阅读说明：本技术 氨基甲酸酯磺酸胆汁酸衍生物的制备方法 (Preparation method of carbamate sulfonic acid bile acid derivative ) 是由 国强·王 勇·何 布雷特·格兰杰 学超·邢 逸·孙·奥拉 于 2018-04-09 设计创作，主要内容包括：本发明涉及制备式(I)的化合物和式(II)的化合物的方法：<Image he="209" wi="700" file="DDA0002268769610000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>或其药学上可接受的盐或溶剂化物。这些化合物和药物组合物可用作FXR或TGR5调节剂。具体的,本发明涉及胆汁酸衍生物及其制备和使用方法。本发明涉及制备式(III),式(IV),式(V)和式(VI)的化合物的方法,<Image he="180" wi="700" file="DDA0002268769610000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image><Image he="241" wi="282" file="DDA0002268769610000013.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>本发明还涉及制备化合物(VII),(VIII)和(IX)的方法,<Image he="150" wi="700" file="DDA0002268769610000014.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image><Image he="312" wi="685" file="DDA0002268769610000015.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention relates to a process for the preparation of compounds of formula (I) and compounds of formula (II): or a pharmaceutically acceptable salt or solvate thereof. These compounds and pharmaceutical compositions are useful as FXR or TGR5 modulators.In particular, the present invention relates to bile acid derivatives and methods of making and using the same. The invention relates to a method for producing compounds of the formulae (III), (IV), (V) and (VI), the invention also relates to a method for producing the compounds (VII), (VIII) and (IX),)

1. A process for preparing a compound of formula (I) characterized in that:

wherein:

R¹selected from the group consisting of:

(1) substituted or unsubstituted-C₁-C₈An alkyl group;

(2) substituted or unsubstituted-C₂-C₈An alkenyl group;

(3) substituted or unsubstituted-C₂-C₈An alkynyl group;

(4) substituted or unsubstituted-C₃-C₈A cycloalkyl group;

(5) substituted or unsubstituted aryl;

(6) substituted or unsubstituted arylalkyl;

(7) substituted or unsubstituted 3 to 12 membered heterocycloalkyl;

(8) substituted or unsubstituted heteroaryl;

(9) substituted or unsubstituted heteroarylalkyl; and

(10)NR_aR_b(ii) a Wherein R is_aAnd R_bEach independently selected from hydrogen, substituted or unsubstituted-C₁-C₈Alkyl, substituted or unsubstituted-C₂-C₈Alkenyl, substituted or unsubstituted-C₂-C₈Alkynyl, substituted or unsubstituted-C₃-C₈Cycloalkyl, substituted, R_aAnd R_bTogether with the nitrogen atom to which they are attached form a 3-to 12-membered heterocyclic ring;

the method comprises the following steps:

step (1a), converting Compound 1 to Compound (III),

wherein PG is a hydroxyl protecting group;

a step (2a) of converting the compound (III) into a compound (IV),

and

step (3a), converting compound (IV) to compound (I).

2. The method of claim 1, wherein: r¹Is that

3. The method of claim 1 or 2, wherein: the step (1a) comprises:

step (1ai), compound 1 and C are reacted under acid catalysis₁-C₆-reaction of an alkanol to form compound 2,

wherein R is⁶Is C₁-C₆-an alkyl group;

step (1aii) of reacting compound 2 with a strong base in the presence of a hydroxyl protecting agent to produce a compound of formula 2a,

and reacting the compound of formula 2a with a halogenating agent to form compound 3,

wherein:

PG¹is a hydroxy protecting group; and

R²selected from Br, I and Cl;

step (1aiii), Compound 3 is reacted with an organic base to eliminate HR²And the compound 4 is generated, and the compound,

step (1aiv), deprotection of compound 4 to yield compound 5,

step (1av), reacting compound 5 with a hydroxyl protecting agent to produce compound 6,

and

step (1avi) of oxidatively cleaving and oxidizing compound 6 in the presence of a base to produce a compound of formula (III),

4. a method as claimed in claim 1,2 or 3, characterized by: the step (2a) comprises:

step (2ai), in alkaliIn the presence of (A), reacting the compound (III) with a compound of the formula R³OC (O) Cl to produce compound 7,

wherein R is³Is an alkyl group; and

step (2aii), reducing compound 7 to produce compound (IV),

5. the method of any of claims 1 to 4, wherein: the step (3a) comprises:

step (3ai), reacting compound IV with a compound of formula 15E,

wherein R is⁴Is imidazol-1-yl, alkyl-O-aryl-O, Cl or-CCl₃In the presence of an organic base to produce a compound of formula 14,

and

step (3aii), deprotecting the compound of formula 14 to yield the compound of formula (I).

6. The method of claim 5, wherein: step (3ai) is carried out in an aprotic solvent at a temperature of about 0 ℃ to about 80 ℃.

7. A process for preparing a compound of formula (II):

wherein:

R¹selected from the group consisting of:

(1) substituted or unsubstituted-C₁-C₈An alkyl group;

(2) substituted or unsubstituted-C₂-C₈An alkenyl group;

(3) substituted or unsubstituted-C₂-C₈An alkynyl group;

(4) substituted or unsubstituted-C₃-C₈A cycloalkyl group;

(5) substituted or unsubstituted aryl;

(6) substituted or unsubstituted arylalkyl;

(7) substituted or unsubstituted 3 to 12 membered heterocycloalkyl;

(8) substituted or unsubstituted heteroaryl;

(9) substituted or unsubstituted heteroarylalkyl; and

(10)NR_aR_b(ii) a Wherein R is_aAnd R_bEach independently selected from hydrogen, substituted or unsubstituted-C₁-C₈Alkyl, substituted or unsubstituted-C₂-C₈Alkenyl, substituted or unsubstituted-C₂-C₈Alkynyl, substituted or unsubstituted-C₃-C₈Cycloalkyl, substituted, R_aAnd R_bTogether with the nitrogen atom to which they are attached form a 3-to 12-membered heterocyclic ring;

the method comprises the following steps:

step (1a), converting Compound 1 to a Compound of formula (III),

wherein PG is a hydroxyl protecting group;

a step (2b) of converting the compound of formula (III) into a compound of formula (V),

a step (3b) of converting the compound of formula (V) into a compound of formula (VI),

and

step (4b), converting the compound of formula (VI) to a compound of formula (II).

8. The method of claim 7, wherein: r¹Is that

9. The method of claim 7 or 8, wherein: the step (1a) comprises:

step (1ai), compound 1 and C are reacted under acid catalysis₁-C₆-reaction of an alkanol to form compound 2,

wherein R is⁶Is C₁-C₆-an alkyl group;

step (1aii) of reacting compound 2 with a strong base in the presence of a hydroxyl protecting agent to produce a compound of formula 2a,

and reacting the compound of formula 2a with a halogenating agent to form compound 3,

wherein:

PG¹is a hydroxy protecting group; and

R²selected from Br, I and Cl;

step (1aiii), Compound 3 is reacted with an organic base to eliminate HR²And the compound 4 is generated, and the compound,

step (1aiv), deprotection of compound 4 to yield compound 5,

step (1av), reacting compound 5 with a hydroxyl protecting agent to produce compound 6,

and

step (1avi) of oxidatively cleaving and oxidizing compound 6 in the presence of a base to produce a compound of formula (III),

10. the method of any of claims 7 to 9, wherein: the step (2b) comprises:

step (2bi), reacting the compound (III) with C under acid catalysis₁-C₆-reaction of an alkanol to form compound 8,

step (2bii) of reacting compound 8 with a silylating agent in the presence of a base to produce compound 9,

wherein PG³Is a silyl group;

step (2biii) of reacting compound 9 with acetaldehyde in the presence of a Lewis acid to produce compound 10,

step (2biv), hydrogenating compound 10 to produce compound 11,

step (2bv) of reacting compound 11 with a base in a protic solvent or a mixture of a protic solvent and an aprotic solvent to produce compound 12,

and

step (2bvi), reacting compound 12 with a hydroxy protecting agent to produce the compound of formula (V).

11. The method of any of claims 7 to 10, wherein: the step (3b) comprises:

step (3bi), reacting the compound of formula (V) with formula R³(ii) reaction of the compound of OC (O) Cl to yield the compound of formula 13,

wherein R is³Is an alkyl group; and

step (3bii), reducing compound 13 to yield a compound of formula (VI).

12. The method of any of claims 7 to 11, wherein: the step (4b) comprises:

step (4bi), reacting compound VI with a compound of formula 15E,

wherein R is⁴Is imidazol-1-yl, alkyl-O-aryl-O, Cl or-CCl₃In the presence of an organic base to produce a compound of formula 17,

and

step (4bii), deprotecting the compound of formula 17 to produce a compound of formula (II).

13. The method of claim 12, wherein: step (4bii) is carried out in an aprotic solvent at a temperature of about 0 ℃ to about 80 ℃.

14. The method of claim 5 or 12, wherein: the compound of formula 15E is selected from compound 15A, compound 15B, compound 15C, and compound 15D:

wherein R is⁵Is an alkyl or aryl group.

15. The method of claim 5 or 12, wherein: the compound of formula 15E is selected from compound 20A, compound 20B, compound 20C, and compound 20D:

wherein R is⁵Is an alkyl or aryl group.

16. The method of any of claims 1 to 15, wherein: PG is TBS.

17. The method of any of claims 3 and 9 to 13, wherein: r⁶Is methyl.

18. The method of any of claims 3 and 9 to 13, wherein: r⁶Is methyl and PG is TBS.

Technical Field

The present invention relates to processes and intermediates for the preparation of biologically active molecules useful as FXR or TGR5 modulators, in particular to bile acid derivatives and processes for their preparation and use.

