluorobenzylhydrazone)-10,10-dimethyl-2-oxooxy-1,2,5,8,9,10-hexahydropyridine [2',3':4,5]pyrrolo[2,3-d]azepine-6-carboxylate.

The title compound was used in a similar manner to compound 2, using isopropyl 2-(benzyloxy)-10,10-dimethyl-5,8,9,10-tetrahydropyridino[2' in step 1. , 3':4,5]pyrrolo[2,3-d]azepine-6-carboxylate (intermediate 4) in place of isopropyl 7-((l1-methyl)(l1-oxygen) Alkyl)boranyl)-2-(benzyloxy)-5,5-dimethyl-5,6,7,10-tetrahydropyrido[3',2':4,5]pyrrolo[ 2,3-d]azepine-9-carboxylate (intermediate 2) was prepared. The title compound (12 mg) was obtained as a yellow solid.

¹ H-NMR (400 MHz, CD ₃ OD), δ=8.03-7.88 (m, 2 H), 7.61 (t, J = 8.8 Hz, 1 H), 7.47-7.38 (m, 2 H), 6.45 (d) , J = 8.8 Hz, 1 H), 5.20-5.05 (m, 1 H), 4.04 (br.s., 1 H), 1.53 (s, 6 H), 1.20 (s, 6 H) + ESI-MS :m/z 456.2[M+H] ⁺ .

Compound 5. Ethyl 7-(3,4-difluorobenzylindenyl)-2-methoxy-5,5-dimethyl-5,6,7,10-tetrahydropyrido[3',2 ':4,5]pyrrolo[2,3-d]azepine-9-carboxylate.

The title compound was used in a similar manner to compound 1 using ethyl 2-methoxy-5,5-dimethyl-5,6,7,10-tetrahydropyrido[3',2':4,5 Pyrrolo[2,3-d]azepine-9-carboxylate (Intermediate 6) and 3,4-difluorobenzylhydrazine chloride, prepared by substituting TEA for DIPEA; 23 mg) of the title compound. ¹ H-NMR: (400MHz, CDCl ₃ ), δ 10.66 (s, 1H), 7.97-7.95 (d, 1H, J = 8 Hz), 7.71 (s, 1H), 7.52-7.48 (m, 1H), 7.37 -7.34(m,1H), 7.25-7.21(m,1H), 6.55-6.53(d,1H, J =8Hz), 4.30-4.25(m,2H),4.14-4.05(m, 2H), 3.97( s, 3H), 1.56 (s, 6H), 1.28-1.23 (m, 3H). +ESI-MS: m/z 455.9 [M+H] ⁺ .

Compound 6. Ethyl 8-(3,4-difluorobenzylidene)-10,10-dimethyl-5,8,9,10-tetrahydropyrido[3',4':4,5] Pyrrolo[2,3-d]azepine-6-carboxylate.

Under N _2, the _{Pd (OH) 2 (20mg,} 20%) was added ethyl 2-benzyl-8- (3,4-difluorobenzyl acyl) 10,10-dimethyl-2, 8,9,10-Tetrahydropyrido[3',4':4,5]pyrrolo[2,3-d]azepine-6-carboxylate (intermediate 9,5 mg, 184.3 μmol) in EtOAc (2 mL) in solution. Under vacuum and the suspension was degassed several times to purge H _2. The mixture was stirred for 2 hours at H ₂ (15 psi) and 20 °C. The reaction was filtered and concentrated under reduced pressure. The residue was purified by EtOAcqqqqqqq ¹ H-NMR (400 MHz, CD ₃ OD), δ 30 12.49 (br.s., 1H), 9.34 (s, 1H), 8.29 (d, J = 6.4 Hz, 1H), 8.19 (s, 1H), 8.01 (d, J = 6.4 Hz, 1H), 7.73 - 7.58 (m, 1H), 7.48 - 7.43 (m, 2H), 4.31 (q, J = 7.2 Hz, 2H), 4.14 (br.s., 2H) ), 1.64 (s, 6H), 1.24 (t, J = 7.2 Hz, 3H). +ESI-MS: m/z 425.9 [M+H] ⁺ .

