HK1194367A - Quinolinyl glucagon receptor modulators - Google Patents

Description

Quinolinyl glucagon receptor modulators

Technical Field

The present invention relates to compounds which are antagonists, mixed agonists/antagonists, partial agonists, negative allosteric modulators or inverse agonists of the glucagon receptor, pharmaceutical compositions comprising said compounds, and uses of said compounds or compositions.

Background

Diabetes is a major public health problem because of its increased prevalence and associated health risks. The disease is characterized by metabolic defects in the production and utilization of sugars, resulting in the inability to maintain proper blood glucose levels. Two major forms of diabetes are recognized. Type I diabetes or insulin dependent diabetes mellitus (IDDMT1DM) is the result of an absolute deficiency of insulin. Type II diabetes, or non-insulin dependent diabetes mellitus (NIDDMT2DM), usually occurs at normal or even elevated insulin levels and appears to be the result of the inability of tissues and cells to respond properly to insulin. Invasive control of NIDDMT2DM with drugs is essential; otherwise, it can progress to β -cell failure and insulin dependence.

Glucagon is a 29 amino acid peptide that is secreted from the alpha cells of the pancreas into the hepatic portal vein, whereby the level of this hormone exposed to the liver is higher than non-hepatic tissue levels. Plasma glucagon levels decrease in response to hyperglycemia, hyperinsulinemia, elevated plasma non-esterified fatty acid levels, and somatostatin, while glucagon secretion increases in response to hypoglycemia and elevated plasma amino acid levels. Glucagon, through activation of its receptor, is a potent activator of glycogen production by activating glycogenolysis and gluconeogenesis.

The glucagon receptor is a 62kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors. Other closely related G-protein coupled receptors include the glucagon-like peptide-1 receptor (GLP-1), glucagon-like peptide-2 receptor (GLP-2), and gastric inhibitory polypeptide receptors. The glucagon receptor is encoded by the GCGR gene in humans, and these receptors are expressed predominantly in the liver, with lesser amounts found in the kidney, heart, adipose tissue, spleen, thymus, adrenal gland, pancreas, cerebral cortex, and gastrointestinal tract. Stimulation of the glucagon receptor results in activation of adenylate cyclase and increased intracellular cAMP levels.

Reports have shown that rare missense mutations in the GCGR gene are associated with type 2 diabetes, and inactivating mutations of the glucagon receptor in humans have been reported to result in glucagon resistance and are associated with pancreatic alpha-cell proliferation, islet cell hyperplasia, hypercholesterolaemia, and pancreatic neuroendocrine tumors. In rodent studies using GCGR knockout mice and mice treated with GCGR antisense oligonucleotides, mice show improved fasting glucose, glucose tolerance, and pancreatic β -cell function. Removal of circulating glucagon with selective and specific antibodies results in a decrease in blood glucose levels in healthy control animals and animal models of type 1 and type 2 diabetes. More specifically, it has been shown that treatment of mice and cynomolgus monkeys with GCGR-antagonistic antibodies (mAb B and mAb Ac) improves glycemic control without causing hypoglycemia. Recent mouse studies further show that antagonism of the glucagon receptor leads to improved glucose homeostasis by mechanisms requiring a functional GLP-1 receptor. Antagonism of the glucagon receptor results in compensatory overproduction of GLP-1, possibly from pancreatic alpha-cells, and this may play an important role in intra-islet regulation and maintenance of beta-cell function.

A promising area of diabetes research involves the use of small molecule antagonists, mixed agonists/antagonists, partial agonists, negative allosteric modulators or inverse agonists of the glucagon receptor to reduce circulating glucagon levels and thereby lower blood glucose levels. Therapeutically, it is expected that inactivation of the glucagon receptor may be an effective strategy for lowering blood glucose by reducing hepatic glucose output and normalizing glucose-stimulated insulin secretion. Thus, glucagon antagonists, mixed agonist/antagonists, partial agonists, negative allosteric modulators or inverse agonists may provide treatment for NIDDM T2DM, IDDM T1DM and related complications, particularly treatment for hyperglycemia, dyslipidemia, insulin resistance syndrome, hyperinsulinemia, hypertension, and obesity.

Several drugs of the 5 main types, each acting through different mechanisms, are available for treating hypertensionHyperglycemia and, hence, NIDDM T2DM (Moller, D.E., "New drug targets for Type 2 diabetes and the metabolic syndromeNature414; 821-. Although this therapy can reduce blood glucose levels, it has limited efficacy and drug resistance, leading to weight gain and often inducing hypoglycemia. (B) Biguanides (e.g., metformin) are believed to act primarily by reducing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use; (C) alpha-glucosidase inhibitors (e.g., acarbose) reduce intestinal glucose absorption. These drugs often cause gastrointestinal disorders; (D) thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on specific receptors in liver, muscle and adipose tissue (peroxisome proliferator-activated receptor- γ). They regulate fat metabolism, thereby promoting the response of these tissues to the action of insulin. Frequent use of these drugs can lead to weight gain and can induce edema and anemia. (E) In more severe cases insulin is used alone or in combination with the above mentioned agents.

Ideally, an effective new treatment for NIDDM T2DM would meet the following criteria: (a) has no significant side effects, including inducing hypoglycemia; (b) does not cause weight gain; (c) at least partial replacement of insulin by acting through a mechanism that is independent of insulin action; (d) metabolic stabilization is desired to reduce frequent use; and (e) can be used in combination with a tolerable amount of any of the types of drugs listed herein.

Numerous publications have been published which disclose non-peptide compounds which act on the glucagon receptor. For example, WO03/048109, WO2004/002480, WO2005/123668, WO2005/118542, WO2006/086488, WO2006/102067, WO2007/106181, WO2007/114855, WO2007/120270, WO2007/123581, WO2009/110520 and Kurukulukusuriya et al, Bioorganic & medicinal chemistry Letters,2004,14(9), 2047-minus 2050 each disclose non-peptide compounds that act as glucagon receptor antagonists. Despite the ongoing research, there remains a need for more effective and safer therapeutic treatments for diabetes, particularly NIDDM and IDDM.

Brief description of the invention

The present invention provides compounds of formula I which act as glucagon receptor modulators, particularly glucagon antagonists; thus, may be useful in the treatment of diseases mediated by such antagonism (e.g., diseases associated with type 2 diabetes, type 1 diabetes, and comorbidities associated with diabetes and with obesity). A first embodiment of the invention are compounds of formula I

Or a pharmaceutically acceptable salt thereof, wherein R¹Is (C)₁-C₆) Alkyl optionally substituted with 1-3 fluoro, hydroxy or methoxy; (C)₃-C₇) Cycloalkyl optionally substituted with one to two fluorines or one to two (C)₁-C₃) Alkyl substituted, each of which is optionally substituted with 1-3 fluorines and wherein (C)₃-C₇) One carbon of the cycloalkyl group may be replaced by O; or (C)₃-C₇) Cycloalkyl- (C)₁-C₆) Alkyl group, wherein (C) is₃-C₇) Cycloalkyl- (C)₁-C₆) Of alkyl radicals (C)₃-C₇) Cycloalkyl is optionally substituted by one to two (C)₁-C₃) Alkyl substituted, each optionally substituted with 1-3 fluorines; r²Is hydrogen or (C)₁-C₃) An alkyl group; r³Is tetrazolyl, -CH₂-tetrazolyl, - (CH)₂)₂SO₃H,、–(CH₂)₂CO₂H、-CH₂CHFCO₂H or-CH₂CH(OH)CO₂H；A¹、A²And A³Each independently is CR⁴Or N, provided that A¹、A²And A³At least one but at most two is N; r⁴Independently at each occurrence is hydrogen, halogen, cyano, (C) optionally substituted with 1-3 fluoro₁-C₃) Alkyl, optionally substituted by 1-3 fluoro (C)₁-C₃) Alkoxy or (C)₃-C₅) A cycloalkyl group; b is¹、B²、B³And B⁴Each independently is CR⁵Or N, provided that B¹、B²、B³And B⁴At most two of which are N; and R is⁵Independently at each occurrence is hydrogen, halogen, cyano, (C) optionally substituted with 1-3 fluoro₁-C₃) Alkyl, or (C) optionally substituted by 1-3 fluorines₁-C₃) Alkoxy or (C)₃-C₅) A cycloalkyl group.

A second embodiment of the present invention is the compound of the first embodiment or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen, and R³Is- (CH)₂)₂CO₂H. A third embodiment of the present invention is a compound of the previous embodiments or a pharmaceutically acceptable salt thereof, wherein R¹Is ethyl, propyl, isopropyl, isobutyl, tert-butyl, pentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl, each optionally substituted with 1-3 fluorines, and wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are each optionally substituted with 1 to 2 methyl groups.

A fourth embodiment of the present invention is a compound of the previous embodiments or a pharmaceutically acceptable salt thereof, wherein B¹、B²、B³And B⁴Each is CR⁵. A fifth embodiment of the present invention is a compound of the previous embodiments or a pharmaceutically acceptable salt thereof, wherein A¹And A²Each is CR⁴And A is³Is N; r⁴Independently at each occurrence is hydrogen, fluoro, chloro, methyl or ethyl; r⁵At each time of dischargeAnd when present are independently hydrogen, fluoro, chloro, methyl, trifluoromethyl or methoxy. A sixth embodiment of the present invention is the compound of the first to fourth embodiments or a pharmaceutically acceptable salt thereof, wherein a¹Is N, and A²And A³Each is CR⁴；R⁴Independently at each occurrence is hydrogen, fluoro, chloro, methyl or ethyl; and R⁵Independently at each occurrence is hydrogen, fluoro, chloro, methyl, trifluoromethyl or methoxy. A seventh embodiment of the present invention is the compound of the first to fourth embodiments or a pharmaceutically acceptable salt thereof, wherein a¹And A³Each is CR⁴And A is²Is N; r⁴Independently at each occurrence is hydrogen, fluoro, chloro, methyl or ethyl; and R⁵Independently at each occurrence is hydrogen, fluoro, chloro, methyl, trifluoromethyl or methoxy.

An eighth embodiment of the present invention is the compound of the second embodiment or a pharmaceutically acceptable salt thereof, wherein a¹And A²Each is CR⁴And A is³Is N; b is¹、B²、B³And B⁴Each is CR⁵. A ninth embodiment of the present invention is the compound of the eighth embodiment or a pharmaceutically acceptable salt thereof, wherein R¹Is ethyl, propyl, isopropyl, isobutyl, tert-butyl, pentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl, each optionally substituted with 1-3 fluorines, and wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are each optionally substituted with 1 to 2 methyl groups. A tenth embodiment of the present invention is the compound of the ninth embodiment or a pharmaceutically acceptable salt thereof, wherein R⁴Independently at each occurrence is hydrogen, fluoro, chloro, methyl or ethyl; and R⁵Independently at each occurrence is hydrogen, fluoro, chloro, methyl, trifluoromethyl or methoxy.

An eleventh embodiment of the present invention is the compound of the second embodiment or a pharmaceutically acceptable salt thereof, wherein a²And A³Each is CR⁴And A is¹Is N; b is¹、B²、B³And B⁴Each is CR⁵. A twelfth embodiment of the present invention is the compound of the eleventh embodiment or a pharmaceutically acceptable salt thereof, wherein R¹Is ethyl, propyl, isopropyl, isobutyl, tert-butyl, pentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl, each optionally substituted with 1-3 fluorines, and wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are each optionally substituted with 1 to 2 methyl groups. A thirteenth embodiment of the present invention is the compound of the twelfth embodiment or a pharmaceutically acceptable salt thereof, wherein R⁴Independently at each occurrence is hydrogen, fluoro, chloro, methyl or ethyl; and R⁵Independently at each occurrence is hydrogen, fluoro, chloro, methyl, trifluoromethyl or methoxy.

Another embodiment of the invention is a compound selected from: (+/-) -3- (4- (1- (3-methylquinolin-2-ylamino) butyl) benzoylamino) propionic acid; (+/-) -3- {4- [ 3-methyl-1- (quinolin-3-ylamino) -butyl ] -benzoylamino } -propionic acid; (+/-) -3- {4- [1- (7-fluoro-quinazolin-2-ylamino) -3-methyl-butyl ] -benzoylamino } -propionic acid; (+/-) -3- {4- [ 3-methyl-1- (quinolin-2-ylamino) -butyl ] -benzoylamino } -propionic acid; (+/-) -3- {4- [1- (8-methoxy-quinolin-2-ylamino) -3-methyl-butyl ] -benzoylamino } -propionic acid; (+/-) -3- {4- [ 3-methyl-1- (3-methyl-quinoxalin-2-ylamino) -butyl ] -benzoylamino } -propionic acid; (+/-) -3- {4- [ 3-methyl-1- (quinoxalin-2-ylamino) -butyl ] -benzoylamino } -propionic acid; (+/-) -3- {4- [ 3-methyl-1- (4-methyl-quinolin-2-ylamino) -butyl ] -benzoylamino } -propionic acid; (+/-) -3- {4- [ 3-methyl-1- (3-methyl-quinolin-2-ylamino) -butyl ] -benzoylamino } -propionic acid; (+/-) -3- {4- [1- (7-fluoro-4-methyl-quinolin-2-ylamino) -3-methyl-butyl ] -benzoylamino } -propionic acid; (+/-) -3- {4- [1- (8-chloro-quinolin-2-ylamino) -3-methyl-butyl ] -benzoylamino } -propionic acid; (+/-) -3- {4- [ 3-methyl-1- (quinazolin-2-ylamino) -butyl ] -benzoylamino } -propionic acid; (+/-)3- (4- (3-methyl-1- (7- (trifluoromethyl) quinolin-2-ylamino) butyl) benzoylamino) propionic acid; (+/-) -3- (4- (3-methyl-1- (6- (trifluoromethyl) quinolin-2-ylamino) butyl) benzoylamino) propionic acid; (+ \\ -) -3- (4- (3-methyl-1- (2-methylquinolin-3-ylamino) butyl) benzoylamino) propionic acid; (+ \\ -) -3- (4- (3-methyl-1- (4-methylquinolin-3-ylamino) butyl) benzoylamino) propionic acid; (+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid; (+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (6-fluoro-3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid; (+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (7-fluoro-3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid; (+/-)3- (4- ((3, 3-dimethylcyclobutyl) (6-fluoroquinolin-3-ylamino) methyl) benzoylamino) propionic acid; (+/-) -3- (4- ((3, 3-dimethylcyclobutyl) (7-fluoroquinolin-3-ylamino) methyl) benzoylamino) propionic acid; (+/-) -3- (4- (4,4, 4-trifluoro-1- (quinolin-3-ylamino) butyl) benzoylamino) propionic acid; (+/-) -3- (4- ((6, 7-difluoroquinolin-3-ylamino) (3, 3-dimethylcyclobutyl) methyl) benzoylamino) propionic acid; (+/-) -3- (4- (3-methyl-1- (7-methylquinolin-3-ylamino) butyl) benzoylamino) propionic acid; (+/-) -3- (4- (3-methyl-1- (8-methylquinolin-3-ylamino) butyl) benzoylamino) propionic acid; (+/-) -3- (4- (3-methyl-1- (6-methylquinolin-3-ylamino) butyl) benzoylamino) propionic acid; and (+/-) -3- (4- (3-methyl-1- (5-methylquinolin-3-ylamino) butyl) benzoylamino) propionic acid; or a pharmaceutically acceptable salt thereof.

Yet another embodiment of the invention is a compound selected from (+) -3- (4- (1- (3-methylquinolin-2-ylamino) butyl) benzoylamino) propionic acid; (-) -3- (4- (1- (3-methylquinolin-2-ylamino) butyl) benzoylamino) propionic acid; (+) -3- (4- (3-methyl-1- (3-methylquinolin-2-ylamino) butyl) benzoylamino) propionic acid; (-) -3- (4- (3-methyl-1- (3-methylquinolin-2-ylamino) butyl) benzoylamino) propionic acid; or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a pharmaceutical composition comprising: (1) a compound of the invention; and (2) a pharmaceutically acceptable excipient, diluent or carrier. Preferably, the composition comprises a therapeutically effective amount of a compound of the invention. The composition may also comprise at least one additional agent (described herein). Preferred active agents include anti-obesity agents and/or anti-diabetic agents (described below).

Yet another aspect of the present invention is a method of treating a disease, condition or disorder mediated by glucagon, particularly inactivation (such as antagonism) of the glucagon receptor in a mammal, said method comprising the step of administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.

Glucagon-mediated diseases, conditions or disorders include type II diabetes, type I diabetes, hyperglycemia, metabolic syndrome, impaired glucose tolerance, diabetes, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia (dysidimia), hypertension, hyperinsulinemia, and insulin resistance syndrome. Preferred diseases, disorders or conditions include type II diabetes, hyperglycemia, impaired glucose tolerance, obesity and insulin resistance syndrome. More preferred are type II diabetes, type I diabetes, hyperglycemia and obesity. Most preferred are type II and type I diabetes.

Yet another aspect of the present invention is a method of lowering blood glucose levels in a mammal, preferably a human, comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.

The compounds of the present invention may be administered in combination with other agents (particularly the anti-obesity and anti-diabetic agents described below). Such combination therapy may be administered as follows: (a) a single pharmaceutical composition comprising a compound of the invention, at least one additional agent described herein, and a pharmaceutically acceptable excipient, diluent, or carrier; or (b) two separate pharmaceutical compositions comprising (i) a first composition comprising a compound of the invention and a pharmaceutically acceptable excipient, diluent or carrier; and (ii) a second composition comprising at least one additional agent described herein and a pharmaceutically acceptable excipient, diluent or carrier. The pharmaceutical compositions may be administered simultaneously or sequentially or in any order.

Definition of

The term "alkyl" as used herein refers to the general formula C_nH_2n+1A hydrocarbon group of (1). The alkyl group may be linear or branched. For example, the term "(C)₁-C₆) Alkyl "refers to a monovalent straight or branched chain aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3-dimethylpropyl, hexyl, 2-methylpentyl, and the like). Similarly, the alkyl portion (i.e., alkyl moiety) of alkoxy, acyl (e.g., alkanoyl), alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups have the same definitions as above. When shown as "optionally substituted," an alkane group or alkyl moiety can be unsubstituted or substituted with one or more substituents (generally, 1-3 substituents, except for halogen substituents, such as perchloro or perfluoroalkyl).

The term "cycloalkyl" refers to a non-aromatic ring that is perhydrogenated and may exist as a monocyclic, bicyclic, or spiro ring. Unless otherwise indicated, carbocycles are generally 3-to 8-membered rings. For example, (C)₃-C₇) Cycloalkyl includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, norbornyl (bicyclo [2.2.1 ] n]Heptyl), and the like. In some embodiments, one or more carbon atoms on a cycloalkyl group may be replaced by a designated group such as O, S, NH or N-alkyl.

The term "cycloalkyl-alkyl" refers to a cycloalkyl group of a specified size attached to an alkyl group of a specified size. For example, the term (C)₃-C₇) Cycloalkyl- (C)₁-C₆) Alkyl refers to a three to seven membered cycloalkyl group attached to a one to six membered alkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The phrase "therapeutically effective amount" refers to the following amounts of the compounds of the present invention: (i) treating or preventing a particular disease, condition or disorder; (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder; or (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition, or disorder described herein.

The term "animal" refers to humans (male or female), companion animals (e.g., dogs, cats and horses), food-derived animals, zoo animals, marine animals, birds and other similar animal species. By "edible animal" is meant a food-derived animal, such as cattle, swine, sheep, and poultry.

The phrase "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients included in the formulation and/or the mammal being treated therewith.

The term "treatment" includes prophylactic, i.e. both prophylactic and curative treatment.

The term "modulate", as used herein, unless otherwise indicated, refers to an alteration in the activity of the glucagon receptor as a result of the action of the compounds of the present invention.

The term "mediate", as used herein, unless otherwise indicated, refers to the treatment or prevention of a particular disease, condition, or disorder by modulation of glucagon; (ii) (ii) alleviating, ameliorating, or eliminating one or more symptoms of a particular disease, condition, or disorder, or (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition, or disorder described herein.

The term "compound of the invention" (unless specifically specified otherwise) refers to compounds of formula I and any pharmaceutically acceptable salts of the compound, as well as all stereoisomers (including diastereomers and enantiomers), tautomers, conformational isomers and isotopically labeled compounds. Hydrates and solvates of the compounds of the invention, wherein the compounds are combined with water or a solvent, respectively, are contemplated as compositions of the invention.

The symbol "", as used herein, refers to a chiral center (carbon atom) having (R) or (S) absolute stereochemistry. The chiral center is at least 51% (R) or (S), preferably at least 80% (R) or (S), most preferably greater than 95% (R) or (S).

Detailed Description

The compounds of the invention may be synthesized by synthetic routes including methods analogous to those well known in the chemical arts, particularly in accordance with the description contained herein. The starting materials are generally obtained from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods well known to those skilled in the art (e.g., by methods generally known in Louis f. fieserand Mary Fieser,Reagents for Organic Synthesis,v.1-19,Wiley,NewYork(1967-1999ed.),or Beilsteins Handbuch der organischen Chemieprepared by the method described in aufl. ed. springer-Verlag, Berlin, including the appendix (also available via Beilstein online database)).

For illustrative purposes, the reaction schemes described below provide possible synthetic routes to the compounds and key intermediates of the invention. For a more detailed description of the individual reaction steps, see the examples section below. It will be appreciated by those skilled in the art that other synthetic routes may be used to synthesize the compounds of the invention. Although specific starting materials and reagents are described in the schemes and discussed below, other starting materials and reagents can be readily substituted to obtain various derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of the disclosure herein using conventional chemical methods well known to those skilled in the art.

In preparing the compounds of the present invention, it may be necessary to protect the remote functionality (e.g., primary or secondary amines) of the intermediate. The need for such protection will vary depending on the nature of the distal functional group and the conditions of the preparation method. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, tert-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Class ISimilarly, "hydroxy-protecting group" refers to a hydroxy substituent that blocks or protects the hydroxy functionality. Suitable hydroxy-protecting groups (O-Pg) include, for example, allyl, acetyl, silyl, benzyl, p-methoxybenzyl, trityl and the like. Suitable carboxylic acid-protecting groups (C (O) O-Pg) include, for example, groups such as methyl, ethyl, t-butyl, benzyl, p-methoxybenzyl and diphenylmethylene. The need for such protection is readily determined by those skilled in the art. For a general description of protecting groups and their use, see t.w. greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991。

reaction schemes I-IV provide general routes that can be used to prepare compounds of formula I. It should be understood that the reaction schemes are exemplary and should not be viewed as being limiting in any way.

Reaction scheme I outlines a general procedure that can be used to obtain the compounds of the invention within formula I.

Reaction scheme I

The first step of reaction scheme I describes the nucleophilic substitution reaction with a nucleophilic amine of formula IV' and a quinoline N-oxide of formula IV to give a compound of formula IIIa. In the compounds of formula IV', the group R represents a suitable carboxylic acid protecting group (i.e. the group Pg within the protected acid group c (O) O-Pg is as described previously), typically a lower alkyl group such as methyl, ethyl or tert-butyl, or a group such as benzyl, p-methoxybenzyl or diphenylmethylene. The N-oxides of formula IV are typically prepared by oxidation of the corresponding compound with non-oxidising nitrogen at elevated temperature such as 80 ℃ by treatment with a suitable oxidising agent such as hydrogen peroxide in acetic acid for a period of 1 to 24 hours. Generally, the nucleophilic addition of the amine IV' with quinoline N-oxide can be carried out under mild conditions in the presence of a suitable base and solvent using a suitable phosphonium salt as an activator. For example, the reaction between the compounds of formula IV and IV' can be carried out using PyBroP (trispyrrolidinylphosphonium bromide hexafluorophosphate) in the presence of a suitable base such as diisopropylethylamine in a suitable solvent such as dichloromethane or tetrahydrofuran at ambient temperature for a period of time of from 1 to 24 hours (see Londregan, A.T.et al; in org.Lett.2010,12, 5254-. The ester moiety in the compound of formula IIIa can then be deprotected under suitable deprotection conditions to provide the free carboxylic acid compound of formula IIa. When the group R in the compound of formula IIIa represents methyl or ethyl, deprotection can be carried out using base-catalyzed hydrolysis. For example, a compound of formula IIIa may be treated with a suitable base such as sodium hydroxide or lithium hydroxide in tetrahydrofuran and methanol at room temperature for a period of 1 to 24 hours. When the group R in the compound of formula IIIa is tert-butyl, p-methoxybenzyl or diphenylmethylene, deprotection can be carried out by treatment with a suitable acid such as hydrochloric acid or trifluoroacetic acid in a suitable solvent such as dichloromethane.

The free acid compound of formula IIa can then be reacted with an amine HNR²R^3′(II ') performing a peptide coupling reaction to obtain the compound of formula Ia'. Peptide coupling was performed using standard literature conditions. The acid of formula IIa can be converted to the corresponding acid chloride using a suitable chlorinating agent such as oxalyl chloride or thionyl chloride at a suitable temperature, typically from 0 ℃ to room temperature, optionally in the presence of catalytic DMF in a suitable solvent such as dichloromethane or toluene. The acid chloride may then be reacted with a compound of formula R in the presence of a base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane or toluene at a temperature of from 0 ℃ to room temperature^3’R²Amine reaction of NH. R^3’Can represent R³By itself or R³Protected form of (1), which may be subsequently deprotected to give R³. Alternatively, the acid of formula IIa can be converted to the appropriate activation with a coupling reagent such as EDCI. HCl, HBTU, HATU, PyBop, DCC or CDI in a suitable solvent such as dichloromethane, acetonitrile or DMFThe kind of the same. HOBT is typically added in the presence of edci.hcl. EDCI is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide; HBTU is O-benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate; HATU is O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate; PyBop is benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate; DCC is dicyclohexylcarbodiimide; CDI is N, N' -carbonyldiimidazole and HOBT is 1-hydroxybenzotriazole. The reaction is also carried out using a suitable base, such as triethylamine or diisopropylethylamine, and is generally carried out at room temperature. In which R is^3′Represents R³In the case of protected forms of (a), subsequent deprotection can then be carried out by methods known in the art to give R³. For example, when R is³In the case of esters, suitable acid or base catalyzed hydrolysis may be carried out as described previously to give the corresponding free acid of the compound of formula Ia.

