Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
阅读说明：本技术 细胞凋亡信号调节激酶1抑制剂及其使用方法 (Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof ) 是由 国强·王 瑞超·沈 江·龙 君·马 学超·邢 勇·何 布雷特·格兰杰 静·何 宾·王 于 2018-05-14 设计创作，主要内容包括：本发明公开一种式(I)的化合物或其药学上可接受的盐类、酯类、立体异构体、互变异构体、溶剂化物、水合物或它们的组合：<Image he="343" wi="687" file="DDA0002358392330000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其抑制细胞凋亡信号调节激酶1(ASK-1),后者与自身免疫性疾病、神经退化性疾病、炎性疾病、慢性肾脏疾病、心血管疾病有关。本发明还关于一种用于给患有ASK-1相关疾病的受试者施用的包含上述化合物的药物组合物。本发明另关于一种通过施用包含本发明化合物的药物组合物来治疗受试者中ASK-1相关疾病的方法。本发明具体关于一种治疗与肝脂肪变性相关的ASK-1的方法,包括非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)。(The invention discloses a compound of formula (I) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, hydrates or other compounds thereofA combination of these: it inhibits apoptosis signal-regulating kinase 1(ASK-1), the latter being associated with autoimmune diseases, neurodegenerative diseases, inflammatory diseases, chronic kidney diseases, cardiovascular diseases. The invention also relates to a pharmaceutical composition comprising the above compound for administration to a subject suffering from an ASK-1 related disease. The invention further relates to a method of treating an ASK-1 related disease in a subject by administering a pharmaceutical composition comprising a compound of the invention. The invention specifically relates to a method of treating ASK-1 associated with hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).)
1. A compound characterized by: the compounds are represented by formula (I) or a pharmaceutically acceptable salt or ester thereof:
wherein the content of the first and second substances,
X1、X2and X3Each independently selected from N or C (R)5)；
R3、R4And R5Each independently selected from:
1) hydrogen;
2) halogen;
3)-NO2；
4) a cyano group;
5) optionally substituted C1-C8An alkyl group;
6) optionally substituted C3-C8A cycloalkyl group;
7) optionally substituted 3-to 8-membered heterocycloalkyl; and
8) optionally substituted C1-C8An alkoxy group;
r is selected from:
each of which may be optionally substituted where possible;
R1selected from the group consisting of:
1) hydrogen;
2) optionally substituted C1-C8An alkyl group;
3) optionally substituted C2-C8An alkenyl group;
4) optionally substituted C2-C8An alkynyl group;
5) optionally substituted C3-C8A cycloalkyl group;
6) optionally substituted aryl;
7) optionally substituted aralkyl;
8) optionally substituted 3-to 8-membered heterocycloalkyl;
9) optionally substituted heteroaryl;
10) optionally substituted heteroarylalkyl; and
11)-N(R6)(R7)；
when R is
1) hydrogen;
2) halogen;
3)-NO2；
4) a cyano group;
5) optionally substituted C1-C8An alkyl group;
6) optionally substituted C2-C8An alkenyl group;
7) optionally substituted C2-C8An alkynyl group;
8) optionally substituted C3-C8A cycloalkyl group;
9) optionally substituted aryl;
10) optionally substituted aralkyl;
11) optionally substituted 3-to 8-membered heterocycloalkyl;
12) optionally substituted heteroaryl;
13) optionally substituted heteroarylalkyl;
14)-N(R6)(R7)；
15)-S(O)2N(R6)(R7)；
16)-N(R6)C(O)(R7) (ii) a And
17)-N(R6)S(O)2(R7)；
wherein R is6And R7Independently selected from hydrogen, preferably C1-C8C of alkyl1-C15Alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, alkyl, alkylamino, dialkylamino, alkyl C (O) NH-, aryl C (O) NH-, heteroaryl C (O) NH, -CN, alkoxy, -CF3Aryl and heteroaryl, or R7And R8Together with the nitrogen to which they are attached, are formed into a heterocyclic ring.
2. The compound of claim 1, wherein: r1Selected from the following:
wherein each of the above plurality of groups is optionally substituted.
3. The compound of claim 1, wherein: r2Selected from the following:
wherein each of the above plurality of groups is optionally substituted.
4. The compound of claim 1, wherein: r3Selected from the following:
wherein each of the above plurality of groups is optionally substituted.
5. The compound of claim 1, wherein: the compound is selected from compounds of formula (Ia), (Ib), (Ic) or (Id) or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
6. The compound of claim 1, wherein: the compound is selected from compounds of formulae (IIa-1) to (IIa-4), or (IIb-1) to (IIb-4), or a pharmaceutically acceptable salt thereof:
wherein R is1、R2、R3And X1As defined in claim 1.
7. The compound of claim 1, wherein: the compound is selected from compounds of formula (IVa-1), (IVa-2), (IVa-3) or (IVa-4) or a pharmaceutically acceptable salt thereof:
wherein R is1、R2As each compound in table 1:
TABLE 1
8. The compound of claim 1, wherein: the compound is selected from compounds of formula (IVb-1), (IVb-2), (IVb-3) or (IVb-4) or a pharmaceutically acceptable salt thereof:
wherein R is1、R2As each compound in table 2:
TABLE 2
9. The compound of claim 1, wherein: the compound is selected from compounds of formula (Va-1), (Va-2), (Va-3) or (Va-4) or pharmaceutically acceptable salts thereof:
wherein R is1、R2As each compound in table 3:
TABLE 3
10. The compound of claim 1, wherein: the compound is selected from compounds of formula (Vb-1), (Vb-2), (Vb-3) or (Vb-4) or a pharmaceutically acceptable salt thereof:
wherein R is1、R2As each compound in table 4:
TABLE 4
11. The compound of claim 1, wherein: the compound is selected from compounds of formula (VIa-1), (VIa-2), (VIa-3) or (VIa-4) or pharmaceutically acceptable salts thereof:
wherein R is1、R2As each compound in table 5:
TABLE 5
12. The compound of claim 1, wherein: the compound is selected from compounds of formula (VIb-1), (VIb-2), (VIb-3) or (VIb-4) or pharmaceutically acceptable salts thereof:
wherein R is1、R2As each compound in table 6:
TABLE 6
13. The compound of claim 1, wherein: the compound is selected from the compounds listed below or a pharmaceutically acceptable salt thereof:
14. a pharmaceutical composition characterized by: the pharmaceutical composition comprises: an effective dose of one or more compounds of formula (I) according to any one of claims 1 to 13; and a pharmaceutically acceptable carrier or excipient.
15. A method for treating an ASK-1 modulated disease or condition in a subject in need thereof, comprising: the method comprises the following steps: administering to said subject a therapeutically effective dose of one or more compounds of formula (I) according to any one of claims 1 to 13.
16. The method of claim 15, wherein: the ASK-1 modulated disease or symptom is selected from the group consisting of: autoimmune diseases, neurodegenerative diseases, inflammatory diseases, chronic kidney diseases, cardiovascular diseases, metabolic diseases or acute or chronic liver diseases.
17. The method of claim 16, wherein the chronic liver disease is selected from the group consisting of Primary Biliary Cirrhosis (PBC), encephaloxanthomatosis (CTX), Primary Sclerosing Cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis during pregnancy, parenteral nutrition-related cholestasis (PNAC), bacterial overgrowth or sepsis-related cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver transplantation associated with graft-versus-host disease, liver regeneration from a transplant donor, liver fibrosis, choledocholithiasis, granulomatous liver disease, intrahepatic or extrahepatic malignancy, sjogren's syndrome, sarcoidosis, Wilson's disease, gaucher's disease, hemochromatosis, or α 1-antitrypsin deficiency.
18. The method of claim 16, wherein: the kidney disease is selected from the group consisting of: diabetic nephropathy, Focal Segmental Glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, renal fibrosis and polycystic kidney disease.
19. The method of claim 16, wherein: the cardiovascular disease is selected from the group consisting of: atherosclerosis, arteriosclerosis, stroke reperfusion/ischemia, cardiac hypertrophy, respiratory diseases, heart attack and myocardial ischemia.