Background

Farnesoid X Receptor (FXR) is the orphan nuclear receptor originally identified from rat liver cDNA library (bm. forman, et al, Cell,1995,81(5), 687-h 693), which is most closely related to the insect ecdysone receptor. FXR is a member of the nuclear receptor family of ligand-activated transcription factors, which include receptors for steroids, retinoids, and thyroid hormones (dj. magelsdorf, et al, Cell,1995,83(6), 841-850). The relevant physiological ligand for FXR is bile acid (D.parks et al, Science,1999,284(5418), 1362-. One of the most potent is chenodeoxycholic acid (CDCA), which regulates the expression of several genes involved in bile acid homeostasis. Farnesol and derivatives, together called farnesoid, were originally described as activating rat orthologous receptors at high concentrations, but they did not activate human or mouse receptors. FXR is expressed in the liver throughout the entire gastrointestinal tract, including the esophagus, stomach, duodenum, small intestine, colon, ovary, adrenal gland, and kidney. In addition to controlling gene expression within cells, FXR appears to be involved in paracrine and endocrine signaling by upregulating the cytokine fibroblast growth factor (J.Holt et al, Genes Dev.,2003,17(13), 1581-.

Small molecule compounds useful as FXR modulators have been disclosed in the following publications: WO 2000/037077, WO 2002/072598, WO 2003/015771, WO 2003/099821, WO 2004/00752, WO 2004/048349, WO 2005/009387, WO 2005/082925, US 2005/0054634, WO 2007/052843, WO 2007/070796, WO 2007/076260, WO 2007/092751, WO 2007/095174, WO 2007/140174, WO 2007/140183, US 2007/0142340, WO 2008/000643, WO 2008/002573, WO 2008/025539, WO 2008/025540, WO 2008/051942, WO 2008/073825, WO 2008/157270, US 2008/0299118, US 2008/0300235, WO 2009/005998, WO 2009/012125, WO 2009/027264, WO 2009/062874, WO 2009/127321, WO 2009/149795, US 2009/0131409, US 2009/0137554, US 2009/0163474, US 2009/0163552, US2009/0215748, WO 2010/043513, WO 2011/020615, WO 2011/117163, WO 2012/087519, WO2012/087520, WO 2012/087521, WO 2013/007387, WO 2013/037482, WO 2013/166176, WO2013/192097, WO 2014/184271, US 2014/0186438, US 2014/0187633, WO 2015/017813, WO2015/069666, WO 2016/073767, WO 2016/116054, WO 2016/103037, WO 2016/096116, WO2016/096115, WO 2016/097933, WO 2016/081918, WO 2016/127924, WO 2016/130809, WO 2016/145295, WO 2016/173524, CN 106632294, CN 106588804, US 2017/0196893, WO 2017/062763, WO 2017/053826, WO 632, CN 106632294, CN 106588804, US 2017/0196893, WO 2017/062763, WO 2017/053826, CN 106518708, CN 106518946, CN 106478759, CN 106478447, CN106478453, WO 2017/027396, WO 2017/049172, WO 2017/049173, WO 2017/049176, WO2017/049177, WO 2017/118294, WO 2017/128896, WO 2017/129125, WO 2017/133521, WO2017/147074, WO 2017/147174, WO 2017/145041 and WO 2017/156024 a1.

Other small molecule FXR modulators have also been reviewed recently (r.c. buijsman et al. curr. med. chem.2005,12, 1017-.

The TGR5 receptor is a G protein-coupled receptor that has been identified as a cell surface receptor responsive to Bile Acids (BAs). The primary structure of TGR5 and its reactivity towards bile acids has been found to be highly conserved in TGR5 in humans, cows, rabbits, rats and mice, thus suggesting that TGR5 has important physiological functions. TGR5 has been found to be widely distributed not only in lymphoid tissues but also in other tissues. High levels of TGR5 mRNA were detected in placenta, spleen and monocytes/macrophages. Bile acids have been shown to induce internalization of TGR5 fusion proteins from the cell membrane into the cytoplasm (Kawamata et al, j.bio.chem.,2003,278,9435). TGR5 has been found to be identical to hGPCR19 reported by Takeda et al, FEBS Lett.2002,520, 97-101.

TGR5 is associated with intracellular accumulation of cAMP, which is widely expressed in different cell types. While activation of this membrane receptor in macrophages reduces pro-inflammatory cytokine production, (Kawamata, y., et al., j.biol. chem.2003,278,9435-9440) stimulation of TGR5 by BA within adipocytes and myocytes enhances energy expenditure (Watanabe, m., et al. nature.2006,439, 484-489). The latter effect involves cAMP-dependent induction of iodothyronine deiodinase type 2 (D2), which causes increased thyroid hormone activity by locally converting T4 to T3. Consistent with the role of TGR5 in controlling energy metabolism, female TGR5 knockout mice showed significant fat accumulation and weight gain when challenged with a high fat diet, suggesting that the lack of TGR5 reduces energy expenditure and causes obesity (Maruyama, t. Furthermore, it has been reported that, in association with the involvement of TGR5 in energy homeostasis, bile acid-activated membrane receptors promote the production of glucagon-like peptide 1(GLP-1) in mouse enteroendocrine cell lines (Katsuma, s., biochem, biophysis, res, commu., 2005,329, 386-390). Based on all the above observations, TGR5 is an attractive target for the treatment of diseases such as obesity, diabetes and metabolic syndrome.

In addition to the treatment and prevention of metabolic diseases using TGR5 agonists, compounds that modulate TGR5 modulators may also be useful in the treatment of other diseases, such as central nervous diseases as well as inflammatory diseases (WO 01/77325 and WO 02/84286). Modulators of TGR5 also provide methods of modulating bile acid and cholesterol homeostasis, fatty acid absorption, and protein and carbohydrate digestion.

There is a need to develop FXR and/or TGR5 modulators for the treatment and prevention of diseases.

Disclosure of Invention

The present invention relates to a process for the preparation of compounds of formula (I) and compounds of formula (II):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R¹selected from the group consisting of:

(1) substituted or unsubstituted-C₁-C₈An alkyl group;

(2) substituted or unsubstituted-C₂-C₈An alkenyl group;

(3) substituted or unsubstituted-C₂-C₈An alkynyl group;

(4) substituted or unsubstituted-C₃-C₈A cycloalkyl group;

(5) substituted or unsubstituted aryl;

(6) substituted or unsubstituted arylalkyl;

(7) substituted or unsubstituted 3 to 12 membered heterocycloalkyl;

(8) substituted or unsubstituted heteroaryl;

(9) substituted or unsubstituted heteroarylalkyl; and

(10)NR_aR_b(ii) a Wherein R is_aAnd R_bEach independently selected from hydrogen, substituted or unsubstituted-C₁-C₈Alkyl, substituted or unsubstituted-C₂-C₈Alkenyl, substituted or unsubstituted-C₂-C₈Alkynyl, substituted or unsubstituted-C₃-C₈Cycloalkyl, substituted, R_aAnd R_bTogether with the nitrogen atom to which they are attached form a 3-to 12-membered heterocyclic ring.

A preferred embodiment of the compound of formula (I) is compound (VII):

a preferred embodiment of the compound of formula (II) is compound (VIII):

another preferred embodiment of the compound of formula (II) is compound (IX):

in certain embodiments, the present invention relates to methods of preparing compounds of formula (III), which are intermediates in the synthesis of compounds of formula (I) and formula (II),

where PG is a hydroxyl protecting group such as, but not limited to, acetyl, THP, MOM, MEM, SEM, or silyl, such as TBS, TES, TMS, TIPS, or TBDPS. Preferably, PG is TBS.

In certain embodiments, the present invention relates to methods of preparing compounds of formula (IV), which are intermediates in the synthesis of compounds of formula (I),

in certain embodiments, the present invention relates to methods of preparing compounds of formula (V) which are intermediates in the synthesis of compounds of formula (II),

in certain embodiments, the present invention relates to processes for preparing compounds of formula (VI), which are useful intermediates in the synthesis of compounds of formula (II),

in one embodiment, a method of preparing a compound of formula (I) comprises the steps of:

step 1(a), converting Compound 1(CDCA) to a Compound of formula (III),

step 2(a), converting the compound of formula (III) to a compound of formula (IV),

step 3(a), converting the compound of formula (IV) to a compound of formula (I),

wherein PG and R¹As previously defined.

In one embodiment, a method of preparing a compound of formula (II) comprises the steps of:

step 1(a), converting Compound 1(CDCA) to a Compound of formula (III),

step 2(b), converting the compound of formula (III) to a compound of formula (V),

step 3(b), converting the compound of formula (V) to a compound of formula (VI),

step 4(b), converting the compound of formula (VI) to a compound of formula (II),

wherein PG and R¹As previously defined.

The invention also relates to a method for increasing the product yield and reducing the process steps for medium and large scale production of compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI).

Compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) are useful for treating chronic liver disease, such as chronic liver disease selected from the group consisting of Primary Biliary Cirrhosis (PBC), Chordophosis (CTX), Primary Sclerosing Cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis during pregnancy, parenteral nutrition-associated cholestasis (PNAC), bacterial overgrowth or sepsis-associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver transplantation-associated graft-versus-host-stone disease, in vivo donor transplanted liver regeneration, congenital liver fibrosis, common bile duct, granulomatous liver disease, intrahepatic or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis and alpha 1-antitrypsin deficiency (WO 2016/086218).

Detailed Description

The present invention relates to a process for the preparation of compounds of formula (I) and compounds of formula (II):or pharmaceutically acceptable thereofA salt or solvate of wherein R¹As previously defined.