Reaction scheme II

Reaction scheme II provides another method for preparing compounds of formula I. In step one of reaction scheme II, a compound of formula V and a compound of formula IV' are coupled. In the compounds of formula V, the group Lg represents a suitable leaving group such as halide, mesylate or triflate. In the compounds of formula IV', the group R represents a suitable carboxylic acid protecting group, typically a lower alkyl group such as methyl, ethyl or tert-butyl or a group such as benzyl, p-methoxybenzyl or diphenylmethylene. The coupling reaction between compounds V and IV' can be carried out under a variety of conditions. For example, compounds of formula V may be coupled to compound IV' using catalytic aryl amination reaction conditions such as those described by Buchwald, S., et al, in J.am.chem.Soc.,2008,130(21), 6686-containing 6687, J.am.chem.Soc.,2008,130(41), 13552-containing 13554and J.am.chem.Soc.,2010,132(45), 15914-containing 15917. Palladium-catalyzed coupling 2- (dicyclohexylphosphino) -3, 6-dimethoxy-2 'may be used'4 ', 6 ' -triisopropyl-1, 1 ' -diphenyl (Brettphos) as ligand and chloro [2- (dicyclohexylphosphino) -3, 6-dimethoxy-2 ', 4 ', 6 ' -triisopropyl-1, 1 ' -diphenyl][2- (2-aminoethyl) phenyl group]Palladium (II) (Brettphos palladacycle) was carried out as procatalyst. The reaction may be carried out at room temperature up to 100 ℃ in a suitable solvent such as dioxane for a period of 1 to 24 hours, followed by work-up to give the compound of formula III. The ester compound of formula III may then be deprotected to give the free acid compound of formula II, which may then be reacted with an amine R^3′R²NH is subjected to a peptide coupling reaction, followed by deprotection if necessary, to give the compound of formula I. Amine R^3′R²Radical R in NH^3′Can represent R³By itself or R³Protected form of (1), which may be subsequently deprotected, when desired, to give R³。

Reaction scheme III

Reaction scheme III outlines another general method that can be used to provide the compounds of the present invention having formula I. The compound of formula V may be coupled with the compound of formula IV "in the first step of reaction scheme II using methods as described previously to provide the compound of formula I'. The compound of formula I' may then be deprotected as necessary as previously described to give the compound of formula I.

Reaction scheme IV

Reaction scheme IV provides another method for preparing compounds of formula I. In step one, an amine compound of formula VII is coupled with a compound of formula VI to provide a compound of formula III. In the compounds of formula VI, the group Lg represents a suitable leaving group such as methanesulfonate, trifluoromethanesulfonate or halide. The nucleophilic substitution reaction between compounds VII and VI is typically carried out in a suitable solvent such as acetonitrile in the presence of a suitable base such as potassium carbonate or potassium phosphate at a temperature in the range of ambient temperature to 80 ℃ for a period of 1 to 24 hours. In some cases, the group Lg in the compound of formula VI may also represent a carbonyl oxygen atom, with which the amine of formula VII may then be reacted under typical reductive amination conditions to give the compound of formula III. The compound of formula III can then be converted to compounds of formulae II, I' and I sequentially as described previously for reaction scheme I.

The compounds of the invention may be isolated and used as such or, where possible, in the form of their pharmaceutically acceptable salts. The term "salt" refers to inorganic and organic salts of the compounds of the present invention. These salts may be prepared in situ during the final isolation and purification of the compound or by separately reacting the compound with a suitable organic or inorganic acid or base and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, hydroiodide, sulfate, bisulfate, nitrate, acetate, trifluoroacetate, oxalate, benzenesulfonate, palmitate, pamoate, malonate, stearate, laurate, malate, borate, benzoate, lactate, phosphate, hexafluorophosphate, benzenesulfonate, tosylate, formate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate salts, and the like. These may include cations based on alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like, and non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, for example, Berge, et al,J.Pharm.Sci.,66,1-19(1977)。

the compounds of the present invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. Unless otherwise specified, all stereoisomeric forms of the compounds of the invention and mixtures thereof, including racemic mixtures, are specified to form part of the invention. In addition, the present invention includes all geometric isomers. For example, if the compounds of the present invention incorporate double bonds or fused rings, both cis-and trans-forms and mixtures are contemplated within the scope of the present invention.

Mixtures of diastereomers may be resolved into their respective diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by the following steps: the enantiomeric mixtures are converted into diastereomeric mixtures by reaction with a suitable optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or masher's acid chloride), the diastereomers are separated and the individual diastereomers are converted (e.g., hydrolyzed) into the corresponding pure enantiomers. Furthermore, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryl compounds) and are considered part of the present invention. Enantiomers can also be separated by using a chiral HPLC column. Alternatively, a particular stereoisomer may be synthesized by converting one stereoisomer into another stereoisomer using optically active starting materials, by asymmetric synthesis, using optically active reagents, substrates, catalysts or solvents, or by asymmetric transformation.

It is also possible that the intermediates and compounds of the invention may exist in different tautomeric forms and all such forms are included within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversion by some recombination of bonding electrons.

Some of the compounds of the invention may exist in different stable conformational forms, which may be separable. Torsional asymmetry due to restricted rotation about asymmetric single bonds, for example due to steric hindrance or tension between rings, may allow separation of different conformers.

The invention also includes isotopically-labeled compounds of the invention, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number actually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, respectively, such as²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、¹²³I、¹²⁵I and³⁶Cl。

some isotopically-labelled compounds of the invention (e.g. with³H and¹⁴c-labeled those) for compound and/or substrate tissue distribution assays. Tritium-labeled (i.e.³H) And carbon-14 (i.e.¹⁴C) Isotopes are particularly preferred for their ease of preparation and detectability. In addition, heavy isotopes such as deuterium (i.e. deuterium)²H) Substitution may result in some therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) due to greater metabolic stability, and may therefore be preferred in some circumstances. Positron emitting isotopes (e.g. of the type¹⁵O、¹³N、¹¹C and¹⁸F) for use in Positron Emission Tomography (PET) studies to detect substrate occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following steps analogous to those disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

Certain compounds of the present invention may exist in more than one crystal form (commonly referred to as "polymorphs"). Polymorphs can be prepared by crystallization under different conditions, e.g., using different solvents or mixtures of different solvents for recrystallization; crystallization at different temperatures; and/or cooling in various ways from very fast to very slow during crystallization. Polymorphs can also be obtained by heating or melting the compounds of the present invention followed by gradual or rapid cooling. The presence of polymorphs can be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.

The compounds of the invention are useful for the treatment of diseases, conditions and/or disorders modulated by glucagon; accordingly, another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent or carrier. The compounds of the invention (including the compositions and methods used herein) may also be used in the manufacture of medicaments for use in the therapeutic applications described herein.

Typical formulations are prepared by mixing a compound of the invention with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient employed will depend upon the mode and purpose for which the compound of the invention is to be administered. The solvent is generally selected based on solvents recognized by those skilled in the art as safe (GRAS) for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic water-soluble or water-miscible solvents. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), and the like, and mixtures thereof. The formulations may also include one or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorants and other known additives to provide an elegant appearance of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or to aid in the preparation of the pharmaceutical product (i.e., a drug).

The formulations may be prepared using conventional dissolution and mixing methods. For example, the drug substance (i.e., a compound of the invention or a stable form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above excipients. Typically, the compounds of the present invention are formulated into pharmaceutical dosage forms, resulting in a product that can be easily controlled in dosage and administered to the patient aesthetically and easily.

Pharmaceutical compositions also include solvates and hydrates of the compounds of formula I. The term "solvate" refers to a molecular complex of a compound represented by formula I (including pharmaceutically acceptable salts thereof) and one or more solvent molecules. Such solvent molecules are commonly used in the pharmaceutical arts and are known to be harmless to recipients, e.g., water, ethanol, ethylene glycol, and the like. The term "hydrate" refers to a complex in which the solvent molecule is water. The solvates and/or hydrates preferably exist in crystalline form. Other solvents may be used as intermediate solvates to prepare more desirable solvates such as methanol, methyl tert-butyl ether, ethyl acetate, methyl acetate, (S) -propylene glycol, (R) -propylene glycol, 1, 4-butyne-diol, and the like.

The pharmaceutical composition (or formulation) to be administered can be packaged in different ways, depending on the method of administration. Generally, the dispensed product includes a container in which the pharmaceutical formulation is stored in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal measuring cylinders and the like. The container may also include tamper-proof means to prevent inadvertent access to the package contents. In addition, the container is provided with a label describing the contents of the container. The tag may also include a suitable warning language.

The present invention also provides a method of treating a disease, condition, and/or disorder modulated by glucagon in an animal comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising an effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or carrier. The methods are particularly useful for treating diseases, conditions and/or disorders that benefit from modulation of glucagon, including eating disorders (e.g., bulimia, anorexia, bulimia, weight loss or control, and obesity), preventing obesity, and insulin resistance.

One aspect of the present invention is the treatment of obesity and obesity related disorders (e.g. overweight, weight gain or weight maintenance).

Obesity and overweight are generally defined in terms of the quality index (BMI), which is related to total body fat and can assess the relative risk of disease. BMI is calculated by dividing body weight in kilograms by the square of height in meters (kg/m)²). Overweight is typically defined as BMI25-29.9kg/m²While obesity is typically defined as BMI30kg/m². See, for example, National Heart, Lung, and laboratory Institute, Clinical Guidelines on The Identification, Evaluation, and Treatment of Overweight and Obesistance in additives, The Evaluation report, Washington, DC, U.S. department of Health and human services, NIH publication No.98-4083 (1998).

Another aspect of the invention is a method for treating or delaying the progression or onset of diabetes or diabetes-related disorders, including type 1 diabetes (insulin-dependent diabetes mellitus, also known as "IDDM") and type 2 diabetes (non-insulin dependent diabetes mellitus, also known as "NIDDM"), impaired glucose tolerance, insulin resistance, hyperglycemia, and diabetic complications such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, nephropathy, hypertension, neuropathy, and retinopathy.

Yet another aspect of the invention is the treatment of diabetes-or obesity-related co-diseases such as metabolic syndrome. The metabolic syndrome includes diseases, conditions or disorders such as dyslipidemia, hypertension, insulin resistance, diabetes (e.g., type 2 diabetes), weight gain, coronary artery disease and heartThe force is exhausted. For more detailed information on Metabolic Syndrome, see, for example, Zimmet, P.Z., et al, "The Metabolic Syndrome: Perhaps an Iologic Mysterbuit Far From a Myth-Where Dos The International diabetes mellitus disposition Stand?Diabetes&Endocrinology,7(2),(2005);andAlberti,K.G.,et al.,“The Metabolic Syndrome–A New WorldwideDefinition,”Lancet,366,1059-62(2005). Preferably, administration of a compound of the invention provides statistical significance (p) in at least one cardiovascular disease risk factor as compared to vehicle control without drug<0.05), for example, plasma leptin, C-reactive protein (CRP) and/or cholesterol. Administration of the compounds of the invention may also provide statistical significance (p) in the blood glucose square<0.05) was reduced.

In yet another aspect of the invention, the condition to be treated is impaired glucose tolerance, hyperglycemia, diabetic complications such as diabetic cataract, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic cardiomyopathy, anorexia nervosa, bulimia, cachexia, hyperuricemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina, hypertension, hypotension, stroke, ischemia reperfusion injury, aneurysm, restenosis, angiostenosis, solid tumor, skin cancer, melanoma, lymphoma, breast cancer, lung cancer, colorectal cancer, myocardial infarction, stroke, Gastric cancer, esophageal cancer, pancreatic cancer, prostate cancer, renal cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer, and ovarian cancer.

The present invention also relates to therapeutic methods for treating conditions in such mammals, including humans, wherein a compound of formula I of the present invention is administered as part of a suitable dosage regimen designed to obtain therapeutic benefit. The appropriate dosage regimen, amount of each dose administered and the interval between compound doses will depend upon the compound of formula (I) of the invention used, the type of pharmaceutical composition used, the characteristics of the subject being treated and the severity of the condition.

In general, an effective dose of a compound of the invention will range from 0.01 mg/kg/day to 30 mg/kg/day, preferably from 0.01 mg/kg/day to 5 mg/kg/day of the active compound, in divided or divided doses. However, some variation within the general dosage range may be desirable depending upon the age and weight of the subject being treated, the intended route of administration, the particular compound being administered, and the like. The determination of dosage ranges and optimal dosages for a particular patient is well within the ability of those skilled in the art having the benefit of the present disclosure. The practitioner will understand that "kg" refers to the patient's body weight measured in kilograms.

The compounds or compositions of the present invention may be administered in a single dose (e.g., once daily) or in multiple doses or via constant infusion. The compounds of the present invention may also be administered alone or in combination with pharmaceutically acceptable carriers, excipients or diluents in single or multiple doses. Suitable pharmaceutical carriers, excipients and diluents include inert solid diluents or fillers, sterile aqueous solutions or various organic solvents.

The compounds or compositions of the present invention can be administered to a subject in need of treatment by a variety of conventional routes of administration, including oral and parenteral (e.g., intravenous, subcutaneous, or intramedullary). In addition, the pharmaceutical compositions of the present invention may be administered intranasally, as suppositories, or using "flash" formulations, i.e., dissolving the drug in the oral cavity without the use of water.

It is also noted that the compounds of the present invention may be used in the form of sustained, controlled and delayed release formulations, which are also well known to those skilled in the art.

The compounds of the present invention may also be used in combination with other agents to treat the diseases, conditions, and/or disorders described herein. Accordingly, methods of treatment comprising administering a compound of the invention in combination with an additional agent are also provided. Suitable agents that may be combined with the compounds of the present invention include anti-obesity (including appetite suppressants), anti-diabetic agents, anti-hyperglycemic agents, lipid lowering agents, and anti-hypertensive agents.

Suitable antidiabetic agents include acetyl-CoA carboxylase- (ACC) inhibitors (such as those described in WO2009144554, WO2003072197, WO2009144555 and WO 2008065508), diacylglycerol O-acyltransferase 1(DGAT-1) inhibitors (such as those described in WO09016462 or WO 2010086820), AZD7687 or LCQ908, diacylglycerol O-acyltransferase 2(DGAT-2) inhibitors, monoacylglycerol O-acyltransferase inhibitors, Phosphodiesterase (PDE) -10 inhibitors, AMPK activators, sulfonylureas (e.g., acetohexamide, chlorpropamide, trycrypsin, glyburide, glipizide, glyburide, glimepiride, gliclazide, glyburide, glisoxomide, tolazamide and tolbutamide), mene, gliclazide inhibitors (e.g., amylase aprotinin, palmatin and AL-3688), gliclazide, and glibenclamide, Alpha-glycoside hydrolase inhibitors (e.g., acarbose), alpha-glycoside inhibitors (e.g., lipolytics, canogliose, emiglitate, miglitol, voglibose, pramipexole-Q, and salbutatin), PPAR gamma agonists (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, and troglitazone), PPAR alpha/gamma agonists (e.g., CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB-219994), biguanides (e.g., metformin), glucagon-like peptide 1(GLP-1) modulators such as agonists (e.g., exendin (exendin) -3 and exendin-4), liraglutide, abilutide, arbutase, and glitazobactam, ExenatideAbilutitane, taslutamide, lixisenatide, dulaglutide, semaglutide, NN-9924, TTP-054, protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., quinamine curvatude, ceteuraldehyde extract, and Zhang, s., et al.,Drug Discovery Today12(9/10),373-381 (2007)), SIRT-1 inhibitors (e.g.Resveratrol, GSK2245840 or GSK184072), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g. those disclosed in WO2005116014, sitagliptin, vildagliptin, alogliptin, dulagliptin, linagliptin and saxagliptin), insulin secretagogues, fatty acid oxidation inhibitors, A2 antagonists, c-jun amino-terminal kinase (JNK) inhibitors, glucokinase activators (GKa) (such as those described in WO2010103437, WO2010103438, WO2010013161, WO 2007122482), TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, insulin mimetics, glycogen phosphorylase inhibitors (e.g. GSK 632885), VPAC2 receptor agonists, GSK 18435 inhibitors (such as those described in Chauge C2010. 9, see Jugla et al, J.559, including those described in WO2005116014, JUN, JUG, JUN, canagliflozin (canagliflozin), BI-10733, tofogliflozin (CSG452), ASP-1941-THR1474, TS-071, ISIS388626 and LX4211 and those in WO 2010023594), glucagon receptor modulators such as those described in Demong, d.e. et al in medical Chemistry 2008,43,119-, j.c., Annual Reports in Medicinal Chemistry,2008,43,75-85, including but not limited to TAK-875, GPR120 modulators, in particular agonists, high affinity nicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors such as GSK1614235, and SGLT2 inhibitors such as (1S,2S,3S,4R,5S) -5- [ 4-chloro-3- (4-ethoxy-benzyl) -phenyl]-1-hydroxymethyl-6, 8-dioxa-bicyclo [3.2.1]Octane-2, 3, 4-triol, sjogren, remogliflozin, dacoglezin, canagliflozin, TA-7284. YM543 and BI 10773. Further representative lists of anti-diabetic agents that can be combined with the compounds of the present invention can be found, for example, on page 28, line 35 to page 30, line 19 of WO 2011005611. Preferred anti-diabetic agents are metformin and DPP-IV inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dulagliptin, linagliptin and saxagliptin) and SGLT2 inhibitors. Other antidiabetic agents may include carnitine palmitoyl transferase inhibitors or modulators, fructose 1, 6-bisphosphatase inhibitors, aldose reductase inhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors, inhibitors of CCR2 and/or CCR5, PKC isoform (e.g., PKC α, PKC β, PKC γ) inhibitors, fatty acid synthase inhibitors, serine palmitoyl transferase inhibitors, GPR81, GPR39, GPR43, GPR41, modulators of GPR105, kv1.3, retinol binding protein 4, glucocorticoid receptor, somatostatin receptor (e.g., SSTR1, SSTR2, SSTR3, and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, MAP4K4 inhibitors, modulators of the IL1 family including IL1 β, RXR α modulators. Additional suitable anti-diabetic agents include those listed by Carpino, p.a., Goodwin, b.expert opin.ther. pat,2010,20(12), 1627-51.

Suitable anti-obesity agents, some of which may also act as anti-diabetic agents, include 11 beta-hydroxysteroid dehydrogenase-1 (11 beta-HSD 1 type) inhibitors, stearoyl-CoA desaturase-1 (SCD-1) inhibitors, MCR-4 agonists, cholecystokinin-a (CCK-a) agonists, monoamine reuptake inhibitors (e.g., sibutramine), sympathomimetics, beta 3 adrenergic agonists, dopamine agonists (such as bromocriptine), melanocyte hormone analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (OB protein), leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (e.g., tetrahydroporiferin, orlistat), anorectic drugs (e.g., bombesin agonists), neuropeptide-Y antagonists (e.g., NPY Y5 antagonists, such as virifibrate), PYY_3-36(including analogs thereof), modulators of BRS3, mixed antagonists of opioid receptor subtypes, thyromimetic agents, dehydroepiandrosterone or analogs thereof, glucocorticoid agonists or antagonists, orexin antagonistsGlucagon-like peptide-1 agonists, ciliary neurotrophic factors (e.g., available from Regeneron Pharmaceuticals, inc., Tarrytown, NY and Procter)&Axokine from Gamble Company, Cincinnati, OH^TM) Human agomelatine-related protein (AGRP) inhibitors, histamine 3 antagonists or inverse agonists, neurointerleukin U agonists, MTP/ApoB inhibitors (e.g. gut-selective MTP inhibitors such as desloratade, JTT130, usiptaside, SLx4090), opioid antagonists, mu opioid receptor modulators (including but not limited to GSK1521498), MetAp2 inhibitors (including but not limited to ZGN-433), agents with mixed modulatory activity of two or more glucagons, GIP and GLP1 receptors such as MAR-701 or ZP2929, norepinephrine transporter inhibitors, cannabinoid-1-receptor antagonists/inverse agonists, gastrin agonists/antagonists, oxyntomodulin modulators and analogs, monoamine uptake inhibitors such as but not limited to tesofensin, orexin antagonists, combination agents (such as bupropion + zonisamide, doxylamine, and the like), Pramlintide + metreleptin, bupropion + naltrexone, phentermine + topiramate), and the like.

Preferred anti-obesity agents for use in the combination aspect of the invention include gut-selective MTP inhibitors (e.g. desloratadine, mitotapine and inputamide, R56918(CAS No.403987) and CAS No.913541-47-6), CCKa agonists (e.g. N-benzyl-2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3,6,10 b-tetraaza-benzo [ e ] described in PCT publication No. WO2005/116034 or US publication No. US2005-0267100A1]Azulen-6-yl]-N-isopropyl-acetamide), 5HT2c agonists (e.g. lorcaserin), MCR4 agonists (e.g. the compounds described in US6,818,658), lipase inhibitors (e.g. cetilistat), PYY_3-36(As used herein "PYY_3-36"includes analogs, such as pegylated PYY_3-36Such as those described in U.S. publication No. 2006/0178501), opioid antagonists (e.g., naltrexone), oleoyl estrone (CASNO.180003-17-2), ornithopril (TM30338), pramlintide (Symlin)) Replacement ropeFencine (NS2330), leptin, bromocriptine, orlistat, AOD-9604(CAS No.221231-10-3), and sibutramine. Preferably, the compounds and combination therapies of the present invention are administered in combination with exercise and a sensible diet.

All of the above U.S. patents and publications are incorporated herein by reference.

The following examples are intended to illustrate embodiments of the present invention. It is to be understood, however, that embodiments of this invention are not limited to the specific details of these examples, since other variations will be apparent or obvious to one of ordinary skill in the art in light of the present disclosure.

Examples

Unless otherwise specified, starting materials are generally available from commercial sources, such as Aldrich Chemicals Co. (Milwaukee, WI), Lancaster Synthesis, Inc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybrid chemical company, Ltd. (Cornwall, England), Tyger Scientific (Princeton, NJ), and AstraZeneca Pharmaceuticals (London, England).

General Experimental methods

At Varian Unity^TMProton NMR spectra were recorded at 400MHz at room temperature on 400 (available from Varian Inc., Palo Alto, Calif.). Chemical shifts are expressed in parts per million (δ) relative to residual solvent as an internal standard. The peak shape is represented as follows: s, singlet; d, doublet; dd, double doublet; t, triplet; q, quartet; m, multiplet; bs, broad singlet; 2s, two single peaks. Using Fisons^TMAtmospheric pressure chemical ionization mass spectrometry (APCI) was obtained on a Platform II spectrometer (carrier gas: acetonitrile: available from Micromass Ltd, Manchester, UK). Using a Hewlett-Packard^TM5989 apparatus (Ammonia ionization, PBMS: available from Hewlett-Packard Company, Palo Alto, Calif.) gave a chemical ionization mass spectrum (CI). By Waters^TMZMD Instrument (Carrier gas: acetonitrile: available from Waters Corp., Milford, Mass.)) Electrospray ionization mass spectrometry (ES) was obtained. In Agilent^TMHigh Resolution Mass Spectra (HRMS) were obtained on Model6210 using the time-of-flight method. If the intensity of the chlorine-or bromine-containing ion is described, the expected intensity ratio (inclusive of³⁵Cl/³⁷Ion of Cl about 3:1, comprising⁷⁹Br/⁸¹Ion 1:1) of Br and only gives the intensity of ions of lower mass. In some cases, only representative are given¹H NMR peaks. By PerkinElmer^TMA 241 polarimeter (available from PerkinElmer inc., wellelsley, MA), measured optical rotation using a sodium D-line (λ =589nm) at the indicated temperature and reported as follows: [ alpha ] to]_D ^tempConcentration (c ═ g/100ml) and solvent.

Using Baker^TMSilica gel (40 μm; J.T.Baker, Phillipsburg, NJ) or silica gel 50(EM Sciences)^TMGibbstown, NJ) on glass columns or on Flash40Biotage^TMColumn (ISC, Inc., Shelton, CT) or Biotage^TMSNAP column KPsil or Redispe Rf silica (from Teledyne)^TM Isco^TM) Above, column chromatography was performed under low nitrogen pressure. Chiral SFC (supercritical fluid chromatography) was performed on the indicated chiral column. The following abbreviations appear herein: BSA, bovine serum albumin; cAMP, cyclic adenosine monophosphate; CsOAc, cesium acetate; DCM, dichloromethane; DIEA, diisopropylethylamine; DMEM-F12, Dulbecco's modified Eagle's Medium nutrient mixture F-12; DMF, N-dimethylformamide; DMSO, dimethylsulfoxide; EtOAc, ethyl acetate; EtOH, ethanol; g, g; h, hours; IBMX, 3-isobutyl-1-methylxanthine; i-PrOH, isopropanol; l, liter; LCMS, liquid chromatography mass spectrometry; MeOH, methanol; mg, mg; mL, mL; mmol, millimole; min, min; n, normal; PVT, polyvinyltoluene; RT, room temperature; SPA, scintillation proximity assay; TEA, triethylamine; THF, tetrahydrofuran; and WGA, wheat germ agglutinin.