20. The method of claim 16, wherein: the metabolic disease is selected from the group consisting of: insulin resistance, type I and type II diabetes, and obesity.
21. The method of claim 16, wherein: the chronic kidney disease is selected from the group consisting of: polycystic kidney disease, pyelonephritis, renal fibrosis and glomerulonephritis.
22. A method for treating a disease selected from the group consisting of: glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, graves ' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, chronic thrombocytopenia, atopic dermatitis, active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, crohn's disease, psoriasis, graft versus host disease, multiple sclerosis, or sjogren's syndrome, characterized by: the method comprises the following steps: administering to said subject a therapeutically effective dose of a compound of formula (I) according to any one of claims 1 to 13.
23. A method for treating a disease selected from the group consisting of: ischemia/reperfusion of cerebral stroke, heart attack, myocardial ischemia, organ hypoxia, vascular proliferation, cardiac hypertrophy, hepatic ischemia, congestive heart failure, pathological immune responses such as those caused by T cell activation and thrombin-induced platelet aggregation, characterized by: the method comprises the following steps: administering to said subject a therapeutically effective dose of a compound of formula (I) according to any one of claims 1 to 13.
24. A method for treating a disease selected from the group consisting of: osteoporosis, osteoarthritis and multiple myeloma-related bone lesions characterized by: the method comprising administering to the subject a therapeutically effective dose of a compound of formula (I) according to any one of claims 1 to 13.
25. A method for treating a disease selected from the group consisting of: alzheimer's disease, parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), epilepsy, seizures, huntington's disease, polyglutamine disease, traumatic brain injury, ischemic and hemorrhagic stroke, cerebral ischemia, or neurodegenerative diseases including those caused by apoptosis due to trauma, acute hypoxia, ischemia, or glutamate neurotoxicity, characterized by: the method comprises the following steps: administering to said subject a therapeutically effective dose of a compound of formula (I) according to any one of claims 1 to 13.
26. Use of a compound characterized by: the use comprising a compound according to any one of claims 1 to 13 for the preparation of a plurality of pharmaceutical compositions for the treatment of ASK-1 modulated diseases or disorders.
Technical Field
The invention relates to a compound and a pharmaceutical composition as an ASK-1 inhibitor. In particular, the invention relates to compounds that are ASK-1 inhibitors and methods of making and using the same.
Background
Apoptosis signal-regulated kinase 1(ASK-1) is a member of the family of mitogen-activated protein kinase kinases (MAPKKK, MAP3K), which upon activation phosphorylate downstream MAP kinase kinases (MAPKK, MAP2K) and in turn activate MAP kinases (MAPK). MAPKs initiate a response by phosphorylating cellular substrates, thereby modulating the activity of transcription factors that ultimately control gene expression. Specifically, ASK-1 is also called MAPKKK5, phosphorylates MAPKK4/MAPKK7 or MAPKK3/MAPKK6, and then phosphorylates and activates c-Jun N-terminal protein kinase (JNK) and p38 MAPKs, respectively (h.ichijo et al, cell communication signal, 2009, 7, 1-10; k.takeda et al, J.Pharmacology revision, 2008, 48, 199-225; h.nagai et al, J.Biochem.Biochem.2007, p.40, 1-6). Activation pathways of JNK and p38 trigger downstream stress responses such as apoptosis, inflammation, or differentiation (H.Ichijo et al, Science 1997, 275, 90-94; K.Takeda et al, J.biol.). And (4) chemical reaction. 2000. 275, 9805 and 9813; tobiume et al, European molecular biology society report, 2001, 222-; sayama et al, journal of biochemistry, 2001, 276, 999-.
The activity of ASK-1 is regulated by thioredoxin (Trx), which binds to the N-terminus of ASK-1 (M.Saitoh et al, European society for molecular biology, 1998, 17, 2596-. ASK-1 is activated after autophosphorylation at Thr838 in response to oxidative stimulation, Lipopolysaccharide (LPS), Reactive Oxygen Species (ROS), Endoplasmic Reticulum (ER) stimulation, cellular calcium ion concentration increase, Fas ligand and various environmental stimuli, and various cytokines such as Tumor Necrosis Factor (TNF) (H.Nishitoh et al, J.Gen.Gen.Gen.Gen.Gen.Gen.Gen.J.2002, 16, 1345-.
ASK-1 is associated with autoimmune diseases, neurodegenerative diseases, inflammatory diseases, chronic kidney diseases, cardiovascular diseases, metabolic diseases, and acute and chronic liver diseases (r. hayakawa et al, japanese journal of pharmaceuticals, B, 2012, 88, 434-.
More specifically, ASK-1 is associated with hepatic steatosis, including nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). In a mouse model, a high-fat diet causes hepatic steatosis, ultimately leading to fat accumulation and fatty acid oxidation. This leads to the production of ROS, which causes dysfunction and death of hepatocytes (s.k. mantena et al, journal of free radical biology and medicine, 2008, 44, 1259-. In addition, tumor necrosis factor is important for hepatocyte apoptosis through the ASK-1-JNK pathway, and tumor necrosis factor-deficient mice exhibit reduced hepatic steatosis and liver fibrosis (w.zhang et al, society of biochemical and psychological research, 2010, 391, 1731-.
Small molecule compounds that are ASK-1 inhibitors are disclosed in the following publications: WO2008/016131, WO2009/027283, WO 2009/0318425, WO 2009/123986, US2009/0318425, WO 2011/041293, WO2011/097079, US 2011/0009410, GP Volynets et al, journal of chemi-medicine, 2011, 54, 2680-.
Therefore, there is a need for ASK-1 inhibitors for the treatment and prevention of diseases. The present invention has identified compounds that inhibit ASK-1 and methods of using these compounds to treat disease.
Disclosure of Invention
The invention relates to a compound and a pharmaceutical composition as an ASK-1 inhibitor. In particular, the invention relates to compounds that are ASK-1 inhibitors and methods of making and using the same. In addition, the invention includes methods of making the compounds.
In its main aspect, the present invention provides a compound having formula (I) or a pharmaceutically acceptable salt or ester thereof:
wherein the content of the first and second substances,
X1、X2and X3Each independently selected from N or C (R)5)；
R3、R4And R5Each independently selected from:
1) hydrogen;
2) halogen;
3)-NO2；
4) a cyano group;
5) optionally substituted C1-C8An alkyl group;
6) optionally substituted C3-C8A cycloalkyl group;
7) optionally substituted 3-to 8-membered heterocycloalkyl; and
8) optionally substituted C1-C8An alkoxy group;
r is selected from:
each triazole or imidazole ring is optionally further substituted;
R1selected from the group consisting ofGroup (2):
1) hydrogen;
2) optionally substituted C1-C8An alkyl group;
3) optionally substituted C2-C8An alkenyl group;
4) optionally substituted C2-C8An alkynyl group;
5) optionally substituted C3-C8A cycloalkyl group;
6) optionally substituted aryl;
7) optionally substituted aralkyl;
8) optionally substituted 3-to 8-membered heterocycloalkyl;
9) optionally substituted heteroaryl;
10) optionally substituted heteroarylalkyl; and
11)-N(R6)(R7)；
wherein R is6And R7Independently selected from hydrogen, preferably C1-C8C of alkyl1-C15Alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, alkyl, alkylamino, dialkylamino, alkyl C (O) NH-, aryl C (O) NH-, heteroaryl C (O) NH, -CN, alkoxy, -CF3Aryl and heteroaryl, or R7And R8Are taken together with the nitrogen to which they are attached to form a heterocyclic ring;
when R isWhen R is1Is different from-N (R)6)(R7)；
R2Selected from the group consisting of:
1) hydrogen;
2) halogen;
3)-NO2；
4) a cyano group;
5) optionally substituted C1-C8An alkyl group;
6) optionally substituted C2-C8An alkenyl group;
7) optionally substituted C2-C8An alkynyl group;
8) optionally substituted C3-C8A cycloalkyl group;
9) optionally substituted aryl;
10) optionally substituted aralkyl;
11) optionally substituted 3-to 8-membered heterocycloalkyl;
12) optionally substituted heteroaryl;
13) optionally substituted heteroarylalkyl;
14)-N(R6)(R7)；
15)-S(O)2N(R6)(R7)；
16)-N(R6)C(O)(R7) (ii) a And
17)-N(R6)S(O)2(R7)；
wherein R is6And R7As previously defined.