In certain embodiments, the present invention relates to processes for preparing compounds of formula (I) and compounds of formula (II), and pharmaceutically acceptable salts thereof, wherein R¹Is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted 3 to 12 membered heterocycloalkyl.

In certain embodiments, the present invention relates to processes for preparing compounds of formula (I) and compounds of formula (II), and pharmaceutically acceptable salts thereof, wherein R¹Is substituted or unsubstituted phenyl; or a substituted or unsubstituted pyridyl group.

In certain embodiments, the present invention relates to processes for preparing compounds of formula (I) and compounds of formula (II), and pharmaceutically acceptable salts thereof, wherein R¹Is substituted or unsubstitutedOr substituted or unsubstituted

In another embodiment, the present invention relates to a process for preparing compound (VII),

in another embodiment, the present invention relates to a process for preparing compound (VIII),

in another embodiment, the present invention relates to a process for the preparation of compound (IX),

in one embodiment, step 1(a) is listed in scheme 1). The method comprises the following steps: step 1(a) (i) with C₁-C₆Esterify chenodeoxycholic acid (CDCA, compound 1) with an alkanol to produce compound 2, preferably methanol or ethanol, more preferably methanol; step 1(a) (ii), reacting compound 2 with a strong base in the presence of a suitable hydroxyl protecting agent and an electrophilic halogen source to produce compound 3; step 1(a) (iii) Elimination of R in Compound 3²To yield compound 4; step 1(a) (iv), deprotection of compound 4 to give compound 5; step 1(a) (v): protecting compound 5 to yield compound 6; step 1(a) (vi), oxidatively decomposing and oxidizing compound 6 to produce compound (III).

Scheme 1:

wherein PG is previously defined; PG (Picture experts group)¹Is a hydroxyl protecting group, preferably selected from silyl groups such as, but not limited to, TMS, TES, TBS, TIPS and TBDPS; and R²Selected from Cl, Br and I. Preferred PG¹Is TMS. Preferably, PG is TBS. R⁶Is C₁-C₆The alkyl group is preferably a methyl group or an ethyl group, and more preferably a methyl group.

Step 2(a) was carried out as described in scheme 2. Thus, in step 2(a) (i), compound (III) is reacted with chloroformate reagent R₃OC (O) Cl to form the anhydride compound 7, followed by step 2(a) (ii) to reduce the compound 7 to form the compound (IV).

Scheme 2:

wherein PG is previously defined; r³Is an alkyl radical, preferably C₁-C₆Alkyl groups such as, but not limited to, methyl, ethyl, isopropyl, or isobutyl. Preferred R³Is an isobutyl group.

The invention will be better understood in connection with steps 1(a) (i) -1(a) (vi) and 2(a) (i) -2(a) (ii), wherein PG, PG¹，R²And R³As previously defined, unless otherwise indicated. It will be apparent to those of ordinary skill in the art that the method of the invention may be practiced by substituting the appropriate reactants, and that the order of the steps themselves may be varied.

Step 1(a) (i), converting compound 1 to compound 2:

step 1(a) (i) is an esterification reaction of CDCA with an alkyl alcohol, preferably a C1-C6-alkanol, more preferably methanol, as known in the art, e.g. Tetrahedron, 57(8), 1449-1481; 2001.

Step 1(a) (ii), converting compound 2 to compound 3:

step 1(a) (ii) is the conversion of compound 2 to compound 3 by halogenation of the intermediate silylketene acetal 2 a. By adding a suitable hydroxy protecting agent PG¹Reacting compound 2 with a strong base (such as, but not limited to LDA) in the presence of X, wherein X is selected from Cl, Br, I and OTf, directly generating silylketene acetal intermediate 2a in situ. A preferred hydroxyl protecting agent is TMS-Cl. In one aspect, the temperature is between-100 ℃ and-50 ℃. In one aspect, the temperature is between-90 ℃ and-60 ℃. In one aspect, the temperature is between-80 to-70 ℃. Silyl ketene acetal intermediate 2a with electrophilic halogenating agents such as, but not limited to, Br₂，I₂I-Cl, I-Br, NBS, NIS and 1, 3-dibromo-5, 5-dimethylhydantoin to give compound 3. Preferred electrophilic halogenating agents are I₂。

Step 1(a) (iii), converting compound 3 to compound 4:

step (ii) of1(a) (iii) is the removal of H-R from Compound 3²To form compound 4. Compound 3 is treated with a suitable organic base, such as, but not limited to, DIPEA, Et, in a solvent or mixture of solvents, such as, but not limited to, THF, DCM, acetonitrile or toluene₃N, DBU, DBN or DABCO, the preferred organic base is DBU. In a preferred aspect, the solvent is THF. In a preferred aspect, compound 3 of step 1(a) (ii) is used directly without further purification. The reaction may be carried out at a temperature in the range of-10 ℃ to 50 ℃. In a preferred aspect, the reaction temperature is from 0 ℃ to 30 ℃. In another preferred aspect, the reaction temperature is about 25 ℃.

Step 1(a) (iv), converting compound 4 to compound 5:

step 1(a) (iv) is to remove the protecting group PG of Compound 4¹To form compound 5. The protecting group may be removed under suitable deprotection conditions known in the art. For example, PG may be removed by a deprotection agent such as, but not limited to, TBAF, or an acid such as HCl¹. Preferably, compound 4 is treated with an acid in an aprotic solvent. In a preferred aspect of step 1(a) (iv), compound 4 from step 1(a) (iii) is used without further purification. Preferably, compound 4 is in an aprotic solvent such as, but not limited to, THF, 1, 4-dioxane, MTBE, Et₂O or a mixture of both with an acid such as HCl. A preferred solvent is 1, 4-dioxane. The reaction may be carried out at a temperature in the range of-10 ℃ to 50 ℃. In a preferred aspect, the reaction temperature is from 0 ℃ to 30 ℃. In another preferred aspect, the reaction temperature is about 25 ℃. In yet another preferred aspect, compound 4 is treated with HCl at room temperature in a solution of 1, 4-dioxane to provide compound 5. Compound 5 can be purified by column chromatography to afford compound 5. After purification of compound 5, the overall yield of compound 1 converted to compound 5 was greater than 60%.

Step 1(a) (v), converting compound 5 to compound 6:

step 1(a) (v) is the protection of the 3-hydroxy group of compound 5 with a suitable hydroxy protecting agent PG-X, where X is a suitable leaving group (preferably Cl, Br, I or OTf) in the presence of an organic base such as but not limited to imidazole, TEA, DIPEA, to yield compound 6. The preferred hydroxyl protecting agent is TBS-Cl. The preferred organic base is imidazole. The reaction may be carried out at a temperature in the range of-10 ℃ to 50 ℃. In a preferred aspect, the reaction temperature is from 0 ℃ to 30 ℃. In another preferred aspect, the reaction temperature is about 25 ℃.

Step 1(a) (vi), converting compound 6 to compound III:

step 1(a) (vi) is in the presence of a stoichiometric (stoichimetric) oxidizing agent, such as, but not limited to, NaIO₄、n-Bu₄N⁺IO^4-And NMO) with a suitable catalyst, such as, but not limited to, RuCl₃Dihydroxylation, oxidative cleavage and 7-OH oxidation of compound 6 were carried out to give compound (III). Reaction in a suitable base such as, but not limited to, K₂CO₃、Na₂CO₃And 2, 6-lutidine. The preferred oxidant is NaIO₄. A preferred base is K₂CO₃. The reaction is carried out in a solvent such as, but not limited to, H₂O，CCl₄，CH₃CN or EtOAc. The preferred solvent is H₂O、CH₃CN or EtOAc. The reaction may be carried out at a temperature in the range of-10 ℃ to 50 ℃. In a preferred aspect, the reaction temperature is from 0 ℃ to 30 ℃. In another preferred aspect, the reaction temperature is about 25 ℃. Compound (III) may be crystallized from an organic solvent or solvent mixture, such as but not limited to hexane/EtOAc, to provide compound (III) with a purity greater than 95%.

Step 2(a) (i), converting compound (III) to compound 7:

step 2(a) (i) is the reaction of compound (III) with chloroformate R³Reaction of OCOCl in the presence of an organic base (such as, but not limited to TEA or DIPEA) to produce the mixed anhydride 7. Step 2(a) (i) is preferably carried out in an aprotic solvent such as, but not limited to, DCM. Preferably, the chloroformate is isobutyl chloroformate, wherein R³Is an isobutyl group. The preferred organic base is TEA. Compound 7 was isolated and used in the next reaction without purification.

Step 2(a) (ii), converting compound 7 to compound (IV):

step 2(a) (ii) is the reaction of Compound 7 with a suitable reducing agent, such as, but not limited to NaBH₄、LiBH₄、LiAlH₄Or DIBAL to yield compound (IV). Step 2(a) (ii) is preferably carried out in a mixture of protic and aprotic solvents, such as, but not limited to, a mixture of water and THF. The reaction may be carried out at a temperature in the range of-10 ℃ to 50 ℃. In a preferred aspect, the reaction temperature is from 0 ℃ to 30 ℃. In another preferred aspect, the reaction temperature is about 25 ℃.

In one embodiment, step 2(b) is performed as described in scheme 3. The method comprises the following steps: step 2(b) (i), compound (III) is simultaneously TBS deprotected and esterified to yield compound 8; step 2(b) (ii) reacting compound 8 with a strong base in the presence of a suitable hydroxyl protecting agent to produce an enol ether compound 9; step 2(b) (iii), reacting compound 9 with acetaldehyde to form compound 10; step 2(b) (iv), hydrogenating compound 10 to produce compound 11; step 2(b) (v): reacting compound 11 with a base in a protic solvent or a mixture of a protic solvent and an aprotic solvent to produce compound (12); step 2(b) (vi), compound 12 is protected to produce compound (V).