Preparation of starting materials and intermediates

Intermediate 1 ethyl 4-butyryl benzoate

Isopropyl magnesium chloride lithium chloride (15.3mL, 1.3M in THF 19.9mmol) was added dropwise to a solution of ethyl 4-iodobenzoate (5000mg, 18.11mmol) in tetrahydrofuran (30mL) at-40 ℃. The solution was stirred at-40 ℃ for 40 minutes. Butyraldehyde (1830mg, 25.4mmol) was added. The mixture was allowed to warm to room temperature over 3 hours. The reaction was quenched with 1N HCl and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give ethyl 4- (1-hydroxybutyl) benzoate.¹H NMR(400MHz，CDCl₃)δ8.02(d，J=8.6Hz，2H)，7.41(d，J=8.0Hz，2H)，4.83-4.66(m，1H)，4.38(q，J=7.2Hz，2H)，1.86(d，J=3.7Hz，1H)，1.83-1.61(m，2H)，1.51-1.42(m，1H)，1.39(t，J=7.2Hz，3H)，1.36-1.23(m，1H)，0.94(t，J=7.6Hz，3H)。

A mixture of crude ethanol (1.0g, 4.5mmol) in dichloromethane (16.7mL), dimethyl sulfoxide (4.79mL) and triethylamine (2.28g, 22.5mmol) was cooled to 0 ℃. Sulfur trioxide pyridine complex (2.15g, 13.5mmol) was added in portions and the mixture was stirred at 0 ℃ for 1 hour. The reaction was then allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with brine and diluted with dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-30% ethyl acetate in heptane) gave ethyl 4-butyrylbenzoate (intermediate 1).¹H NMR(400MHz，CDCl₃)δ8.05-8.17(m，2H)，8.04-7.92(m，2H)，4.40(q，J=7.15Hz，2H)，2.96(t，J=7.22Hz，2H)，1.86-1.69(m，2H)，1.40(t，J=7.12Hz，3H)，1.00(t，J=7.22Hz，3H)。

Intermediate 2 Ethyl (+/-) -4- (1-aminobutyl) benzoate

Sodium cyanoborohydride (29.8g, 0.450mol) was added to a solution of intermediate 1(66.1g, 0.300mol) and ammonium acetate (236g, 3.00mol) in methanol (1000 mL). The solution was fitted to a reflux condenser and heated to 60 ℃ for 16 h. The solution was allowed to cool to room temperature. The reaction was quenched by dropwise addition of 1N HCl (300mL) and allowed to stir at room temperature for 1 h. The reaction mixture was concentrated to remove methanol. This mixture was diluted by careful addition of 1N NaOH (500mL) and then extracted with dichloromethane (3 × 500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (methanol/dichloromethane) gave ethyl (+/-) -4- (1-aminobutyl) benzoate (intermediate 2).¹H NMR(400MHz，CDCl₃)δ8.01(d，J=8.2Hz，2H)，7.40(d，J=8.2Hz，2H)，4.38(q，J=7.2Hz，2H)，3.98(t，J=6.9Hz，1H)，1.95(br.s.，2H)，1.74-1.56(m，2H)，1.40(t，J=7.1Hz，3H)，1.16-1.37(m，2H)，0.91(t，J=7.4Hz，3H)。

Intermediate 3: 3-methylquinoline 1-oxide

3-methylquinoline (30.0mL, 224mmol) was dissolved in acetic acid (85mL) and 30% aqueous hydrogen peroxide (30.4mL) was added. The reaction was stirred at 80 ℃ for 16h and then cooled in an ice bath. Adding 10% Na₂SO₃Aqueous solution (199mL, 0.5 equiv.) then sodium iodide (2.358g, 0.05 equiv.) was added. This mixture was stirred for 5 min. Peroxide test strips showed no peroxide remaining. Then 5N NaOH in water was added, maintaining the internal temperature below 24 ℃. A black color formed indicating that the solution was basic (test pH 10). The solution was extracted with four portions of dichloromethane. The combined organic layers were over MgSO₄Dried and filtered, and the filtrate concentrated under reduced pressure. Purification by flash chromatography on silica gel (methanol/ethyl acetate) gave 3-methylquinoline 1-oxide (intermediate 3, 32.09g) as a yellow solid。¹H NMR(400MHz，CDCl₃)δ8.69(d，J=8.8Hz，1H)，8.42(s，1H)，7.77(d，J=8.2Hz，1H)，7.68(td，J=7.8，1.1Hz，1H)，7.56-7.63(m，1H)，7.52(s，1H)，2.45(s，3H)；MS(M+1):160.2。

Intermediate 4 Ethyl (+/-) -4- (1- ((3-methylquinolin-2-yl) amino) butyl) benzoate

Intermediate 2(22.9g, 104mmol) was combined with 3-methylquinoline-N-oxide (intermediate 3, 17.3g, 109mmol) and dichloromethane (414 mL). Diisopropylethylamine (68.0mL, 389mmol) was added followed by the addition of the trispyrrolidinylphosphonium bromide (bromopyrolidinophosphonium) hexafluorophosphate (61.0g, 130 mmol). The solution was stirred at room temperature for 12h and then saturated NaHCO₃Aqueous solution (400 mL). The mixture was extracted with ethyl acetate (3 × 400 mL). The combined organic layers were passed over Na₂SO₄Dried and filtered, and the filtrate concentrated under reduced pressure. Purification by flash chromatography on silica gel (ethyl acetate/heptane) gave ethyl (+/-) -4- (1- ((3-methylquinolin-2-yl) amino) butyl) benzoate (intermediate 4).¹H NMR(400MHz，CDCl₃)δ7.99(d，J=8.2Hz，2H)，7.65-7.58(m，2H)，7.56-7.48(m，3H)，7.43(t，J=7.5Hz，1H)，7.16(t，J=7.4Hz，1H)，5.50(q，J=7.2Hz，1H)，4.79(d，J=7.0Hz，1H)，4.35(q，J=7.0Hz，2H)，2.30(s，3H)，2.04-1.83(m，2H)，1.54-1.39(m，2H)，1.37(t，J=7.1Hz，3H)，0.98(t，J=7.4Hz，3H)。

Intermediate 5 (+/-) -4- (1- ((3-methylquinolin-2-yl) amino) butyl) benzoic acid

To intermediate 4(34.29g,94.60mmol) in tetrahydrofuran (234mL) and methanol (234mL) was added 1N aqueous sodium hydroxide (473 mL). The solution was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure to remove tetrahydrofuran and methanol. 3N aqueous hydrochloric acid was added dropwise to a pH of 2. The resulting slurry was filtered and the solid was washed with water (300mL then 100 mL). Removal of water by azeotropy first with toluene then heptane (7x100mL) and drying of the solid under reduced pressure by heating to 70 ℃ provided (+/-) -4- (1- ((3-methylquinolin-2-yl) amino) butyl) benzoic acid (intermediate 5).¹H NMR(400MHz，CD₃OD)δ8.09(s，1H)，8.02(d，J=8.4Hz，2H)，7.84(d，J=8.4Hz，1H)，7.72(d，J=7.8Hz，1H)，7.66-7.58(m，3H)，7.40(t，J=7.6Hz，1H)，5.56(dd，J=6.0，8.6Hz，1H)，2.49(s，3H)，2.24-2.10(m，1H)，2.08-1.95(m，1H)，1.66-1.52(m，1H)，1.52-1.39(m，1H)，1.03(t，J=7.4Hz，3H)。

Intermediate 6 methyl (+) -3- (4- (1- ((3-methylquinolin-2-yl) amino) butyl) benzoylamino) propionate and intermediate 7 methyl (-) -3- (4- (1- ((3-methylquinolin-2-yl) amino) butyl) benzoylamino) propionate

Intermediate 5(31.64g, 94.61mmol), beta-alanine ethyl ester hydrochloride (45.9g, 284mmol) and 1-hydroxybenzotriazole hydrate (80%, 20wt% water, 47.9g, 284mmol) were suspended in dichloromethane (946 mL). Triethylamine (119mL, 852mmol) was added followed by N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (46.0g, 237mmol) and the solution was stirred at room temperature for 10 h. The reaction mixture was washed with water (3 × 900mL) then saturated aqueous NaCl (300 mL). The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel (ethyl acetate/heptane) followed by chiral SFC (Chiralpak AD-H column, 30X250, 20% methanol/carbon dioxide eluent, 0.2% isopropylamine modifier) afforded methyl (+) -3- (4- (1- ((3-methylquinolin-2-yl)) Amino) butyl) benzoylamino) propionate (intermediate 6, analyzed for chiral sfc4.6min retention time) and methyl (-) -3- (4- (1- ((3-methylquinolin-2-yl) amino) butyl) benzoylamino) propionate (intermediate 7, analyzed for chiral sfc6.5min retention time), noting the conversion of the ethyl ester to the methyl ester during the reaction and/or purification sequence.¹H NMR(400MHz，CDCl₃)δ7.71(d，J=8.4Hz，2H)，7.64-7.58(m，2H)，7.55-7.48(m，3H)，7.44(t，J=7.7Hz，1H)，7.16(t，J=7.4Hz，1H)，6.76(t，J=5.5Hz，1H)，5.48(q，J=7.2Hz，1H)，4.78(d，J=7.0Hz，1H)，3.76(q，J=6.0Hz，2H)，3.70(s，3H)，2.64(t，J=5.9Hz，2H)，2.29(s，3H)，2.04-1.82(m，2H)，1.52-1.29(m，2H)，0.98(t，J=7.3Hz，3H)。

Intermediate 8 (+/-) -4- (1-hydroxy-3-methyl-butyl) -benzoic acid ethyl ester

To a solution of ethyl 4-iodobenzoate (140g, 507mmol) in tetrahydrofuran was added dropwise a solution of isopropyl magnesium chloride lithium chloride complex (1.0M in tetrahydrofuran, 429mL, 558mmol) at-40 ℃ while maintaining the internal temperature below-30 ℃. The mixture was stirred for 30 minutes, at which time isobutyraldehyde (61g, 710mmol) was added dropwise while maintaining the temperature below-35 ℃. The mixture was stirred at this temperature for 15 minutes and then slowly warmed to room temperature. The reaction was quenched with 1N HCl (3L) and the mixture was extracted with ethyl acetate (2Lx 2). The combined organics were washed with brine (1L) and water (1L), then passed over anhydrous Na₂SO₄And (5) drying. It was concentrated in vacuo to give (+/-) -ethyl 4- (1-hydroxy-3-methyl-butyl) -benzoate (120g, 100%) as an oil.¹H NMR(400MHz，CDCl₃)δ7.95(d，J=8.4Hz，2H)，7.47(s，J=7.2Hz，2H)，4.76-4.73(m，1H)，4.33-4.28(m，2H)，1.71-1.60(m，2H)，1.46-1.41(m，1H)，1.39-1.31(m，3H)，0.92-0.87(m，6H)。

Intermediate 9 (+/-) -4- (1-hydroxy-3-methyl-butyl) -benzoic acid

To a solution of intermediate 8(15g, 63mmol) in tetrahydrofuran (63.5mL) was added 2N NaOH (63.5 mL). The resulting mixture was stirred at room temperature for 2h and then at 60 ℃ overnight. The mixture was acidified to pH4 with 1N HCl and then extracted with ethyl acetate (3 × 50 mL). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure yielded (+/-) -4- (1-hydroxy-3-methyl-butyl) -benzoic acid (11g, 83%) as a yellow solid.¹H NMR(400MHz，CD₃OD)δ(d，J=8.4Hz，2H)，7.51(d，J=8.4Hz，2H)，4.81(q，J=8.4Hz，5.2Hz，1H)，1.81-1.71(m，2H)，1.55-1.51(m，1H)，1.03(q，J=6.4Hz，2.4Hz，6H)。

Intermediate 10 (+/-) -3- [4- (1-hydroxy-3-methyl-butyl) -benzoylamino ] -propionic acid tert-butyl ester

To a solution of intermediate 9(9.5g, 46mmol) in DMF (120mL) was added HATU (34.7g, 91.2mmol) at room temperature. The mixture was stirred for 20min and beta-alanine tert-butyl ester (13.2g, 91.2mmol) and diisopropylethylamine (35.4g, 274mmol) were slowly added to the reaction mixture at 0 ℃. The resulting mixture was stirred at room temperature for 1.5h then ethyl acetate (50mL) and brine (100mL) were added. The separated aqueous layer was extracted with ethyl acetate (4 × 50mL) and the combined organic layers were washed with brine (50mL), over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave crude compound (40g) as a brown oil. Purification by flash chromatography on silica gel (ethyl acetate/petroleum ether) to yield (+/-) -3- [4- (1-hydroxy-3-methyl-butyl) -benzoylamino]-propionic acid tert-butyl esterButyl ester (14g, 90%) as yellow solid.¹H NMR(400MHz，CD₃OD)δ7.84(d，J=8.4Hz，2H)，7.50(d，J=8.4Hz，2H)，4.80(dd，J=8.4Hz，5.6Hz，1H)，3.67(t，J=7.2Hz，2H)，2.64(t，J=5.6Hz，2H)，1.78-1.72(m，2H)，1.55-1.52(m，1H)，1.50(s，9H)，1.02(d，J=6.4Hz，6H)。

Intermediate 11 (+/-) -3- {4- [1- (1, 3-dioxo-1, 3-dihydroisoindol-2-yl) -3-methyl-butyl ] -benzoylamino } -propionic acid tert-butyl ester

Intermediate 10(14g, 42mmol), phthalimide (12.3g, 83.5mmol) and PPh at 0 deg.C₃(21.9g, 83.5mmol) in tetrahydrofuran was added diisopropyl azodicarboxylate (16.9g, 83.5 mmol). The resulting mixture was stirred at room temperature overnight, then water (60mL) and ethyl acetate (50mL) were added. The aqueous layer was extracted with ethyl acetate (3 × 50mL) and the combined organic extracts were passed over Na₂SO₄Drying, filtration and concentration in vacuo afforded crude (+/-) -3- {4- [1- (1, 3-dioxo-1, 3-dihydroisoindol-2-yl) -3-methyl-butyl]-benzoylamino } -propionic acid tert-butyl ester (26g) as yellow oil. The crude compound was used directly in the next step.

Intermediate 12 (+/-) -3- [4- (1-amino-3-methyl-butyl) -benzoylamino ] -propionic acid tert-butyl ester

To a solution of crude intermediate 11(26g, 26mmol) in ethanol (100mL) was added hydrazine hydrate (30 mL). The reaction mixture was heated to reflux and stirred overnight. After cooling, water (100mL) and ethyl acetate (50mL) were added, the layers were separated, and the aqueous layer was extracted with ethyl acetate (3X75mL). The combined organic extracts were passed over Na₂SO₄Dried, filtered and concentrated under vacuum to give crude compound (20g) as a yellow oil. Purification by flash chromatography on silica gel (methanol/dichloromethane) to yield (+/-) -3- [4- (1-amino-3-methyl-butyl) -benzoylamino]Tert-butyl propionate (6.8g, 79%) as a yellow solid.¹H NMR(400MHz，CDCl₃)δ7.72(d，J=8.0Hz，2H)，7.38(d，J=8.0Hz，2H)，6.87(s，1H)，4.01(t，J=6.8Hz，1H)，3.69(t，J=6.0Hz，2H)，2.55(t，J=6.0Hz，2H)，2.05-1.81(m，2H)，1.59-1.48(m，3H)，1.46(s，9H)，0.94-0.89(m，6H)；MS(M+23):357.3。

Intermediate 13 (E) -methyl 3- (2-amino-4- (trifluoromethyl) phenyl) acrylate

In a 100ml three-necked flask with magnetic stirrer were placed 2-bromo-5- (trifluoromethyl) aniline (500mg, 2.08mmol), methacrylate (538mg, 6.25mmol), Pd (OAc)₂(23.3mg, 0.104mmol), P (o-tolyl)₃(64mg, 0.21mmol), triethylamine (422mg, 4.7mmol) and acetonitrile (20 mL). N for flask₂Purged and heated to 90 ℃ overnight. Adding saturated NH₄Aqueous Cl (40mL) and the mixture was extracted with ethyl acetate (10mLx 3). The combined organic layers were passed over Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give (E) -methyl 3- (2-amino-4- (trifluoromethyl) phenyl) acrylate (180.9mg, 37%) as a pale green solid.¹H NMR(400MHz，CDCl₃):δ7.71(d，J=16Hz，1H)，δ7.38(d，J=8Hz，1H)，δ6.92(d，J=8Hz，1H)，δ6.86(s，1H)，δ6.34(d，J=8Hz，1H)，δ4.05(s，2H)，δ3.73(s，3H)。

Intermediate 14:7- (trifluoromethyl) quinolin-2-ol

A100 mL flask equipped with a magnetic stirrer was charged with intermediate 13(600mg, 2.44mmol), concentrated aqueous HCl (893mg), THF (6mL) and water (6 mL). The mixture was heated at reflux overnight. The mixture was extracted with ethyl acetate (3 × 10 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. The crude residue was purified by silica gel chromatography to give 7- (trifluoromethyl) quinolin-2-ol (440mg, 84.3%) as a green solid.¹H NMR(400MHz，DMSO-d₆)δ12.56(s，1H)，7.99(d，J=15.6Hz，1H)，7.81(d，J=8Hz，1H)，7.20(s，1H)，6.97(d，J=8Hz，1H)，6.59(d，J=15.6Hz，1H)。

Intermediate 15: 2-chloro-7- (trifluoromethyl) quinoline

A50 mL round bottom flask with magnetic stirrer was charged with intermediate 14(100mg, 0.47mmol) and POCl₃(5 mL). The mixture was heated to reflux for 3 hours. Removal of POCl under reduced pressure₃And saturated NaHCO was added₃Aqueous solution (20 mL). The mixture was extracted with ethyl acetate (3 × 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give 2-chloro-7- (trifluoromethyl) quinoline (27.7mg, 25.4%) as a yellow solid.¹H NMR(400MHz，MeOD):δ8.35(d，J=8.8Hz，1H)，8.16(s，1H)，δ8.08(d，J=8.4Hz，1H)，δ7.75(d，J=8.4Hz，1H)，δ7.57(d，J=8.8Hz，1H)。

Intermediate 16 (E) -methyl 3- (2-amino-5- (trifluoromethyl) phenyl) acrylate

In a 100ml three-necked flask with magnetic stirrer were placed 2-bromo-4- (trifluoromethyl) aniline (500mg, 2.08mmol), methyl acrylate (538mg, 6.25mmol), Pd (OAc)₂(23.3mg, 0.104mmol), P (o-tolyl)₃(64mg, 0.21mmol), triethylamine (422mg, 4.7mmol) and acetonitrile (20 mL). N for flask₂Purged and heated to 90 ℃ overnight. Adding saturated NH₄Aqueous Cl (40ml) and the mixture was extracted with ethyl acetate (10ml x 3). The organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel chromatography to give (E) -methyl 3- (2-amino-5- (trifluoromethyl) phenyl) acrylate (185.9mg, 36.5%) as a yellow solid.¹H NMR(400MHz，CDCl₃)δ7.69(d，J=16Hz，1H)，7.53(s，1H)，7.32(d，J=8.8Hz，1H)，6.67(d，J=8.8Hz，1H)，6.34(d，J=16Hz，1H)，4.20(s，2H)，3.74(s，3H)。

Intermediate 17: 2-chloro-6- (trifluoromethyl) quinoline

A100 mL flask equipped with a magnetic stirrer was charged with intermediate 16(740mg, 3.02mmol), concentrated aqueous HCl (3.1mL), THF (7mL) and water (7 mL). The mixture was heated at reflux overnight. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were passed over Na₂SO₄Drying, filtration and evaporation gave 560mg of a yellow solid. The crude residue was dissolved in POCl₃(20 mL). The mixture was heated to reflux for 3 hours. Removal of POCl under reduced pressure₃And saturated NaHCO was added₃Aqueous solution (40 mL). The solution was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were passed over Na₂SO₄Dried, filtered, and concentrated to dryness. The crude product was purified by silica gel chromatography to give 2-chloro-6- (trifluoromethyl) quinoline (438mg, 63%) as a colorless solid.¹H NMR(400MHz，CDCl₃)δ8.14(d，J=8.4Hz，1H)，8.08-8.06(m，2H)，7.85-7.90(m，1H)，7.44(d，J=8.4Hz，1H)。

Intermediate 18: 3-amino-2-methylquinoline

A solution of 2-methyl-3-nitroquinoline (400mg, 2.13mmol) in concentrated HCl (8mL) was heated to 50 ℃. Tin (II) chloride dihydrate (1.2g, 5.3mmol) was added. The mixture was stirred at 50 ℃ overnight. The mixture was diluted with water (20 mL). The pH was brought to 9 by addition of 5N NaOH in water. The mixture was cooled to 4 ℃ and extracted with ethyl acetate (2 × 30 mL). The combined extracts were washed with ice cold water (40mL) and over anhydrous Na₂SO₄Drying, filtration and concentration gave 3-amino-2-methylquinoline (270mg, 80%) as a yellow solid. 1HNMR (400MHz, CDCl3): δ 7.84(d, J =8.4Hz, 1H), 7.51(dd, J =1.2, 8.0Hz,1H), 7.39-7.30(m, 2H), 7.16(s, 1H), 3.77(s, 2H), 2.56(s, 3H).

Intermediate 19 Ethyl 4- (3-methyl-1- (methylsulfonyloxy) butyl) benzoate

To a solution of intermediate 8(350mg, 1.48mmoL) in anhydrous dichloromethane (20mL) at 0 deg.C was added triethylamine (449.4mg, 16.7mmoL) followed by methanesulfonyl chloride (186.8mg, 1.63 mmoL). The resulting mixture was stirred at 0 ℃ for 1h and at room temperature for 30 min. The reaction mixture was quenched with water (10mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were passed over Na₂SO₄Drying, filtration and concentration under reduced pressure gave ethyl 4- (3-methyl-1- (methylsulfonyloxy) butyl) benzoate (180mg, 39%) as an oil containing some triethylammonium hydrochloride. The substance does not needFurther purifying and using.¹HNMR(400MHz，CDCl₃) δ 8.01(d, J =8.0Hz, 2H), 7.40(d, J =8.0Hz, 2H), 5.56(m, 1H), 4.32(q, J =7.2Hz, 2H), 2.01-1.92(m, 1H), 1.69-1.51(m, 2H), 1.31-1.40(m, 3H, overlap with the triethylammonium hydrochloride peak), 0.89-0.95(m, 6H).

Intermediate 20: 3-amino-4-methylquinoline

A solution of 4-methyl-3-nitroquinoline (500mg, 2.66mmol) in concentrated HCl (10mL) was heated to 50 ℃. Tin (II) chloride dihydrate (1.5g, 6.6mmol) was added. The mixture was stirred at 50 ℃ overnight. The mixture was diluted with water (20 mL). The mixture was adjusted to pH9 by the addition of 5N aqueous sodium hydroxide. The mixture was cooled to 4 ℃ and extracted twice with ethyl acetate (30 mL). The combined extracts were washed with ice cold water (40mL) and over anhydrous Na₂SO₄Drying, filtration and concentration gave 3-amino-4-methylquinoline (340mg, 80%) as a yellow solid.¹H NMR(400MHz，CDCl₃)δ8.42(s，1H)，7.89-7.91(m，1H)，7.79-7.82(m，1H)，7.44-7.38(m，2H)，3.77(br s，2H)，2.37(s，3H)。

Intermediate 21 Ethyl 4- (3-methyl-1- (4-methylquinolin-3-ylamino) butyl) benzoate

A mixture of intermediate 20(200mg, 1.26mmol), intermediate 19(476mg) and potassium carbonate (349mg,2.53mmol) in acetonitrile (10mL) was stirred at 80 ℃ overnight. The reaction mixture was poured into brine (20mL) and extracted with ethyl acetate (30mLx 2). The combined organic layers were washed with brine (30mL x2) and water (30mL), then over anhydrous Na₂SO₄The mixture is dried and then is dried,filtered and concentrated under reduced pressure. Purification by silica gel chromatography afforded ethyl 4- (3-methyl-1- (4-methylquinolin-3-ylamino) butyl) benzoate (40mg, 10%) as a yellow solid.¹H NMR(400MHz，CDCl₃)δ8.23(s，1H)，7.91(d，J=8.4Hz，2H)，7.86(d，J=8.0Hz，1H)，7.80(d，J=8.0Hz，1H)，7.42-7.33(m，4H)，4.62-4.65(m，1H)，4.27(q，J=7.2Hz，2H)，2.44(s，3H)，1.78-1.70(m，1H)，1.68-1.64(m，2H)，1.17(q，J=7.2Hz，3H)，0.97(d，J=6.4Hz，3H)，0.90(d，J=6.4Hz，3H)。

Intermediate 22, 3-dimethylcyclobutanecarbonyl chloride

3, 3-dimethyl-cyclobutanecarboxylic acid (Parkway Scientific, New York, NY, USA) (500mg, 3.90mmol) was dissolved in dichloromethane (3mL) and oxalyl chloride (1.02mL, 11.7mmol) was added. The solution was stirred at room temperature for 4h and then concentrated in vacuo to afford 3, 3-dimethylcyclobutanecarbonyl chloride, which was used without further purification.¹H NMR(400MHz，CDCl₃) δ 3.49 (quintuple, J =8.9Hz, 1H)2.15-2.27(m, 2H)2.06-2.14(m, 2H)1.18(s, 3H)1.12(s, 3H).

Intermediate 23 ethyl 4- (3, 3-dimethyl-cyclobutanecarbonyl) -benzoate

Ethyl 4-iodobenzoate (600mg, 2.17mmol) was dissolved in tetrahydrofuran (6.0mL) and brought to-40 ℃. A solution of isopropyl magnesium chloride lithium chloride complex (1.0M in tetrahydrofuran, 0.365mL, 2.17mmol) was added dropwise and the yellow-red solution was stirred at-40 ℃ for 40 min. A portion of CuI (124mg, 0.65mmol) was added and the mixture was stirred at-15 ℃ for 20min to dissolve all solids. The yellow solution was then brought back to-40 ℃ and 3, 3-dimethylcyclobutanecarbonyl chloride (intermediate 22) (450mg, 3.07mmol) was added dropwise. The color changed from light green to yellow, then red, then yellow. The mixture was warmed to 0 ℃ over 2 hours in the same bath. The mixture was diluted with 1N HCl and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated in vacuo. The crude material fraction was purified by flash chromatography on silica gel (ethyl acetate/heptane) to give impure ethyl 4- (3, 3-dimethyl-cyclobutanecarbonyl) -benzoate (588 mg).¹H NMR(400MHz，CDCl₃) δ 8.11(d, J =8.4Hz, 2H)7.94(d, J =8.4Hz, 2H)4.38-4.48(m, 2H)3.90 (quintuple peak, J =8.8Hz, 1H)2.16-2.29(m, 2H)2.04-2.13(m, 2H)1.42(t, J =7.2Hz, 3H)1.28(s, 3H)1.09(s, 3H); MS (M +1): 261.4.

Intermediate 24 (+/-) -4- [ amino- (3, 3-dimethyl-cyclobutyl) -methyl ] -benzoic acid ethyl ester

Ethyl 4- (3, 3-dimethyl-cyclobutanecarbonyl) -benzoate (intermediate 23) (235mg, 0.903mmol) was dissolved in methanol (5 mL). Ammonium acetate (710mg, 9.03mmol) was added followed by sodium cyanoborohydride (89.6mg, 1.36 mmol). It was heated to 60 ℃ for 17h, then cooled and 1N HCl (3mL) was added. It was stirred for 15min and then 1N NaOH (10mL) was added. The material was extracted into two portions of ethyl acetate and the combined organics were passed over MgSO₄And (5) drying. Purification by flash chromatography on silica gel (methanol/ethyl acetate) to obtain (+/-) -4- [ amino- (3, 3-dimethyl-cyclobutyl) -methyl]-ethyl benzoate (137mg) as a pale yellow oil.¹H NMR(400MHz，CDCl₃) δ 7.99(d, J =8.4Hz, 2H)7.37(d, J =8.2Hz, 2H)4.38(q, J =7.0Hz, 2H)3.82(d, J =9.2Hz, 1H)2.39 (hexameric peak, J =8.7Hz, 1H)1.90-2.02(m, 1H)1.60-1.70(m, 1H)1.46-1.57(m, 2H)1.40(t, J =7.1Hz, 3H)1.11(s, 3H)1.06(s, 3H); GCMS (261).