In another embodiment, the invention provides a pharmaceutical composition comprising a therapeutically effective dose of a compound or combination of compounds of the invention, or a pharmaceutically acceptable salt form, stereoisomer, solvate, hydrate, or combination thereof, and a pharmaceutically acceptable carrier or excipient.
In another embodiment, the invention provides a method for preventing or treating an ASK-1 modulated disease or disorder. The method comprises administering a therapeutically effective dose of a compound of formula (I). The invention also provides the use of a compound of formula (I) in the manufacture of a medicament for the prevention or treatment of an ASK-1 modulated disease or condition. Such diseases include autoimmune diseases, neurodegenerative diseases, inflammatory diseases, chronic kidney diseases, cardiovascular diseases, metabolic disorders, and acute and chronic liver diseases.
Detailed Description
A first embodiment of the invention is a compound represented by formula (I) or a pharmaceutically acceptable salt or ester thereof, as described above.
In certain embodiments, the present invention relates to compounds of formula (I), and pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, hydrates, or combinations thereof, wherein
wherein each of these radicals is optionally substituted where possible, and R5And R4Each as defined previously.
In certain embodiments, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts and esters thereof, wherein X1is-N-, -C (F) or-C (OMe) -.
In certain embodiments, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts and esters thereof, wherein R1Selected from the group consisting of:
wherein each of these groups is optionally substituted.
In certain embodiments, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts and esters thereof, wherein R2Selected from the group consisting of:
wherein each of these groups is optionally substituted.
In certain embodiments, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts and esters thereof, wherein R3Selected from the group consisting of:
wherein each of the above plurality of groups is optionally substituted.
In one embodiment, the present invention relates to a compound of formula (Ia), (Ib), (Ic), or (Id) or a pharmaceutically acceptable salt or ester thereof:
wherein the content of the first and second substances,
In one embodiment, the present invention provides a compound of formula (IIa) or (IIb):
therein markedThe valency being bound to the pyridine or thiazole ring, labelled
In one embodiment, the present invention provides a compound represented by one of formulae (IIa-1) to (IIa-4) and formulae (IIb-1) to (IIb-4), or a pharmaceutically acceptable salt or ester thereof:
wherein R is1、R2、R3And X1As previously defined.
In one embodiment, the present invention provides a compound represented by formula (IIIa) or formula (IIIb), or a pharmaceutically acceptable salt or ester thereof:
wherein the content of the first and second substances,
In one embodiment, the present invention provides a compound represented by one of formulae (IIIa-1) to (IIIa-4) and formulae (IIIb-1) to (IIIb-4), or a pharmaceutically acceptable salt or ester thereof:
wherein R is1、R2And X1As previously defined.
In one embodiment, the present invention provides a compound represented by formula (IVa) or formula (IVb), or a pharmaceutically acceptable salt or ester thereof:
wherein the content of the first and second substances,
In one embodiment, the present invention provides a compound represented by one of formulae (IVa-1) to (IVa-4) and formulae (IVb-1) to (IVb-4), or a pharmaceutically acceptable salt or ester thereof:
wherein R is1And R2As previously defined.
In one embodiment, the present invention provides a compound represented by formula (Va) or formula (Vb), or a pharmaceutically acceptable salt or ester thereof:
wherein the content of the first and second substances,
In one embodiment, the present invention provides a compound represented by one of formulae (Va-1) to (Va-4) and formulae (Vb-1) to (Vb-4), or a pharmaceutically acceptable salt or ester thereof:
wherein R is1And R2As previously defined.
In one embodiment, the present invention provides a compound represented by formula (VIa) or formula (VIb), or a pharmaceutically acceptable salt or ester thereof:
wherein the content of the first and second substances,
In one embodiment, the present invention provides a compound represented by one of formulae (VIa-1) to (VIa-4) and formulae (VIb-1) to (VIb-4), or a pharmaceutically acceptable salt or ester thereof:
wherein R is1And R2As previously defined.
Representative compounds of the invention include, but are not limited to, compounds according to formula (IVa) (item 1 to item 100 in table 1) below, wherein R1And R2Is represented as each compound in Table 1, and
TABLE 1
Representative compounds of the invention include, but are not limited to, compounds according to formula (IVb) (item 101 to item 200 in table 2) below, wherein R1And R2Is represented as each compound in Table 2, and
TABLE 2
Representative compounds of the invention include, but are not limited to, compounds according to formula (Va) (items 201 through 300 in table 3) below, wherein R is1And R2Is represented as each compound in Table 3, and
TABLE 3
Representative compounds of the present invention include, but are not limited to, compounds according to formula (Vb) (entry 301 to entry 400 in table 4) below, wherein R1And R2Is represented as each compound in Table 4, and
TABLE 4
Representative compounds of the invention include, but are not limited to, compounds according to formula (VIa) below (items 401 to 500 in table 5), wherein R is1And R2Is represented as each compound in Table 5, and
TABLE 5
Representative compounds of the invention include, but are not limited to, compounds according to formula (VIb) below (items 501 to 600 in table 6), wherein R is1And R2Is represented as each compound in Table 6, andas previously defined, without further substitution.
TABLE 6
In certain embodiments, the invention provides methods for preventing or treating ASK-1 modulated diseases or disorders. The method comprises administering a therapeutically effective dose of a compound of formula (I). The invention also provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment of an ASK-1 modulated disease or condition.
In certain embodiments, the ASK-1 modulated disease or disorder is an autoimmune disease, a neurodegenerative disease, an inflammatory disease, a chronic kidney disease, a cardiovascular disease, a metabolic abnormality, and an acute or chronic liver disease.
In certain embodiments, the chronic liver disease is Primary Biliary Cirrhosis (PBC), encephaloxanthomatosis (CTX), Primary Sclerosing Cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis during pregnancy, parenteral nutrition-related cholestasis (PNAC), bacterial overgrowth or sepsis-related cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver transplantation associated with graft versus host disease, live donor transplant liver regeneration, congenital liver fibrosis, choledocholistic liver disease, granulomatous liver disease, intrahepatic or extrahepatic malignancy, sjogren's syndrome, sarcoidosis, Wilson's disease, gaucher's disease, hemochromatosis, or α 1-antitrypsin deficiency.
In certain embodiments, the kidney disease is diabetic nephropathy, Focal Segmental Glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, or polycystic kidney disease.
In certain embodiments, the cardiovascular disease is atherosclerosis, arteriosclerosis, stroke reperfusion/ischemia, cardiac hypertrophy, respiratory disease, heart attack, and myocardial ischemia.
In certain embodiments, the metabolic disease is insulin resistance, type I and type II diabetes, and obesity.
In certain embodiments, the chronic kidney disease is polycystic kidney disease, pyelonephritis, renal fibrosis, and glomerulonephritis.
Another object of the invention is a method of making any of the compounds described herein using any of the synthetic methods described herein.
Defining:
the following sets forth definitions of various terms used to describe the present invention. These definitions apply to the terms used herein and in the claims, either individually or as part of a broader term unless otherwise limited in specific instances.
The term "alkyl" as used herein describes a saturated, straight or branched chain hydrocarbyl radical. "C1-C3Alkyl group "," C1-C6Alkyl group "," C1-C10Alkyl group "," C2-C4Alkyl "or" C3-C6Alkyl "refers to alkyl groups containing 1 to 3, 1 to 6, 1 to 10, 2 to 4, and 3 to 6 carbon atoms, respectively. C1-C8Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butylRadicals, neopentyl, n-hexyl, heptyl and octyl radicals.
The term "alkenyl" as used herein refers to a straight or branched hydrocarbon radical having at least one carbon-carbon double bond by the removal of a single hydrogen atom. "C2-C10Alkenyl group "," C2-C8Alkenyl group "," C2-C4Alkenyl "or" C3-C6Alkenyl "refers to alkenyl groups containing 2 to 10, 2 to 8, 2 to 4, or 3 to 6 carbon atoms, respectively. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octyl, and the like.