Scheme 3:

wherein PG is as previously defined; PG (Picture experts group)³Is a hydroxyl protecting group selected from silyl groups such as, but not limited to, TMS, TES, TBS, TIPS, and TBDPS. Preferred PG³Is TMS. R₆As previously defined.

The invention will be better understood in connection with steps 2(b) (i) to 2(b) (vi), where PG, unless otherwise stated³And R³As previously defined. It will be apparent to those of ordinary skill in the art that the method of the invention may be practiced by substituting the appropriate reactants, and that the order of the steps themselves may be varied.

Step 2(b) (i), converting compound (III) to compound 8:

step 2(b) (i) is esterification and removal of the PG protecting group of compound (III) to form compound 8. The preferred protecting group is TBS. The protecting group may be removed under suitable deprotection conditions known in the art. For example, the protecting group may be removed by a deprotection agent, such as, but not limited to, an acid such as HCl. Preferably, the compound (III) is at C₁-C₆Treatment with an acid in an alkanol, preferably in MeOH or EtOH, more preferably in MeOH. The reaction may be carried out at a temperature in the range of 25 ℃ to 100 ℃. In a preferred aspect, the reaction temperature is from 35 ℃ to 80 ℃. In another preferred aspect, the reaction temperature is about 50 ℃. Compound 8 can be purified by recrystallization (recrystallization) to provide compound 8 with a purity greater than 95%.

Step 2(b) (ii), converting compound 8 to compound 9:

step 2(b) (ii) is reacting compound 8 with a silylating agent in an aprotic solvent such as, but not limited to, DCM and THF in the presence of a base to form silyl ether compound 9.

In one aspect of step 2(b) (ii), the silylating agent is TMSCl, the base is a strong organic base such as, but not limited to NaHMDS, LiHMDS or LDA, and the reaction is carried out at a lower temperature, such as-78 ℃.

In another preferred aspect of step 2(b) (ii), the silylating agent is TMSOTf and is used with an organic base such as, but not limited to, TEA or DIPEA at a reaction temperature of-20 ℃ to 30 ℃. In a preferred aspect, the reaction temperature is from about-5 ℃ to about 15 ℃. In another aspect, the temperature is about 0 ℃. The molar ratio of TMSOTf to compound 8 is preferably between 3 and 12. In one aspect, the molar ratio is between 3 and 6. In one aspect, the molar ratio is between 4.5 and 5.5.

In a preferred aspect, compound 9 is used directly in step 2(b) (iii) without purification.

Prior to performing step 2(b) (iii), residual moisture in crude compound 9 is preferably removed from step 2(b) (ii) to control decomposition of compound 9. Step 2(b) (ii) is dissolved in an aprotic solvent such as but not limited to DCM, heptane, hexane or toluene and washed thoroughly with water to remove traces (trace amount) of base. The water content was limited to < 0.5% by co-distillation with anhydrous aprotic solvents (e.g. DCM, hexane, heptane, toluene or THF) (Karl Fisher titration).

Step 2(b) (iii), converting compound 9 to compound 10:

step 2(b) (iii) is the reaction of compound 9 with an aldol acetal of acetaldehyde to form intermediate compound 9a, followed by reaction with a Lewis acid (such as but not limited to BF)₃Et₂O or Ti (OiPr)₄. In one aspect of step 2(b) (iii), the Lewis acid is BF₃Et₂And O. The reaction is carried out in an aprotic solvent, such as, but not limited to, DCM. The reaction temperature is preferably about-78 ℃ to 25 ℃. In one aspect, the reaction temperature is from about-78 ℃ to about-50 ℃. In another preferred aspect, the reaction temperature is about-60 ℃.

After reaction of compound 9 with acetaldehyde at about-78 ℃ to about-50 ℃ (step 2(b) (iii) (a)), an aldol product compound 9a is initially formed as the primary product. Methanol is then added to the reaction mixture to quench (quench) the reaction and promote the elimination reaction, thereby forming the olefinic compound 10 (step 2(b) (iii) (b)). Alternatively, the reaction is allowed to proceed at higher temperatures, e.g., from-10 ℃ to room temperature, without the addition of methanol to promote olefin formation, thereby providing compound 10.

In one aspect of step 2(b) (iii), compound 10 is a mixture of E-and Z-olefin isomers, as shown below in the structure of compound 10A. The E/Z ratio may be from 1/1 to greater than 9/1(> 9/1).

Compound 10 can be purified by column chromatography to provide compound 10 with a purity greater than 95%. In a preferred aspect, compound 10 can be used directly in step 2(b) (iv) without purification.

In one aspect of step 2(b) (iii), E-isomer compound 10 is obtained as the major isomer (E-isomer 10 is greater than 80% and Z-isomer is less than 20%). In another aspect, the E-isomer is greater than 90% and the Z-isomer is less than 10%. In another aspect, the E-isomer is greater than 95% and the Z-isomer is less than 5%.

In one aspect of step 2(b) (iii), crude product 10 contains less than 5% of ketone compound 8. In another aspect, crude product 10 contains less than 3% of ketone compound 8. Crude product 10 contains less than 2% of ketone compound 8.

Step 2(b) (iv), converting compound 10 to compound 11:

in step 2(b) (iv), compound 10 from step 2(b) (iii) is converted to compound 11 by catalytic hydrogenation to reduce the olefin. In one aspect of step 2(b) (iv), compound 10 from step 2(b) (iii) has been purified by column chromatography. In a preferred aspect of step 2(b) (iv), the crude product 10 obtained after the treatment in step 2(b) (iii) is used without purification. In one aspect of step 2(b) (iv), the crude product 10 comprises both E-and Z-olefin isomers (10A). The percentage of Z-isomer is preferably from 0% to 50%.

Catalytic hydrogenation is carried out in the presence of a catalyst such as, but not limited to, carbon on palladium (Pd/C), Pd (OAc)₂、Pd(OH)₂And PtO₂. The preferred catalyst is Pd/C. The palladium content of the Pd/C can be in the range of about 5% to about 10%. The amount of catalyst may range from about 1 mol% to about 10 mol%. The hydrogen source can be, but is not limited to, hydrogen gas and ammonium formate. The pressure of the hydrogen gas is preferably in the range of atmospheric pressure to about 500 psi. In one aspect of step 2(b) (iv), the pressure of the hydrogen is atmospheric. In one aspect, the hydrogen gas has a pressure of about 50 to about 150 psi. The reaction temperature is preferably from about 5 ℃ to about 120 ℃. In one aspect, the reaction temperature is from about 5 ℃ to about 80 ℃. In one aspect of step 2(b) (iv), the reaction temperature is from about 20 ℃ to about 50 ℃. In one aspect, the reaction temperature is about 25 ℃. The reaction can be carried out in a protic or aprotic solvent or a mixture of two solvents. Suitable solvents include, but are not limited to, methanol, ethanol, isopropanol, tert-butanol, and THF. In one aspect of step 2(b) (iv), the solvent is a mixture of methanol and THF. In another aspect of step 2(b) (iv), a mixture of ethanol and THF is used as the solvent.

In certain embodiments, compound 11 is a mixture of the 6 α -ethyl isomer and the 6 β -ethyl isomer. In certain embodiments, the 6 β -ethyl isomer is the major isomer in the product. In one aspect of step 2(b) (iv), crude compound 11 contains less than 20% of the 6 α -ethyl isomer. In one aspect of step 2(b) (iv), crude compound 11 contains less than 10% of the 6 α -ethyl isomer. In one aspect of step 2(b) (iv), crude compound 11 contains less than 5% of the 6 α -ethyl isomer. Compound 11 was used directly in step 2(b) (v) without purification.

Although compound 11 is shown above as the 6 β -ethyl isomer, in embodiments where the compound is a mixture of the 6 α and 6 β -ethyl isomers, it may be represented as compound 11A below.

Step 2(b) (v), converting compound 11 to compound 12:

step 2(b) (v) is the epimerization of the 6 β -ethyl isomer of compound 11 to the 6 α -ethyl isomer (compound 12) under basic conditions. In one aspect of step 2(b) (v), the crude product obtained from step 2(b) (iv) is used in step 2(b) (vi) without further purification, wherein the crude product comprises both the 6 β -ethyl isomer and the 6 α -isomer.

The base may be, but is not limited to, sodium hydroxide or potassium hydroxide. In one aspect, the base is aqueous sodium hydroxide. In one aspect of step 2(b) (vi), the base is a 50% sodium hydroxide solution in water.

In one aspect of step 2(b) (v), the crude product of step 2(b) (iv) is used directly in step 2(b) (v) after removal of the catalyst, e.g., Pd/C, by filtration. In one aspect of step 2(b) (v), the crude product 11 is used after removal of the catalyst and solvent.

Step 2(b) (v) is preferably carried out in a protic solvent such as, but not limited to, methanol or ethanol, or a mixture of protic and aprotic solvents such as, but not limited to, methanol or ethanol and tetrahydrofuran.

In one aspect of step 2(b (v)), the solvent is ethanol; in another aspect of step 2(b) (v), the solvent is methanol. In another aspect of step 2(b) (v), the solvent is a mixture of ethanol and THF. In another aspect of step 2(b) (v), the solvent is a mixture of methanol and THF. Compound 12 was used directly in step 2(b) (vi) without purification.