Intermediate 25 (+/-) -4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl ] -benzoic acid ethyl ester

Reacting (+/-) -4- [ amino- (3, 3-dimethyl-cyclobutyl) -methyl]Ethyl benzoate (intermediate 24) (45mg, 0.17mmol) was combined with 3-methylquinoline-N-oxide (27.4mg, 0.172mmol, Alfa Aesar, Ward Hill, MA, USA) and dichloromethane (2 mL). Diisopropylethylamine (0.112mL, 0.645mmol) was added followed by the addition of trispyrrolidinylphosphonium bromide hexafluorophosphate (109mg, 0.224 mmol). The solution was stirred at room temperature for 28h, then in ethyl acetate and saturated NaHCO₃The aqueous solution was partitioned. The separated aqueous layer was extracted with additional ethyl acetate and the combined organics were over MgSO₄And (5) drying. Purification by flash chromatography on silica gel (ethyl acetate/heptane) to yield (+/-) -4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl]Ethyl benzoate (44.0mg) as a clear oil.¹HNMR(400MHz，CDCl₃) δ 7.96(d, J =8.4Hz, 2H)7.56-7.62(m, 2H)7.46-7.53(m, 3H)7.38-7.46(m, 1H)7.12-7.20(m, 1H)5.33(dd, J =9.5, 6.7Hz, 1H)4.77(d, J =6.6Hz, 1H)4.34(q, J =7.2Hz, 2H)2.67 (sextuple peak, J =8.8Hz, 1H)2.30(s, 3H)1.97(ddd, J =11.1, 8.1, 3.2Hz, 1H)1.74-1.85(m, 1H)1.66-1.73(m, 2H)1.36(t, J =7.1, 3H)1.16 (m,2H) 1.36(t, 3H)1.10(s, 3H)1.10 Hz; MS (M +1): 403.3.

Intermediate 26 (+/-) -4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl ] -benzoic acid

The (+/-) -4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinoline-2-ylamino) -methyl]Ethyl benzoate (intermediate 25) (43mg, 0.11mmol) was dissolved in tetrahydrofuran (3mL) and methanol (1mL), and 1.0M NaOH (2mL) was added. It was stirred at 50 ℃ for 4h, first as a suspension and then as a clear solution, and then cooled to room temperature. 1N HCl was added until the solution was pH 5. It was extracted 2 times with ethyl acetate and the combined organics were then over MgSO₄And (5) drying. The solution was concentrated in vacuo to give (+/-) -4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl]Benzoic acid (37.7mg) as a white solid. MS (M +1): 375.1.

Intermediate 27 (+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid ethyl ester

(+/-) -4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl]-benzoic acid (intermediate 26) (37mg, 0.099mmol) was combined with 1-hydrobenzotriazole hydrate (23.0mg, 0.149mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (29.0mg, 0.149mmol) and beta-alanine ethyl ester hydrochloride (18.0mg, 0.119 mmol). Anhydrous dichloromethane (5mL) was added followed by triethylamine (0.027mL, 0.198 mmol). The solution was stirred at room temperature for 3d and then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The separated aqueous layer was extracted with ethyl acetate and the combined organics were passed over MgSO₄And (5) drying. Purification by flash chromatography on silica gel (ethyl acetate/heptane) to yield (+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl]-benzoylamino } -propionic acid ethyl ester (37.9mg) as a clear oil.¹H NMR(400MHz，CDCl₃)δ7.68(d，J=8.2Hz，2H)7.59(t，J=3.9Hz，2H)7.46-7.52(m，3H)7.37-7.45(m，1H)7.11-7.19(m，1H)6.75(t，J=5.8Hz，1H)5.32(dd，J=9.7，6.7Hz，1H)4.75(d，J=6.6Hz，1H)4.10-4.21(m，2H)3.70(q，J=6.0Hz，2H)2.55-2.74(m，3H)2.29(s，3H)1.96(ddd，J=11.1，8.2，2.9Hz，1H)1.75-1.84(m，1H)1.64-1.73(m，2H)1.26(m，3H)1.16(s，3H)1.09(s，3H)；MS(M+1):474.7。

Intermediate 28: 6-fluoro-3-methyl-quinoline

(4-fluoro-phenyl) -carbamic acid tert-butyl ester (2.11g, 10.0mmol, ABCR, Karlsruhe, Germany) was added to a round bottom flask and purged with nitrogen. Anhydrous tetrahydrofuran (200mL) was added to dissolve the solids and the flask was placed in a dry ice/acetone bath (internal temperature-74 ℃ uncorrected). Addition of tert-butyllithium (1.7M in pentane, 14.2mL, 24.0mmol) over 5 minutes resulted in the formation of a yellow color. After the addition was complete, the reaction was stirred in a-20 ℃ bath for 1 h. At this point, 3-ethoxymethacrolein (1.43mL, 12.0mmol) was added dropwise over 5 minutes, maintaining the temperature below-19 ℃. The reaction was stirred at-20 ℃ for 2h, then trifluoroacetic acid (14mL) was added slowly over 5 minutes. The red solution was stirred at room temperature for 16h and then brought to pH12 with 1N NaOH. It was extracted 2 times with ethyl acetate and the combined organics were over MgSO₄And (5) drying. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave the impure desired material. It was extracted into three portions of 1N HCl, the combined aqueous layers were brought to pH12 with 6N NaOH, and then extracted into two portions of ethyl acetate. The combined organics were over MgSO₄Dried and concentrated in vacuo to give 6-fluoro-3-methyl-quinoline (48.0mg) as an orange oil.¹H NMR(400MHz，CDCl₃)δ8.74(s，1H)8.07(dd，J=9.1，5.4Hz，1H)7.88(s，1H)7.33-7.46(m，2H)2.53(s，3H)；MS(M+1):162.1。

Intermediate 29 6-fluoro-3-methyl-quinoline 1-oxide

6-fluoro-3-methyl-quinoline (intermediate 28) (48.0mg, 0.298mmol) was dissolved in acetic acid (1mL) and 30% H was added₂O₂Aqueous solution (0.040mL, 0.396 mmol). It was stirred at 80 ℃ for 16h and then cooled. A few mL of 10% Na were added₂SO₃The aqueous solution was then added with a spoon of the spiked sodium iodide. It was stirred for 10min then in ethyl acetate and saturated NaHCO₃And (6) distributing. The separated aqueous layer was extracted with ethyl acetate and the combined organics were over MgSO₄And (5) drying. Purification by flash chromatography on silica gel (methanol/ethyl acetate) afforded 6-fluoro-3-methyl-quinoline 1-oxide (29.4mg) as a white solid.¹H NMR(400MHz，CDCl₃)δ8.72(dd，J=9.4，5.3Hz，1H)8.38(s，1H)7.36-7.50(m，3H)2.46(s，3H)；MS(M+1):178.1。

Intermediate 30: 3-bromo-7-fluoro-quinoline

6-Fluoroindole (500mg, 3.70mmol) was combined with benzyltriethylammonium chloride (44.4mg, 0.185mmol) and toluene (0.32mL) was added. Bromoform (0.342mL, 3.70mmol) was added and the temperature was brought to 40 ℃. A solution of NaOH (1.110g, 7.50mmol) in water (2.22mL) was then added over 15 minutes. This results in a very dark color. The reaction was stirred as a biphasic mixture at 40 ℃ for 16h, then cooled and partitioned between ethyl acetate and water. The separated aqueous layer was extracted with ethyl acetate and the combined organics were passed over MgSO₄And (5) drying. Purification by flash chromatography on silica gel (ethyl acetate/heptane) gave 3-bromo-7-fluoro-quinoline (171.9mg) as a white solid.¹H NMR(400MHz，CDCl₃)δ8.93(d，J=2.1Hz，1H)8.33(d，J=2.0Hz，1H)7.68-7.82(m，2H)7.39(td，J=8.6，2.5Hz，1H)；MS(M+1):226.0。

Intermediate 31: 7-fluoro-3-methyl-quinoline

3-bromo-7-fluoro-quinoline (intermediate 30) (100mg, 0.442mmol) with K₂CO₃(153mg, 1.10mmol), dry 1, 4-dioxane (3mL) and trimethylcyclotriboroxane (0.092mL, 0.663mmol) were combined. Nitrogen bubbling to degas the reaction and Pd (PPh) was added₃)₄(50.9mg, 0.044 mmol). It was degassed again and then heated to 90 ℃ for 5 h. The reaction was cooled and washed with ethyl acetate and saturated NaHCO₃And (4) distributing in an aqueous solution. The separated aqueous layer was extracted with ethyl acetate and the combined organics were passed over MgSO₄And (5) drying. Purification by flash chromatography on silica gel (ethyl acetate/heptane) afforded 7-fluoro-3-methyl-quinoline (52.7mg) as a yellow solid.¹H NMR(400MHz，CDCl₃)δ8.78(d，J=1.8Hz，1H)7.93(s，1H)7.65-7.79(m，2H)7.32(td，J=8.6，2.5Hz，1H)2.52(s，3H)；MS(M+1):162.1。

Intermediate 32 Ethyl 4- (3, 3-dimethylcyclobutanecarbonyl) benzoate

Ethyl 4-iodobenzoate (25.0g, 89.0mmol) contained in anhydrous tetrahydrofuran (148mL) in a three-necked flask at-30 deg.C (monitored by thermocouple), and isopropyl magnesium chloride (51.0mL,20.4mmol) was added dropwise over 30 min. Then stirred at the same temperature for another 105 min. Then copper iodide (5.07g, 26.6mmol) was added in one portion quickly. The mixture was held at-20 ℃ for 25min to ensure that the solids had dissolved. The reaction was then returned to-40 ℃.3, 3-dimethylcyclobutanecarbonyl chloride (15.6g, 106mmol) was then added over 5 min. Then warm reaction to 0 ℃ over 4 h. The mixture was then diluted with 1N HCl and extracted 3 times with ethyl acetate. The combined organic layers were then washed 2 times with brine and then dried over sodium sulfate, filtered and concentrated to provide 26.6g of a crude brown oil. Purification by flash chromatography on silica gel twice (0-5% ethyl)Ethyl acetate in heptane) gave ethyl 4- (3, 3-dimethylcyclobutanecarbonyl) benzoate (17.2g, 74% yield) as an oil.¹H NMR(400MHz，CDCl₃δ) 8.11(d, J =8.2Hz, 2H), 7.93(d, J =8.2Hz, 2H), 4.40(q, J =7.2Hz, 2H), 3.89 (quintuple peak, J =8.8Hz, 1H), 2.27-2.14(m, 2H), 2.12-2.02(m, 2H), 1.41(t, J =7.1Hz, 3H), 1.27(s, 3H), 1.08(s, 3H). MS (M +1): 261.2.

Intermediate 33:4- (3, 3-dimethylcyclobutanecarbonyl) benzoic acid

To a flask containing ethyl 4- (3, 3-dimethylcyclobutanecarbonyl) benzoate (3.00g, 12.0mmol) were added anhydrous tetrahydrofuran (28.8mL), methanol (28.8mL), and 1N sodium hydroxide (28.8mL, 28.8 mmol). After 1h, the reaction was concentrated to a white solid. The solid was redissolved in 700mL of water. With vigorous stirring, 1N HCl (29.0mL) was added dropwise and the suspension was stirred at room temperature for 30 min. The solid was then collected with a buchner funnel and washed 2 times with water. The solid was then azeotroped with toluene to give 4- (3, 3-dimethylcyclobutanecarbonyl) benzoic acid (2.15g, 92% yield) as a white solid.¹H NMR(400MHz，CDCl₃δ 8.21-8.15(m, 2H), 8.01-7.94(m, 2H), 3.91 (quintuple, J =8.9Hz, 1H), 2.28-2.17(m, 2H), 2.15-2.04(m, 2H), 1.28(s, 3H), 1.09(s, 3H). MS (M-1): 231.4.

Intermediate 34 tert-butyl 4- (3, 3-dimethylcyclobutanecarbonyl) benzoate

To a flask containing 4- (3, 3-dimethylcyclobutanecarbonyl) benzoic acid (1.89g, 8.14mmol) in anhydrous dichloromethane (20.3mL) was added 2-Tert-butyl-1, 3-diisopropylurea (6.28g, 31.3 mmol). The reaction was refluxed for 24 h. The reaction was then diluted with dichloromethane and quenched with saturated sodium bicarbonate solution. The aqueous layer was extracted three times with chloroform. The combined organic layers were washed with brine and dried over sodium sulfate, filtered, and concentrated to give 3.09g of a crude oil. Purification by flash chromatography on silica gel (0-10% ethyl acetate in heptane) afforded tert-butyl 4- (3, 3-dimethylcyclobutanecarbonyl) benzoate (1.33g, 57% yield) as a white solid.¹H NMR(400MHz，CDCl₃，δ):8.08-8.02(m，2H)，7.94-7.88(m，2H)，3.89(quin，J=8.8Hz，1H)，2.24-2.16(m，2H)，2.11-2.02(m，2H)，1.62-1.59(m，9H)，1.27(s，3H)，1.08(s，3H)。MS(M+1):289.3。

Intermediate 35 tert-butyl 4- (amino (3, 3-dimethylcyclobutyl) methyl) benzoate

To a solution of tert-butyl 4- (3, 3-dimethylcyclobutanecarbonyl) benzoate (1.46g, 5.06mmol) and ammonium acetate (3.98g, 50.6mmol) in dry methanol (25.3mL) was added sodium cyanoborohydride (502mg, 7.60 mmol). The reaction was heated at 60 ℃ for 18 h. The reaction was then cooled to room temperature and 1N hydrochloric acid (18.6mL) was added dropwise. The clear colorless solution turned cloudy white. The mixture was stirred for 1 h. The remaining methanol was removed and 1N sodium hydroxide (32.0mL) was added slowly. The mixture was extracted 3 times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 1.62g of an oil. Purification by flash chromatography on silica gel (30-100% ethyl acetate in heptane) afforded tert-butyl 4- (amino (3, 3-dimethylcyclobutyl) methyl) benzoate (860mg, 59% yield) as an oil.¹H NMR(400MHz，CDCl₃，δ):7.92(d，J=8.4Hz，2H)，7.34(d，J=8.0Hz，2H)，3.80(d，J=9.2Hz，1H)，2.45-2.30(m，1H)，2.01-1.88(m，1H)，1.68-1.60(m，2H)，1.60-1.56(m，10H)，1.48(d，J=9.0Hz，2H)，1.10(s，3H)，1.05(s，3H)。MS(M+1):290.2。

Intermediate 36 3-bromo-6-fluoroquinoline

To a solution of 5-fluoroindole (2.00g, 14.8mmol) and benzyltriethylammonium chloride (168.5mg, 0.740mmol) in toluene (3.00mL) and tribromomethane (3.00mL) at 40 deg.C was added a solution of sodium hydroxide (4.44g, 111mmol) in water (12.0mL) dropwise. The reaction was then stirred at 40 ℃ for 48 h. After cooling, the solvent was evaporated and the residue was diluted with methyl tert-butyl ether (100mL) and water (100 mL). The aqueous layer was extracted with methyl tert-butyl ether. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 2.00g of crude material. Purification by silica gel flash chromatography (0-2% ethyl acetate in petroleum ether) afforded 3-bromo-6-fluoroquinoline (503mg, 15% yield) as a white solid.¹H NMR(400MHz，CD₃OD，δ):8.87(d，J=2.0Hz，1H)，8.27(d，J=2.0Hz，1H)，8.08(dd，J=9.2，5.6Hz，1H)，7.52-7.41(m，1H)，7.35(dd，J=8.8，2.8Hz，1H)。(M+1):225.6。

Intermediate 37 tert-butyl 4- ((3, 3-dimethylcyclobutyl) (7-fluoroquinolin-3-ylamino) methyl) benzoate

Containing chlorine (2-dicyclohexylphosphino-3, 6-dimethoxy-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl) [2- (2-aminoethyl) phenyl group]To a solution of palladium (II) (11.2mg, 0.0140mmol) and (intermediate 30) 3-bromo-7-fluoroquinoline (65.6mg, 0.290mmol) were added anhydrous tetrahydrofuran (1.00mL) and a solution of tert-butyl 4- (amino (3, 3-dimethylcyclobutyl) methyl) benzoate (80.0mg, 0.280mmol) in anhydrous tetrahydrofuran (0.380 mL). Lithium Hexamethyldisilazide (bis) was added dropwiseLithium (trimethylsilyl) amide) (0.690mL, 0.690mmol, 1M in THF). The clear pale yellow solution turned green, yellow, then brown. The reaction was heated at 65 ℃ for 18 h. The reaction was then cooled to room temperature and diluted with water and extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 138mg of a brown oil. Purification by silica gel flash chromatography (0-30% ethyl acetate in heptane) afforded tert-butyl 4- ((3, 3-dimethylcyclobutyl) (7-fluoroquinolin-3-ylamino) methyl) benzoate (12.0mg, 10% yield) as a brown oil.¹H NMR(400MHz，CDCl₃，δ):8.55-8.48(m，1H)，7.97-7.90(m，2H)，7.59-7.52(m，1H)，7.42(d，J=8.4Hz，2H)，7.40-7.33(m，1H)，7.14(td，J=8.7，2.7Hz，1H)，6.71(d，J=2.7Hz，1H)，4.24(dd，J=9.1，4.2Hz，1H)，2.53(q，J=8.8Hz，1H)，2.08-1.98(m，1H)，1.72(t，J=9.7Hz，2H)，1.67-1.59(m，1H)，1.57(s，9H)，1.13(s，3H)，1.09(s，3H)。MS(M+1):435.3。

Intermediate 38- ((3, 3-dimethylcyclobutyl) (7-fluoroquinolin-3-ylamino) methyl) benzoic acid

To a vial of tert-butyl 4- ((3, 3-dimethylcyclobutyl) (7-fluoroquinolin-3-ylamino) methyl) benzoate (12.0mg, 0.0280mmol) were added dichloromethane (0.140mL) and trifluoroacetic acid (0.140mL, 0.0280 mmol). The reaction was stirred at room temperature for 1.5 h. The mixture was concentrated and azeotroped with toluene to give crude 4- ((3, 3-dimethylcyclobutyl) (7-fluoroquinolin-3-ylamino) methyl) benzoic acid (11mg, 99% yield) as an oil. (M +1): 379.2.

Intermediate 39 Ethyl 3- (4- ((3, 3-dimethylcyclobutyl) (7-fluoroquinolin-3-ylamino) methyl) benzoylamino) propionate

To a vial containing 4- ((3, 3-dimethylcyclobutyl) (7-fluoroquinolin-3-ylamino) methyl) benzoic acid (11.0mg, 0.0290mmol) were added ethyl 3-aminopropionate hydrochloride (4.90mg, 0.0320mmol), 1-hydroxy-7-azabenzotriazole (4.80mg, 0.0350mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (6.70mg, 0.0350 mmol). Anhydrous dichloromethane (0.290mL) was added followed by triethylamine (0.005mL, 0.0380 mmol). After 2h, the reaction was diluted with dichloromethane and quenched with a saturated solution of ammonium chloride. The aqueous layer was extracted three times with chloroform. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 16.0mg of crude material. Purification by silica gel flash chromatography (0-70% ethyl acetate in heptane) gave ethyl 3- (4- ((3, 3-dimethylcyclobutyl) (7-fluoroquinolin-3-ylamino) methyl) benzoylamino) propionate (6.20mg, 45% yield) as a yellow solid.¹HNMR(400MHz，CDCl₃δ):8.50(d, J =2.3Hz, 1H), 7.75-7.68(m, 2H), 7.54(dd, J =9.9, 2.5Hz, 1H), 7.45-7.41(m, 2H), 7.38(dd, J =9.1, 6.0Hz, 1H), 7.14(td, J =8.7, 2.7Hz, 1H), 6.80(t, J =5.9Hz, 1H), 6.70(d, J =2.7Hz, 1H), 4.40(s, 1H), 4.23(dd, J =9.4, 4.1Hz, 1H), 4.20-4.08(m, 2H), 3.70(q, J =6.2Hz, 2H), 2.62(t, J =6.0Hz, 2H), 2.52 (six-fold = 8.19H), 1.09 (1H), 3.70 (dd, 1H), 1H =6.0, 1H), 3.09 (1H, 1H), 2.13.13.13H, 1H), 3.09 (dd, 1H). (M +1): 478.3.

Intermediate 40 tert-butyl 4- ((3, 3-dimethylcyclobutyl) (6-fluoroquinolin-3-ylamino) methyl) benzoate

To a solution containing 2- (dicyclohexylphosphino) -3, 6-dimethoxy-2 '-4' -6 '-triisopropyl-1, 1' -biphenyl (16.3mg, 0.0300mmol) and chlorine (2-dicyclohexylphosphino-3, 6)-dimethoxy-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl) [2- (2-aminoethyl) phenyl]To a solution of palladium (II) (25.0mg, 0.0300mmol) and 3-bromo-6-fluoroquinoline (164mg, 0.670mmol) were added anhydrous tetrahydrofuran (6.00mL) and tert-butyl 4- (amino (3, 3-dimethylcyclobutyl) methyl) benzoate (175mg, 0.600 mmol). The mixture was warmed gently and then potassium tert-butoxide (150mg, 1.30mmol) was added as a solid. The reaction was heated at reflux for 18 h. The reaction was then cooled to room temperature and quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 401mg of a red oil. Purification by flash chromatography on silica gel (0-50% ethyl acetate in heptane) gave tert-butyl 4- ((3, 3-dimethylcyclobutyl) (6-fluoroquinolin-3-ylamino) methyl) benzoate (14.0mg, 5.3% yield) as a brown oil.¹H NMR(400MHz，CDCl₃，δ):8.43(s，1H)，7.97-7.92(m，2H)，7.86(dd，J=9.1，5.8Hz，1H)，7.43-7.37(m，2H)，7.10(td，J=8.7，2.7Hz，1H)，7.01(dd，J=9.6，2.7Hz，1H)，6.61(d，J=2.5Hz，1H)，4.25(dd，J=9.3，4.6Hz，1H)，2.59-2.46(m，1H)，2.00(s，1H)，1.76-1.67(m，2H)，1.66-1.58(m，1H)，1.56(s，9H)，1.13(s，3H)，1.09(s，3H)。MS(M+1):435.3。

Intermediate 41- ((3, 3-dimethylcyclobutyl) (6-fluoroquinolin-3-ylamino) methyl) benzoic acid

To a flask of tert-butyl 4- ((3, 3-dimethylcyclobutyl) (6-fluoroquinolin-3-ylamino) methyl) benzoate (13.0mg, 0.0300mmol) were added anhydrous dichloromethane (0.150mL) and trifluoroacetic acid (0.150mL, 0.0300 mmol). The reaction was stirred at room temperature for 1 h. The mixture was concentrated and azeotroped with toluene to give crude 4- ((3, 3-dimethylcyclobutyl) (6-fluoroquinolin-3-ylamino) methyl) benzoic acid (11mg, 96% yield) as an oil. (M +1): 379.2.