Compound 7. Isopropyl 8-(3,4-difluorobenzyl)-10,10-dimethyl-5,8,9,10-tetrahydropyridine And [3', 4': 4,5]pyrrolo[2,3-d]azepine-6-carboxylate.

Add Pd(OH) ₂ (20 mg, 20%) to isopropyl 2-benzyl-8-(3,4-difluorobenzyl)-10,10-dimethyl-2,8,9, 10-tetrahydropyrido[3',4':4,5]pyrrolo[2,3-d]azepine-6-carboxylate (Intermediate 10, 95.0 mg, 184.3 μmol) in EtOAc (3 mL) In the solution. Under vacuum and the suspension was degassed several times to purge H _2. The mixture was stirred for 2 hours at H ₂ (15 psi) and 20 °C. The reaction was filtered and concentrated under reduced pressure. The residue was purified by EtOAcqqqqqq ^{1 H-NMR (400MHz, CD} 3 OD), δ 9.36 (s, 1H), 8.31 (d, J = 5.6Hz, 1H), 8.20 (s, 1H), 8.03 (d, J = 5.6Hz, 1H) , 7.76-7.57 (m, 1H), 7.56-7.32 (m, 2H), 5.27-5.08 (m, 1H), 4.14 (br, s., 2H), 1.65 (s, 6H), 1.23 (d, J =6.4 Hz,6H).+ESI-MS:m/z 439.9[M+H] ⁺

Compound 8. Isopropyl 8-(3-fluorobenzylidene)-10,10-dimethyl-5,8,9,10-tetrahydropyrido[3',4':4,5]pyrrole [2,3-d]azepine-6-carboxylate.

Step 1. Isopropyl 2-benzyl-10,10-dimethyl-2,8,9,10-tetrahydropyrido[3',4':4,5]pyrrolo[2,3-d Azinium-6-carboxylate. At 20 ° C and N ₂ , HCl / II Alkane (4M, 1.4 mL) was added in one portion to 2-(5-benzyl-3a,4,5,6,7,7a-hexahydro-1H-pyrrolo[3,2-c]pyridin-3-yl -2-methylpropan-1-amine (intermediate 8, product from step 4, 800 mg, 2.8 mmol) in two A solution of alkane (5 mL). The mixture was stirred at 20 ° C for 30 minutes and the solvent was removed in vacuo. The residue was dissolved in propan-2-ol (10 mL) and isopropyl 3-bromo-2-oxopropionate (885.11 mg, 4.23 mmol, 1.5 eq) was added and the mixture was heated to 80 ° C and stirred 5 hour. The mixture was concentrated under reduced pressure and diluted with pyridine (10 mL) and then warmed to 100 ° C for 3 hr. The mixture was cooled to 20 ° C and concentrated under reduced pressure. The residue was poured into ice water (w/w = 1/1) (30 mL) and stirred for 2 min. The aqueous phase was extracted with DCM (50 mL * 3). The combined organic phases of (30mL * 2) and washed with brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc) +ESI-MS: m/z 390.2[M+H] ⁺