Step 2(b) (vi), converting compound 12 to compound (V):

step 2(b) (vi) is the protection of the 3-hydroxy group of compound 12 and the acid with a suitable hydroxy protecting agent PG-X, where X is a suitable leaving group, preferably Cl, Br, I or OTf. Intermediate compound 12a is produced in the presence of an organic base such as, but not limited to, imidazole, TEA, DIPEA, followed by deprotection of the carboxylic acid with a suitable base in a protic solvent to produce compound (V). The preferred hydroxyl protecting agent is TBS-Cl. The preferred organic base is imidazole. A preferred base is K₂CO₃. The preferred protic solvent is MeOH. The reaction may be carried out at a temperature in the range of-10 ℃ to 50 ℃. In a preferred aspect, the reaction temperature is from 0 ℃ to 30 ℃. In another preferred aspect, the reaction temperature is about 25 ℃.

Compound (V) may be crystallized from an organic solvent or a mixture of organic solvents, such as but not limited to hexane/CH₂Cl₂To provide compound (V) with a purity of greater than 95%.

In one embodiment, step 3(b) is performed as described in scheme 4. The method comprises the steps of 3(b) (i) reacting compound (V) with a suitable acylating agent to yield compound 13; and step 3(b) (ii), reducing compound 13 to give compound (VI).

Scheme 4:

wherein R is³As previously defined.

The methods of the present application have not been reported in the art. The synthesis of compound (VI) is described in US 2016/0289262 in 6 steps starting from obeticholic acid. The synthesis of obeticholic acid in 6 steps starting from KLCA is reported in US 2013/0345188. In general, the known process for the preparation of alcohol compounds (VI) involves a 12-step synthesis from KLCA. The previous methods involve low yield steps and require multiple column chromatography steps, which are expensive and not suitable for large-scale commercialization. In addition, several toxic and hazardous agents are used. The process of the present invention for preparing compound (V) is carried out in six steps starting from compound (III), with good overall yields and requiring only one column chromatography operation. Key intermediates, such as compound 12, can be obtained by crystallization at high purity. The compound (V) can be obtained in high purity by crystallization. Compound (V) can be converted to compound (VI) by mixed anhydride formation followed by reduction.

Step 3(b) (i), converting compound (V) to compound 13:

step 3(b) (i) is the reaction of compound (V) with the appropriate chloroformate R₃Reaction of OCOCl in the presence of an organic base such as, but not limited to, TEA or DIPEA to produce the mixed anhydride 13. Step 3(b) (i) may be carried out in an aprotic solvent such as, but not limited to, DCM. A preferred chloroformate is isobutyl chloroformate, wherein R³Is an isobutyl group. The preferred organic base is TEA. Compound 13 was isolated as crude and used without further purification.

Step 3(b) (ii), converting compound 13 to compound (VI):

step 3(b) (ii) is the reaction of Compound 13 with a suitable reducing agent such as, but not limited to NaBH₄、LiBH₄、LiAlH₄Or DIBAL to yield compound (VI). Step 3(b) (ii) is preferably carried out in a mixture of protic and aprotic solvents, such as, but not limited to, a mixture of water and THF. The reaction may be carried out at a temperature in the range of-10 ℃ to 50 ℃. In a preferred aspect, the reaction temperature is from 0 ℃ to 30 ℃. In another preferred aspect, the reaction temperature is about 25 ℃.

Compound VI can be purified by column chromatography to provide compound VI with a purity greater than 95%.

A process for preparing a compound of formula (I):

the invention also includes a process for the preparation of compounds of formula (I) starting from compound (IV) in the manner shown in scheme 5.

Scheme 5:

wherein R is⁴Is imidazol-1-yl, alkyl-O-aryl-O, Cl or CCl₃；R¹As previously defined.

Step 3(a) (i), converting compound (IV) to compound 14:

step 3(a) (i) comprises reacting compound (IV) with a compound represented by 15E in the presence of an organic base,(wherein R is⁴Is imidazole-), to convert compound (IV) to a compound of formula 14, wherein R is⁴Is 1-yl, alkyl-O-aryl-O, Cl or CCl₃And R is¹As previously defined. The reaction is preferably carried out in an aprotic solvent, such as but not limited to THF, DCM or toluene. In a preferred aspect, the reaction solvent is THF. Suitable organic bases include, but are not limited to, triethylamine and diisopropylethylamine. DMAP can be added in the range of 1 to 50 mol% to facilitate the reaction. The reaction temperature is preferably from about 0 ℃ to about 80 ℃. In one aspect, the reaction is carried out at about 0 ℃. In another aspect, the reaction is carried out at about room temperature (about 25 ℃). In another aspect, the reaction is carried out at about 50 ℃.

Preferably, R in compound 15E⁴Is imidazol-1-yl, MeO-, EtO-or PhO-. More preferably, R⁴Is PhO-.

Step 3(a) (ii), converting the compound of formula 14 to formula (I):

step 3(a) (ii) is the removal of the PG protecting group of Compound 14 to form Compound (I), wherein R¹As previously defined. The PG protecting group may be removed under suitable deprotection conditions known in the art. The preferred PG protecting group is TBS. Preferably, the protecting group is removed by a deprotecting agent, such as, but not limited to, TBAF, or an acid such as HCl. Preferably, compound 14 is treated with an acid in a protic solvent. Preferably, compound 14 is in a solvent such as, but not limited to, MeOH, EtOH, i-PrOH, H₂O or a mixture of both in a protic solvent with an acid such as HCl. The preferred solvent is MeOH. The reaction may be carried out at a temperature in the range of-10 ℃ to 50 ℃. In a preferred aspect, the reaction temperature is from 0 ℃ to 30 ℃. In another preferred aspect, the reaction temperature is about 25 ℃.

A process for producing compound (VII):

the process of the present invention also includes a process for preparing compound (VII) starting from compound (IV) according to the process described in scheme 6.

Scheme 6:

the process comprises converting an alcohol compound (IV) to a sulphamic sulphonyl ester 16 in the presence of an organic base, using a suitable reagent, for example a reagent selected from 15A, 15B, 15C and 15D;

in one aspect, the reagent is 15B, which can be formed by reacting sulfonamide compound 15A with CDI.

In another aspect, the agent is a sulfonyl carbamate compound 15C, where R is⁵Is alkyl or aryl, preferably methyl, ethylA radical or a phenyl radical. The preferred agent is 15D.

In one aspect, the alcohol compound (IV) is reacted with 15D in an aprotic solvent such as, but not limited to, THF, DCM or toluene. In a preferred aspect, the reaction solvent is THF. Suitable organic bases include, but are not limited to, triethylamine, diisopropylethylamine. DMAP can be added in the range of 1 to 50 mol% to facilitate the reaction. The reaction temperature is preferably from about 0 ℃ to about 80 ℃. In one aspect, the reaction is carried out at about 0 ℃. In another aspect, the reaction is carried out at about room temperature (about 25 ℃). In another aspect, the reaction is carried out at 50 ℃. Compound 16 can be purified by column chromatography to provide compound 16 with a purity greater than 95%.

In one aspect, compound 16 is reacted with a deprotection agent, such as, but not limited to, TBAF, or an acid such as HCl. Preferably, compound 16 is treated with an acid in a protic solvent. Preferably, compound 16 is in a solvent such as, but not limited to, MeOH, EtOH, i-PrOH, H₂O or a mixture of both, with an acid such as HCl. The preferred solvent is MeOH. The reaction may be carried out at a temperature in the range of-10 ℃ to 50 ℃. In a preferred aspect, the reaction temperature is from 0 ℃ to 30 ℃. In another preferred aspect, the reaction temperature is about 25 ℃. Compound (VII) may be purified by column chromatography to provide compound (VII) with a purity greater than 95%.

A process for preparing a compound of formula (II):

the present invention also includes a process for preparing the compound of formula (II) starting from compound (VI) as shown in scheme 7.

Scheme 7:

step 4(b) (i), converting compound (VI) to a compound of formula 17:

wherein R is₁And R₄As described previouslyAnd (4) defining. Preferably, R in compound 15E₄Is imidazol-1-yl, MeO-, EtO-or PhO-. More preferably, R₄Is PhO-.

The reaction is preferably carried out in an aprotic solvent, such as but not limited to THF, DCM or toluene. In a preferred aspect, the reaction solvent is THF. Suitable organic bases include, but are not limited to, triethylamine, diisopropylethylamine, and DMAP. The reaction temperature is preferably from about 0 ℃ to about 80 ℃. In one aspect, the reaction is carried out at about 0 ℃. In another aspect, the reaction is carried out at about room temperature (about 25 ℃). In another aspect, the reaction is carried out at about 50 ℃.

Step 4(b) (II), converting the compound of formula 17 to a compound of formula (II):

step 4(b) (II) is removing the PG protecting group of compound of formula 17 to form compound (II), wherein PG and R¹As previously defined. The PG protecting group may be removed under suitable deprotection conditions. Are known in the art. The preferred PG protecting group is TBS. Preferably, the protecting group is removed by a deprotecting agent, such as, but not limited to, TBAF, or an acid such as HCl. Preferably, the compound of formula 17 is treated with an acid in a protic solvent. Preferably, in a solvent such as, but not limited to, MeOH, EtOH, i-PrOH, H₂O or a mixture of the two in a protic solvent, treating the compound of formula 17 with an acid such as HCl. The preferred solvent is MeOH. The reaction may be carried out at a temperature in the range of-10 ℃ to 50 ℃. In a preferred aspect, the reaction temperature is from 0 ℃ to 30 ℃. In another preferred aspect, the reaction temperature is about 25 ℃.

A method for preparing compound (VIII):

the process of the present invention also includes a process for preparing compound (VIII) starting from compound (VI) according to the process described in scheme 8.

Scheme 8:

the process comprises converting an alcohol compound (VI) to a sulfamoyl compound 18, followed by deprotection to yield compound (VIII). The conditions of the method described for scheme 8 are the same as those previously defined for scheme 7.

The process comprises converting the alcohol of compound (VI) to the sulfonyl sulfamate 18 with a suitable reagent (e.g., selected from 15A-15D) in the presence of an organic base.