Intermediate 42 Ethyl 3- (4- ((3, 3-dimethylcyclobutyl) (6-fluoroquinolin-3-ylamino) methyl) benzoylamino) propionate

To a vial containing 4- ((3, 3-dimethylcyclobutyl) (6-fluoroquinolin-3-ylamino) methyl) benzoic acid (11.0mg, 0.0290mmol) were added ethyl 3-aminopropionate hydrochloride (4.90mg, 0.0320mmol), 1-hydroxy-7-azabenzotriazole (4.80mg, 0.0350mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (6.70mg, 0.0350 mmol). Anhydrous dichloromethane (0.290mL) was added followed by triethylamine (0.005mL, 0.0380 mmol). After 18h, the reaction was diluted with dichloromethane and quenched with a saturated solution of ammonium chloride. The aqueous layer was extracted three times with chloroform. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 28.6mg of crude material. Purification by silica gel flash chromatography (0-70% ethyl acetate in heptane) afforded ethyl 3- (4- ((3, 3-dimethylcyclobutyl) (6-fluoroquinolin-3-ylamino) methyl) benzoylamino) propionate (7.40mg, 54% yield) as an oil.¹HNMR(400MHz，CDCl₃，δ):7.86(s，1H)，7.72(d，J=8.2Hz，2H)，7.42(d，J=8.4Hz，2H)，7.14-7.06(m，1H)，7.05-6.96(m，1H)，6.80(t，J=5.9Hz，1H)，6.60(s，1H)，4.45(s，1H)，4.24(dd，J=9.3，4.4Hz，1H)，4.19-4.08(m，2H)，3.70(q，J=6.0Hz，2H)，2.62(t，J=6.0Hz，2H)，2.58-2.44(m，1H)，2.06-1.96(m，1H)，1.75-1.67(m，2H)，1.67-1.55(m，2H)，1.28-1.22(m，3H)，1.13(s，3H)，1.09(s，3H)。(M+1):478.3。

Intermediate 43 Ethyl 4- ((3, 3-dimethylcyclobutyl) (quinolin-3-ylamino) methyl) benzoate

A flask containing ethyl 4- (3, 3-dimethylcyclobutanecarbonyl) benzoate (397mg, 1.53mmol) was charged with toluene (13.9mL), quinolin-3-amine (200mg, 1.39mmol), and p-toluenesulfonic acid (26.8mg, 0.139 mmol). The reaction was refluxed with Dean-Stark for 24 h. The reaction was quenched with water and extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 508mg of crude material. To the crude material was added anhydrous methanol (6.47mL) and the solution was cooled to 0 ℃. Sodium borohydride (147mg, 3.88mmol) was then added. After 5h, the reaction was partially concentrated and quenched with saturated aqueous ammonium chloride. The reaction mixture was extracted three times with ethyl acetate. The combined organic layers were then dried over sodium sulfate, filtered and concentrated to give 560mg of crude material. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded ethyl 4- ((3, 3-dimethylcyclobutyl) (quinolin-3-ylamino) methyl) benzoate (17.0mg, 3.4% yield) as an oil.¹H NMR(400MHz，CDCl₃)δ:8.47(d，J=2.9Hz，1H)，8.03-7.97(m，2H)，7.90-7.86(m，1H)，7.46-7.42(m，2H)，7.42-7.30(m，3H)，6.69(d，J=2.7Hz，1H)，4.40-4.31(m，2H)，4.27(dd，J=9.2，4.3Hz，1H)，2.58-2.47(m，1H)，2.03(ddd，J=11.2，7.6，4.2Hz，1H)，1.79-1.67(m，2H)，1.67-1.55(m，1H)，1.36(t，J=7.1Hz，3H)，1.14(s，3H)，1.09(s，3H)。MS(M+1):389.3。

Intermediate 44- ((3, 3-dimethylcyclobutyl) (quinolin-3-ylamino) methyl) benzoic acid

To a flask containing ethyl 4- ((3, 3-dimethylcyclobutyl) (quinolin-3-ylamino) methyl) benzoate (17.0mg, 0.0440mmol) were added tetrahydrofuran (0.110mL), methanol (0.110mL), and 1N sodium hydroxide (0.110mL, 0.110 mmol). The reaction was stirred at room temperature for 18 h. The reaction was then diluted with ethyl acetate and water. 1N hydrochloric acid (0.110mL) was then added dropwise to bring the pH to 3. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfateFiltered and concentrated to provide 4- ((3, 3-dimethylcyclobutyl) (quinolin-3-ylamino) methyl) benzoic acid; (14.8mg, 93% yield) as a solid.¹H NMR(400MHz，CDCl₃)δ:8.67(br.s.，1H)，8.06(d，J=8.2Hz，2H)，7.96(d，J=7.4Hz，1H)，7.48(d，J=8.4Hz，2H)，7.46-7.32(m，3H)，6.76(d，J=2.5Hz，1H)，4.30(d，J=9.4Hz，1H)，2.62-2.50(m，1H)，2.10-1.98(m，1H)，1.80-1.69(m，2H)，1.69-1.58(m，1H)，1.14(s，3H)，1.09(s，3H)。MS(M+1):361.2。

Intermediate 45 Ethyl 3- (4- ((3, 3-dimethylcyclobutyl) (quinolin-3-ylamino) methyl) benzoylamino) propionate

To a vial containing 4- ((3, 3-dimethylcyclobutyl) (quinolin-3-ylamino) methyl) benzoic acid (14.0mg, 0.0390mmol) were added ethyl 3-aminopropionate hydrochloride (hydrochloric) (6.60mg, 0.0430mmol), 1-hydroxy-7-azabenzotriazole (6.40mg, 0.0470mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (9.00mg, 0.0470 mmol). Anhydrous dichloromethane (0.390mL) was added followed by triethylamine (0.007mL, 0.0510 mmol). After 18h, the reaction was diluted with dichloromethane and quenched with a saturated solution of ammonium chloride. The aqueous layer was extracted three times with chloroform. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 26.0mg of crude material. Purification by column chromatography (0-70% ethyl acetate in heptane) afforded ethyl 3- (4- ((3, 3-dimethylcyclobutyl) (quinolin-3-ylamino) methyl) benzoylamino) propionate (11.9mg, 66% yield) as an oil.¹HNMR(400MHz，CDCl₃)δ:8.48(d，J=2.7Hz，1H)，7.88(dd，J=8.3，1.3Hz，1H)，7.74-7.67(m，2H)，7.46-7.41(m，2H)，7.41-7.29(m，3H)，6.81(t，J=6.1Hz，1H)，6.69(d，J=2.7Hz，1H)，4.42(br.s.，1H)，4.25(dd，J=9.3，4.4Hz，1H)，4.19-4.08(m，2H)，3.70(q，J=6.0Hz，2H)，2.61(t，J=5.7Hz，2H)，2.59-2.45(m，1H)，2.07-1.97(m，1H)，1.76-1.67(m，2H)，1.66-1.55(m，1H)，1.28-1.21(m，3H)，1.13(s，3H)，1.09(m，3H)。MS(M+1):460.4。

Intermediate 46 Ethyl 4- (1-amino-3-methylbutyl) benzoate

A mixture of ethyl 4- (3-methyl-butyryl) -benzoate (2000mg, 8.536mM), ammonium acetate (6580mg, 85.4mM) and sodium cyanoborohydride (1070mg, 17.1mmol) in methanol (17.1mL) was heated to 60 ℃ for 6 h. Cooling the reaction with NH₄Cl solution (10 mL). MeOH was removed under reduced pressure. The aqueous solution was extracted with EtOAc (3 × 30 mL). The organic solution was separated and dried (Na)₂SO₄) And concentrated. The crude material was passed through a 40g HC silica gel column with 0-15% MeOH in DCM. The desired product was collected as a colorless oily substance (1560mg, 77.7%).¹H NMR(500MHz，CDCl₃)δppm0.91(dd，J=13.66，6.59Hz，6H)1.40(t，J=7.07Hz，3H)1.84-1.99(m，3H)4.27-4.42(m，3H)6.36(br.s.，2H)7.51(d，J=8.05Hz，2H)8.05(d，J=8.05Hz，2H)。GC:m/z235。

Intermediate 47 ethyl 4- [ 3-methyl-1- (8-methyl-quinolin-3-ylamino) -butyl ] -benzoate

To a reaction vial containing 4- (1-amino-3-methyl-butyryl) -benzoic acid ethyl ester (340mg, 1.5mM) was added DMSO (4.88mL), 3-bromo-8-methylquinoline (325mg, 1.46mM), followed by CuI catalyst (27.8mg, 0.146mM) and CsOAc (562mg, 2.93 mM). The mixture was purged with argon and the tube was sealed. The reaction mixture was heated to 100 ℃ for 24 h. The reaction mixture was cooled, diluted with EtOAc (10mL), then washed with water (3 × 5mL) and dried(Na₂SO₄) And concentrated. The crude material was isolated by 40g of silica gel using 0-50% EtOAc in heptane to afford the product as a yellow solid (62mg, 11%).¹H NMR(400MHz，CDCl₃)δppm0.95(d，J=6.25Hz，3H)1.00(d，J=6.25Hz，3H)1.35(t，3H)1.58-1.68(m，1H)1.68-1.84(m，2H)2.70(s，3H)4.33(q，2H)4.36-4.42(m，1H)4.44-4.54(m，1H)6.74(d，J=2.93Hz，1H)7.18-7.30(m，3H)7.43(d，J=8.39Hz，2H)8.00(d，2H)8.48(d，J=2.93Hz，1H)。LC-MS:m/z377.2(M+1)。

Intermediate 48 4- [ 3-methyl-1- (8-methyl-quinolin-3-ylamino) -butyl ] -benzoic acid

Reacting 4- [ 3-methyl-1- (8-methyl-quinolin-3-ylamino) -butyl]A mixture of ethyl benzoate (62mg, 0.16mM) and 1N aqueous NaOH solution (0.413mL, 0.413mM) in THF-MeOH (1:1, 3.3mL) was heated to 50 deg.C for 4 h. The reaction was cooled and concentrated to remove the organic solvent. The aqueous solution was diluted with DCM (5mL) and acidified to pH =3-4 by 1N HCl solution. The organic solution was separated and the aqueous solution was extracted with 10% i-PrOH-DCM (5X5 mL). Drying (Na)₂SO₄) The combined organic solutions were concentrated to give the product as a yellow solid (45.7mg, 79%).¹H NMR(400MHz，CD₃OD) δ ppm0.98(d, J =6.44Hz, 3H)1.03(d, J =6.25Hz, 3H)1.56-1.68(m, 1H)1.73-1.93(m, 2H)2.68(d, 3H)4.60-4.68(m, 1H)7.23-7.35(m, 2H)7.38(d, 1H)7.44(d, 1H)7.48-7.61(m, 2H)7.96(d, 2H)8.53(dd, 1H), two protons (COOH and NH) exchanged. The material can be used for the next step without further treatment.

Intermediate 49 methyl 3- {4- [ 3-methyl-1- (8-methyl-quinolin-3-ylamino) -butyl ] -benzoylamino } -propionate

To 4- [ 3-methyl-1- (8-methyl-quinolin-3-ylamino) -butyl]-benzoic acid (5) (45mg, 0.131mM) in DCM (1mL) was added TEA (66.3mg, 0.655mM), followed by 3-amino-propionic acid methyl ester hydrochloride (6) (27.5mg, 0.197mM) and then HBTU (59.5mg, 0.157 mM). The reaction was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc (5mL) and washed with water (2 × 2 mL). Separating the organic layer over Na₂SO₄Dried and concentrated. The crude material was isolated by a 12g silica gel column using 10-80% EtOAc in heptane to give the desired product (44mg, 77%).¹H NMR(500MHz，CDCl₃)δppm0.98(d，J=6.34Hz，3H)1.05(d，3H)1.62-1.71(m，1H)1.71-1.86(m，2H)2.62-2.67(m，2H)2.72(s，3H)3.67-3.79(m，5H)4.39(d，J=5.37Hz，1H)4.49-4.55(m，1H)6.76(d，J=2.44Hz，1H)6.77-6.85(m，1H)7.20-7.27(m，1H)7.28(s，1H)7.30(d，J=7.07Hz，1H)7.46(d，J=8.05Hz，2H)7.74(d，J=8.29Hz，2H)8.50(d，J=2.68Hz，1H)。LC-MS:m/z434.2(M+1)。

Intermediate 50 ethyl 4- [ 3-methyl-1- (7-methyl-quinolin-3-ylamino) -butyl ] -benzoate

To a reaction vial containing 4- (1-amino-3-methyl-butyryl) -benzoic acid ethyl ester (2) (440mg, 1.9mM) was added DMSO (6.33mL), 3-bromo-7-methylquinoline (9) (420mg, 1.9mM), followed by CuI catalyst (36mg, 0.19mM) and CsOAc (726mg, 3.78 mM). The mixture was purged with argon and the tube was then sealed. The reaction mixture was heated to 100 ℃ for 48 h. The reaction mixture was cooled, diluted with EtOAc (10mL), washed with water (3 × 5mL), dried (Na)₂SO₄) And concentrated. The crude material was taken up in 0-80% EtOAc in heptane and separated by 40g silica gel to give the yellow product (108mg, 15%).¹H NMR(500MHz，CDCl₃)δppm0.98(d，J=6.34Hz，3H)1.04(d，J=6.34Hz，3H)1.39(t，3H)1.61-1.71(m，1H)1.71-1.86(m，2H)2.46(s，3H)4.36(q，2H)4.38-4.43(m，1H)4.47-4.56(m，1H)6.75(d，J=1.95Hz，1H)7.20(d，J=8.29Hz，1H)7.36(d，J=8.05Hz，1H)7.47(d，J=8.29Hz，2H)7.69(s，1H)8.03(d，2H)8.47(br.s.，1H)。LC-MS:m/z377.2(M+1)。

Intermediate 51 4- [ 3-methyl-1- (8-methyl-quinolin-3-ylamino) -butyl ] -benzoic acid

Reacting 4- [ 3-methyl-1- (7-methyl-quinolin-3-ylamino) -butyl]A mixture of ethyl benzoate (48mg, 0.13mM) and 1N aqueous NaOH (0.318mL, 0.318mM) in THF-MeOH (1:1, 1.5mL) was heated to 50 ℃ for 5 h. The reaction was cooled and concentrated to remove the organic solvent. The aqueous solution was diluted with DCM (5mL) and acidified with 1N HCl solution pH = 3-4. The organic solution was separated and the aqueous solution was extracted with DCM (3 × 5 mL). Drying (Na)₂SO₄) The combined organic solutions were concentrated to give the product as a yellow solid (44mg, 100%).¹H NMR(400MHz，CD₃OD) δ ppm0.97(d, J =6.44Hz, 3H)1.02(d, J =6.44Hz, 3H)1.54-1.67(m, 1H)1.73-1.91(m, 2H)2.43(s, 3H)4.57-4.65(m, 1H)7.14(d, J =2.54Hz, 1H)7.28(dd, J =8.49, 1.27Hz, 1H)7.46-7.58(m, 4H)7.97(d, 2H)8.44(d, J =2.34Hz, 1H), two protons (COOH and NH) exchanged. LC-MS: M/z349.1(M + 1). The material can be used for the next step without further treatment.

Intermediate 52 methyl 3- {4- [ 3-methyl-1- (7-methyl-quinolin-3-ylamino) -butyl ] -benzoylamino } -propanoate

To 4- [ 3-methyl-1- (7-methyl-quinolin-3-ylamino) -butyl]To a solution of benzoic acid (44mg, 0.13mM) in DCM (1mL) was added TEA (63.6mg, 0).629mM), then 3-amino-propionic acid methyl ester hydrochloride (6) (26.4mg, 0.189mM) and then HBTU (57.3mg, 0.151mM) are added. The reaction was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc (5mL) and washed with water (2 × 2 mL). Separating the organic layer over Na₂SO₄Dried and concentrated. The crude material was separated by a 12g silica gel column with 10-100% EtOAc in heptane to provide the desired product (49mg, 90%).¹H NMR(500MHz，CDCl3)δppm0.98(d，J=6.10Hz，3H)1.04(d，J=6.34Hz，3H)1.61-1.70(m，1H)1.71-1.86(m，2H)2.66(t，2H)2.82(s，3H)3.68-3.76(m，5H)4.36(d，J=4.88Hz，1H)4.44-4.54(m，1H)6.73(d，J=2.20Hz，1H)6.80(t，J=5.49Hz，1H)7.20(d，J=8.29Hz，1H)7.35(d，J=8.54Hz，1H)7.45(d，J=8.29Hz，2H)7.67(s，1H)7.75(d，2H)8.45(d，J=2.44Hz，1H)。LC-MS:434.2(M+1)。

Intermediate 53 3-bromo-6-methylquinoline

6-methylquinoline (1.9906g, 13.903mmol) was dissolved in 20mL of carbon tetrachloride. Bromine (0.72mL, 14mmol) was added dropwise to the reaction solution and the suspension was heated to reflux (80 deg.C). Pyridine (1.15mL, 13.9mmol) was added while the reaction was heated to 80 ℃ and the reaction was stirred at reflux for 1.5 h. The reaction was cooled to room temperature and diluted with dichloromethane. The reaction was washed with water and the organics were dried over sodium sulfate, filtered and concentrated to give a thick brown oil, which solidified on standing. The crude solid was purified over an 80g silica gel ISCO column, eluting with a very low gradient: 0% to 15% to 20% ethyl acetate (ethyl acetate) in heptane to give the desired 3-bromo-6-methylquinoline.¹H NMR(400MHz，CDCl₃) δ ppm2.52(s, 3H)7.47(s, 1H)7.54(dd, J =8.59, 1.95Hz, 1H)7.95(d, J =8.59Hz, 1H)8.19(d, J =2.15Hz, 1H)8.81(d, J =2.34Hz, 1H). GCMS =221 at 2.93 minutes.

Intermediate 54 Ethyl (+/-) -4- (4,4, 4-trifluoro-1-hydroxybutyl) benzoate

To a solution of ethyl 4-iodobenzoate (1.21ml, 7.24mmol) in tetrahydrofuran (12ml) was added dropwise isopropyl magnesium chloride lithium chloride complex (6.13ml, 7.97mmol, 1.3M in tetrahydrofuran) at-40 ℃. The mixture was stirred for about 1 hour, followed by dropwise addition of 4,4, 4-trifluorobutanal (0.761ml, 0.724 mmol). The mixture was stirred at-40 ℃ for 15 minutes and slowly warmed to ambient temperature over 12 hours. The reaction was quenched with 1.0M aqueous hydrochloric acid and the aqueous layer was extracted with ethyl acetate (3 ×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give ethyl (+/-) -4- (4,4, 4-trifluoro-1-hydroxybutyl) benzoate, which was used without purification.

Intermediate 55 Ethyl (+/-) -4- (4,4, 4-trifluoro-1- ((methylsulfonyl) oxy) butyl) benzoate

To a solution of ethyl (+/-) -4- (4,4, 4-trifluoro-1-hydroxybutyl) benzoate (264mg, 0.956mmoL) in tert-butyl methyl ether (4.8mL) was added triethylamine (0.201mL, 1.43mmoL) followed by methanesulfonyl chloride (0.091mL, 1.15 mmoL). The resulting mixture was stirred for 1 hour. The reaction mixture was then diluted with tert-butyl methyl ether (25mL) and washed with water (15mL), saturated aqueous sodium bicarbonate (15mL), then saturated aqueous sodium chloride (15 mL). The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give ethyl (+/-) -4- (4,4, 4-trifluoro-1- ((methylsulfonyl) oxy) butyl) benzoate. This material was used without further purification.¹HNMR(400MHz，CDCl₃)δ8.12(d，J=8.4Hz，2H)，7.48(d，J=8.2Hz，2H)，5.63(dd，J=7.9，4.8Hz，1H)，4.41(q，J=7.0Hz，2H)，2.77(s，3H)，2.39-2.08(m，4H)，1.41(t，J=7.1Hz，3H)。

Intermediate 56 Ethyl (+/-) -4- (4,4, 4-trifluoro-1- (quinolin-3-ylamino) butyl) benzoate

To a solution of ethyl (+/-) -4- (4,4, 4-trifluoro-1- ((methylsulfonyl) oxy) butyl) benzoate (123mg, 0.347mmoL) in acetonitrile (1.74mL) was added 3-aminoquinoline (60.6mg, 0.416mmoL) followed by potassium phosphate (155mg, 0.694 mmoL). The resulting mixture was heated to 60 ℃ for 20 hours. The reaction mixture was cooled to room temperature, diluted with water (20mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel (ethyl acetate/heptane) gave ethyl (+/-) -4- (4,4, 4-trifluoro-1- (quinolin-3-ylamino) butyl) benzoate.¹H NMR(400MHz，CDCl₃)δ8.51(d，J=2.5Hz，1H)，8.06(d，J=8.4Hz，2H)，7.92(d，J=7.8Hz，1H)，7.50-7.44(m，3H)，7.44-7.35(m，2H)，6.81(d，J=2.5Hz，1H)，4.62-4.54(m，1H)，4.44-4.33(m，3H)，2.36-2.10(m，4H)，1.38(t，J=7.1Hz，3H)。

Intermediate 57 (+/-) -4- (4,4, 4-trifluoro-1- (quinolin-3-ylamino) butyl) benzoic acid

To a solution of ethyl (+/-) -4- (4,4, 4-trifluoro-1- (quinolin-3-ylamino) butyl) benzoate (95mg, 0.24mmol) in methanol (1.2mL) and tetrahydrofuran (1.2mL) was added a 1N aqueous solution of sodium hydroxide (1.2mL, 1.2 mmol). After 17 hours, the solution was concentrated under reduced pressure to remove methanol and tetrahydrofuran. The mixture was then acidified to pH5 with 1N aqueous hydrochloric acid and washed with waterSaturated aqueous sodium chloride (20 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give (+/-) -4- (4,4, 4-trifluoro-1- (quinolin-3-ylamino) butyl) benzoic acid.¹HNMR(400MHz，CD₃OD)δ8.50(br.s，1H)，8.02(d，J=8.2Hz，2H)，7.80-7.73(m，1H)，7.57(d，J=8.2Hz，2H)，7.53-7.47(m，1H)，7.40-7.32(m，2H)，6.95(d，J=2.5Hz，1H)，4.73-4.64(m，1H)，2.55-2.39(m，1H)，2.39-2.22(m，1H)，2.22-2.04(m，2H)。

Intermediate 58 Ethyl (+/-) -3- (4- (4,4, 4-trifluoro-1- (quinolin-3-ylamino) butyl) benzoylamino) propionate

To a suspension of (+/-) -4- (4,4, 4-trifluoro-1- (quinolin-3-ylamino) butyl) benzoic acid (74.0mg, 0.200mmol), beta-alanine ethyl ester hydrochloride (96.0mg, 0.594mmol), and 1-hydroxybenzotriazole hydrate (80%, 20% by weight water, 100mg, 0.594mmol) in dichloromethane (2mL) was added triethylamine (0.250mL, 1.78mmol) followed by N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (96.3mg, 0.495mmol), and the solution was stirred at room temperature for 19 hours. The reaction mixture was diluted with dichloromethane (15mL) and washed with water (3 × 15mL) then saturated aqueous sodium chloride (10 mL). The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel (ethyl acetate/heptane) gave ethyl (+/-) -3- (4- (4,4, 4-trifluoro-1- (quinolin-3-ylamino) butyl) benzoylamino) propionate.¹H NMR(400MHz，CDCl₃)δ8.69-8.59(m，1H)，7.96(d，J=7.6Hz，1H)，7.78(d，J=8.2Hz，2H)，7.52-7.46(m，3H)，7.46-7.37(m，2H)，6.88-6.79(m，2H)，4.61-4.52(m，1H)，4.16(q，J=7.0Hz，2H)，3.72(q，J=6.1Hz，2H)，2.63(t，J=5.9Hz，2H)，2.37-2.08(m，4H)，1.26(t，J=7.1Hz，4H)。

Intermediate 59 tert-butyl 4- (3-methylbutyryl) benzoate

To a slurry of 4- (3-methylbutyryl) benzoic acid (499mg, 2.42mmoL) in dichloromethane (6mL) was added O-tert-butyl-N, N' -diisopropylisourea (1.82g, 9.07 mmoL). The mixture was stirred at room temperature for 50 hours, then washed with tert-butyl methyl ether (75 mL). The mixture was washed with saturated aqueous sodium bicarbonate (50mL) over anhydrous Na₂SO₄Dried and filtered, and the filtrate concentrated. Purification by silica gel flash chromatography (ethyl acetate/heptane) afforded tert-butyl 4- (3-methylbutyryl) benzoate as a colorless oil.¹H NMR(400MHz，CDCl₃)δ8.09-8.04(m，2H)，8.00-7.94(m，2H)，2.86(d，J=6.8Hz，2H)，2.37-2.23(m，1H)，1.62(s，9H)，1.01(d，J=6.7Hz，6H)。

Intermediate 60 tert-butyl (+/-) -4- (1-amino-3-methylbutyl) benzoate

To a solution of tert-butyl 4- (3-methylbutyryl) benzoate (500mg, 1.91mmoL) and ammonium acetate (1.50g, 19.1mmoL) in methanol (9.5mL) was added sodium cyanoborohydride (189mg, 2.86 mmoL). The mixture was heated to 60 ℃ for 21 hours and then cooled to room temperature. 1N hydrochloric acid (7mL) was added dropwise. After 1 hour, the mixture was concentrated under reduced pressure to remove methanol. 1N sodium hydroxide (10mL) was added and the mixture was extracted with dichloromethane (3X25 mL). The combined organics were washed with saturated aqueous sodium chloride (15mL) and over anhydrous Na₂SO₄Dried and filtered, and the filtrate concentrated. Purification by flash chromatography on silica gel (methanol/dichloromethane) gave tert-butyl (+/-) -4- (1-ammonia3-methylbutyl) benzoate as a colorless oil.¹H NMR(400MHz，CDCl₃)δ7.99-7.94(m，2H)，7.41-7.37(m，2H)，4.08-4.01(m，1H)，1.60(s，9H)，1.59-1.43(m，3H)，0.92(d，J=6.5Hz，3H)，0.90(d，J=6.3Hz，3H)。

Intermediate 61 tert-butyl (+/-) -4- (3-methyl-1- ((3-methylquinolin-2-yl) amino) butyl) benzoate

To a solution of tert-butyl (+/-) -4- (3-methylbutyryl) benzoate (527mg, 2.00mmoL) and 3-methylquinoline N-oxide (318mg, 2.00mmoL) in dichloromethane (8.0mL) was added diisopropylethylamine (1.31mL, 7.50mmoL) followed by brominated tripyrrolidinyl hexafluorophosphate (1.18g, 2.50 mmoL). The solution was stirred at room temperature for 18 hours and then diluted with saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organics were passed over anhydrous Na₂SO₄Dried and filtered, and the filtrate concentrated. Purification by flash chromatography on silica gel (ethyl acetate/heptane) afforded tert-butyl (+/-) -4- (3-methyl-1- ((3-methylquinolin-2-yl) amino) butyl) benzoate as a white solid.¹HNMR(400MHz，CDCl₃)δ7.94(d，J=8.2Hz，2H)，7.63(d，J=8.2Hz，1H)，7.59(s，1H)，7.54-7.48(m，3H)，7.47-7.41(m，1H)，7.19-7.13(m，1H)，5.56(q，J=7.4Hz，1H)，4.73(d，J=7.0Hz，1H)，2.28(s，3H)，1.94-1.83(m，1H)，1.81-1.70(m，1H)，1.70-1.60(m，1H)，1.57(s，9H)，1.04(d，J=6.6Hz，3H)，0.97(d，J=6.6Hz，3H)。

Intermediate 62 (+/-) -4- (3-methyl-1- ((3-methylquinolin-2-yl) amino) butyl) benzoic acid trifluoroacetate

To a solution of tert-butyl (+/-) -4- (3-methyl-1- ((3-methylquinolin-2-yl) amino) butyl) benzoate (325mg, 0.803mmoL) in dichloromethane (8.0mL) was added trifluoroacetic acid (0.62mL, 8.0mmoL L). The solution was stirred at room temperature for 17 hours and then concentrated under reduced pressure. Toluene (3mL) was added and the solution was again concentrated under reduced pressure to remove excess trifluoroacetic acid to give (+/-) -4- (3-methyl-1- ((3-methylquinolin-2-yl) amino) butyl) benzoic acid trifluoroacetate as a white solid.¹H NMR(400MHz，CD₃OD)δ8.26(s，1H)，8.06(d，J=8.4Hz，2H)，7.84(d，J=7.8Hz，1H)，7.80-7.75(m，1H)，7.75-7.69(m，1H)，7.58(d，J=8.4Hz，2H)，7.55-7.48(m，1H)，5.50(dd，J=5.0，9.5Hz，1H)，2.56(s，3H)，2.24-2.14(m，1H)，1.92-1.75(m，2H)，1.08(d，J=6.4Hz，3H)，1.05(d，J=6.2Hz，3H)。

Intermediate 63 Ethyl 3- (4- (3-methyl-1- ((3-methylquinolin-2-yl) amino) butyl) benzoylamino) propionate, isomer 1 and isomer 2

