TW201249837A - New compounds, pharmaceutical compositions and uses thereof - Google Patents

Abstract

The present invention relates to compounds of general formula I, wherein the groups R1, LP, LQ, X1, X2, X3, A, n and m are as defined in the application, which have valuable pharmacological properties, and in particular bind to the GPR119 receptor and modulate its activity.

Description

201249837 VI. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to novel compounds, in particular, to compounds of formula I:

Wherein the groups R1, Lp, LQ, X1, X2, X3, a, η and m are as defined below; methods of preparing such compounds; pharmaceutical compositions; their use as modulators of the G protein coupling receptor GPR119; Its therapeutic use (especially for diseases and conditions mediated by modulation of the G protein-coupled receptor GPR119); and pharmaceutical compositions comprising the same. [Prior Art] Diabetes is a severe metabolic disease that affects more than one million people worldwide. There are more than 12 million people with diabetes in the United States, and 600,000 new cases are diagnosed each year. The prevalence of diabetes is increasing, in more detail, this means that the frequency of complications is high, resulting in a reduction in the quality of life and life expectancy. Because of the microvascular complications associated with diabetes, 'type 2 diabetes is currently the most common cause of adult-onset vision loss, renal insufficiency, and resection in industrialized countries. In addition, type 2 diabetes is associated with a 2 to 5 fold increase in the risk of cardiovascular disease. UKPDS Study (UK Prospective Diabetes Study; United Kingdom)

Prospective Diabetes Study) showed that intensive treatment with commonly used therapeutic agents such as metformin, sulfonyl urea or insulin produced only a limited improvement in glycemic control (HbAlc values differ by about 0.9%). This 161177.doc 201249837 outside, even in patients in the intensive treatment group, glycemic control significantly worsened over time, and this phenomenon was attributed to deterioration of β-cell function. Diabetes is also a major cause of retinal damage in the back of the eye and increases the risk of cataracts and glaucoma. Finally, 'diabetes is associated with nerve damage, especially nerve damage in the legs and feet', thereby affecting the patient's ability to feel pain and causing serious infection. All in all, diabetes complications are among the leading causes of death worldwide. Excessive fat (obesity) is the result of an imbalance between calorie intake and energy expenditure. It is highly associated with insulin resistance and diabetes. However, the molecular mechanisms involved in obesity/diabetes syndrome remain unclear. In the early stages of obesity development, increased insulin secretion counteracts insulin resistance and prevents patients from developing hyperglycemia. However, after a certain period of time, the function of the sputum cells deteriorated and non-insulin-dependent diabetes occurred in about 20 〇/〇 in the obese group. Therefore, obesity has become a key risk factor for diabetes, but the factors that make the membrane secretion of a group of patients susceptible to pathological changes with fat accumulation are still unknown. Obesity also significantly increases the risk of cardiovascular disease development. Diabetes is also involved in the development of kidney disease, eye disease and nervous system problems. Kidney disease, also known as nephropathy, occurs when the kidney's filtration mechanism is disrupted and excess protein escapes into the urine and eventually causes kidney failure. Therefore, there is a medical need for drugs for preventing and/or treating metabolic disorders (especially diabetes, mainly type 2 diabetes) and their complications. In detail, it is necessary to control blood sugar, improve the nature of the disease, and reduce cardiovascular disease. A drug that has good activity in terms of rate and mortality and also has a better safety profile. Dyslipidemia is a lipoprotein metabolism disorder, including lipoprotein overproduction or lipid I61I77.doc 201249837 protein deficiency. Dyslipidemia can be manifested by an increase in total cholesterol in the blood, an increase in the concentration of LDL cholesterol and triglycerides and free fatty acids, and a decrease in the concentration of high density lipoprotein (HDL) cholesterol. Dyslipidemia usually occurs when diabetes is involved, and diabetes is a common cause of lipemia. For adults with diabetes, it is recommended to measure LDL, HDL, and total cholesterol and triglyceride levels annually. For adults with diabetes, the optimal LDL cholesterol content is less than 100 mg/dL (2_60 mmol/L), the optimal HDL cholesterol content is equal to or greater than 40 mg/dL (1.02 mmol/L), and the ideal triacid The glycerol δ content is less than 1 50 mg/dL (1.7 mmol/L). GPR119 is a G protein-coupled receptor (also known as GPCR2, RUP3, SNORF25 or GDIR), which is mainly expressed in pancreatic beta cells and K cells and L cells of the intestine. GPR119 receptors and isoforms have been identified in mammalian species including humans, rats, mice, hamsters, chimpanzees, rhesus monkeys, cattle and dogs. The expression of GPR119 in the pancreas and especially in pancreatic beta cells raises the hypothesis that GPR119 receptors may affect insulin secretion. Activation of this receptor stimulates the cAMP signaling pathway and increases the intracellular content of cAMP in these cells. Thereby, the diabetic condition is improved by the dual action of the compound: activation of GPR119 in these cells directly stimulates cAMP in β cells, and in addition, stimulates intestinal release of neuroendocrine peptides (such as GIP and GLP-1 and PYY) to indirectly stimulate β. cAMP in cells. The release of these peptides may also have other beneficial effects, such as food intake, gastric emptying, and other functions that are still unknown. In addition, GPR119 agonists can be expected to improve beta cell function and beta cell mass. In fact, GPR119 activation stimulates insulin secretion in a glucose-dependent manner both in vitro and in vivo (in rodents). Two 161177.doc 201249837 endogenous ligands (lysophosphatidylcholine (LPC) and oil-based ethanolamine (OEA)) and more potent GPR119 agonists have made GPR119 available as insulin and intestine Insulin (GLP-1 and GIP) is characterized by a secretagogue receptor that reduces plasma glucose and thereby promotes glycemic control without the risk of hypoglycemia (6丨〇〇1^111.8丨〇卩11}^.1^ 8.0〇111111.2005, 744-751; Cell Metabolism 2006, 167-175; Endocrinolgy 2007, 2601-9). It has recently been shown that GPR119 agonists are effective in reducing blood glucose levels in diabetic rodents without the risk of hypoglycemia. GPR119 gene knockout animals have shown that insulin and intestinal insulin secretion induced by the GPR119 agonist is dependent on the GPR119 receptor. In addition, GPR119 agonists have been shown to reduce food intake, causing weight loss in Sprague Dawley rats. Therefore, GPR119 agonists are expected to have therapeutic benefit in metabolic diseases. Examples of such diseases include type 1 diabetes, type 2 diabetes, insufficient glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, syndrome X, metabolic syndrome, obesity, Hypertension, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, endothelial dysfunction and bone related diseases (such as osteoporosis, rheumatoid arthritis or osteoarthritis). For comparison and other information, see also: 1. Dhayal, S., Morgan, N. G. The significance of GPR119 agonists as a future treatment for type 2 diabetes. Drug News Perspect· 2010, 23(7), 418-24. 2. Yoshida, S., Tanaka, H., Oshima, H., Yamazaki, T., 161177.doc 201249837