In one aspect, the reagent is 15B, which can be formed by reacting sulfonamide compound 15A with CDI.

In another aspect, the reagent can be a sulfonyl carbamate compound 15C, where R is⁵Is an alkyl or aryl group, preferably a methyl, ethyl or phenyl group. The preferred agent is 15D.

In one aspect, the alcohol compound (VI) is reacted with 15D in an aprotic solvent such as, but not limited to, THF, DCM or toluene. In a preferred aspect, the reaction solvent is THF. Suitable organic bases include, but are not limited to, triethylamine and diisopropylethylamine. DMAP can be added in the range of 1 mol% to 50 mol% to facilitate the reaction. The reaction temperature is preferably from about 0 ℃ to about 80 ℃. In one aspect, the reaction is carried out at about 0 ℃. In another aspect, the reaction is carried out at about room temperature (about 25 ℃). In another aspect, the reaction is carried out at 50 ℃. Compound 18 can be purified by column chromatography to provide compound 18 with a purity greater than 95%.

In one aspect, compound 18 is reacted with a deprotection agent, such as, but not limited to, TBAF, or an acid such as HCl. Preferably, compound 18 is treated with an acid in a protic solvent. Preferably, compound 18 is in a solvent such as, but not limited to, MeOH, EtOH, i-PrOH, H₂O or a mixture of both in a protic solvent with an acid such as HCl. The preferred solvent is MeOH. The reaction may be carried out at a temperature in the range of-10 ℃ to 50 ℃. In a preferred aspect, the reaction temperature is from 0 ℃ to 30 ℃. In another preferred aspect, the reaction temperature is about 25 ℃. Compound (VIII) can be purified by column chromatography to provide compound (VIII) with a purity of greater than 95%.

A process for preparing compound (IX):

the process of the present invention also includes a process for preparing compound (IX) starting from compound (VI) according to the process described in scheme 9.

Scheme 9:

the process comprises converting an alcohol of compound (VI) or compound (VIb) to the sulfamoyl compound (19) with a suitable reagent, such as one of compounds 20A, 20B, 20C or 20D, in the presence of an organic base,

in one aspect, the reagent is 20B, which can be formed by reacting sulfonamide compound 20A with CDI.

In another aspect, the reagent can be a sulfonyl carbamate compound 20C, where R⁵Is an alkyl or aryl group, preferably a methyl, ethyl or phenyl group. The preferred agent is 20D.

In one aspect, the alcohol of compound (VI) is reacted with 20D in an aprotic solvent such as, but not limited to, THF, DCM or toluene. In a preferred aspect, the reaction solvent is THF. Suitable organic bases include, but are not limited to, triethylamine, diisopropylethylamine, and DMAP. The reaction temperature is preferably from about 0 ℃ to about 80 ℃. In one aspect, the reaction is carried out at about 0 ℃. In another aspect, the reaction is carried out at about room temperature (about 25 ℃). In another aspect, the reaction is carried out at 50 ℃. Compound 19 can be purified by column chromatography to provide compound 19 with a purity greater than 95%.

In one aspect, compound 19 is reacted with a deprotection agent, such as, but not limited to, TBAF, or an acid such as HCl. Preferably, compound 19 is treated with an acid in a protic solvent. Preferably, compound 19 is in a solvent such as, but not limited to, MeOH, EtOH, i-PrOH, H₂O or a mixture of both in a protic solvent with an acid such as HCl. The preferred solvent is MeOH. The reaction may be carried out at a temperature in the range of-10 ℃ to 50 ℃. In a preferred aspect, the reaction temperature is from 0 ℃ to 30 ℃. In another preferred aspect, the reaction temperature is about 25 ℃. Compound (IX) can be purified by column chromatography to provide compound (IX) with a purity of greater than 95%.

In another embodiment, the present invention also includes a process for preparing the compound of formula (II) starting from compound (VIb) of formula (10), and a process for preparing compound (VIb) of formula 11.

Scheme 10:

scheme 11:

defining:

listed below are definitions of various terms used to describe the present invention. Unless otherwise limited in specific instances, these definitions apply to the terms used throughout the specification and claims, either individually or as part of a larger group.

As used herein, the term "alkyl" refers to a saturated monovalent straight or branched chain hydrocarbon group. Preferred alkyl groups include C₁-C₆Alkyl and C₁-C₈An alkyl group. C₁-C₆Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl, n-hexyl; and C₁-C₈Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl, n-hexyl, heptyl, and octyl.

The term "alkenyl" as used herein, means a monovalent group derived from a hydrocarbon moiety by the removal of a single hydrogen atom, wherein the hydrocarbon moiety has at least one carbon-carbon double bond. Preferred alkenyl groups include C₂-C₆Alkenyl and C₂-C₈An alkenyl group. Alkenyl groups include, but are not limited toSuch as ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

The term "alkynyl" as used herein, means a monovalent group derived from a hydrocarbon moiety by the removal of a single hydrogen atom, wherein the hydrocarbon moiety has at least one carbon-carbon triple bond. Preferred alkynyl groups include C₂-C₆Alkynyl and C₂-C₈Alkynyl. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

As used herein, the term "cycloalkyl" refers to a fused, bridged or spiro ring system of monocyclic or polycyclic saturated carbocyclic or bicyclic or tricyclic groups, and carbon atoms may be optionally substituted with an oxyalkylene group or with an exocyclic olefinic double bond. Preferred cycloalkyl groups include C₃-C₈Cycloalkyl and C₃-C₁₂A cycloalkyl group. C₃-C₈Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and C₃-C₁₂Examples of-cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, bicyclo [2.2.1]Heptyl, bicyclo [2.2.2]Octyl, spiro [2.5]]Octyl, 3-methylenebicyclo [3.2.1]]Octyl, spiro [4.4]]Nonyl, bicyclo [3.1.0]Hexyl, spiro [2.3 ]]Hexyl, bicyclo [3.1.1]Heptyl, spiro [2.5]]Octyl, bicyclo [4.1.0]Heptyl, bicyclo [3.1.0]Hexane-6-yl, spiro [2.3 ]]Hexane-5-yl, bicyclo [3.1.1]Heptane-3-yl, spiro [2.5]]Octane-4-yl, and bicyclo [4.1.0]Heptane-3-yl, and the like.

As used herein, the term "cycloalkenyl" refers to a fused, bridged, or spiro ring system of monocyclic or polycyclic carbocyclic or bi-or tricyclic groups having at least one carbon-carbon double bond, and carbon atoms may be optionally substituted with an oxyalkylene group or with an exocyclic olefinic double bond. Preferred cycloalkenyl groups include C₃-C₈Cycloalkenyl radical and C₃-C₁₂A cycloalkenyl group. C₃-C₈Examples of-cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and C₃-C₁₂Examples of-cycloalkenyl include, but are not limited toCyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo [2.2.1]Hept-2-enyl, bicyclo [3.1.0]Hex-2-enyl, spiro [2.5]]Oct-4-enyl, spiro [4.4]]Non-1-alkenyl, bicyclo [4.2.1]Non-3-en-9-yl, and the like.

The terms "heterocycle" or "heterocycloalkyl" are used interchangeably and refer to a non-aromatic ring or a fused, bridged or spiro ring system of bi-or tricyclic groups in which (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system may be saturated or unsaturated, (iii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iv) the nitrogen heteroatom may be optionally quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms, which may be optionally substituted with an oxyalkylene group or optionally substituted with an exocyclic olefinic double bond. Representative heterocycloalkyl groups include, but are not limited to, [1,3] dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuranyl, 2-azabicyclo [2.2.1] -heptyl, 8-azabicyclo [3.2.1] octyl, 5-azaspiro [2.5] octyl, 1-oxa-7-azaspiro [4.4] nonyl, 7-oxoylideneoxepin-4-yl, and tetrahydrofuranyl. These heterocyclic groups may be further substituted. The heteroaryl or heterocyclic group may be C-linked or N-linked (if possible).

The term "aryl" as used herein refers to a monocyclic or polycyclic carbocyclic ring system comprising at least one aromatic ring, including but not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl and indenyl. Polycyclic aryl is a polycyclic ring system containing at least one aromatic ring. Polycyclic aryl groups can include fused rings, covalently linked rings, or combinations thereof.

The term "arylalkyl" as used herein refers to a functional group in which an alkylene chain is attached to an aryl group, e.g., -CH₂CH₂-phenyl. The term "substituted arylalkyl" refers to an arylalkyl functional group in which the aryl group is substituted. Examples include, but are not limited to, benzyl, phenethyl, and the like. Preferred arylalkyl groups include arylradical-C₁-C₈-an alkyl group.

The term "heteroaryl" as used herein refers to a monocyclic, bicyclic or tricyclic group comprising at least one 5 or 6 membered aromatic ring containing at least one ring atom selected from S, O and N. Preferred heteroaryl groups are monocyclic or bicyclic. Heteroaryl groups include monocyclic groups having 5 or 6 ring atoms and fused bicyclic groups containing 8 to 10 ring atoms. Heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, triazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothienyl, quinoxalyl, indolyl, indazolyl, benzisoxazolyl, benzofuryl, benzotriazolyl, benzothiazolyl, and the like.

The term "heteroarylalkyl" as used herein means an alkylene chain attached to a heteroaryl group. The term "substituted heteroarylalkyl" refers to a heteroarylalkyl functionality in which the heteroaryl group is substituted. Examples include, but are not limited to, pyridylmethyl, pyrimidinylethyl, and the like. Preferred heteroarylalkyl groups include heteroaryl-C₁-C₈-an alkyl group.