Step 2. Isopropyl 2-benzyl-8-(3-fluorobenzylidene)-10,10-dimethyl-2,8,9,10-tetrahydropyrido[3',4':4 , 5] pyrrolo[2,3-d]azepine-6-carboxylate. HATU (146.4 mg, 385.1 μmol) was added in one portion to a solution of 3-fluorobenzoic acid (53.9 mg, 385.1 μmol) and DIPEA (66.3 mg, 513.5 μmol) in DMF (1.5 mL) at 20 ° C under N ₂ in. The mixture was stirred at 20 ° C for 30 minutes and then isopropyl 2-benzyl-10,10-dimethyl-2,8,9,10-tetrahydropyridinium [3' in DMF (1 mL). , 4':4,5]pyrrolo[2,3-d]azepine-6-carboxylate (100 mg, 256.7 μmol) was added. The mixture was stirred at 20 ° C for 3 hours. The mixture was poured into ice water (w/w = 1/1) (20 mL) and stirred for 2 min. The aqueous phase was extracted with DCM (30 mL * 2). The combined organic phases were washed with water (40mL * 2) washed, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc) +ESI-MS: m/z 512.1[M+H] ⁺

Step 3. Isopropyl 8-(3-fluorobenzylidene)-10,10-dimethyl-5,8,9,10-tetrahydropyrido[3',4':4,5]pyrrole [2,3-d]azepine-6-carboxylate. Add Pd(OH) ₂ (38.4 mg, 20%) to isopropyl 2-benzyl-8-(3-fluorobenzylidene)-10,10-dimethyl-2,8,9,10- A solution of tetrahydropyrido[3',4':4,5]pyrrolo[2,3-d]azepine-6-carboxylate (70 mg, 136.8 mol) in EtOAc (2 mL). Under vacuum and the suspension was degassed several times to purge H _2, and stirred at 20 ℃ and H ₂ (15psi) 1.5 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (neutral conditions). The product was dissolved in H ₂ O-MeCN (w/w = 1:1) (30 mL) and HCl / Alkane (4M, 0.5 mL) was added in one portion. The mixture was stirred for 10 minutes. The solution was concentrated in vacuo and lyophilized to afford a pale yellow solid (18.7 g, 29.3%). ¹ H-NMR (400 MHz, CD ₃ OD), δ 9.36-9.30 (m, 1 H), 8.31-8.25 (m, 1 H), 8.23-8.18 (m, 1 H), 8.04-7.97 (m, 1 H), 7.61-7.53 (m, 1 H), 7.44-7.38 (m, 3 H), 5.18-5.11 (m, 1 H), 4.19-4.09 (m, 2 H), 1.65 (s, 6 H) , 1.19 (d, J = 6.4 Hz, 6 H). +ESI-MS: m/z 422.1 [M+H] ⁺ .

Compound 9. Isopropyl 8-(4-fluorobenzylidene)-10,10-dimethyl-5,8,9,10-tetrahydropyrido[3',4':4,5]pyrrole [2,3-d]azepine-6-carboxylate.

The title compound was prepared in a procedure analogous to Compound 8 using 4-fluorobenzoic acid in EtOAc (EtOAc) ¹ H-NMR (400 MHz, CD ₃ OD), δ 9.36-9.32 (m, 1 H), 8.31-8.26 (m, 1 H), 8.23-8.19 (m, 1 H), 8.04-7.99 (m, 1 H), 7.74-7.67 (m, 2 H), 7.33-7.26 (m, 2 H), 5.20-5.12 (m, 2 H), 4.19-4.11 (m, 2 H), 1.65 (s, 6 H) , 1.20 (d, J = 6.4 Hz, 6 H). + ESI-MS: m/z 422.1 [M+H] ⁺

Compound 10. Isopropyl 8-(3-chlorobenzylidene)-10,10-dimethyl-5,8,9,10-tetrahydropyrido[3',4':4,5]pyrrole [2,3-d]azepine-6-carboxylate.

The title compound was prepared in a procedure analogous to compound 8 using 3-chlorobenzoic acid in 3-chlorobenzoic acid to afford (12.8 mg) as a yellow solid. ¹ H-NMR (400 MHz, CD ₃ OD), δ 9.33 (s, 1 H), 8.31-8.25 (m, 1 H), 8.21 (s, 1 H), 8.04-7.97 (m, 1 H), 7.69 -7.62 (m, 2 H), 7.57-7.50 (m, 2 H), 5.19-5.12 (m, 1 H), 4.18-4.09 (m, 2 H), 1.65 (s, 6 H), 1.20 (d) , J = 6.4 Hz, 6 H). + ESI-MS: m/z 438.1 [M+H] ⁺

Compound 11. Isopropyl 8-(4-chlorobenzylidene)-10,10-dimethyl-5,8,9,10-tetrahydropyrido[3',4':4,5]pyrrole [2,3-d]azepine-6-carboxylate.