(+/-) -4- (3-methyl-1- ((3-methylquinolin-2-yl) amino) butyl) benzoic acid trifluoroacetate (461mg, 1.00mmol), beta-alanine ethyl ester hydrochloride (645mg, 3.99mmol), and 1-hydroxybenzotriazole hydrate (80%, 20% by weight water, 674mg, 3.99mmol) were suspended in dichloromethane (10.0 mL). Triethylamine (1.40mL, 9.97mmol) was added followed by N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (776mg, 3.99mmol) and the solution was stirred at room temperature for 66 hours. The reaction mixture was diluted with dichloromethane (40mL), washed with water (3X30mL) and saturated aqueous NaCl (20mL), and washed with Na₂SO₄Dried and filtered, and the filtrate concentrated under reduced pressure. Flash chromatography on silica gel (ethyl acetate/heptane) followed by chiral SFC (Chiralpak AD-H column, 10mmx250cm, 25% methanol/carbon dioxide eluent,0.2% isopropylamine modifier) to ethyl 3- (4- (1- ((3-methylquinolin-2-yl) amino) butyl) benzoylamino) propionate, isomer 1 (analytical chiral sfc6.1min retention time) and 3- (4- (1- ((3-methylquinolin-2-yl) amino) butyl) benzoylamino) propionate as a mixture of methyl and ethyl esters, isomer 2 (analytical chiral sfc6.7min retention time). Ethyl ester:¹H NMR(400MHz，CDCl₃) δ 7.71(d, J =8.2Hz, 2H), 7.66-7.57(m, 2H), 7.56-7.48(m, 3H), 7.44(t, J =7.4Hz, 1H), 7.16(t, J =7.4Hz, 1H), 6.81-6.73(m, 1H), 5.60-5.52(m, 1H), 4.73(d, J =6.8Hz, 1H), 4.16(q, J =7.0Hz, 2H), 3.71(q, J =6.0Hz, 2H), 2.62(t, J =5.9Hz, 2H), 2.28(s, 3H), 1.93-1.82(m, 1H), 1.81-1.70(m, 1H), 1.69-1.60(m, 1H), 1.26(t = 7.2H), 1.04 (J = 3.6H), 3.04, 3H), d, 3H, 1H, 3H, 1.0 (d = 6H). Methyl ester:¹H NMR(400MHz，CDCl₃)δ7.71(d，J=8.2Hz，2H)，7.66-7.57(m，2H)，7.56-7.48(m，3H)，7.44(t，J=7.4Hz，1H)，7.16(t，J=7.3Hz，1H)，6.81-6.71(m，1H)，5.60-5.52(m，1H)，4.77-4.69(m，1H)，3.76-3.66(m，5H)，2.66-2.59(m，2H)，2.28(s，3H)，1.93-1.82(m，1H)，1.81-1.70(m，1H)，1.69-1.60(m，1H)，1.04(d，J=6.4Hz，3H)，0.97(d，J=6.4Hz，3H)。

intermediate 64 (+/-) -methyl 4- (1-hydroxybutyl) benzoate

A solution of methyl 4-iodobenzoate (151.3g, 565.8mmol) in tetrahydrofuran (908mL) was cooled to-30 ℃. To this solution was added dropwise a solution of isopropyl magnesium chloride (2M in tetrahydrofuran, 325.4mL, 650.7mmol) over 20 minutes. The reaction was stirred at-33 ℃ for 1 hour, then butyraldehyde (61.09mL, 679.0mmol) was added dropwise over 15 minutes. The reaction was warmed to 0 ℃. Methyl tert-butyl ether (1000mL) and citric acid solution (5wt% aq, 1000mL) were added and the mixture was stirred for 1 hour. The layers were separated and the organic phase was washed with water (500 mL). Combined aqueous phase is used asTert-butyl ether (250mL) was back-extracted. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to afford intermediate 64 as a yellow oil.¹H NMR(400MHz，CDCl₃，δ):7.97-8.02(m，2H)，7.40(d，J=8.4Hz，2H)，4.74(dd，J=7.8，5.7Hz，1H)，3.90(s，3H)，1.61-1.82(m，2H)，1.23-1.49(m，2H)，0.92(t，J=7.32Hz，3H)。

Intermediate 65 methyl 4-butyryl benzoate

To a solution of intermediate 64(129.5g, 565.9mmol) in dichloromethane (129.5mL) was added triethylamine (394.4mL, 2.83 moL). The solution was cooled to 10 ℃ and then a solution of sulfur trioxide pyridine complex (202.2g, 1.24mol) in dimethyl sulfoxide (777.0mL) was added slowly over 30 minutes, maintaining the internal temperature below 15 ℃. The reaction was warmed to 25 ℃. After 16 hours, the mixture was slowly diluted with hydrochloric acid (1.22M in water, 2780 mL). The reaction was stirred for 15 minutes, and then the layers were separated. The organic layer was washed with water (1000mL), then treated with DarcoKB-B (13g), magnesium sulfate (13g), and celite, and then slurried for 30 minutes. The slurry was filtered and the solid was washed with methyl tert-butyl ether (250 mL). The filtrate was concentrated at atmospheric pressure (internal temperature 55-58 ℃) to a volume of about 500 mL. The solution was cooled to 15 ℃ at 2 ℃/min. Heptane (250mL) was added, then the slurry was cooled to 10 ℃ and stirred for 1 hour. The slurry was filtered and the solids were washed with 1:2 methyl tert-butyl ether heptane (260mL, cooled to 5 ℃ C.) followed by heptane (250 mL). The resulting off-white solid was dried under vacuum to afford intermediate X202.¹HNMR(400MHz，CDCl₃，δ):8.08-8.13(m，2H)，7.97-8.01(m，2H)，3.94(s，3H)，2.96(t，J=7.3Hz，2H)，1.77(m，2H)，1.00(t，J=7.4Hz，3H)。

Intermediate 66 (S) -methyl 4- (1-hydroxybutyl) benzoate

To a solution of borane-diethylaniline complex (49.79mL, 280.0mmol) and (R) - (+) -2-methyl-CBS-oxorolidine (1M in toluene, 18.67mL, 18.67mmol) in tetrahydrofuran (154mL) at 20 ℃ was added a solution of intermediate 65(77.00g, 373.4mmol) in tetrahydrofuran (385mL) over a period of 2 hours. After stirring for 10min, the reaction was quenched by slow addition of methanol (34.75mL, 858.7mmol) over 30min while maintaining the temperature below 20 ℃. Hydrochloric acid (1N in water, 373.4mL, 373.4mmol) was then added over 10 minutes while maintaining the temperature below 20 ℃. Methyl tert-butyl ether (385mL) was added and the mixture was stirred for 30 min. And (5) separating the layers. Hydrochloric acid (1N in water, 373.4mL) was added to the organic layer, and the mixture was stirred for 10 minutes. The layers were separated and the organic layer was diluted with water (77.0 mL). The mixture was stirred for 5 minutes, and then the layers were separated. The combined aqueous layers were back-extracted with methyl tert-butyl ether (2 × 150 mL). The combined organic layers were distilled at atmospheric pressure (temperature below 80 ℃) until 250mL of solution remained. The solution was then diluted with heptane (847mL) and distilled at atmospheric pressure (100-. Heptane (462mL) was added again and the solution was distilled at atmospheric pressure (100 ℃ C.) and 110 ℃ C. until the internal temperature reached 100 ℃. Heptane was added until a total volume of 700mL was reached. The solution was then cooled to-15 ℃ with vigorous stirring. The slurry was warmed to 15 ℃ and stirred overnight. The mixture was then cooled to-15 ℃ and stirred for 3.5 hours. The resulting slurry was filtered and the solid washed with heptane (50mL, cooled to 0 ℃). The resulting solid was dried under vacuum to afford intermediate 66.¹H NMR(400MHz，CDCl₃，δ):7.97-8.02(m，2H)，7.40(d，J=8.4Hz，2H)，4.74(dd，J=7.8，5.7Hz，1H)，3.90(s，3H)，1.61-1.82(m，2H)，1.23-1.49(m，2H)，0.92(t，J=7.32Hz，3H)。

Intermediate 67 (R) -methyl 4- (1-aminobutyl) benzoate

A solution of intermediate 66(20.00g, 96.04mmol) in tetrahydrofuran (120mL) was cooled to 5 ℃. Triethylamine (10.24g, 101.2mmol) and then methanesulfonyl chloride (11.75g, 102.6mmol) were added while maintaining the reaction temperature below 20 ℃. The resulting slurry was filtered and the solid was washed with tetrahydrofuran (40 mL). To the combined filtrates was added azidotrimethylsilane (18.80g, 163.2 mmol). The flow system used two feed streams, the reaction solution and tetrabutylammonium fluoride (75wt% in water). The feed streams were combined at a rate such that the instantaneous stoichiometry through the system was maintained at 1.6 equivalents tetrabutylammonium fluoride to intermediate 66. The combined stream was discharged into a nitrogen purged reactor that was pre-filled with zinc dust (14.6g, 223.3mmol) and ammonium formate (14.3g, 226.8 mmol). The mixture was stirred vigorously until the reaction was complete. The mixture was then filtered and the resulting solid was washed with tetrahydrofuran. The combined filtrates were diluted with saturated aqueous potassium carbonate (300mL) and water (900 mL). The layers were separated and the aqueous layer was extracted with methyl tert-butyl ether (5x700 mL). The combined organics were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate 67 as a yellow oil.¹H NMR(400MHz，CDCl₃，δ):8.03-7.98(m，2H)，7.42-7.37(m，2H)，3.97(t，J=6.9Hz，1H)，3.92(s，3H)，1.73-1.59(m，4H)，1.43-1.20(m，2H)，0.91(t，J=7.3Hz，3H)。

Intermediate 68 (R) -methyl 4- (1- ((3-methylquinolin-2-yl) amino) butyl) benzoate

The title compound was prepared from intermediate 67 by a method analogous to that described for intermediate 4.¹H NMR(400MHz，CDCl₃，δ):8.01-7.96(m，2H)，7.64-7.59(m，2H)，7.55-7.49(m，3H)，7.43(ddd，J=8.5，7.0，1.5Hz，1H)，7.17(ddd，J=8.0，7.0，1.3Hz，1H)，5.51(q，J=7.2Hz，1H)，4.79(d，J=7.2Hz，1H)，3.89(s，3H)，2.30(d，J=0.8Hz，3H)，2.04-1.82(m，2H)，1.39(s，2H)，1.02-0.94(m，3H)。

Intermediate 69 (R) -Ethyl 3- (4- (1- ((3-methylquinolin-2-yl) amino) butyl) benzoylamino) propionate

The title compound was prepared by a method analogous to that described for intermediate 6, using intermediate 68.¹H NMR(400MHz，CDCl₃，δ):7.73-7.68(m，2H)，7.64-7.59(m，2H)，7.54-7.49(m，3H)，7.43(ddd，J=8.4，6.9，1.5Hz，1H)，7.16(ddd，J=8.0，6.9，1.2Hz，1H)，6.78(t，J=5.9Hz，1H)，5.48(q，J=7.2Hz，1H)，4.78(d，J=7.0Hz，1H)，4.16(q，J=7.0Hz，2H)，3.71(q，J=6.0Hz，2H)，2.65-2.58(m，2H)，2.29(d，J=1.0Hz，3H)，2.04-1.82(m，2H)，1.53-1.30(m，2H)，1.26(t，J=7.1Hz，3H)，0.97(t，J=7.4Hz，3H)。

Intermediate 70- {4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid methyl ester, isomer 1

In a similar manner as described in the experiment for intermediate 27, (+/-) -4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl]Benzoic acid (intermediate 26, 1.0eq.), 1-hydrobenzotriazole hydrate (1.2eq.), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.2eq.), beta-alanine methyl ester hydrochloride (1.1eq.), and triethylamine (1.3eq.) were combined in anhydrous dichloromethane to provide (+/-) -3- {4- [ (3, 3-dimethyl-cyclobutane.)Yl) - (3-methyl-quinolin-2-ylamino) -methyl]-benzoylamino } -propionic acid methyl ester, which is resolved by chiral chromatography to provide the title compound. Preparative chiral SFC (Chiralpak AD-H column, 21mmx25cm, 40% methanol/carbon dioxide eluent, 0.2% isopropylamine modifier, 65.0mL/min flow rate, 2.71 retention time);¹H NMR(400MHz，CDCl₃)δ7.63-7.69(m，2H)，7.58(t，J=3.9Hz，2H)，7.45-7.51(m，3H)，7.41(ddd，J=8.4，7.0，1.6Hz，1H)，7.14(ddd，J=8.0，6.9，1.2Hz，1H)，6.72(t，J=6.0Hz，1H)，5.31(dd，J=9.7，6.7Hz，1H)，4.75(d，J=6.8Hz，1H)，3.69(q，J=6.2Hz，5H)，2.55-2.71(m，3H)，2.28(d，J=0.8Hz，3H)，1.95(ddd，J=11.2，8.0，3.0Hz，1H)，1.78(dd，J=11.1，9.0Hz，1H)，1.64-1.72(m，2H)，1.15(s，3H)，1.08(s，3H)；MS(M+1):460.4。

intermediate 71 3- {4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid methyl ester, isomer 2

(+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl]Resolution of-benzoylamino } -propionic acid methyl ester by chiral chromatography provided the title compound. Preparative chiral SFC (Chiralpak AD-H column, 21mmx25cm, 40% methanol/carbon dioxide eluent, 0.2% isopropylamine modifier, 65.0mL/min flow rate, 5.17 retention time);¹H NMR(400MHz，CDCl₃)δ7.67(d，J=8.0Hz，2H)，7.60(br.s.，2H)，7.46-7.55(m，3H)，7.36-7.46(m，1H)，7.15(br.s，1H)，6.73(t，J=5.7Hz，1H)，5.30(br.s，1H)，4.73(br.s，1H)，3.62-3.75(m，5H)，2.56-2.74(m，3H)，2.30(br.s.，3H)，1.95(ddd，J=11.2，8.1，2.5Hz，1H)，1.75-1.88(m，1H)，1.61-1.75(m，2H)，1.14(s，3H)，1.09(s，3H)；MS(M+1):460.4。

intermediate 72(+/-) -4- [ (3, 3-dimethyl-cyclobutyl) - (6-fluoro-3-methyl-quinolin-2-ylamino) -methyl ] -benzoic acid ethyl ester

The title compound was prepared by treating intermediate 29 in a similar manner as described in the experiment with intermediate 25.

Intermediate 73 (+/-) -4- ((3, 3-dimethylcyclobutyl) ((6-fluoro-3-methylquinolin-2-yl) amino) methyl) benzoic acid

The title compound was prepared by treating the (+/-) -4- [ (3, 3-dimethyl-cyclobutyl) - (6-fluoro-3-methyl-quinolin-2-ylamino) -methyl ] -benzoic acid ethyl ester intermediate in a similar manner as described in the experiment with intermediate 26.

Intermediate 74- {4- [ (3, 3-dimethyl-cyclobutyl) - (6-fluoro-3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid methyl ester, isomer 1

In a similar manner as described in the experiment for intermediate 27, (/ -) -4- ((3, 3-dimethylcyclobutyl) (6-fluoroquinolin-3-ylamino) methyl) benzoic acid (intermediate 73, 1.0eq.), 1-hydrobenzotriazole hydrate (1.2eq.), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.2eq.), β -alanine methyl ester hydrochloride (1.1eq.) and triethylamine (1.3eq.) were combined in anhydrous dichloromethane, providing (+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (6-fluoro-3-methyl-quinolin-2-ylamino) -methyl.]-benzoylamino } -propionic acid methyl ester, its general formulaResolution by chiral chromatography provided the title compound. Preparative chiral SFC (Chiralpak AD-H column, 10mmx25cm,30% propanol/carbon dioxide eluent, flow rate of 10.0mL/min, 4.16 retention time);¹H NMR(400MHz，CDCl₃)δ7.67(d，J=8.1Hz，2H)，7.50-7.59(m，2H)，7.42-7.50(m，2H)，7.08-7.22(m，2H)，6.65-6.80(m，1H)，5.18-5.28(m，1H)，4.68-4.75(m，1H)，3.62-3.75(m，5H)，2.55-2.72(m，3H)，2.28(s，3H)，1.95(ddd，J=11.1，8.1，3.0Hz，1H)，1.73-1.83(m，1H)，1.61-1.73(m，2H)，1.14(s，3H)，1.09(s，3H)；MS(M+1):478.3。

intermediate 75- {4- [ (3, 3-dimethyl-cyclobutyl) - (6-fluoro-3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid methyl ester, isomer 2

(+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (6-fluoro-3-methyl-quinolin-2-ylamino) -methyl]Resolution of-benzoylamino } -propionic acid methyl ester by chiral chromatography provided the title compound. Preparative chiral SFC (Chiralpak AD-H column, 10mmx25cm,30% propanol/carbon dioxide eluent, 10.0mL/min flow rate, 5.88 retention time);¹H NMR(400MHz，CDCl₃)δ7.67(d，J=7.8Hz，2H)，7.51-7.59(m，2H)，7.47(d，J=8.1Hz，2H)，7.08-7.22(m，2H)，6.66-6.78(m，1H)，5.19-5.27(m，1H)，4.72(d，J=5.4Hz，1H)，3.62-3.74(m，5H)，2.52-2.71(m，3H)，2.28(s，3H)，1.90-2.00(m，1H)，1.71-1.81(m，1H)，1.62-1.71(m，2H)，1.14(s，3H)，1.08(s，3H)；MS(M+1):478.3。

preparation of Compounds of formula I

Example 1 (+) -3- (4- (1- ((3-methylquinolin-2-yl) amino) butyl) benzoylamino) propionic acid

To a solution of intermediate 6(17.66g, 42.10mmol) in tetrahydrofuran (210mL) and methanol (210mL) was added 1N aqueous sodium hydroxide (210 mL). The solution was stirred at room temperature for 10 min. The solution was concentrated under reduced pressure to remove tetrahydrofuran and methanol. 1N aqueous hydrochloric acid solution was added dropwise to pH 4.75. The resulting slurry was filtered and the solid was washed with water (2x50 mL). The solid was dried in a vacuum oven for 16 h. The resulting solid was slurried in water and ethyl acetate. The mixture was filtered and the resulting two-phase filtrate was separated. The aqueous layer was extracted with ethyl acetate. The aqueous layer was then used to slurry the filtered solids. The pH was adjusted to 4 with 1N aqueous NaOH solution, and ethyl acetate was then added. The filtration, separation, extraction, reslurry, and pH adjustment processes were repeated until no solids remained and thin layer chromatography showed no product remaining in the aqueous layer. The combined organic layers were concentrated under reduced pressure and dried in a vacuum oven to afford (+) -3- (4- (1- ((3-methylquinolin-2-yl) amino) butyl) benzoylamino) propionic acid (example 1).¹H NMR(400MHz，DMSO-d₆)δ12.18(s，1H)，8.40(t，J=5.6Hz，1H)，7.74(d，J=8.4Hz，2H)，7.68(s，1H)，7.57(d，J=8.2Hz，2H)，7.53(d，J=7.4Hz，1H)，7.45-7.40(m，1H)，7.40-7.33(m，1H)，7.13-7.06(m，1H)，6.62(br.s.，1H)，5.46-5.35(m，1H)，3.48-3.38(m，2H)，2.48(t，J=7.1Hz，2H)，2.32(s，3H)，2.06-1.93(m，1H)，1.85-1.74(m，1H)，1.52-1.38(m，1H)，1.38-1.23(m，1H)，0.92(t，J=7.3Hz，3H)；HPLC:XBridgeC₁₈150mmx4.6mm,5 μm column, flow rate 1.50mL/min, linear gradient 5% acetonitrile/water (0.1% trifluoroacetic acid modifier) to 100% acetonitrile over 11min, retention time =6.34 min; MS (M +1): 406.5.

The hydrochloride of the compound of example 1 was additionally prepared as follows, (+) -3- (4- (1- ((3-methylquinolin-2-yl) amino) butyl) benzoylamino) propanoic acid hydrochloride:

to a solution of intermediate 69(33.55g, 77.38mmol) in tetrahydrofuran (161mL) and methanol (161mL) was added sodium hydroxide (1N in water, 161mL, 161 mmol). The solution was stirred for 10 minutes and then concentrated under reduced pressure to remove tetrahydrofuran and methanol. Hydrochloric acid (1N in water, 130mL) was added dropwise with vigorous stirring. After 1.5 hours, the slurry was diluted with saturated aqueous sodium chloride (600mL) and extracted with dichloromethane (3 × 1000 mL). The aqueous layer was then acidified to pH5 with hydrochloric acid and extracted with dichloromethane (5x500 mL). The combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a viscous yellow solid.¹HNMR(400MHz，DMSO-d₆)δ12.18(s，1H)，8.40(t，J=5.6Hz，1H)，7.74(d，J=8.4Hz，2H)，7.68(s，1H)，7.57(d，J=8.2Hz，2H)，7.53(d，J=7.4Hz，1H)，7.45-7.40(m，1H)，7.40-7.33(m，1H)，7.13-7.06(m，1H)，6.62(br.s.，1H)，5.46-5.35(m，1H)，3.48-3.38(m，2H)，2.48(t，J=7.1Hz，2H)，2.32(s，3H)，2.06-1.93(m，1H)，1.85-1.74(m，1H)，1.52-1.38(m，1H)，1.38-1.23(m，1H)，0.92(t，J=7.3Hz，3H)；HPLC:XBridge C₁₈150mmx4.6mm,5 μm column, flow rate 1.50mL/min, linear gradient from 5% acetonitrile/water (0.1% trifluoroacetic acid modifier) to 100% acetonitrile over 11min, retention time =6.34 min; MS (M +1): 406.5.

To the viscous yellow solid was added dichloromethane (1520 mL). Slight heating of the mixture was required to fully dissolve the solids. Hydrogen chloride (2M in diethyl ether 37.7mL, 75.5mmol) was added dropwise over 30 min. The resulting white slurry was stirred for 10 minutes and then filtered. The resulting solid was dried under vacuum. The solid was suspended in water (250mL) and heated to 60 ℃. Methanol (280mL) was added slowly with stirring until all the solids dissolved. The solution was allowed to cool to room temperature. After 11 hours, the mixture was cooled to 0 ℃ over 2 hours. The resulting white solid was filtered and the solid was dried under vacuum to provide the hydrochloride of example 1. Additional solids can be obtained by concentrating the filtrate under vacuum to a total volume of about 300mL and filtering the resulting slurry.

Example 2 (-) -3- (4- (1- ((3-methylquinolin-2-yl) amino) butyl) benzoylamino) propionic acid

Example 2 was prepared from intermediate 7 in a similar manner to example 1.¹H NMR(400MHz，DMSO-d₆)δ12.18(s，1H)，8.40(t，J=5.6Hz，1H)，7.74(d，J=8.4Hz，2H)，7.68(s，1H)，7.57(d，J=8.2Hz，2H)，7.53(d，J=7.4Hz，1H)，7.45-7.40(m，1H)，7.40-7.33(m，1H)，7.13-7.06(m，1H)，6.62(br.s.，1H)，5.46-5.35(m，1H)，3.48-3.38(m，2H)，2.48(t，J=7.1Hz，2H)，2.32(s，3H)，2.06-1.93(m，1H)，1.85-1.74(m，1H)，1.52-1.38(m，1H)，1.38-1.23(m，1H)，0.92(t，J=7.3Hz，3H)；HPLC:XBridge C₁₈150mmx4.6mm,5 μm column, flow rate 1.50mL/min, linear gradient from 5% acetonitrile/water (0.1% trifluoroacetic acid modifier) to 100% acetonitrile over 11min, retention time =6.34 min; MS (M +1): 406.5.

EXAMPLE 3 (+/-)3- {4- [ 3-methyl-1- (quinolin-3-ylamino) -butyl ] -benzoylamino } -propionic acid

Intermediate 12 was dissolved in 1, 4-dioxane to form a 0.1M solution. 3-bromo-quinoline (100 μmol, 1.0eq.) was added to an 8mL vial followed by 1mL (100 μmol, 1.0eq.) of intermediate 12 dioxane solution. To the vial was added sodium tert-butoxide (19mg, 200. mu. mol, 2.0eq.), brettphos-procatalyst (4mg, 5. mu. mol, 0.05eq.) and brettphos (3mg, 5. mu. mol, 0.05 eq.). The vial was capped, filled with nitrogen, and shaken at 80 ℃ for 16 h. Water (100 μ L) was added to the vial to quench the reaction. Dioxane was removed by Speedvac. Adding saturated NaHCO₃(2mL) of aqueous solution and the resulting mixture extracted with ethyl acetate (2mLx 2). Collecting organic phase, purifying with a filterWater Na₂SO₄Dried, filtered, and the filtrate concentrated with Speedvac. In DIKMA Diamond (2) C₁₈200X20mm on a 5 μm column, eluting with a gradient of aqueous acetonitrile (0.1% trifluoroacetic acid modifier) and purifying by reverse phase HPLC to give (+/-) -3- {4- [ 3-methyl-1- (quinolin-3-ylamino) -butyl-)]-benzoylamino } -propionic acid. Analysis LCMS Retention time 2.356 min (Xbridge C)₁₈2.1 × 50mm,5 μm column; 10% acetonitrile (0.01875% trifluoroacetic acid modifier)/water (0.0375% trifluoroacetic acid modifier) for 0.5 minute, linear gradient to 100% acetonitrile over 3.5 minutes, linear gradient to 10% acetonitrile/water over 0.3 minute, held at 10% acetonitrile/water for 0.4 minute; flow rate 0.8 mL/min); MS (M +1): 506.

EXAMPLE 4 (+/-) -3- {4- [1- (7-fluoro-quinazolin-2-ylamino) -3-methyl-butyl ] -benzoylamino } -propionic acid

Step A intermediate 12 was dissolved in DMSO to form a 0.1M solution. 2-chloro-7-fluoro-quinazoline (100 μmol, 1.0eq.) was added to an 8mL vial followed by 1mL (100 μmol, 1.0eq.) of intermediate 12DMSO solution. Diisopropylethylamine (35 μ L, 200 μmol, 2.0eq.) was added and the vial capped and shaken at 80 ℃ for 16 h. The solvent was removed by lyophilization and the residue was used for the next step.