The term "alkynyl" as used herein refers to a straight or branched hydrocarbon radical having at least one carbon-carbon triple bond by removal of a single hydrogen atom. "C2-C10Alkynyl group "," C2-C8Alkynyl group "," C2-C4Alkynyl "or" C3-C6Alkynyl "refers to alkynyl groups containing 2 to 10, 2 to 8, 2 to 4, or 3 to 6 carbon atoms, respectively. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propyl, 1-butyl, heptyl, octyl, and the like.
The term "cycloalkyl" as used herein 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 oxygen or optionally with an exocyclic alkene, imine or oxime double bond. Preferred cycloalkyl groups include C3-C12Cycloalkyl radical, C3-C6Cycloalkyl radical, C3-C8Cycloalkyl and C4-C7A cycloalkyl group. C3-C12Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylenecyclohexyl, bicyclo [2.2.1]Heptyl, bicyclo [3.1.0]Hexyl, spiro [2.5]]Octyl, 3-methylenebicyclo [3.2.1]]Octyl, spiro [4.4]]Nonyl, and the like.
The term "cycloalkenyl" as used herein 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, andand the carbon atoms may be optionally substituted with oxygen or optionally with an outer cyclic alkene, imine group or oxime double bond. Preferred cycloalkenyl groups include C3-C12Cycloalkenyl radical, C3-C8Cycloalkenyl or C5-C7A cycloalkenyl group. C3-C12Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo [2.2.1] alkenyl]Hept-2-enyl, bicyclo [3.1.0]Hexagon-2-alkenyl, 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 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 groups are polycyclic ring systems containing at least one aromatic ring. The polycyclic aryl groups can contain fused rings, covalently linked rings, or combinations thereof.
The term "heteroaryl" as used herein refers to a monocyclic or polycyclic aromatic group having one or more ring atoms selected from S, O and N. The remaining ring atoms are carbon, wherein any N or S contained in the ring may be optionally oxidized. Heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl. The polycyclic heteroaryl group can comprise fused rings, covalently linked rings, or combinations thereof.
According to the invention, the aromatic group may be substituted or unsubstituted. The term "bicyclic aryl" or "bicyclic heteroaryl" as used herein refers to a ring system consisting of two rings, at least one of which is aromatic; the two rings may be fused or covalently linked.
The term "aralkyl" as used herein refers to a functional group in which one alkylene chain is attached to one aryl group, e.g., -CH2CH2A phenyl group. The term "substituted arylalkyl" as used herein refers to an arylalkyl functional group in which the aryl group is substituted. Similarly, theThe term "heteroarylalkyl" as used herein refers to a functional group wherein an alkylene chain is attached to a heteroaryl group. The term "substituted heteroarylalkyl" as used herein refers to a heteroarylalkyl functional group in which the heteroaryl group is substituted.
The term "alkylene" as used herein refers to a diradical of a branched or straight saturated hydrocarbon chain, typically having 1 to 20 carbon atoms (e.g., 1 to 10 carbon atoms, or 1,2,3,4, 5, or 6 carbon atoms). The term is defined as such as methylene (-CH)2-) ethylene (-CH2CH2-), propylene isomers (e.g., -CH2CH2CH2-and-CH (CH)3)CH2-) etc. groups are examples.
The term "substituted" as used herein means that one, two, or three or more hydrogen atoms thereon are independently substituted with substituents including, but not limited to, deuterium, -F, -Cl, -Br, -I, -OH, protected hydroxyl, -NO2、-CN、-NH2、N3Protected amino, alkoxy, thioalkoxy, oxy substituent, C1-C6Alkyl radical, C2-C12-alkenyl, C2-C12-alkynyl, -halo-C1-C12-alkyl, -halo-C2-C12-alkenyl, -halo-C2-C12-alkynyl, -halo-C3-C12-cycloalkyl, -NH-C1-C12-alkyl, -NH-C2-C12-alkenyl, -NH-C2-C12-alkynyl, -NH-C3-C12-cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C1-C12-alkyl, -O-C2-C12-alkenyl, -O-C2-C12-alkynyl, -O-C3-C12-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C (O) -C1-C12Alkyl, -C (O) -C2-C12-alkenyl, -C (O) -C2-C12-alkynyl, -C (O) -C3-C12-cycloalkyl, -C (O) -aryl, -C (O) -heteroarylCycloalkyl, -CONH2、-CONH-C1-C12-alkyl, -CONH-C2-C12-alkenyl, -CONH-C2-C12-alkynyl, -CONH-C3-C12-cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C1-C12-alkyl, -OCO2-C2-C12-alkenyl, -OCO2-C2-C12-alkynyl, -OCO2-C3-C12-cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -OCONH2、-OCONH-C1-C12-alkyl, -OCONH-C2-C12-alkenyl, -OCONH-C2-C12-alkynyl, -OCONH-C3-C12-cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC (O) -C1-C12-alkyl, -NHC (O) -C2-C12-alkenyl, -NHC (O) -C2-C12-alkynyl, -NHC (O) -C3-C12-cycloalkyl, -NHC (O) -aryl, -NHC (O) -heteroaryl, -NHC (O) -heterocycloalkyl, -NHCO2-C1-C12-alkyl, -NHCO2-C2-C12-alkenyl, -NHCO2-C2-C12-alkynyl, -NH CO2-C3-C12-cycloalkyl, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocycloalkyl, -NHC (O) NH2、-NHC(O)NH-C1-C12Alkyl, -NHC (O) NH-C2-C12-alkenyl, -NHC (O) NH-C2-C12-alkynyl, -NHC (O) NH-C3-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-C12-alkenyl, -NHC (S) NH-C2-C12-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-C12-alkyl, -NHC(NH)NH-C2-C12-alkenyl, -NHC (NH) NH-C2-C12-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-C12-alkenyl, -NHC (NH) -C2-C12-alkynyl, -NHC (NH) -C3-C12-cycloalkyl, -NHC (NH) -aryl, -NHC (NH) -heteroaryl, -NHC (NH) -heterocycloalkyl, -C (NH) NH-C1-C12Alkyl, -C (NH) NH-C2-C12-alkenyl, -C (NH) NH-C2-C12-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-C12-alkenyl, -S (O) -C2-C12-alkynyl, -S (O) -C3-C12-cycloalkyl, -S (O) -aryl, -S (O) -heteroaryl, -S (O) -heterocycloalkyl-SO2NH2、-SO2NH-C1-C12-alkyl, -SO2NH-C2-C12-alkenyl, -SO2NH-C2-C12-alkynyl, -SO2NH-C3-C12-cycloalkyl, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocycloalkyl, -NHSO2-C1-C12Alkyl, -NHSO2-C2-C12Alkenyl, -NHSO2-C2-C12Alkynyl, -NHSO2-C3-C12-cycloalkyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2，-CH2SO2CH3-aryl, -aralkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-C12-cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C1-C12-alkyl, -S-C2-C12-alkenyl, -S-C2-C12-alkynyl, -S-C3-C12-cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, methylthiomethyl or-L ' -R ', wherein L ' is C1-C6Alkylene radical, C2-C6Alkenylene or C2-C6Alkynylene, R' is aryl, heteroaryl, heterocycle, C3-C12Cycloalkyl or C3-C12A cycloalkenyl group. It is understood that aryl, heteroaryl, alkyl, and the like may be further substituted. In some cases, each of the substituents is further optionally substituted with one or more groups, each group independently selected from C1-C6Alkyl, -F, -Cl, -Br, -I, -OH, -NO2-CN or-NH2。
According to the present invention, any of the aromatic, substituted aryl, heteroaryl and substituted heteroaryl groups described herein may 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 comprise 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. The aliphatic group can be straight, branched, or cyclic, and preferably contains 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, for example, polyalkoxyalkyl groups such as polyalkylene glycols, polyamines, and polyimines. Such aliphatic groups may be further substituted. It is to be understood that aliphatic moieties may be substituted for the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylene groups described herein.
The term "alicyclic" as used herein refers to 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. Such cycloaliphatic groups may be further substituted.