As used herein, the term "biaryl" refers to a moiety consisting of two aryl groups, two heteroaryl groups, or an aryl group and a heteroaryl group, wherein the two groups are connected by a single bond. A substituted biaryl group is a biaryl moiety wherein at least one attached group has at least one non-hydrogen substituent. Examples of biaryl groups include biphenyl, pyridylphenyl, pyrimidylphenyl, pyrimidylpyridinyl, and pyrimidinyloxadiazolyl groups.

The term "aryl-heterocyclyl" refers to a bicyclic group comprising a monocyclic aryl or heteroaryl group connected to a heterocyclyl group by a single bond. Examples of aryl-heterocyclyl groups include phenyl-piperidinyl and pyridyl-piperidinyl groups.

As used herein, unless otherwise specified, the terms used alone or in combination with other termsThe term "alkoxy" refers to an alkyl group having the indicated number of carbon atoms attached to the remainder of the molecule through an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), and higher homologs and isomers. Preferred alkoxy is (C)₁-C₃) An alkoxy group.

The term "substituted" refers to the replacement of one, two or three or more hydrogen atoms independently by substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, C₁-C₁₂-an aryl group; c₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl, protected hydroxy, -NO₂、-N₃、-CN、-NH₂Protected amino, oxylidene (oxo), thiolidene, -NH-C₁-C₁₂-alkyl, -NH-C₂-C₈-alkenyl, -NH-C₂-C₈-alkynyl, -NH-C₃-C₁₂-cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C₁-C₁₂-alkyl, -O-C₂-C₈-alkenyl, -O-C₂-C₈-alkynyl, -O-C₃-C₁₂-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C (O) -C₁-C₁₂Alkyl, -C (O) -C₂-C₈-alkenyl, -C (O) -C₂-C₈-alkynyl, -C (O) -C₃-C₁₂-cycloalkyl, -C (O) -aryl, -C (O) -heteroaryl, -C (O) -heterocycloalkyl, -CONH₂、-CONH-C₁-C₁₂-alkyl, -CONH-C₂-C₈-alkenyl, -CONH-C₂-C₈-alkynyl, -CONH-C₃-C₁₂-cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO₂-C₁-C₁₂-alkyl, -OCO₂-C₂-C₈-alkenyl, -OCO₂-C₂-C₈-alkynyl, -OCO₂-C₃-C₁₂-cycloalkyl, -OCO₂-aryl, -OCO₂-heteroaryl, -OCO₂-heterocycloalkyl, -CO₂-C₁-C₁₂Alkyl, -CO₂-C₂-C₈Alkenyl, -CO₂-C₂-C₈Alkynyl, CO₂-C₃-C₁₂-cycloalkyl, -CO₂Aryl, CO₂-heteroaryl, CO₂-heterocycloalkyl, -OCONH₂、-OCONH-C₁-C₁₂-alkyl, -OCONH-C₂-C₈-alkenyl, -OCONH-C₂-C₈-alkynyl, -OCONH-C₃-C₁₂-cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocyclo-alkyl, -NHC (O) H, -NHC (O) -C₁-C₁₂-alkyl, -NHC (O) -C₂-C₈-alkenyl, -NHC (O) -C₂-C₈-alkynyl, -NHC (O) -C₃-C₁₂-cycloalkyl, -NHC (O) -aryl, -NHC (O) -heteroaryl, -NHC (O) -heterocycle-alkyl, -NHCO₂-C₁-C₁₂-alkyl, -NHCO₂-C₂-C₈-alkenyl, -NHCO₂-C₂-C₈-alkynyl, -NHCO₂-C₃-C₁₂-cycloalkyl, -NHCO₂-aryl, -NHCO₂-heteroaryl, -NHCO₂-heterocycloalkyl, -NHC (O) NH₂、-NHC(O)NH-C₁-C₁₂Alkyl, -NHC (O) NH-C₂-C₈-alkenyl, -NHC (O) NH-C₂-C₈-alkynyl, -NHC (O) NHC₃-C₁₂-cycloalkyl, -NHC (O) NH-aryl, -NHC (O) NH-heteroaryl, -NHC (O) NH-heterocycloalkyl, NHC (S) NH₂、-NHC(S)NH-C₁-C₁₂Alkyl, -NHC (S) NH-C₂-C₈-alkenyl, -NHC (S) NH-C₂-C₈-alkynyl, -NHC (S) NH-C₃-C₁₂-cycloalkyl, -NHC (S) NH-aryl, -NHC (S) NH-heteroaryl, -NHC (S) NH-heterocycloalkyl, -NHC (NH) NH₂、-NHC(NH)NH-C₁-C₁₂Alkyl, -NHC (NH) NH-C₂-C₈-alkenyl, -NHC (NH) NH-C₂-C₈-alkynyl, -NHC (NH) NH-C₃-C₁₂-cycloalkyl, -NHC (NH) NH-aryl, -NHC (NH) NH-heteroaryl, -NHC (NH) NH-heterocycloalkyl, -NHC (NH) -C₁-C₁₂-alkyl, -NHC (NH) -C₂-C₈-alkenyl, -NHC (NH) -C₂-C₈-alkynyl, -NHC (NH) -C₃-C₁₂-cycloalkyl, -NHC (NH) -aryl, -NHC (NH) -heteroaryl, -NHC (NH) -heterocycloalkyl, -C (NH) NH-C₁-C₁₂Alkyl, -C (NH) NH-C₂-C₈-alkenyl, -C (NH) NH-C₂-C₈-alkynyl, -C (NH) NH-C₃-C₁₂-cycloalkyl, -C (NH) NH-aryl, -C (NH) NH-heteroaryl, -C (NH) NH-heterocycloalkyl, -S (O) -C₁-C₁₂-alkyl, -S (O) -C₂-C₈-alkenyl, -S (O) -C₂-C₈-alkynyl, -S (O) -C₃-C₁₂-cycloalkyl, -S (O) -aryl, -S (O) -heteroaryl, -S (O) -heterocycloalkyl, -SO₂NH₂、-SO₂NH-C₁-C₁₂-alkyl, -SO₂NH-C₂-C₈-alkenyl, -SO₂NH-C₂-C₈-alkynyl, -SO₂NH-C₃-C₁₂-cycloalkyl, -SO₂NH-aryl, -SO₂NH-heteroaryl, -SO₂NH-heterocycloalkyl, -NHSO₂-C₁-C₁₂-alkyl, -NHSO₂-C₂-C₈-alkenyl, -NHSO₂-C₂-C₈-alkynyl, -NHSO₂-C₃-C₁₂-cycloalkyl, -NHSO₂-aryl, -NHSO₂-heteroaryl, -NHSO₂-heterocycloalkyl, -CH₂NH₂、-CH₂SO₂CH₃-aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C₃-C₁₂-cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C₁-C₁₂-alkyl, -S-C₂-C₈-alkenyl, -SC₂-C₈-alkynyl, -S-C₃-C₁₂-cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl or methylthio-methyl. It is understood that aryl, heteroaryl, alkyl, cycloalkyl, and the like may be additionally substituted. In some cases, each substituent in the substituted moiety is additionally optionally substituted with one or more groups, each group independently selected from-F, -Cl, -Br, -I, -OH, -NO₂-CN or-NH₂。

As used herein, the term "optionally substituted" means that the referenced group may be substituted or unsubstituted. In one embodiment, the recited groups are optionally substituted with 0 substituents, i.e., the recited groups are unsubstituted. In another embodiment, the recited groups are optionally substituted with one or more additional groups individually and independently selected from the groups described herein.

According to the present invention, any of the aryl, substituted aryl, heteroaryl and substituted heteroaryl groups described herein can be any aromatic group. The aromatic group may be substituted or unsubstituted.

It is to be understood that any of the alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl moieties described herein can also be aliphatic, alicyclic, or heterocyclic groups. An "aliphatic group" is a non-aromatic moiety that may contain any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen, or other atoms, and optionally one or more units of unsaturation, such as double and/or triple bonds. Aliphatic groups may be straight chain, branched chain or cyclic and preferably contain from about 1 to about 24 carbon atoms, more typically from about 1 to about 12 carbon atoms. Aliphatic groups include, in addition to aliphatic hydrocarbon groups, polyalkoxyalkyl groups such as polyalkylene glycols, polyamines and polyimines, for example. These aliphatic groups may be further substituted. It is understood that aliphatic groups may be used in place of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylene groups described herein.

The term "alicyclic" as used herein means a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic compound by the removal of a single hydrogen atom. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. These cycloaliphatic groups may be further substituted.

It will be apparent that in various embodiments of the invention, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl, and heterocycloalkyl are intended to be monovalent or divalent. Thus, alkylene, alkenylene and alkynylene, cycloalkylene, cycloalkenylene, cycloalkynylene, arylenealkyl, heteroarylenealkyl and heterocycloalkylene groups are encompassed by the above definitions and are suitable for use in providing the formula herein with the appropriate valency.

The term "hydroxy protecting agent" as used herein is composed of PG-X, PG¹-X or PG³-X, wherein PG, PG¹And PG³As defined herein, and X is a suitable leaving group, preferably halogen, alkyl sulfonate or fluoro alkyl sulfonate. Preferably, X is Cl, Br, I or triflate (OTf), and the hydroxy protecting agent in which PG, PG1 or PG3 is a silyl group may alternatively be referred to herein as a "silylating agent".

The terms "halo" and "halogen" as used herein refer to an atom selected from the group consisting of fluorine, chlorine, bromine and iodine.

The term "hydrogen" includes hydrogen and deuterium. In addition, recitation of an atom includes other isotopes of that atom, provided that the resulting compound is pharmaceutically acceptable.