Step B preparation of a solution of trifluoroacetic acid in dichloromethane (v/v =1: 4). 1.0mL of this solution was added to the vial containing the residue from step A. The vial was capped and shaken at 30 ℃ for 2 h. The solvent was removed by Speedvac. In Agella Venusil ASB C₁₈150X21.2mmx5 μm column, gradient eluted with acetonitrile (0.225% formic acid modifier) in water, purified by reverse phase HPLC and yielded (+/-) -3- {4- [1- (7-fluoro-quinazolin-2-ylamino) -3-methyl-butyl]-benzoylamino } -propionic acid. Analysis LCMS Retention time 2.456 min (Xbridge C)₁₈2.1 × 50mm,5 μm column; 10% acetonitrile (0.01875% trifluoroacetic acid modifier) Water (0.0375% trifluoroacetic acid modifier) for 0.5 min, linear gradient to 100% acetonitrile over 3.5 min, linear gradient to 10% acetonitrile/water over 0.3 min, held at 10% acetonitrile/water for 0.4 min; flow rate 0.8 mL/min); MS (M +1): 425.

Example 5 (+/-) -3- {4- [ 3-methyl-1- (quinolin-2-ylamino) -butyl ] -benzoylamino } -propionic acid

This example was synthesized by a procedure similar to example 3, by using 2-chloro-quinoline. In Phenomenex Gemini C₆₈On a 250X21.2mm, 8 μm column, collected for NH₄Gradient elution of OH in acetonitrile (pH10) and purification by reverse phase HPLC gave (+/-) -3- {4- [ 3-methyl-1- (quinolin-2-ylamino) -butyl]-benzoylamino } -propionic acid. Analysis of LCMS Retention time 2.263 min (Xbridge C)₁₈2.1 × 50mm,5 μm column; 10% acetonitrile (0.01875% trifluoroacetic acid modifier)/water (0.0375% trifluoroacetic acid modifier) for 0.5 minute, linear gradient to 100% acetonitrile over 3.5 minutes, linear gradient to 10% acetonitrile/water over 0.3 minute, held at 10% acetonitrile/water for 0.4 minute; flow rate 0.8 mL/min); MS (M +1):406.

EXAMPLE 6 (+/-) -3- {4- [1- (8-methoxy-quinolin-2-ylamino) -3-methyl-butyl ] -benzoylamino } -propionic acid

This example was synthesized by a procedure similar to example 3, by using 2-chloro-8-methoxy-quinoline. In Phenomenex Gemini C₁₈On a 250X21.2mm, 8 μm column, collected for NH₄Gradient elution of acetonitrile in OH (pH10) and purification by reverse phase HPLC gave (+/-) -3- {4- [1- (8-methoxy-quinolin-2-ylamino) -3-methyl-butyl]-benzoylamino-propionic acid. Analysis of LCMS Retention time 2.342 min (Xbridge C)₁₈2.1 × 50mm,5 μm column; 10% acetonitrile (0.01875% trifluoroacetic acid modifier)/water (0.0375% trifluoroacetic acid modifier) for 0.5 minute, linear gradient to 100% acetonitrile over 3.5 minutes, linear gradient to 10% acetonitrile/water over 0.3 minute, held at 10% acetonitrile/water for 0.4 minute; flow rate 0.8 mL/min); MS (M +1): 436.

Example 7 (+/-) -3- {4- [ 3-methyl-1- (quinoxalin-2-ylamino) -butyl ] -benzoylamino } -propionic acid

This example was synthesized by a procedure similar to example 3, by employing 2-chloro-quinoxaline. In Phenomenex Gemini C₁₈250X21.2mm, 8 μm column, using NH₄Gradient elution of OH in acetonitrile (pH10) and purification by reverse phase HPLC gave (+/-) -3- {4- [ 3-methyl-1- (quinoxalin-2-ylamino) -butyl]-benzoylamino } -propionic acid. Analysis of LCMS Retention time 2.689 min (Xbridge C)₁₈2.1 × 50mm,5 μm column; 10% acetonitrile (0.01875% trifluoroacetic acid modifier)/water (0.0375% trifluoroacetic acid modifier) for 0.5 minute, linear gradient to 100% acetonitrile over 3.5 minutes, linear gradient to 10% acetonitrile/water over 0.3 minute, held at 10% acetonitrile/water for 0.4 minute; flow rate 0.8 mL/min); MS (M +1): 407.

Example 8 (+/-) -3- {4- [ 3-methyl-1- (3-methyl-quinoxalin-2-ylamino) -butyl ] -benzoylamino } -propionic acid

This example was synthesized using a procedure similar to example 3, using 2-chloro-3-methyl-quinoxaline. In DIKMA Diamond (2) C₁₈200X20mm,5 μm column, modified with acetonitrile in water (0.1% trifluoroacetic acidSex agent) was eluted, purified by reverse phase HPLC to give (+/-) -3- {4- [ 3-methyl-1- (3-methyl-quinoxalin-2-ylamino) -butyl]-benzoylamino } -propionic acid. Analysis of LCMS Retention time 2.837 min (Xbridge C)₁₈2.1 × 50mm,5 μm column; 10% acetonitrile (0.01875% trifluoroacetic acid modifier)/water (0.0375% trifluoroacetic acid modifier) for 0.5 minute, linear gradient to 100% acetonitrile over 3.5 minutes, linear gradient to 10% acetonitrile/water over 0.3 minute, held at 10% acetonitrile/water for 0.4 minute; flow rate 0.8 mL/min); MS (M +1): 421.

EXAMPLE 9 (+/-) -3- {4- [1- (isoquinolin-3-ylamino) -3-methyl-butyl ] -benzoylamino } -propionic acid trifluoroacetate

This example was synthesized by a procedure similar to example 3, by employing 3-chloro-isoquinoline. In DIKMA Diamond (2) C₁₈200X20mm,5 μm column eluted with a gradient of acetonitrile in water (0.1% trifluoroacetic acid modifier) and purified by reverse phase HPLC to yield (+/-) -3- {4- [1- (isoquinolin-3-ylamino) -3-methyl-butyl]-benzoylamino } -propionic acid trifluoroacetate salt. Analysis of LCMS Retention time 2.423 min (Xbridge C)₁₈2.1 × 50mm,5 μm column; 10% acetonitrile (0.01875% trifluoroacetic acid modifier)/water (0.0375% trifluoroacetic acid modifier) for 0.5 minute, linear gradient to 100% acetonitrile over 3.5 minutes, linear gradient to 10% acetonitrile/water over 0.3 minute, held at 10% acetonitrile/water for 0.4 minute; flow rate 0.8 mL/min); MS (M +1):406.

EXAMPLE 10 (+/-) -3- {4- [ 3-methyl-1- (4-methyl-quinolin-2-ylamino) -butyl ] -benzoylamino } -propionic acid

By analogy with example 3Procedure the example was synthesized by using 2-chloro-4-methyl-quinoline. In Phenomenex Gemini C₁₈250X21.2mm, 10 μm column, dissolved in NH₄Acetonitrile in OH (pH10) was gradient eluted and purified by reverse phase HPLC to give (+/-) -3- {4- [ 3-methyl-1- (4-methyl-quinolin-2-ylamino) -butyl]-benzoylamino } -propionic acid. Analysis of LCMS Retention time 2.368 min (Xbridge C)₁₈2.1 × 50mm,5 μm column; 10% acetonitrile (0.01875% trifluoroacetic acid modifier)/water (0.0375% trifluoroacetic acid modifier) for 0.5 minute, linear gradient to 100% acetonitrile over 3.5 minutes, linear gradient to 10% acetonitrile/water over 0.3 minute, held at 10% acetonitrile/water for 0.4 minute; flow rate 0.8 mL/min); MS (M +1):420.

EXAMPLE 11 (+/-) -3- {4- [ 3-methyl-1- (3-methyl-quinolin-2-ylamino) -butyl ] -benzoylamino } -propionic acid

This example was synthesized by a procedure similar to example 3, by using 2-chloro-3-methyl-quinoline. In Phenomenex Gemini C₁₈250X21.2mm, 10 μm column, dissolved in NH₄Acetonitrile in OH (pH10) was gradient eluted and purified by reverse phase HPLC to give (+/-) -3- {4- [ 3-methyl-1- (3-methyl-quinolin-2-ylamino) -butyl]-benzoylamino } -propionic acid. Analysis of LCMS Retention time 2.326 min (Xbridge C)₁₈2.1 × 50mm,5 μm column; 10% acetonitrile (0.01875% trifluoroacetic acid modifier)/water (0.0375% trifluoroacetic acid modifier) for 0.5 minute, linear gradient to 100% acetonitrile over 3.5 minutes, linear gradient to 10% acetonitrile/water over 0.3 minute, held at 10% acetonitrile/water for 0.4 minute; flow rate 0.8 mL/min); MS (M +1):420.

EXAMPLE 12 (+/-) -3- {4- [1- (7-fluoro-4-methyl-quinolin-2-ylamino) -3-methyl-butyl ] -benzoylamino } -propionic acid

This example was synthesized by a procedure similar to example 3, by using 2-chloro-7-fluoro-4-methyl-quinoline. In Phenomenex Gemini C₁₈250X21.2mm, 8 μm column, dissolved in NH₄Acetonitrile in OH (pH10) was gradient eluted and purified by reverse phase HPLC to give (+/-) -3- {4- [1- (7-fluoro-4-methyl-quinolin-2-ylamino) -3-methyl-butyl]-benzoylamino } -propionic acid. Analysis of LCMS Retention time 2.404 min (Xbridge C)₁₈2.1 × 50mm,5 μm column; 10% acetonitrile (0.01875% trifluoroacetic acid modifier)/water (0.0375% trifluoroacetic acid modifier) for 0.5 minute, linear gradient to 100% acetonitrile over 3.5 minutes, linear gradient to 10% acetonitrile/water over 0.3 minute, held at 10% acetonitrile/water for 0.4 minute; flow rate 0.8 mL/min); MS (M +1): 438.

EXAMPLE 13 (+/-) -3- {4- [1- (8-chloro-quinolin-2-ylamino) -3-methyl-butyl ] -benzoylamino } -propionic acid

This example was synthesized by a procedure similar to example 3, by using 2, 8-dichloro-quinoline. In Phenomenex Gemini C₁₈250X21.2mm, 8 μm column, dissolved in NH₄Gradient elution of OH in acetonitrile (pH10) and purification by reverse phase HPLC gave (+/-) -3- {4- [1- (8-chloro-quinolin-2-ylamino) -3-methyl-butyl]-benzoylamino } -propionic acid. Analysis of LCMS Retention time 2.462 min (Xbridge C)₁₈2.1 × 50mm,5 μm column; 10% acetonitrile (0.01875% trifluoroacetic acid modifier)/water (0.0375% trifluoroacetic acid modifier) for 0.5 minute, linear gradient to 100% acetonitrile over 3.5 minutes, linear gradient to 10% acetonitrile/water over 0.3 minute, held at 10% acetonitrile/water for 0.4 minute; flow rate 0.8 mL/min); MS (M +1): 440.

EXAMPLE 14 (+/-) -3- {4- [ 3-methyl-1- (quinazolin-2-ylamino) -butyl ] -benzoylamino } -propionic acid

This example was synthesized by a procedure similar to that of example 4, by using 2-chloro-quinazoline. In Phenomenex Gemini C₁₈250X21.2mm, 10 μm column, dissolved in NH₄Gradient elution of OH in acetonitrile (pH10) and purification by reverse phase HPLC gave (+/-) -3- {4- [ 3-methyl-1- (quinazolin-2-ylamino) -butyl]-benzoylamino } -propionic acid. Analysis of LCMS Retention time 2.401 min (Xbridge C)₁₈2.1 × 50mm,5 μm column; 10% acetonitrile (0.01875% trifluoroacetic acid modifier)/water (0.0375% trifluoroacetic acid modifier) for 0.5 minute, linear gradient to 100% acetonitrile over 3.5 minutes, linear gradient to 10% acetonitrile/water over 0.3 minute, held at 10% acetonitrile/water for 0.4 minute; flow rate 0.8 mL/min); MS (M +1): 407.

Example 15 (+/-)3- (4- (3-methyl-1- (7- (trifluoromethyl) quinolin-2-ylamino) butyl) benzoylamino) propionic acid

A10 mL vial equipped with a magnetic stirrer was charged with intermediate (150mg, 0.65mmol), intermediate 12(240mg, 0.72mmol), 2- (dicyclohexylphosphino) -3, 6-dimethoxy-2 '-4' -6 '-triisopropyl-1, 1' -biphenyl (17mg, 0.032mmol), Pd (OAc)₂(26mg, 0.032mmol), sodium tert-butoxide (153mg, 1.37mmol) and THF (7 mL). With N₂The vial was purged, sealed and heated to 90 ℃ overnight. The mixture was diluted with water and extracted with ethyl acetate (10ml x 3). The combined organic layers were dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel chromatography to give (+/-)3- (4- (3-methyl-1- (7- (trifluoromethyl) quinolin-2-ylamino) butyl) benzoylamino) propanoic acid (26.5mg, 8.6%) as a colorless oil.¹H NMR(400MHz，MeOD)δ7.79(d，J=8.8Hz，1H)，7.64(m，4H)，7.44(d，J=8.4Hz，2H)，7.24(d，J=7.2Hz，1H)，6.83(d，J=8.8Hz，1H)，5.29-5.28(m，1H)，3.52-3.49(m，2H)，2.51-2.48(m，2H)，1.8.-1.73(m，1H)，1.70-1.64(m，1H)，1.59-1.52(m，1H)，0.94-0.90(m，6H)。MS(M+1)=474.2。

EXAMPLE 16 (+/-)3- (4- (3-methyl-1- (6- (trifluoromethyl) quinolin-2-ylamino) butyl) benzoylamino) propionic acid

A50 mL vial equipped with a magnetic stirrer was charged with intermediate 17(150mg, 0.65mmol), intermediate 12(240mg, 0.72mmol), 2- (dicyclohexylphosphino) -3, 6-dimethoxy-2 '-4' -6 '-triisopropyl-1, 1' -biphenyl (17mg, 0.032mmol), Pd (OAc)₂(26mg, 0.032mmol), sodium tert-butoxide (153mg, 1.37mmol) and THF (7 mL). With N₂The vial was purged, sealed, and heated to 90 ℃ overnight. The mixture was diluted with water and extracted with ethyl acetate (10ml x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel chromatography to give (+/-)3- (4- (3-methyl-1- (6- (trifluoromethyl) quinolin-2-ylamino) butyl) benzoylamino) propanoic acid (20mg, 6.5%) as a colorless solid.¹H NMR(400MHz，CD₃OD)δ7.91(d，J=8.8Hz，2H)，7.75(d，J=8.0Hz，2H)，7.62(m，2H)，7.53(d，J=8.4Hz，2H)，6.90(d，J=8.8Hz，2H)，5.40(br s，1H)，3.62-3.58(m，2H)，2.62-2.58(s，2H)，1.89-1.83(m，1H)，1.82-1.68(m，1H)，1.65-1.62(m，1H)，1.04-1.00(m，6H）。MS(M+1)=474.0。

Example 17 (+ \ -) -3- (4- (3-methyl-1- (2-methylquinolin-3-ylamino) butyl) benzoylamino) propionic acid

A mixture of intermediate 18(200mg,1.26mmol), intermediate 19(476mg) and potassium carbonate (349mg,2.53mmol) in acetonitrile (10mL) was stirred at 80 ℃ overnight. The reaction mixture was poured into a saturated aqueous solution of sodium chloride (20mL) and extracted with ethyl acetate (2X30 mL). The combined organic layers were washed with brine (2 × 30mL) and water (30mL), then over anhydrous Na₂SO₄Drying, filtering and concentrating under reduced pressure, then, passing over anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give ethyl 4- (3-methyl-1- (2-methylquinolin-3-ylamino) butyl) benzoate (50mg, 12%) as a yellow solid. This material was dissolved in methanol (6mL) and cooled to 0 ℃. 2N aqueous sodium hydroxide (6mL,12mmol) was added. The reaction was heated to reflux and stirred for 90 min. The mixture was acidified to pH3 by addition of 1N aqueous HCl and extracted with ethyl acetate (2X30 mL). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave crude 4- (3-methyl-1- (2-methylquinolin-3-ylamino) butyl) benzoic acid (42mg, 94%) as a yellow solid. The crude acid was dissolved in DMF (6 mL). HATU (114mg,0.3mmol), diisopropylamine (40mg,0.3mmol) and methyl 3-aminopropionate hydrochloride (27mg,0.18mmol) were added in this order. The resulting mixture was stirred at 30 ℃ for 1 h. The mixture was poured into brine (20mL) and extracted with ethyl acetate (2X30 mL). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave crude methyl 3- (4- (3-methyl-1- (2-methylquinolin-3-ylamino) butyl) benzoylamino) propionate (55mg, 98%) as an oil. The crude ester was dissolved in THF (4mL) and cooled to 0 ℃. 2N aqueous lithium hydroxide (4mL,8mmol) was added. The reaction mixture was stirred at 30 ℃ for 12 hours. The mixture was acidified to pH3 by addition of 1N aqueous HCl. The mixture was extracted with ethyl acetate (2X30 mL). Through anhydrous Na₂SO₄The combined organic layers were dried, filtered and concentrated. By reaction in Phenomenex Synergi C₁₈Preparative HPLC purification on a 150X30mmX4 μm column with 22% to 42% acetonitrile in waterEluted with a solution (0.225% formic acid modulator) to give (+ \ -) -3- (4- (3-methyl-1- (2-methylquinolin-3-ylamino) butyl) benzoylamino) propionic acid as a yellow solid (17.2 mg).¹H NMR(400MHz,CD₃OD):δ7.76-7.78(m,3H),7.57(d,J=8.0Hz,2H),7.50-7.52(m,1H),7.40-7.35(m,2H),7.03(s,1H),4.69-4.65(m,1H),3.62-3.58(m,2H),2.75(s,3H),2.59-2.62(m,2H),2.03-1.97(m,1H),1.86-1.83(m,1H),1.72-1.66(m,1H),1.07(d,J=6.4Hz,3H),1.00(d,J=6.4Hz,3H).MS(M+1)=420.1。

Example 18 (+ \ -) -3- (4- (3-methyl-1- (4-methylquinolin-3-ylamino) butyl) benzoylamino) propionic acid

To a solution of intermediate 21(40mg,0.11mmol) in methanol (4mL) at 0 deg.C was added a 2N aqueous solution of sodium hydroxide (4mL,8 mmol). The reaction mixture was heated to reflux and stirred for 1.5 h. The mixture was acidified to pH3 by addition of 1N aqueous HCl and extracted twice with ethyl acetate (30 mL). The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated to give a yellow solid, which was dissolved in DMF (5 mL). HATU (98mg, 0.25mmol), diisopropylethylamine (32mg, 0.25mmol) and methyl 3-aminopropionate hydrochloride (22mg, 0.15mmol) were added. The resulting mixture was stirred at 30 ℃ for 1 hour. The mixture was poured into brine (20mL) and extracted twice with ethyl acetate (30 mL). The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered, and concentrated to give 50mg of oil, which was dissolved in THF (4 mL). 2N aqueous lithium hydroxide (4mL,8mmol) was added. The reaction mixture was stirred at 30 ℃ for 12 hours. The mixture was acidified to pH3 by addition of 1N aqueous HCl and extracted with ethyl acetate (30mL × 2). The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated. In Phenomenex Synergi C₁₈HPLC purification on a 150X30mmX4 μm column eluting with 49% to 69% aqueous acetonitrile (0.225% formic acid regulator) gave a yellow solid3- (4- (3-methyl-1- (4-methylquinolin-3-ylamino) butyl) benzoylamino) propionic acid (12.2mg) of the isomer.¹H NMR(400MHz,CD₃OD)δ8.26(s,1H),8.02(d,J=8.4Hz,1H),7.74-7.77(m,3H),7.54-7.45(m,4H),4.82-4.78(m,1H),3.57-3.61(m,2H),2.58-2.62(m,5H),2.03-1.97(m,1H),1.86-1.83(m,1H),1.73-1.68(m,1H),1.07(d,J=6.4Hz,3H),1.00(d,J=6.4Hz,3H).MS(M+1)=420.1。

EXAMPLE 19 (+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid

(+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl]-benzoylamino } -propionic acid ethyl ester (intermediate 27) (36mg,0.076mmol) was dissolved in tetrahydrofuran (3mL) and methanol (1mL) and 1.0M sodium hydroxide (2mL) was added. The solution was stirred at room temperature for 45 minutes, after which 1N HCl was added to bring it to pH 4.5. It was extracted twice with ethyl acetate and over MgSO₄The combined organics were dried. The solution was concentrated in vacuo to give (+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl as a white solid]-benzoylamino } -propionic acid (40.8mg), doped with ethyl acetate. MS (M +1): 446.3. HPLC: Xbridge C₁₈150mmx4.6mm,5 μm column, flow rate 1.50mL/min, linear gradient: over 11 minutes, 5% acetonitrile/water (0.1% trifluoroacetic acid modulator) to 100% acetonitrile, retention time =7.046 min.

EXAMPLE 20 (+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (6-fluoro-3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid

To prepare intermediate 27 from intermediate 29Method for the preparation of (+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (6-fluoro-3-methyl-quinolin-2-ylamino) -methyl]-benzoylamino } -propionic acid ethyl ester (14.3mg,0.029mmol), dissolved in tetrahydrofuran (1.5mL) and methanol (0.5mL), and 1.0M sodium hydroxide (1mL) added. The solution was stirred at room temperature for 20 minutes, after which 1N HCl was added to reach pH 5. It was extracted twice with ethyl acetate and over MgSO₄The combined organics were dried and concentrated in vacuo. Purification by reverse phase HPLC gave (+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (6-fluoro-3-methyl-quinolin-2-ylamino) -methyl]-benzoylamino } -propionic acid (10 mg). Analysis LCMS retention time 2.3998 minutes (Watersaltmatic dC)₁₈4.6 × 50mm,5 μm column; linearly gradient to 95% acetonitrile/water over 4.0 min, 5% acetonitrile/water (0.05% trifluoroacetic acid modifier), held at 95% acetonitrile/water for 1.0 min; flow rate 2.0 mL/min); MS (M +1): 464.0.

Example 21 (+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (7-fluoro-3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid

Example 21 was prepared from intermediate 31 in analogy to the procedure of example 20. Purification by reverse phase HPLC gave (+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (7-fluoro-3-methyl-quinolin-2-ylamino) -methyl]-benzoylamino } -propionic acid (9.6 mg). Analysis LCMS Retention time 2.4302 minutes (Waters Atlantic dC)₁₈4.6 × 50mm,5 μm column; over 4.0 minutes, 5% acetonitrile/water (0.03% NH)₄OH conditioner) linear gradient to 95% acetonitrile/water, held at 95% acetonitrile/water for 1.0 min; flow rate 2.0 mL/min); MS (M +1): 464.0.

Example 22 (+/-)3- (4- ((3, 3-dimethylcyclobutyl) (7-fluoroquinolin-3-ylamino) methyl) benzoylamino) propionic acid

To a flask containing ethyl 3- (4- ((3, 3-dimethylcyclobutyl) (7-fluoroquinolin-3-ylamino) methyl) benzoylamino) propionate (6.20mg,0.0130mmol) were added tetrahydrofuran (0.0330mL), methanol (0.0330mL) and 1N sodium hydroxide (0.0330mL,0.0330 mmol). The reaction was stirred at room temperature for 18 h. The reaction was then diluted with ethyl acetate and water. Then, 1N hydrochloric acid (0.0330mL) was added dropwise to bring the pH to 3. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 3- (4- ((3, 3-dimethylcyclobutyl) (7-fluoroquinolin-3-ylamino) methyl) benzoylamino) propionic acid as a solid (3.5mg, 60% yield).¹H NMR(400MHz,CD₃OD,δ):8.53(d,J=2.7Hz,1H),8.45(t,J=5.7Hz,1H),7.80-7.72(m,2H),7.59-7.51(m,3H),7.43(dd,J=10.0,2.6Hz,1H),7.23(td,J=8.8,2.5Hz,1H),6.99(d,J=2.5Hz,1H),4.38(d,J=9.6Hz,1H),3.67-3.57(m,2H),2.67-2.60(m,3H),2.16-2.06(m,1H),1.78(d,J=2.5Hz,2H),1.63-1.52(m,1H),1.18(s,3H),1.13(s,3H).(M+1):450.3。

Example 23 (+/-)3- (4- ((3, 3-dimethylcyclobutyl) (6-fluoroquinolin-3-ylamino) methyl) benzoylamino) propionic acid

To a flask containing ethyl 3- (4- ((3, 3-dimethylcyclobutyl) (6-fluoroquinolin-3-ylamino) methyl) benzoylamino) propionate (7.4mg,0.0420mmol) were added tetrahydrofuran (0.105mL), methanol (0.105mL), and 1N sodium hydroxide (0.105mL,0.105 mmol). The reaction was stirred at room temperature for 4.5 h. Then, the reaction was diluted with ethyl acetate and water. Next, 1N hydrochloric acid (0.105mL) was added dropwise to bring the pH to 3. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 3- (4- ((3, 3-dimethylcyclobutyl) (6-fluoroquinolin-3-ylamino) methyl) benzoylamino) propionic acid as a solid (6.7mg, 99% yield).¹H NMR(400MHz,CD₃OD,δ):8.46(d,J=2.7Hz,1H),7.83-7.72(m,3H),7.57-7.50(m,2H),7.17-7.09(m,2H),6.85(d,J=2.7Hz,1H),4.38(d,J=9.8Hz,1H),3.62(t,J=6.9Hz,2H),2.69-2.54(m,3H),2.11(ddd,J=11.4,7.7,4.2Hz,1H),1.77(ddd,J=11.2,9.0,2.6Hz,2H),1.63-1.52(m,1H),1.18(s,3H),1.13(s,3H).(M+1):450.3。

Example 24 3- (4- ((3, 3-dimethylcyclobutyl) (quinolin-3-ylamino) methyl) benzoylamino) propionic acid

To a flask containing ethyl 3- (4- ((3, 3-dimethylcyclobutyl) (quinolin-3-ylamino) methyl) benzoylamino) propionate (11.9mg,0.0650mmol) were added tetrahydrofuran (0.0650mL), methanol (0.0650mL) and 1N sodium hydroxide (0.0650mL,0.0650 mmol). The reaction was stirred at room temperature for 18 h. The reaction was then diluted with ethyl acetate and water. Then, 1N hydrochloric acid (0.0650mL) was added dropwise to bring the pH to 3. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 3- (4- ((3, 3-dimethylcyclobutyl) (quinolin-3-ylamino) methyl) benzoylamino) propionic acid as a solid (9.3mg, 83% yield).¹H NMR(400MHz,CD₃OD)δ:8.50(d,J=2.7Hz,1H),8.45(t,J=5.8Hz,1H),7.81-7.70(m,3H),7.61-7.52(m,2H),7.52-7.41(m,1H),7.41-7.21(m,2H),6.93(d,J=2.7Hz,1H),4.39(d,J=9.8Hz,1H),3.69-3.55(m,2H),2.71-2.51(m,3H),2.11(ddd,J=11.4,7.8,4.1Hz,1H),1.85-1.70(m,2H),1.57(ddd,J=11.3,7.8,4.1Hz,1H),1.18(s,3H),1.13(s,3H).MS(M+1):432.3。

EXAMPLE 25 3- {4- [ 3-methyl-1- (8-methyl-quinolin-3-ylamino) -butyl ] -benzoylamino } propionic acid

To the 3- {4- [ 3-methyl-1- (8-methyl-quinolin-3-ylamino group) -butyl radical]To a mixture of-benzoylamino } -propionic acid methyl ester (44mg,0.1mM) in a 1:1 mixture of THF/MeOH (1mL) was added a 1N NaOH solution (0.25mL,0.25 mM). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to remove the organic solvent. The aqueous solution was diluted with DCM (5mL) and acidified to pH =3-4 by 1N HCl solution. The organic solution was separated and the aqueous solution was extracted with 10% i-PrOH-DCM (3X5 mL). The combined organic solutions were dried (NaSO)₄) And concentrated to give the product as a yellow solid (-100%).¹H NMR(500MHz,DMSO-d₆) δ ppm0.93(d, J =6.59Hz,3H)0.98(d, J =6.34Hz,3H)1.56(dt, J =13.30,6.77Hz,1H)1.71(dt, J =13.36,6.62Hz,1H)1.76-1.85(m,1H)2.46(t, J =7.07Hz,2H)2.59(s,3H)3.36-3.46(m,2H)4.64(t, J =7.07Hz,1H)7.10(br.s.,1H)7.21(br.s.,1H)7.26(d, J =6.83Hz,1H)7.32(t, J =7.56Hz,1H)7.45(d, J =8.05, 1H)7.53, J = 8.53, J =8.5 Hz, 8H) 7.49 Hz,1H)7.32(t, J =7.56Hz,1H)7.45(d, J =8.05, 1H)7.53 Hz, 8.8H = 8Hz, 8H, 1H) 1H, 1H) 7.49 Hz,1H, 8H, 1H, 8Hz,1H, 8H. LC-MS:420.2(M + 1).