As herein describedThe term "alkoxy", employed alone or in combination with other terms, means, unless otherwise stated, an alkyl group having the indicated number of carbon atoms attached to the remainder of the molecule through an oxygen atom, such as methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), and higher homologs and isomers. Preferred alkoxy is (C)1-C3) An alkoxy group.
The term "aryloxy" as used herein refers to the aryl group-O-, wherein aryl is as defined above and includes optionally substituted aryl is also as defined above. The term "arylthio" as used herein refers to the group R-S-, wherein R is as defined for aryl.
The terms "heterocycle" or "heterocycloalkyl" as used herein are used interchangeably and refer to a non-aromatic ring or a fused, bridged or spiro bi-or tricyclic group in which (i) each ring system independently contains at least one heteroatom, (ii) each ring system may be saturated or unsaturated, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (v) any one of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be substituted by oxo or by exocyclic alkene, imino or oximino double bonds. Representative heterocycloalkyl groups include, but are not limited to, 1, 3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, 2-isothiazolidinyl [2.2.1] -heptyl, 8-azabicyclo [3.2.1] octyl, 5-azaspiro [2.5] octyl, 1-oxa-7-azaspiro [4.4] nonyl, 7-oxooxa-4-yl, and tetrahydrofuranyl. Such heterocyclic groups may be further substituted. The heteroaryl or heterocyclic group may be C-linked or N-linked (if possible).
It is to be understood that any of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, and cycloalkenyl moieties described herein can also be an aliphatic or alicyclic radical.
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, alkynylene, cycloalkylene, cycloalkenylene, cycloalkynylene, arylalkylene, heteroarylalkylene, and heterocyclylene groups are intended to be encompassed by the above definitions and may be used to provide the appropriate valency for the formulae herein.
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 "optionally substituted" as used herein means that the group referred to may be substituted or unsubstituted. In one embodiment, the reference group is optionally substituted with zero substituents, i.e., the reference group is unsubstituted. In another embodiment, the mentioned groups are optionally substituted with one or more additional groups individually and independently selected from the groups described herein.
The term "hydrogen" as used herein includes hydrogen and deuterium. In addition, the list of atoms includes other isotopes of the atoms provided the resulting compounds are pharmaceutically acceptable.
In certain embodiments, compounds of each formula herein are defined as including isotopically labeled compounds. An "isotopically labeled compound" is a compound in which at least one atomic position is enriched in a particular isotope of a specified element at a level significantly greater than the natural abundance of the isotope. For example, one or more hydrogen atom positions in a compound may be increased to a level of deuterium that is significantly greater than the natural abundance of deuterium, e.g., to at least 1%, preferably at least 20% or at least 50%. Such deuterated compounds, for example, can be metabolized more slowly than their non-deuterated analogs, and thus exhibit a longer half-life when administered to a subject. Such compounds can be synthesized using methods known in the art, for example, by using deuterated starting materials. Unless otherwise indicated, isotopically-labeled compounds are pharmaceutically acceptable.
The compounds described herein contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers and other stereoisomeric forms which can be defined in absolute stereochemistry as (R) -or (S) -or (D) -or (L) -representing amino acids. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolution of the racemic mixture. 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. For more details on the resolution, see Jacques et al, enantiomers, racemates and resolution (John Wiley & Sons, 1981). When a compound described herein contains olefinic double bonds, other unsaturated bonds, or other centers of geometric asymmetry, the compound is intended to include both E-and Z-geometric isomers or both cis-and trans-isomers, unless otherwise specified. Likewise, all tautomeric forms are also intended to be included. Tautomers can be cyclic or acyclic. The configuration of any carbon-carbon double bond present herein is selected for convenience only and is not intended to designate a particular configuration unless the context indicates otherwise; thus, a carbon-carbon double bond or a carbon-heteroatom double bond, any of which is described herein as trans, may be cis, trans, or a mixture of both in any proportion.
The term "subject" as used herein refers to a mammal. Thus, a subject refers to, for example, a dog, cat, horse, cow, pig, guinea pig, and the like. Preferably, the subject is a human. When the subject is a human, the subject may be referred to herein as a patient.
The term "pharmaceutically acceptable salts" as used herein 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 at a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.
Belger et al, journal of pharmaceutical sciences, 66:1-19(1977), describe in detail pharmaceutically acceptable salts. These salts can 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, for example, salts of amino groups formed from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids or with organic acids such as acetic, maleic, tartaric, citric, etc., succinic or malonic acids or 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, sodium bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cypionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, gluconates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydrogen iodide, 2-hydroxy-ethanesulfonates, lactates, laurates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, nylonates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, 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. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl, sulfonate and arylsulfonate salts having from 1 to 6 carbon atoms, as appropriate.
The term "pharmaceutically acceptable esters" as used herein refers to those esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or salt thereof. Suitable esters include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, naphthenic and alkanedioic acids, in which each alkyl or alkenyl moiety is advantageouslyHaving no more than 6 carbon atoms. Examples of specific esters include, but are not limited to, C1-C6Esters of alkanoic acids, such as acetate, propionate, butyrate and pivalate.
The term "hydroxyl activating group" as used herein refers to a labile chemical moiety known in the art that activates a hydroxyl group so that it will be liberated during synthetic procedures such as substitution or elimination reactions. Examples of hydroxyl activating groups include, but are not limited to, mesylate, tosylate, triflate, p-nitrophenyl carbonate, phosphonate, and the like.
The term "activated hydroxy" as used herein refers to a hydroxy group activated by a hydroxy activating group as defined above, including for example mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate.
The term "hydroxyl protecting group" as used herein refers to a labile chemical moiety known in the art for protecting hydroxyl groups from undesired reactions during synthesis. Following the synthetic step, the hydroxyl protecting groups described herein may be selectively removed. Hydroxy protecting groups known in the art are generally described in t.h.greene and p.g.m.wuts, protecting groups in organic synthesis, 3 rd 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, t-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 by a hydroxy protecting group as defined above, including for example benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl.
The term "hydroxy prodrug group" as used herein refers to groups known in the art to alter the physicochemical properties of the parent drug, and thus its parent biological properties, in a transient manner by covering or masking the hydroxy group. The hydroxy prodrug group described herein must be capable of being reduced to a hydroxy group in vivo after the one or more synthetic methods. Hydroxy prodrug groups known in the art are described in Kenneth b. sloan, prodrug, topical and ocular drug delivery (drugs and pharmaceuticals; volume 53), Marcel Dekker, inc., new york (1992); and prodrugs of alcohols and phenols, written by s.s.dhares and v.j.stella, in section 2 of prodrug challenges and rewards, (biotechnology: pharmaceutical), and edited by VJ Stella et al, Springer and AAPSPress, 2007, pages 31-99.
The term "amino" as used herein refers to the group-NH2。
The term "substituted amino" as used herein refers to the group-NRR, wherein each R is independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, provided that neither R group is hydrogen, or a-Y-Z group, wherein Y is optionally substituted alkylene and Z is alkenyl, cycloalkenyl, or alkynyl.
The term "amino protecting group" as used herein refers to a labile chemical moiety that is known in the art to protect an amino group from undesired reactions during synthesis. Following the synthetic steps, the amino protecting groups described herein may be selectively removed. Known amino protecting groups are generally described in t.h. green and PG m.wuts, protecting groups in organic synthesis, third edition, john wili father-son press, new york (1999). Examples of amino protecting groups include, but are not limited to, t-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl and the like.
The term "leaving group" as used herein refers to a functional group or atom that can be substituted by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. Representative leaving groups include, for example, chloro, bromo, and iodo; sulfonate groups such as methanesulfonate, toluenesulfonate, bromosulfonate, methanesulfonic acid, and the like; acyloxy groups such as acetoxy and trifluoroacetyloxy.
The term "pharmaceutically acceptable esters" as used herein refers to esters of compounds formed by the process of the present invention which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, alkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethyl succinates.