The title compound was prepared in a procedure analogous to Compound 8 using 4-chlorobenzoic acid in EtOAc (EtOAc) ¹ H-NMR (400 MHz, CD ₃ OD), δ 9.36-9.31 (m, 1 H), 8.30-8.25 (m, 1 H), 8.21-8.16 (m, 1 H), 8.03-7.98 (m, 1 H), 7.66-7.61 (m, 2 H), 7.60-7.55 (m, 2 H), 5.19-5.12 (m, 1 H), 4.17-4.11 (m, 2 H), 1.65 (s, 6 H) , 1.20 (d, J = 6.4 Hz, 6 H). + ESI-MS: m/z 438.1 [M+H] ⁺ .

Compound 12. Isopropyl 7-(3,4-difluorobenzylidene)-5,5-dimethyl-5,6,7,10-tetrahydropyrido[4',3':4,5 Pyrrolo[2,3-d]azepine-9-carboxylate.

Isopropyl 5,5-dimethyl-7,10-dihydro-6H-pyrido[2,3]pyrrolo[2,4-c]azepine-9-carboxylate (Intermediate 13, 57.4 mg, 200.3 μmol) was added to a solution of 3,4-difluorobenzoic acid (63.3 mg, 400.8 μmol), HATU (91.4 mg, 240.5 μmol) and DIPEA (51.8 mg, 400.8 μmol) in DMF (4 mL). The mixture was stirred at 25 ° C for 20 minutes. The reaction by H ₂ O (100mL) and extracted with quenched with DCM (50mL). The organic layer was washed with brine (50mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative EtOAc (EtOAc) ¹ H-NMR (400 MHz, CD ₃ OD), δ = 12.69 (br, 1H), 9.00 (s, 1H), 8.39 (s, 1H), 8.30 (d, J = 6.4 Hz, 1H), 8.12 (d) , J = 6.4 Hz, 1H), 7.70-7.65 (m, 1H), 7.50-7.46 (m, 2H), 5.20-5.14 (m, 1H), 4.14 (br, 1H), 2.82 (s, 2H), 1.64 (m, 6H), 1.23 (s, 3H), 1.21. (s, 2H). ESI-MS: m/z 440.0 [M+H] ⁺ .

Compound 13. 8-(3,4-Difluorobenzylidene)-N-isopropyl-N,10,10-trimethyl-5,8,9,10-tetrahydropyrido[3',4 ':4,5]pyrrolo[2,3-d]azepine-6-formamide.

Add a solution of Et ₃ N (250.7 mg, 2.48 mmol) and 3,4-difluorobenzylhydrazine chloride (218.7 mg, 1.24 mmol) in DCM (2 mL) to N-isopropyl-N,10,10 -trimethyl-5,8,9,10-tetrahydropyrido[3',4':4,5]pyrrolo[2,3-d]azepine-6-carboxamide (intermediate 14, A solution of 129 mg, 412.92 umol) in DCM (10 mL). The resulting solution was stirred at 25 ° C under N ₂ for 1 hour. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to afford 1013 (10mg, 5.35%). ¹ H-NMR (400 MHz, CD ₃ OD), δ = 9.36 (s, 1H), 8.30 (d, J = 6.4 Hz, 1H), 7.86 (d, J = 6.4 Hz, 1H), 7.58 (t, J = 9.2 Hz, 1H), 7.46-7.35 (m, 2H), 6.93 (s, 1H), 4.15 (br.s., 3H), 2.93 (br.s., 3H), 1.65 (s, 6H), 1.12(br.s.,6H).+ESI-MS:m/z 453.1[M+H] ⁺