Example 26- {4- [ 3-methyl-1- (7-methyl-quinolin-3-ylamino) -butyl ] -benzoylamino } -propionic acid

To the 3- {4- [ 3-methyl-1- (8-methyl-quinolin-3-ylamino) -butyl]To a mixture of-benzoylamino } -propionic acid methyl ester (12) (49mg,0.11mM) in a 1:1 mixture of THF/MeOH (1mL) was added a 1N NaOH solution (0.283mL,0.283 mM). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to remove the organic solvent. The aqueous solution was diluted with DCM (5mL) and acidified to pH =3-4 by 1N HCl solution. The organic solution was separated and the aqueous solution was extracted with 10% i-PrOH-DCM (3X5 mL). The combined organic solutions were dried (Na)₂SO₄) And concentrated to give the product as a yellow solid (-78%).¹H NMR(500MHz,DMSO-d₆)δppm0.93(d,J=6.59Hz,3H)0.98(d,J=6.59Hz,3H)1.53-1.60(m,1H)1.70(dt,J=13.72,6.68Hz,1H)1.76-1.83(m,1H)2.43(s,3H)2.47(t,J=7.07Hz,2H)3.35-3.46(m,2H)4.65(t,1H)7.23(br.s.,1H)7.37(d, J =8.54Hz,1H)7.41(br.s, 1H)7.54(d, J =8.29Hz,2H)7.59-7.67(m,2H)7.76(d, J =8.29Hz,2H)8.43(t, J =5.49Hz,1H)8.61(d, J =2.68Hz,1H), one proton is exchanged. LC-MS: M/z420.2(M + 1).

Example 27N- (4- { 3-methyl-1- [ (6-methylquinolin-3-yl) amino ] butyl } benzoyl) -beta-alanine

Prepared in analogy to 3- {4- [ 3-methyl-1- (8-methyl-quinolin-3-ylamino) -butyl ] -benzoylamino } -propionic acid of example 25 using 3-bromo-6-methylquinoline. M/z (M +1) = 420.2.

Example 28 3- (4- ((6, 7-Difluoroquinolin-3-ylamino) (3, 3-dimethylcyclobutyl) methyl) benzoylamino) propionic acid

The title compound was prepared in analogy to the procedure of example 27.

Example 29 (+/-) -3- (4- (4,4, 4-trifluoro-1- (quinolin-3-ylamino) butyl) benzoylamino) propionic acid

To a solution of ethyl (+/-) -3- (4- (4,4, 4-trifluoro-1- (quinolin-3-ylamino) butyl) benzoylamino) propionate (74mg,0.16mmol) in methanol (0.78mL) and tetrahydrofuran (0.78mL) was added a 1N aqueous solution of sodium hydroxide (0.78mL,0.78 mmol). After 10 minutes, the solution was concentrated under reduced pressure to remove methanol and tetrahydrofuran. The mixture is then acidified to pH4 with 1N aqueous hydrochloric acid and saturatedAnd diluted with aqueous sodium chloride (10 mL). The aqueous layer was extracted with ethyl acetate (3X15 mL). The combined organic layers were passed over Na₂SO₄Drying and filtration, and concentration of the filtrate under reduced pressure gave (+/-) -3- (4- (4,4, 4-trifluoro-1- (quinolin-3-ylamino) butyl) benzoylamino) propionic acid.¹HNMR(400MHz,DMSO-d₆)δ12.18(br.s.,1H),8.56(d,J=2.7Hz,1H),8.44(t,J=5.6Hz,1H),7.78(d,J=8.4Hz,2H),7.76-7.72(m,1H),7.54(d,J=8.2Hz,2H),7.52-7.48(m,1H),7.37-7.27(m,2H),7.03(d,J=7.8Hz,1H),6.86(d,J=2.5Hz,1H),4.73-4.61(m,1H),3.46-3.37(m,2H),2.47(t,J=7.0Hz,2H),2.39-2.23(m,1H),2.14-1.92(m,2H),1.20-1.13(m,1H);(M+1):446.2。

Example 30 3- (4- (3-methyl-1- ((3-methylquinolin-2-yl) amino) butyl) benzoylamino) propionic acid, isomer 1

To a solution of ethyl 3- (4- (1- ((3-methylquinolin-2-yl) amino) butyl) benzoylamino) propionate, isomer 1(96.2mg,0.215mmol) in tetrahydrofuran (1.1mL) and methanol (1.1mL) was added 1N aqueous sodium hydroxide solution (1.1mL,1.1 mmol). The solution was stirred at room temperature for 10 minutes. The solution was concentrated under reduced pressure to remove tetrahydrofuran and methanol. 1N aqueous hydrochloric acid was added dropwise to a pH of 6. The aqueous layer was extracted with ethyl acetate (4X5 mL). The combined organic layers were concentrated under reduced pressure and dried in a vacuum oven to give 3- (4- (3-methyl-1- ((3-methylquinolin-2-yl) amino) butyl) benzoylamino) propionic acid as a single isomer.¹HNMR(400MHz,DMSO-d₆) δ 8.67-8.57(m,1H),7.73-7.66(m,3H),7.59-7.51(m,3H),7.45-7.40(m,1H),7.39-7.32(m,1H),7.09(ddd, J =7.9,6.7,1.4Hz,1H),6.61(d, J =8.6Hz,1H),5.56-5.45(m,1H),3.40-3.33(m,2H),2.34-2.25(m,5H),2.01-1.90(m,1H),1.71-1.57(m,2H),0.96(d, J =6.4Hz,3H),0.91(d, J =6.2Hz, 3H); chiral SFC (Chiralpak AD-H column, 4.6mm × 25cm,25% methanol/carbon dioxide eluent, 0.2% isopropylamine modulator, retention time 3.75 min); MS (M +1): 420.3.

Example 31 3- (4- (3-methyl-1- ((3-methylquinolin-2-yl) amino) butyl) benzoylamino) propionic acid, isomer 2

3- (4- (3-methyl-1- ((3-methylquinolin-2-yl) amino) butyl) benzoylamino) propionic acid, isomer 2, was prepared from a mixture of methyl and ethyl 3- (4- (1- ((3-methylquinolin-2-yl) amino) butyl) benzoylamino) propanoate, isomer 2, by an analogous method to example 30.¹HNMR(400MHz,DMSO-d₆) δ 8.86-8.76(m,1H),7.73-7.65(m,3H),7.59-7.49(m,3H),7.45-7.39(m,1H),7.39-7.33(m,1H),7.09(ddd, J =8.0,6.7,1.2Hz,1H),6.61(d, J =8.0Hz,1H),5.56-5.45(m,1H),3.36-3.29(m,2H),2.30(d, J =1.0Hz,3H),2.17(t, J =6.9Hz,2H),2.01-1.90(m,1H),1.71-1.57(m,2H),0.96(d, J =6.5Hz,3H),0.91(d, J = 6.81H), chiral 3.81H, 2mm, 4% chiral 2 pa-c/min eluent with a chiral column (4% of methanol); MS (M +1): 420.3.

Example 32- {4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid, isomer 1.

By treating 3- {4- [ (3, 3-dimethyl-cyclobutyl) - (3-methylquinolin-2-ylamino) -methyl with 1N NaOH (2.5eq.) in methanol/THF in a similar manner to that described in example 19]-benzoylamino } -propionic acid methyl ester, isomer 1 (intermediate 70) the title compound was prepared to give the title compound. Chiral SFC was analyzed (Chiralpak AD-H column, 4.6mmX25cm,30% methanol/carbon dioxide eluent, flow rate 2.5ml/min, retention time 2.78);¹H NMR(400MHz,CDCl₃)δ7.66(d,J=8.4Hz,2H),7.56-7.63(m,2H),7.44-7.52(m,3H),7.37-7.44(m,1H),7.11-7.19(m,1H),5.30(d,J=9.8Hz,1H),3.67(q,J=5.9Hz,2H),2.62-2.70(m,3H),2.29(s,3H),1.94(ddd,J=11.2,8.2,3.0Hz,1H),1.70-1.82(m,1H),1.62-1.70(m,2H),1.13(s,3H),1.08(s,3H);MS(M+1):446.4。

example 33- {4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid, isomer 2

By treating 3- {4- [ (3, 3-dimethyl-cyclobutyl) - (3-methylquinolin-2-ylamino) -methyl with 1N NaOH (2.5eq.) in methanol/THF in a similar manner to that described in example 19]-benzoylamino } -propionic acid methyl ester, isomer 2 (intermediate 71) the title compound was prepared to give the title compound. Chiral SFC was analyzed (Chiralpak AD-H column, 4.6mmX25cm,30% methanol/carbon dioxide eluent, flow rate 2.5ml/min, retention time 4.60);¹H NMR(400MHz,CDCl₃)δ7.66(d,J=8.4Hz,2H),7.58-7.63(m,2H),7.44-7.51(m,3H),7.37-7.44(m,1H),7.10-7.18(m,1H),6.81(t,J=5.8Hz,1H),5.30(d,J=9.6Hz,1H),3.67(q,J=5.9Hz,2H),2.52-2.70(m,3H),2.29(s,3H),1.94(ddd,J=11.1,8.0,3.1Hz,1H),1.72-1.82(m,1H),1.63-1.72(m,2H),1.13(s,3H),1.08(s,3H);MS(M+1):446.3。

example 34- {4- [ (3, 3-dimethyl-cyclobutyl) - (6-fluoro-3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid, isomer 1

By treating 3- {4- [ (3, 3-dimethyl-cyclobutyl) - (6-fluoro-3-methylquinolin-2-ylamino) -methyl- ] with 1N NaOH (2.5eq.) in methanol/THF in a similar manner to that described in example 19]-benzoylamino } -propionic acidMethyl ester, isomer 1 (intermediate 74) the title compound was prepared to give the title compound. Chiral SFC was analyzed (Chiralpak IC column, 4.6mmX25cm,25% methanol/carbon dioxide eluent, flow rate 2.5ml/min, retention time 4.33);¹H NMR(400MHz,DMSO-d₆)δ12.14(s,1H),8.38(br.s.,1H),7.63-7.76(m,3H),7.55(d,J=7.8Hz,2H),7.39-7.50(m,1H),7.30-7.39(m,1H),7.21-7.30(m,1H),6.45-6.60(m,1H),5.11-5.28(m,1H),3.41(dd,J=12.7,7.1Hz,2H),2.75-2.91(m,1H),2.46(t,J=7.1Hz,2H),2.29(s,3H),1.92-2.00(m,1H),1.56-1.67(m,2H),1.42-1.55(m,1H),1.12(s,3H),1.07(s,3H);MS(M+1):464.3。

example 35- {4- [ (3, 3-dimethyl-cyclobutyl) - (6-fluoro-3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid, isomer 2

By treating 3- {4- [ (3, 3-dimethyl-cyclobutyl) - (6-fluoro-3-methylquinolin-2-ylamino) -methyl- ] with 1N NaOH (2.5eq.) in methanol/THF in a similar manner to that described in example 19]-benzoylamino } -propionic acid methyl ester, isomer 2 (intermediate 75) the title compound was prepared to give the title compound. Chiral SFC was analyzed (Chiralpak IC column, 4.6mmX25cm,25% methanol/carbon dioxide eluent, flow rate 2.5ml/min, retention time 4.81);¹H NMR(400MHz,DMSO-d₆)δ12.13(s,1H),8.37(t,J=5.5Hz,1H),7.65-7.71(m,3H),7.54(d,J=8.3Hz,2H),7.39-7.47(m,1H),7.29-7.37(m,1H),7.19-7.29(m,1H),6.53(d,J=8.1Hz,1H),5.13-5.23(m,1H),3.41(dd,J=12.4,6.8Hz,2H),2.77-2.90(m,1H),2.46(t,J=7.1Hz,2H),2.28(s,3H),1.92-2.00(m,1H),1.56-1.66(m,2H),1.42-1.53(m,1H),1.11(s,3H),1.07(s,3H);MS(M+1):464.2。

biological data

Glucagon cAMP assay

Cisbio cAMP detection assay for determination of putative (punitive) glucagon antagonismThe agent blocks the ability of glucagon-induced cAMP production. The potential glucagon antagonists were resuspended and diluted with 100% DMSO. The 100xDMSO compound stock solution was diluted 20x with DMEM-F12 medium (Invitrogen) containing 0.1% or 4% BSA before use in glucagon cAMP assay. Mu.l of 5 Xcompound stock solution was spotted into appropriate wells of a low-binding white firm-bottomed 384-well plate (Corning). 2 μ l of 5% DMSO or a known glucagon antagonist was added to each plate to define the assay window. CHOK1 cells stably transfected with human glucagon receptor were removed from the culture flasks with cell dissociation buffer. To 8.3e in DMEM-F12 with or without 4% BSA and 200uMIBMX⁵Cell particles were resuspended at a concentration of cells/ml. Mu.l of the cell suspension was added to the assay plate. The plates were incubated at room temperature for 20min, then a 100pM challenge dose of glucagon was added. Running glucagon dose response curves to determine the EC of glucagon on separate culture plates₅₀. After incubation at room temperature for 30min, the reaction was stopped by adding lysis buffer containing cAMP detection reagent. The plates were incubated at room temperature for a further 60min before reading with a Perkin Elmer fluorescence plate reader. Raw data were converted to nM of cAMP based on cAMP standard curve. The transformed data was then analyzed using the Pfizer data analysis program. Determining IC from the resulting sigmoidal dose response curve₅₀The value is obtained. The Kb value is calculated using a modified Cheng-Prusoff equation.

cAMP data sheet

Example numbering	N	cAMP Kb(nM)
			Example 1	28	110
Example 2	24	520
			Example 3	10	270
Example 4	2	5,100
			Example 5	8	380
Example 6	2	620
			Example 7	2	1,000
Example 8	2	1,000
			Example 9	6	450
Example 10	6	220
			Example 11	6	91
Example 12	6	310
			Example 13	6	140
Example 14	1	3,100
			Example 15	6	1,100
Example 16	6	800
			Example 17	8	880
Example 18	8	100
			Example 19	8	64
Example 20	10	64
			Example 21	5	160
Example 22	2	47
			Example 23	4	63
Example 24	4	140
			Example 25	-	-
Example 26	-	-
			Example 27	4	250
Example 28	-	-
			Example 29	9	930
Example 30	6	69
			Example 31	6	1300
Example 32	6	23
			Example 33	6	1820
Example 34	2	1180
			Example 35	2	33

Human glucagon SPA assay

The glucagon SPA assay is used to determine the ability of a test compound to block the binding of glucagon-cex to the glucagon receptor. Test compounds were resuspended and serially diluted in 100% DMSO. Mu.l of the desired concentration of test compound was spotted into appropriate wells of a 96-well low-binding white clear-bottomed plate (Corning). Mu.l DMSO was spotted into all binding wells. Mu.l of a 20. mu.M concentration of a known glucagon antagonist was added to the non-specific binding wells. The [2 ] gene from human glucagon receptor (Millipore), 125pM¹²⁵I]0.3-0.75. mu.g membrane plus Glucagon-Cex (Perkin Elmer) and 175. mu.g of WGA PVT SPA bead (Perkin Elmer stabilized) transfected chem-1 cellsInto all wells of the assay plate. All assay components except the test compound were resuspended in the following buffer: 50mM Hepes pH 7.4; 5mM MgCl₂(ii) a 1mM CaCl; 5% glycerol and 0.2% BSA. After 6-10h incubation at room temperature, the amount of thermal ligand bound to the cell membrane was determined by reading the plates on a Wallac Trilux radioactive emission detector. The data was analyzed using the Pfizer data analysis program. IC is then determined from the resulting sigmoidal dose response curve₅₀The value is obtained. Ki values were calculated using the Cheng-Prusoff equation.

SPA binding data sheet

Example numbering	N	Binding Ki (nM)
			Example 1	11	173
Example 2	5	280
			Example 3	5	240
Example 4	1	7355
			Example 5	5	452
Example 6	1	1855
			Example 7	-	-
Example 8	1	979
			Example 9	4	531
Example 10	4	198

Example 11	4	101
			Example 12	4	242
Example 13	4	199
			Example 14	-	-
Example 15	4	479
			Example 16	4	91
Example 17	3	360
			Example 18	3	109
Example 19	4	74
			Example 20	3	39
Example 21	2	133
			Example 22	2	25
Example 23	2	50
			Example 24	-	-
Example 25	-	-
			Example 26	-	-
Example 27	2	160
			Example 28	-	-
Example 29	4	930
			Example 30	2	76
Example 31	1	1237
			Example 32	2	53
Example 35	2	14

Claims (15)

1. A compound of formula I

Or a pharmaceutically acceptable salt thereof, wherein

R¹Is (C)₁-C₆) Alkyl optionally substituted with 1-3 fluoro, hydroxy or methoxy; (C)₃-C₇) Cycloalkyl optionally substituted by 1-2 fluorines or 1-2 (C)₁-C₃) Alkyl substituted, each of which is optionally substituted with 1-3 fluorines and wherein (C)₃-C₇) One carbon of the cycloalkyl group may be replaced by O; or (C)₃-C₇) Cycloalkyl- (C)₁-C₆) Alkyl group, wherein (C) is₃-C₇) Cycloalkyl- (C)₁-C₆) Of alkyl radicals (C)₃-C₇) Cycloalkyl is optionally substituted by 1-2 (C)₁-C₃) Alkyl substituted, each of which is optionally substituted with 1-3 fluoro;

R²is hydrogen or (C)₁-C₃) An alkyl group;

R³is tetrazolyl, -CH₂-tetrazolyl, - (CH)₂)₂SO₃H，-(CH₂)₂CO₂H，-CH₂CHFCO₂H or-CH₂CH(OH)CO₂H；

A¹，A²And A³Each independently is CR⁴Or N, provided that A¹，A²And A³At least one but at most two of is N;

R⁴independently at each occurrence is hydrogen, halogen, cyano, (C) optionally substituted by 1-3 fluoro₁-C₃) Alkyl, optionally substituted by 1-3 fluoro (C)₁-C₃) Alkoxy or (C)₃-C₅) A cycloalkyl group;

B¹，B²，B³and B⁴Each independently is CR⁵Or N, provided that B¹，B²，B³And B⁴At most two of (a) is N; and is

R⁵Independently at each occurrence is hydrogen, halogen, cyano, (C) optionally substituted by 1-3 fluoro₁-C₃) Alkyl, or (C) optionally substituted by 1-3 fluorines₁-C₃) Alkoxy or (C)₃-C₅) A cycloalkyl group.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen and R³Is- (CH)₂)₂CO₂H。

3. A compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R¹Is ethyl, propyl, isopropyl, isobutyl, tert-butyl, pentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl; each of which is optionally substituted with 1-3 fluorines and wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are each optionally substituted with 1-2 methyl groups.

4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein B¹，B²，B³And B⁴Each is CR⁵。

5. A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein

A¹And A²Each is CR⁴And A is³Is N;

R⁴independently for each occurrence is hydrogen, fluoro, chloro, methyl or ethyl; and

R⁵independently for each occurrence is hydrogen, fluoro, chloro, methyl, trifluoromethyl or methoxy.

6. A compound according to claim 1 selected from

(+/-) -3- (4- (1- (3-methylquinolin-2-ylamino) butyl) benzoylamino) propionic acid;

(+/-) -3- {4- [ 3-methyl-1- (quinolin-3-ylamino) -butyl ] -benzoylamino } -propionic acid;

(+/-) -3- {4- [1- (7-fluoro-quinazolin-2-ylamino) -3-methyl-butyl ] -benzoylamino } -propionic acid;

(+/-) -3- {4- [ 3-methyl-1- (quinolin-2-ylamino) -butyl ] -benzoylamino } -propionic acid;

(+/-) -3- {4- [1- (8-methoxy-quinolin-2-ylamino) -3-methyl-butyl ] -benzoylamino } -propionic acid;

(+/-) -3- {4- [ 3-methyl-1- (3-methyl-quinoxalin-2-ylamino) -butyl ] -benzoylamino } -propionic acid;

(+/-) -3- {4- [ 3-methyl-1- (quinoxalin-2-ylamino) -butyl ] -benzoylamino } -propionic acid;

(+/-) -3- {4- [ 3-methyl-1- (4-methyl-quinolin-2-ylamino) -butyl ] -benzoylamino } -propionic acid;

(+/-) -3- {4- [ 3-methyl-1- (3-methyl-quinolin-2-ylamino) -butyl ] -benzoylamino } -propionic acid;

(+/-) -3- {4- [1- (7-fluoro-4-methyl-quinolin-2-ylamino) -3-methyl-butyl ] -benzoylamino } -propionic acid;

(+/-) -3- {4- [1- (8-chloro-quinolin-2-ylamino) -3-methyl-butyl ] -benzoylamino } -propionic acid;

(+/-) -3- {4- [ 3-methyl-1- (quinazolin-2-ylamino) -butyl ] -benzoylamino } -propionic acid;

(+/-)3- (4- (3-methyl-1- (7- (trifluoromethyl) quinolin-2-ylamino) butyl) benzoylamino) propionic acid;

(+/-) -3- (4- (3-methyl-1- (6- (trifluoromethyl) quinolin-2-ylamino) butyl) benzoylamino) propionic acid;

(+ \\ -) -3- (4- (3-methyl-1- (2-methylquinolin-3-ylamino) butyl) benzoylamino) propionic acid;

(+ \\ -) -3- (4- (3-methyl-1- (4-methylquinolin-3-ylamino) butyl) benzoylamino) propionic acid;

(+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid;

(+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (6-fluoro-3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid;

(+/-) -3- {4- [ (3, 3-dimethyl-cyclobutyl) - (7-fluoro-3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid;

(+/-)3- (4- ((3, 3-dimethylcyclobutyl) (6-fluoroquinolin-3-ylamino) methyl) benzoylamino) propionic acid;

(+/-) -3- (4- ((3, 3-dimethylcyclobutyl) (7-fluoroquinolin-3-ylamino) methyl) benzoylamino) propionic acid;

(+/-) -3- (4- (4,4, 4-trifluoro-1- (quinolin-3-ylamino) butyl) benzoylamino) propionic acid;

(+/-) -3- (4- ((6, 7-difluoroquinolin-3-ylamino) (3, 3-dimethylcyclobutyl) methyl) benzoylamino) propionic acid;

(+/-) -3- (4- (3-methyl-1- (7-methylquinolin-3-ylamino) butyl) benzoylamino) propionic acid;

(+/-) -3- (4- (3-methyl-1- (8-methylquinolin-3-ylamino) butyl) benzoylamino) propionic acid;

(+/-) -3- (4- (3-methyl-1- (6-methylquinolin-3-ylamino) butyl) benzoylamino) propionic acid; and

(+/-) -3- (4- (3-methyl-1- (5-methylquinolin-3-ylamino) butyl) benzoylamino) propionic acid;

or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 selected from

(+) -3- (4- (1- (3-methylquinolin-2-ylamino) butyl) benzoylamino) propionic acid;

(-) -3- (4- (1- (3-methylquinolin-2-ylamino) butyl) benzoylamino) propionic acid;

(+) -3- (4- (3-methyl-1- (3-methylquinolin-2-ylamino) butyl) benzoylamino) propionic acid; and

(-) -3- (4- (3-methyl-1- (3-methylquinolin-2-ylamino) butyl) benzoylamino) propionic acid;

or a pharmaceutically acceptable salt thereof.

3- {4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid, isomer 1, or a pharmaceutically acceptable salt thereof.

3- {4- [ (3, 3-dimethyl-cyclobutyl) - (3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid, isomer 2, or a pharmaceutically acceptable salt thereof.

3- {4- [ (3, 3-dimethyl-cyclobutyl) - (6-fluoro-3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid, isomer 1, or a pharmaceutically acceptable salt thereof.

3- {4- [ (3, 3-dimethyl-cyclobutyl) - (6-fluoro-3-methyl-quinolin-2-ylamino) -methyl ] -benzoylamino } -propionic acid, isomer 2, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising (i) a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable excipient, diluent or carrier.

13. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of obesity and obesity related disorders.

14. The use of a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or delaying the development or onset of type 2 diabetes, type 1 diabetes and diabetes related disorders.

15. Use of a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease, condition, or disorder modulated by inactivation of the glucagon receptor.