The term "pharmaceutically acceptable prodrug" as used herein refers to those prodrugs 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 undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention. The term "prodrug" as used herein refers to a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to provide any of the compounds described by the formulations of the present invention. Various forms of prodrugs are known in the art, e.g., prodrug design by Bundgaard (editors), Elsevier (1985); method in enzymology by Widder et al (ed.), Vol.4, academic Press (1985); Krogsgaard-Larsen et al (eds.) "prodrug design and application, drug design and development textbook, Chapter 5, 113-; bundgaard et al, J.Red.Med.Med.8: 1-38 (1992); bundgaard, journal of pharmaceutical sciences 77:285, etc. (1988) (ii) a Higuchi and Stella (ed), "prodrugs as a novel drug delivery system", american chemical society (1975); BernardTesta and Joachim Mayer, hydrolysis in drug and prodrug metabolism: chemistry, biochemistry and enzymology, john willi father press (2002).
The term "treating" as used herein refers to alleviating, slowing, reducing, eliminating, modulating or ameliorating, i.e., causing regression of a disease state or condition. Treatment may also include inhibition (i.e., arresting the development of an existing disease state or condition) and remission or amelioration (i.e., causing regression of an existing disease state or condition), for example, when the disease state or condition may already be present.
The term "preventing" as used herein 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 susceptible to such disease or is at risk for a disease state.
In addition, the compounds of the present invention, e.g., salts of the compounds, may exist in hydrated or non-hydrated (anhydrous) form, 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 "solvate" as used herein is meant to encompass stoichiometric or non-stoichiometric solvent addition forms. Some compounds tend to trap a fixed molar ratio of solvent molecules in a crystalline solid state, 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. Hydrates are formed by combining one or more water molecules with a substance that maintains the water in its molecular state as H2O, which combination is capable of forming one or more hydrates.
The term "analog" as used herein refers to a compound that is structurally similar to another but slightly different in composition (e.g., one atom is replaced by an atom of a different element or a particular functional group is present, or one functional group is replaced by another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound.
The term "aprotic solvent" as used herein refers to a solvent that is relatively inert to proton 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 dichloromethane, ethyl chloride, chloroform and the like, heterocyclic compounds such as tetrahydrofuran and N-methylpyrrolidone, and ethers such as diethyl ether, bismethoxymethyl ether. Such solvents are well known to those skilled in the art, and for a particular compound and reaction conditions, either solvent alone or a mixture thereof may be preferred, depending on factors such as the solubility of the reagents, the reactivity of the reagents, and the preferred temperature range. Further discussion of aprotic solvents may be found in textbooks or specialist monographs of organic chemistry. For example: physical properties of organic solvents and purification methods, 4 th edition, edited by John a. riddic et al, second edition of the series of chemical technology books, John willi father press, new york, 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 for a particular compound and reaction conditions, either solvent alone or a mixture thereof may be preferred, depending on factors such as the solubility of the reagents, the reactivity of the reagents, and the preferred temperature range. Further discussion of protic solvents may be found in textbooks or specialist books of organic chemistry. For example: physical properties of organic solvents and purification methods, 4 th edition, edited by John a. riddic et al, second edition of the series of chemical technology books, John willi father press, new york, 1986.
Combinations of substituents and variables contemplated by the present invention are only those that result in the formation of stable compounds. The term "stable" as used herein refers to a compound that has sufficient stability to allow manufacture and maintains the integrity of the compound long enough for the purposes detailed herein (e.g., a compound that is therapeutic or prophylactic for 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, etc. described herein are for illustration purposes only, and variations in reaction conditions can produce the desired isoxazole products of the present invention. Synthetic chemical transformations and protecting group methods (protection and deprotection) useful in the synthesis of the compounds described herein include: for example, in r.larock, integrated organic switching, VCH press (1989); t.w. green and p.g.m. wutz, protective groups in organic synthesis, second edition, john william publishing (1991); fieser and m.fieser, organic synthesis reagents of Fieser and Fieser, john wili father press (1994); and those described in encyclopedia of organic Synthesis reagents, edited by L.Patette, John, Willi, parent-child Press (1995).
The compounds of the invention may be modified by the synthetic methods described herein with the addition of various functionalities to enhance selective biological properties. These modifications include increasing bio-penetration to specific biological systems (e.g., blood, lymphatic system, central nervous system), increasing oral dose, increasing solubility to allow administration by injection, altering metabolism and altering excretion rates.
The pharmaceutical composition comprises:
the pharmaceutical compositions of the invention comprise a therapeutically effective dose of a compound of the invention formulated with one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" as used herein refers to any type of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid. Some examples of materials that can be used as pharmaceutically acceptable carriers are sugars, such as lactose, glucose, and sucrose, among others; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; astragalus powder malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oil such as peanut oil, cottonseed oil, and the like; safflower oil; sesame oil; olive oil; corn oil and soybean oil; ethylene glycol; or is propylene glycol; esters such as ethyl oleate and ethyl laurate; agar buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid pyrogen-free water; isotonic saline; a ringer's solution; ethanol and phosphate buffer solution; and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; as well as coloring agents, mold release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants, at the discretion of the formulator. The pharmaceutical compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracerebrally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally, or by oral or nasal spray.
The pharmaceutical compositions of the invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or by injection. The pharmaceutical compositions of the present invention may comprise any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle. In certain instances, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulation compound or its delivery form. The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and pellets. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters sorbitan and mixtures thereof. In addition to inert diluents, the oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations may be formulated according to the prior art using suitable dispersing or wetting agents and suspending agents, for example, sterile injectable aqueous or oleaginous suspensions. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that may be used are water, ringer's solution of the United states pharmacopoeia and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material that is poorly water soluble. The rate of absorption of the drug then depends on its rate of dissolution, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered pharmaceutical form is achieved by dissolving or suspending the drug in an oily vehicle. Injectable depot forms are prepared by forming a microencapsulated matrix of the drug in a biodegradable polymer, such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of release of the drug can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations can also be prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert, pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate) and/or: a) fillers or extenders (e.g., starch, lactose, sucrose, glucose, mannitol); b) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) retarders (e.g., paraffin); f) absorption promoters, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents such as kaolin and bentonite clays; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
As mentioned above, the active compound may also be present in microencapsulated form with one or more excipients. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings and the like and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent (e.g., sucrose, lactose or starch). Such dosage forms may also include, as is conventional, other substances in addition to inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of an ingredient that it releases the active ingredient only, or preferably, of an ingredient that releases the active ingredient in a particular part of the intestinal tract, optionally, in a delayed manner. Examples of embedding components that can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers as may be required. Ophthalmic formulations, ear drops, eye ointments, powders, and solutions are also contemplated as being within the scope of the present invention.
Ointments, pastes, creams and gels may contain, in addition to an active compound of the invention, excipients, for example animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to a compound of the invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays can also contain conventional propellants, such as chlorofluorohydrocarbons.
Transdermal patches also have the additional advantage of providing a controlled release of the compound to the body. Such dosage forms may be prepared by dissolving or dispensing the compound in the appropriate medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications, patents, published patent applications and other references mentioned herein are incorporated by reference in their entirety.
Abbreviations:
abbreviations used in the example descriptions and examples below are:
BOP-Cl is bis (2-oxo-3-oxazolidinyl) phosphinic chloride;
CDI is carbonyldiimidazole;
DBU is 1, 8-diazabicycloundecyl-7-ene;
DC is N, N' -dicyclohexylcarbodiimide;
DCM is dichloromethane;
DIPEA is N, N-diisopropylethylamine;
DMAP is N, N-dimethylaminopyridine;
DME is 1, 2-dimethoxyethane;
DMF is N, N-dimethylformamide;
DMPU is 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2 (1H) -pyrimidinone;
EDC is 1- (3-diethylaminopropyl) -3-ethylcarbodiimide hydrochloride;
Et3n is triethylamine;
EtOAc is ethyl acetate;
HATU is 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide hexafluorophosphate;
HCl is hydrochloric acid;
mCPBA is m-chloroperoxybenzoic acid;
NMO is N-methylmorpholine-N-oxide;
PhMe is toluene;
PyAOP is 7-azabenzotriazol-1-yloxy) trispyrrolidinylhexafluorophosphorus;
PyBOP is benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate;
THF is tetrahydrofuran.