As used herein, the term "hydroxyl protecting group" refers to a labile chemical moiety known in the art to protect a hydroxyl group from undesired reactions during synthesis. Following the synthetic process, the hydroxyl protecting group as described herein may be selectively removed. Hydroxyl protecting Groups known in the art are generally described in T.H.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis,3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, tert-butyl, 2,2, 2-trichloroethyl, 2-trimethylsilylethyl, allyl, benzyl, triphenyl-methyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2- (trimethylsilyl) -ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl and the like.

The term "protected hydroxy" as used herein refers to a hydroxy group protected with a hydroxy protecting group as defined above (including, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl).

When the compounds described herein contain one or more asymmetric centers, they give rise to enantiomers, diastereomers, and other stereoisomeric forms, which in terms of absolute stereochemistry may be defined as (R) -or (S) -, or (D) -or (L) -for amino acids. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers can be prepared from their respective optically active precursors by the above-described procedures, or by resolution of racemic mixtures. Resolution may be carried out by chromatography or by repeated crystallization in the presence of a resolving agent or by some combination of these techniques known to those skilled in the art. Additional details regarding the resolution can be found in Jacques, et al, eneriomers, racemes, and solutions (John Wiley & Sons, 1981). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, the compounds include both E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are intended to be included. The configuration of any carbon-carbon double bond appearing herein is chosen for convenience only and is not intended to represent a particular configuration unless the text so states; thus, any carbon-carbon double bond described herein as trans can be cis, trans, or a mixture of both in any proportion.

As used herein, the term "pharmaceutically acceptable salts" refers to those salts of the compounds formed by the methods of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.

Pharmaceutically acceptable salts are described in detail by Berge et al in J.pharmaceutical Sciences,66:1-19 (1977). Salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base functionality with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts, e.g., salts of amino groups can be formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or with organic acids such as acetic, maleic, tartaric, citric, succinic, or malonic acids, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurylsulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, Picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, if appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkylsulfonate and arylsulfonate groups having from 1 to 6 carbon atoms.

As used herein, the term "treating" refers to alleviating, reducing, eliminating, modulating, or ameliorating, i.e., causing regression of a disease state or condition. Treatment may also include inhibiting, i.e., arresting the development of, and ameliorating, i.e., causing regression of, an existing disease state or condition, e.g., when the disease state or condition may already be present.

As used herein, the term "preventing" refers to completely or almost completely preventing a disease state or disorder from occurring in a patient or subject, particularly when the patient or subject is predisposed to having such a disease state or disorder or is at risk of contracting a disease state or disorder.

In addition, the compounds of the present invention, e.g., salts of the compounds, may exist in hydrated or non-hydrated (anhydrous) forms or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrate, dihydrate, and the like. Non-limiting examples of solvates include ethanol solvates, acetone solvates, and the like.

The term "lewis acid" refers to a substance that accepts an electron pair from a base and forms a covalent bond with the base. Also published by Wiely Interscience, version 4, "Advanced Organic Chemistry", defined by JerryMarch.

"solvate" refers to a solvent adduct form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds in the crystalline solid state tend to trap a fixed molar ratio of solvent molecules, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. The hydrate is maintained in its molecular state such as H by one or more water molecules with water therein₂O, which combination is capable of forming one or more hydrates.

As used herein, the term "analog" refers to a chemical compound that is structurally similar to another chemical compound but slightly different in composition (e.g., one atom is replaced with an atom of a different element, or a particular functional group is present, or one functional group is replaced with another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance to the recited compound.

As used herein, the term "aprotic solvent" refers to a solvent that is relatively inert to protonic activity, i.e., does not act as a proton donor. Examples include, but are not limited to, hydrocarbons such as hexane and toluene, for example halogenated hydrocarbons such as, for example, dichloromethane, dichloroethane, chloroform and the like, heterocyclic compounds such as, for example, tetrahydrofuran and N-methylpyrrolidone, and ethers such as diethyl ether, bismethoxymethyl ether. Such solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for particular compounds and reaction conditions, depending on factors such as, for example, the solubility of the reagents, the reactivity of the reagents, and the preferred temperature range. Other discussions of aprotic solvents can be found in textbooks or professional monographs of organic chemistry, for example: organic solvent Physical Properties and Methods of Purification,4th ed., edited by John A.Riddick et al, Vol.II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term "protic organic solvent" or "protic solvent" as used herein refers to a solvent that tends to donate protons, such as alcohols, e.g., methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, and the like. Such solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for particular compounds and reaction conditions, depending on factors such as, for example, the solubility of the reagents, the reactivity of the reagents, and the preferred temperature range. Other discussions of proton donating solvents can be found in textbooks or professional monographs of organic chemistry, for example: organic solvent Physical Properties and Methods of Purification,4th ed., edited by John A.Riddick et al, Vol.II, in the techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

Combinations of substituents and variables contemplated by the present invention are only those that result in the formation of stable compounds. As used herein, the term "stable" refers to a compound that has sufficient stability to allow manufacture and maintains the integrity of the compound for a sufficient period of time for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

The synthesized compound may be separated from the reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography or recrystallization. In addition, the various synthetic steps may be performed in alternating order or sequence to obtain the desired compounds. In addition, the solvents, temperatures, reaction durations, and the like described herein are for illustration purposes only, and variations in reaction conditions can produce the desired isoxazole products of the present invention. Synthetic chemical transformation and protecting group methods (protection and deprotection) useful for the synthesis of the compounds described herein include, for example, r.larock, Comprehensive organic transformations, VCH Publishers (1989); t.w.greene and p.g.m.wuts, protective groups in Organic Synthesis,2d.ed., John Wiley and Sons (1991); l. Fieser and m. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and sons (1994); and those described in L.Patquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995).

The compounds of the present invention may be modified by the synthetic methods described herein to add various functional groups to enhance selective biological properties. These modifications include those that increase bio-penetration to a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and alter rate of excretion.

Abbreviations:

abbreviations used in the description of the schemes and examples below are:

ac is acetyl;

AcOH is acetic acid;

ACN is acetonitrile;

aq. is aqueous (water solution);

BA is bile acid;

saline (Brine) is a sodium chloride solution in water;

n-BuLi is n-butyl lithium;

cAMP is cyclic adenosine monophosphate;

CDCA is chenodeoxycholic acid;

CDI is carbonyldiimidazole;

CTX is brain tendon xanthomatosis;

d2 is type 2 iodothyroxine deiodinase;

DABCO is 1, 4-diazabicyclo [2.2.2] octane;

DBN is 1, 5-diazabicyclo [4.3.0] non-5-ene;

DBU is 1, 8-diazabicyclo [5.4.0] undec-7-ene;

DCM is dichloromethane;

DIBAL is diisobutylaluminum hydride;

DIPEA or (i-Pr)₂EtN is N, N-diisopropylethylamine;

dess-martin periodinane is 1,1, 1-tris (acetoxy) -1, 1-dihydro-1, 2-benziodoxa furan-3- (1H) -one;

DMAP is 4-dimethylamino-pyridine;

DMF is N, N-dimethylformamide;

DMSO is dimethyl sulfoxide;

DPPA is diphenylphosphoryl azide;

EtOAc is ethyl acetate;

EtOH is ethanol;

Et₂o is diethyl ether;

eq. is equivalent;

FXR is farnesoid x receptor;

GLP-1 is glucagon-like peptide 1

hrs is hours;

IBX is 2-iodoxybenzoic acid;

KHMDS is potassium bis (trimethylsilyl) amide;

KLCA is 7-ketocholelithiasis;

OTf or trifluoromethanesulfonic acid (triflate) is a salt of trifluoromethanesulfonic acid;

ph is phenyl;

LDA is lithium diisopropylamide;

LiHMDS is lithium bis (trimethylsilyl) amide;

min is min;

MOM is methoxymethyl;

MEM is methoxyethoxymethyl;

NAFLD is non-alcoholic fatty liver;

NaHMDS is sodium bis (trimethylsilyl) amide;

NASH is non-alcoholic steatohepatitis;

NBS is N-bromosuccinimide;

NIS is N-iodosuccinimide;

NMO is N-methylmorpholine N-oxide;

o/n is overnight;

PBC is primary biliary cirrhosis;

PCC is pyridinium chlorochromate;

PDC is pyridinium dichromate;

Pd/C is carbon-supported palladium;

PNAC is parenteral nutrition-related cholestasis;

PSC is primary sclerosing cholangitis;

i-PrOAc is isopropyl acetate;

psi is pounds per square inch;

rt is room temperature;

sat. is saturated;

SEM is 2-trimethylsilylethoxymethyl;

TBAF is tetrabutylammonium fluoride;

TBDPS is tert-butyldiphenylsilyl;

TBS is tert-butyldimethylsilyl;

TEA or Et₃N is triethylamine;

TES is triethylsilyl;

TFA or CF₃COOH is trifluoroacetic acid;

THF is tetrahydrofuran;

THP is tetrahydropyranyl;

TIPS is triisopropylsilyl;

TMS is trimethylsilyl;

TMSCl is trimethylsilyl chloride;

TMSOTf is trimethylsilyl trifluoromethanesulfonate;

TBME or MTBE is tert-butyl methyl ether;

TLC is thin layer chromatography.

All other abbreviations used herein that are not specifically described above shall have the meaning that would be appended by a person of ordinary skill in the art.

All references cited herein, whether in the form of printed boards, electronic plates, computer readable storage media, or other forms, are expressly incorporated herein by reference in their entirety, including, but not limited to, abstracts, articles, journals, publications, text, articles, internet web sites, databases, patents, and patent publications.

Example (b):

the compounds and methods of the present invention will be better understood in conjunction with the following examples, which are included merely for purposes of illustration and are not intended to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications, including but not limited to those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention, may be made without departing from the spirit of the invention and scope of the appended claims.