Farnesoid X receptor assay

The farnesoid X receptor (FXR) assay was performed by Indigo Biosciences (cat# IB00601-32) as a set of cell-based reporter assays sold. Briefly, compounds were diluted in cell recovery medium (CRM) at a 2 fold final concentration. Indigo's FXR reporter cells were thawed and added to 96-well plates at 100 μl per well. Compounds were tested at a maximum concentration of 100 [mu]M with an 8-point dilution curve (3-fold dilution between points). Chenodeoxycholic acid ( CDCA ) was used as a positive control group with a maximum concentration of 1200 μM. 100 μl of the diluted compound was added to each well-inoculated well. The treated cells were then incubated at 37 ° C, 5% CO ₂ for 22 to 25 hours. The next day, the medium was removed from the cells and luciferase detection reagent was added to the wells (100 μl/well). The assay plate was allowed to stand at room temperature for 25 minutes without shaking. Luminescence was read on a Victor X3 multi-label reader (Perkin Elmer, Waltham, MA) and was set to read at 0.5 second per well. The results of some of the illustrative compounds disclosed herein are shown in Table 1.

TR-FRET FXR Verification

FXR agonists were tested in a cell-free FXR co-activation assay. The FXR activation assay was performed using the LanthaScreen ^® TR-FRET FXR Coactivator Kit (ThermoFisher Scientific) to determine the EC50. In total, 20 [mu]L of reaction was performed in 384 well plates containing different concentrations of agonist, 5 nM FXR/LBD, 500 nM fluorescent agent and 5 nM AntiGST antibody. The plate was incubated at 37 ° C for 90 minutes. Fluorescence changes were monitored using a Victor X3 multi-label reader (PerkinElmer). All binding curves were generated by plotting the emission ratio versus ligand concentration, and % activation was reported as a function of CDCA% activation. The results of some of the illustrative compounds disclosed herein are shown in Table 1.

Claims (26)