The synthesis method comprises the following steps:
the compounds and methods of the present invention will be better understood in conjunction with the following synthetic schemes which illustrate the methods of making the compounds of the present invention, which are intended to be illustrative only and not limiting in scope. Various changes and modifications to the disclosed embodiments, including but not limited to those relating to chemical structures, substituents, derivatives, and variations and modifications which may be made to the invention and/or the method of the invention without departing from the spirit of the invention and the scope of the appended claims, will be apparent to those skilled in the art.
As shown in scheme 1, the compounds of formula (I) can be prepared by coupling a carboxylic acid compound (1) and an amine compound (2) under suitable amide coupling conditions, wherein, R, R2、R3、X1And
Scheme 1
Alternatively, the compounds of formula (I) may also be prepared by: the compound of formula (I) is prepared by first converting the carboxylic acid compound (1) into the acid chloride compound (3), and then reacting the acid chloride compound (3) with the amine compound (2) in the presence of an organic base, as shown in scheme 2.
Scheme 2
Thus, treatment of carboxylic acid compound (1) with thionyl chloride or oxalyl chloride or other acid chloride forming reagents in an aprotic solvent such as, but not limited to, DCM or DMF affords acid chloride compound (3). The acid chloride compound (3) is then reacted with the amine compound (2) in an aprotic solvent such as, but not limited to, DCM or DMF in the presence of an organic base such as, but not limited to, TEA, DIPEA, DMAP or pyridine to provide the compound of formula (I).
An alternative method of preparing the compound of formula (I) is to first convert the carboxylic acid compound (1) to the mixed anhydride compound (4) and then react the mixed anhydride compound (4) with the amine compound (2) in the presence of an organic base (as shown in scheme 3).
Scheme 3
Thus, treatment of carboxylic acid compound (1) with a chloroformate reagent such as, but not limited to, isobutyl chloroformate in an aprotic solvent such as, but not limited to, DCM in the presence of a base such as, but not limited to, TEA or DIPEA produces mixed anhydride compound (4). The mixed anhydride compound (4) is then reacted with the amine compound (2) in the presence of an organic base (such as, but not limited to, TEA, DIPEA, DMAP) in an aprotic solvent (such as, but not limited to, DCM or DMF) to provide the compound of formula (I).
Schemes 4 to 6 illustrate the synthesis of the tetrazole compound (2 a). Scheme 7 illustrates the synthesis of tetrazole compound (2 b). The synthesis of tetrazoles is discussed in more detail in the literature, for example, widenin, Mingmen and Gong's bloom (moleculars), 2015, 20, 5528-5553.
As shown in scheme 4, the tetrazole compound (6a) is produced by performing [3+ 2] reaction between hydrazine acid and a nitrile compound (5a)]Cycloaddition. Thus, compound (5a) is reacted with NaN in the presence of a lewis acid at elevated temperature in a solvent (such as, but not limited to, DMF)3Or TMSN3Treatment gives the compound (6 a). The lewis acid may be, but is not limited to, ammonium chloride Bu3SnO. The reaction temperature is 50 ℃ to 150 ℃. The compound (6a) is further treated with R in the presence of a base1X is alkylated, wherein R1As previously defined, preferably optionally substituted alkyl and X is halogen, preferably chlorine or bromine or iodine, to give compound (2 a).
Scheme 4
An alternative method for preparing compound (2a) is shown in scheme (5). The tetrazole compound (9a) is synthesized by the reaction of an amine compound (8a) with triethyl orthoformate and sodium buntanide in acetic acid. Compound (9a) is further coupled with compound (10a) wherein X is halogen, preferably chlorine or bromine or iodine, to give compound (2 a). The solvent in the coupling reaction may be, but is not limited to, 1, 4-dioxane. The catalyst used for the reaction may be, but is not limited to, bis (triphenylphosphine) palladium (II) chloride. The base used in the reaction may be, but is not limited to, cesium carbonate. The reaction temperature is 0 ℃ to 50 ℃.
Scheme 5
An alternative method for preparing compound (2a) is shown in scheme (6). The compound (12a) can be prepared by coupling the carboxylic acid compound (11a) with the amine compound (8 a). Thus, a mixture of the carboxylic acid compound (11a) and the amine compound (8a) in an aprotic solvent is treated with a suitable coupling agent in the presence of an organic base to form the amide compound (12 a). Suitable coupling agents may be, for example but not limited to, BOP-Cl, CDI, DCC, EDC, HATU, PyAOP or PyBOP, and the organic base may be, for example but not limited to, Et3N, DIPEA, pyridine or N-methylmorpholine. The aprotic solvent may be, for example, but is not limited to, THF, DCM, and DMF. The reaction temperature is-20 ℃ to 80 ℃. Then, the amide compound (12a) is further converted into the tetrazole compound (13a) by treatment with sodium azide and trifluoromethanesulfonic anhydride in an aprotic solvent. Such aprotic solvent may be, but is not limited to, acetonitrile. The reaction temperature is-20 ℃ to 50 ℃.
Scheme 6
As shown in scheme 7, the diamine compound (5a) is protected with a P group to give compound (6 b). P can be any amine protecting group such as, but not limited to, Cbz, Boc, and PMB. Methods, reagents and strips for protecting amine groupsA more detailed discussion of the article is described in the literature, for example by t.w. green and p.g.m. wutz in "protecting groups in organic synthesis", third edition, john wili-father-press, 1999. The compound (8b) can be produced by coupling the obtained amine compound (6b) with a carboxylic acid compound (7 b). Thus, a mixture of the carboxylic acid compound (7b) and the amine compound (6b) in an aprotic solvent is treated with a suitable coupling agent in the presence of an organic base to form the amide compound (8 b). Suitable coupling agents may be, for example but not limited to, BOP-Cl, CDI, DCC, EDC, HATU, PyAOP or PyBOP, and the organic base may be, for example but not limited to, Et3N, DIPEA, pyridine or N-methylmorpholine. The aprotic solvent may be, for example, but is not limited to, THF, DCM, and DMF. The reaction temperature is-20 ℃ to 80 ℃. The amide compound (8b) is then further converted to the tetrazole compound (9b) by treatment with phosphorus pentachloride and a trimethylsilyl azide in an aprotic solvent. Such aprotic solvents may be, but are not limited to, acetonitrile and dichloroethane. The reaction temperature is-20 ℃ to 60 ℃. Deprotection of the P group then affords the tetrazole compound (2 b). A more detailed discussion of methods, reagents and conditions for deprotection of amine protecting groups is described in the literature, for example by t.w.w. green and p.g.m. wutz in "protecting groups in organic synthesis" third edition, john wili parent-child press, 1999.
Scheme 7
Experimental example:
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, including but not limited to those relating to chemical structures, substituents, derivatives, and variations and modifications which may be made to the invention and/or the method of the invention without departing from the spirit of the invention and the scope of the appended claims, will be apparent to those skilled in the art.
Synthesis of 6- (1-isopropyl-1H-tetrazol-5-yl) pyridin-2-amine (Compound 3 a):
route 1
Step 1 Synthesis of 1-isopropyl-1H-tetrazole (Compound 1a)
A solution of propan-2-amine (3.44 ml, 40 mmol), sodium bunanide (3.64 g, 56 mmol) and triethyl orthoformate (9.31 ml, 56.0 mmol) in acetic acid (20 ml) was heated to 90 ℃ and stirred for 1 day behind a burst disk. The reaction mixture was then cooled to room temperature and diluted with EtOAc. The mixture was washed with 1N HCl, saturated NaHCO3(x3) and brine wash. Through Na2SO4Drying, filtration and concentration in vacuo gave the desired product as a pale yellow oil (1.52 g, 34%). Hydrogen nuclear magnetic resonance spectroscopy (400 mhz, chloroform-d) δ 8.62(s, 1H), 4.90(p, J ═ 6.7 hz, 1H), 1.68(d, J ═ 6.7 hz, 6H).
Step 2. Synthesis of 6- (1-isopropyl-1H-tetrazol-5-yl) pyridin-2-amine (Compound 3 a).
1-isopropyl-1H-tetrazole (560 mg, 4.99 mmol), 6-chloropyridin-2-amine (2a) (642 mg, 4.99 mmol), copper (I) iodide (47.6 mg, 0.250 mmol), a mixture of bis (triphenylphosphine) -palladium (II) chloride (351 mg, 0.499 mmol) and cesium carbonate (3254 mg, 9.99 mmol) in 1, 4-dioxane (2 mL) was degassed and heated to 100 ℃ and stirred for 24H behind a burst disk. The reaction was cooled to room temperature and then diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, Na2SO4Dried, filtered and concentrated. The residue was purified by silica chromatography using hexane/acetone (100/0 to 50/50, 15 min) to give compound 3a as a pale yellow solid (330 mg, 32%). MS (m/z): 205.10[ M + H]+Hydrogen nucleiMagnetic resonance spectroscopy (400 mhz, chloroform-d) δ 7.75-7.60 (m, 2H), 6.66(dd, J ═ 7.3, 1.8 hz, 1H), 5.87(dq, J ═ 13.4, 6.7 hz, 1H), 4.62(s, 2H), 1.68(d, J ═ 6.7 hz, 6H).
Route 2
Step 1: synthesis of N-isopropyl-6-nitrosobenzamide (Compound 5a)
To a solution of 6-nitrosoformic acid (10 g, 59.5 mmol) and Hunig's base (31.1 ml, 178 mmol, 3 eq.) in dry DMF (200 ml) was added isopropylamine (6.64 ml, 77 mmol, 1.3 eq.) followed by HATU (29.4 g, 77 mmol, 1.3 eq.) at 0 ℃. The resulting mixture was warmed to room temperature, stirred for several hours, and then quenched by the addition of water (500 ml). The mixture was extracted with EtOAc (3 × 200 ml) and the combined organic layers were washed with water (2 × 200 ml), brine (200 ml) and dried (Na)2SO4) And concentrated. The residue was purified by silica chromatography (80 g column, 100% hexanes to 40% EtOAc/hexanes) to give the compound N-isopropyl-6-nitrosobenzamide (10.81 g, 87% yield) as a light yellow solid. Hydrogen nuclear magnetic resonance spectroscopy (400 mhz, chloroform-d) δ 8.58(dd, J ═ 7.7, 1.0 hz, 1H), 8.36(dd, J ═ 8.0, 1.0 hz, 1H), 8.21(t, J ═ 7.8 hz, 1H), 7.70(s, 1H), 4.31(hept, J ═ 6.6 hz, 1H), 1.32(d, J ═ 6.6 hz, 6H).
Step 2: synthesis of 2- (1-isopropyl-1H-tetrazol-5-yl) -6-nitropyridine (Compound 6 a).
To a mixture of N-isopropyl-6-nitrosobenzamide (350 mg, 1.673 mmol) and sodium azide (120 mg, 1.840 mmol) in anhydrous acetonitrile (5.58 ml) was added dropwise trifluoromethanesulfonic anhydride (1M DCM solution, 1.84 ml, 1.840 mmol) at 0 ℃ after explosion-proof hood under nitrogen protection. The resulting mixture was stirred at 0 ℃ for 1 hour, then at room temperature for 2 hours. The reaction was then cooled to 0 ℃ and saturated NaHCO was used3Quench (50 ml). The mixture was extracted twice with EtOAc. The combined organic layers were washed with saturated NaHCO3And washed with brine and concentrated. The dark red solid of the residue was purified by silica chromatography (12 g column, 100% hexanes to 35% EtOAc/hexanes) to give compound 6a (170 mg, 43% yield) as a colorless solid. Hydrogen nuclear magnetic resonance spectroscopy (400 mhz, chloroform-d) δ 8.74(dd, J ═ 7.7, 0.9 hz, 1H), 8.41(dd, J ═ 8.1, 0.9 hz, 1H), 8.32(t, J ═ 7.9 hz, 1H), 5.95(hept, J ═ 6.7 hz, 1H), 1.72(d, J ═ 6.7 hz, 6H).
And step 3: synthesis of 6- (1-isopropyl-1H-tetrazol-5-yl) pyridin-2-amine (Compound 3 a):
a mixture of 2- (1-isopropyl-1H-tetrazol-5-yl) -6-nitropyridine (100 mg, 0.427 mmol) and Pd/C (10% Pd on dry basis, 50% water, 23 mg, 0.025eq) in methanol (1 mL)/EtOAc (1 mL) at room temperature was H2Stir in a balloon overnight. The catalyst was then filtered and the filtrate was concentrated to afford compound 3a (85 mg, 97% yield), which was used in the next step without further purification. MS (m/z): 163.05[ M + H]+. Hydrogen nuclear magnetic resonance spectroscopy (400 mhz, chloroform-d) δ 7.72-7.54 (m, 2H), 6.63(dd, J ═ 7.4, 1.7 hz, 1H), 5.85(hept, J ═ 6.7 hz, 1H), 4.57(s, 2H), 1.65(d, J ═ 6.7 hz, 6H).
Route 3
A reaction mixture of 6-aminopicolinic acid nitrile (542 mg, 4.55 mmol), dibutyltin oxide (566 mg, 2.275 mmol), toluene (10 ml) and azidotrimethylsilane (1.812 ml, 13.65 mmol) was irradiated with microwave radiationStirred at 200 ℃ for 5 minutes. TLC showed complete reaction. The yellow suspension was filtered, washed with toluene and dried in vacuo to give 6- (1H-tetrazol-5-yl) pyridin-2-amine (1.2 g, quantitative yield) as a yellow powder. The hydrogen and carbon nuclear magnetic resonance spectroscopy showed that the product contained dibutyltin oxide, which did not affect the next reaction. MS (m/z): 205.10[ M + H]+. Hydrogen nuclear magnetic resonance spectroscopy (400 mhz, DMSO-d6) δ 7.67(t, J ═ 7.9 hz, 1H), 7.36(d, J ═ 7.2 hz, 1H), 6.71(d, J ═ 8.4 hz, 1H), 6.57(s, 2H).
To a 50 ml two-necked round bottom flask was added 6- (1H-tetrazol-5-yl) pyridin-2-amine (300 mg, 1.850 mmol), DMF (9.250 ml), and the solution was cooled to 0 ℃ before sodium hydride (133 mg, 3.33 mmol) was added. Foaming was observed. After stirring at 0 ℃ for 20 minutes, 2-iodopropane (0.333 ml, 3.33 mmol) was added and the reaction was stirred at 0 ℃ for 9 hours. The reaction mixture was cooled to 0 ℃ and quenched with water (-30 ml). Extract with DCM (-70 ml) and wash with brine. Drying, filtration, concentration and purification with CombiFlash (24 g silica, MeOH/DCM ═ 0-100%) afforded 6- (1-isopropyl-1H-tetrazol-5-yl) pyridin-2-amine as a white solid (24 mg, 6.35% yield). MS (m/z): 205.10[ M + H]+。
Synthesis of 6- (1-cyclopropyl-1H-tetrazol-5-yl) pyridin-2-amine (Compound 7 a):
compound 7a is prepared according to scheme 2, using procedures analogous to those described for compound 3 a. Hydrogen nuclear magnetic resonance spectroscopy (400 mhz, DMSO-d6) δ 7.61(dd, J ═ 8.4, 7.3 hz, 1H), 7.29(dd, J ═ 7.3, 0.8 hz, 1H), 6.65(dd, J ═ 8.4, 0.9 hz, 1H), 6.38(s, 2H), 4.79(m, 1H), 1.33-1.12 (m, 4H).
Synthesis of 6- (1- (1- (1-methylcyclopropyl) -1H-tetrazol-5-yl) pyridin-2-amine (Compound 8 a):
compound 8a is prepared according to scheme 2 by using an analogous method to that described for compound 3 a. Hydrogen nuclear magnetic resonance spectroscopy (400 mhz, DMSO-d6) δ 7.59(dd, J ═ 8.4, 7.3 hz, 1H), 7.18(dd, J ═ 7.3, 0.8 hz, 1H), 6.64(dd, J ═ 8.4, 0.9 hz, 1H), 6.29(s, 2H), 1.72(s, 3H), 1.12(m, 4H).