a compound of formula I, or a tautomer thereof: Wherein R ¹ is selected from the group consisting of H, halogen, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, -OC _1-6 alkyl and -OC _3-6 cycloalkyl; ² is selected from the group consisting of halogen, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, -OC _1-6 alkyl and -OC _3-6 cycloalkyl; R ³ is selected from a group consisting of C _1-6 alkyl and C _3-6 cycloalkyl; R ⁴ and R ⁵ are each independently selected from the group consisting of H and C _1-6 alkyl; A, B, D and E At least one of them is N and the other is CH or CR ⁶ ; R ⁶ is selected from the group consisting of halogen, -CN, OH, -OC _1-6 alkyl and C _1-6 alkyl; Z system O; G is selected from the group consisting of CH and N; J is selected from the group consisting of C, CH and N; A single or double bond; or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein R ¹ is H and R ² is selected from the group consisting of F and Cl. The compound of claim 1, wherein R ¹ and R ² are each F. The compound of any one of the preceding claims, wherein R ³ is C _1-6 alkyl. The compound of any one of the preceding claims, wherein R ³ is C ₃ alkyl. The compound of any one of the preceding claims, wherein R ⁴ and R ⁵ are each independently C _1-6 alkyl. The compound of any one of the preceding claims, wherein R ⁴ and R ⁵ are each methyl. The compound of any one of the preceding claims, wherein the A-line N and the B, D and E systems are each independently selected from the group consisting of CH and CR ⁶ . The compound of any one of claims 1 to 7, wherein the B-line N and the A, D, and E systems are each independently selected from the group consisting of CH and CR ⁶ . The compound of any one of claims 1 to 7, wherein the D system N and the A, B and E systems are each independently selected from the group consisting of CH and CR ⁶ . The compound of any one of claims 1 to 7, wherein the E-line N and the A, B and D systems are each independently selected from the group consisting of CH and CR ⁶ . The compound of any one of claims 1 to 11, wherein R ⁶ is -OH. The compound of any one of claims 1 to 11, wherein R ⁶ is -OC _1-6 alkyl. The compound of any one of the preceding claims, wherein G is N. A compound according to any one of the preceding claims, wherein J is C and Double key. The compound of any one of claims 1 to 19, wherein Formula I is selected from the group consisting of: The compound of claim 1, wherein R ¹ is selected from the group consisting of H and halogen; R ² is halogen; R ³ is C _1-6 alkyl; and R ⁶ is selected from OH and -OC _1-6 a group of alkyl groups; G system N; J system C; Double key. The compound of claim 1, wherein R ³ is C _1-6 alkyl; G is N; J is C; Double key. A compound as shown in Table 1. The compound of claim 1, wherein the compound is selected from the group consisting of ethyl 8-(3,4-difluorobenzyl)-10,10-dimethyl-5,8,9 , 10-tetrahydropyrido[3',4':4,5]pyrrolo[2,3-d]azepine-6-carboxylate, ethyl 7-(3,4-difluorobenzyl) )-2-methoxy-5,5-dimethyl-5,6,7,10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine -9-carboxylate, isopropyl 8-(3,4-difluorobenzyl)-10,10-dimethyl-5,8,9,10-tetrahydropyrido[3',4' :4,5]pyrrolo[2,3-d]azepine-6-carboxylate, isopropyl 7-(3,4-difluorobenzylidene)-5,5-dimethyl-5, 6,7,10-tetrahydropyrido[4',3':4,5]pyrrolo[2,3-d]azepine-9-carboxylate, isopropyl 7-(3,4-di Fluobenzyl)-5,5-dimethyl-5,6,7,10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-9 -carboxylate, isopropyl 8-(3,4-difluorobenzyl)-10,10-dimethyl-5,8,9,10-tetrahydropyrido[2',3':4 , 5] pyrrolo[2,3-d]azepine-6-carboxylate, isopropyl 8-(3,4-difluorobenzyl)-10,10-dimethyl-2-oxo Base-1,2,5,8,9,10-hexahydropyrido[2',3':4,5]pyrrolo[2,3-d]azepine-6-carboxylate, isopropyl 7-(3,4-Difluorobenzylhydrazone)-5,5-dimethyl-2-oxooxy-1,2,5,6,7,10-hexahydropyrido[3',2' :4,5]pyrrolo[2,3-d]azin-9-carboxylate, isopropyl 8-(3-fluorobenzylidene)-10,10-dimethyl-5,8,9 , 10-tetrahydropyrido[3',4':4,5]pyrrolo[2,3-d]azepine-6-carboxylate, isopropyl 8-(4-fluorobenzylidene)- 10,10-Dimethyl-5,8,9,10-tetrahydropyrido[3',4':4,5]pyrrolo[2,3-d]azepine-6-carboxylate, different Propyl 8-(3-chlorobenzylidene)-10,10-dimethyl-5,8,9,10-tetrahydropyrido[3',4':4,5]pyrrolo[2,3 -d]azepine-6-carboxylate, and Isopropyl 8-(4-chlorobenzyl)-10,10-dimethyl-5,8,9,10-tetrahydropyrido[3',4':4,5]pyrrolo[2, 3-d]azepine-6-carboxylate. The compound of claim 1, wherein the compound is selected from the group consisting of: A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. A method of modulating a farnesoid X receptor comprising contacting the receptor with a compound of any one of claims 1 to 21. A method of treating a patient diagnosed with a disease or condition modulated by a farnesoid X receptor, comprising administering to the patient an effective amount of a compound of any one of claims 1 to 21. The method of claim 24, wherein the disease or condition is nonalcoholic steatohepatitis. A method of making a compound of formula 1.