Yonetoku, Y., Ohishi, T., Matsui, T., Shibasaki, Μ. AS1907417, a novel GPR119 agonist, as an insulinotropic and β-cell preservative agent for the treatment of type 2 diabetes. Biochem Biophys Res Commun. 2010, 400 (4), 745-51. 3. Jones, R. M., Leonard, J. N., Buzard, D. J., Lehman, J. GPR119 agonists for the treatment of type 2 diabetes. Expert Opinion on Therapeutic Patents 2009, Vol. 19, No. 10: 1339-1359. OBJECTS OF THE INVENTION The object of the present invention is to provide novel compounds, in particular novel 2,3-dihydro-benzofuran-2-yl-piperidine derivatives, which are coupled to G proteins. The body GPR119 is active. Another object of the present invention is to provide novel compounds, in particular novel 2,3-dihydro-benzofuran-2-yl-piperidine derivatives, which are agonists of the G-protein coupled receptor GPR119. . Another object of the present invention is to provide novel compounds, in particular novel 2,3-dihydro-benzofuran-2-yl-piperidine derivatives, which are capable of G protein in vitro and/or in vivo. The coupling receptor GPR119 has an activating effect and has pharmacological properties and pharmacokinetic properties suitable for use as a drug. Another object of the present invention is to provide an effective GPR119 agonist, in particular for the treatment of metabolic disorders such as diabetes, dyslipidemia and/or obesity. Another object of the present invention is to provide a method of treating a disease or condition mediated by activation of the G protein-coupled receptor GPR119 in a patient. Another object of the present invention is to provide a pharmaceutical composition comprising at least one compound of the present invention. Another object of the invention is to provide a combination of at least one compound of the invention and one or more other therapeutic agents. Another object of the present invention is to provide a process for the synthesis of these novel compounds as 2,3-dihydro-benzofuran-2-yl-piperidine derivatives. Another object of the invention is to provide starting compounds and/or intermediate compounds which are suitable for use in the process for the synthesis of such novel compounds. Other objects of the present invention will become apparent to those skilled in the art from the <RTIgt; OBJECTS OF THE INVENTION It has been found that the compounds of the invention which are described in more detail in the T have surprising and particularly advantageous properties and, in particular, are useful as GpRu9 agonists. Thus, in a first aspect, the invention relates to a formula compound:

R1 is selected from the group Ri_Gi consisting of 丨, 2 or 3, which are independently selected from N, 〇 and S, a 5-member or 6-membered heteroaromatic ring; and wherein the second ring is visible to the hetero a family ring condensation wherein the second 161177.doc 201249837 ring is a 5- or 6-membered unsaturated or aromatic ring and may contain 2 heteroatoms independently selected from N, 〇 and s, and 5 '1 or 2 even-groups in the second ring may be replaced by _ ( )-, -c(=0)_, -s(=〇)- or -s(=0)2-; = in the heteroaromatic ring and / or in the second ring ... or a plurality of NH groups in the atomic group may be replaced by rN; and it is such that each of the heteroaromatic ring and / or the second ring - Alternatively, independently of each other, one or more substituents may be substituted; and wherein the heteroaromatic or second ring may optionally be substituted by a group;

Rn A are independently selected from the group RN_G1 consisting of 丨, Ρ h ** 由 from HC丨-4 alkyl, Cm alkyl_C(=〇)_ and Cl-4 alkyl 4(= 0)2- And is selected from the group consisting of: i'2, 3'6-tetrahydro W-based ring, phenyl ring, and /, 2 substituted by Ci_4 alkyl group s(=0)2- Or 3 5 or 6 membered heteroaromatic rings independently selected from the heteroatoms of N, 0 and s and wherein the second ring may optionally be condensed with the phenyl or heteroaromatic ring, &amp; The second ring is a 5- or 6-membered unsaturated or aromatic ring, and may contain 2 or 3 heteroatoms independently selected from N, 〇M, and wherein in the second ring, 1 or 2 The -CH2- group may be replaced by ·n(rN)_, _c(=〇)·, •S(=〇)_ or -S(=〇)2_ as appropriate; and wherein the heteroaromatic ring and/or Or in the second ring, the ortho atom in the or more NH groups may be replaced by 11^; and wherein the phenyl ring, the heteroaromatic ring and/or the second ring are each 16M77.doc 201249837 The substituents selected from 1^ of the second day may be substituted with the phenyl ring or the heteroaromatic group; 1 , f or the second ring may be used independently of each other; Optionally, the group τ is selected from the group consisting of: F, C1, B..., CN, OH, N02, Cl_6 alkyl ^ 0 丨 -6 alkenyl, (V6 alkynyl _, C3-6 Cycloalkyl, c, _6, _Q_, w L3-6 cycloalkyl _ 〇 _, c alkyl group - s ·, H 〇 - C (=0) _, Ci 6 alkyl 〇 c (which, c "院基-c (Which, c3.6 ring yard base.c (which, Ci 4 burning base ♦ 〇) / Cw alkyl-S (= 〇) 2 ·, Rnt1rNT2n, rNT1rNt2n, RNTns (= o) 2_, rNT1rNT2n_c(tetra)mrN)n-, heterocyclyl, heterocyclyl-hydrazine, aryl, aryl, hydrazine, heteroaryl and heteroaryl-hydrazine, wherein each alkyl, alkenyl, alkynyl and cyclic The base may be substituted by a substituent selected from the group consisting of: F, a, CN, OH, c]. 3M, C36W; Cw alkyl-0·, RNT1RNT2N_, rNT1rNT2n_c (=〇), c alkyl-s(=o)-, c丨·4 alkyl-s(=0)2_, rNT1rNT2n s(=〇)2_, aryl, heteroaryl and heterocyclic; and wherein aryl represents stupid Or a naphthyl group; and wherein the heteroaryl group is a 5- or 6-membered aromatic ring containing 1 ' 2, 3 or 4 heteroatoms independently selected from the group consisting of ruthenium, osmium and S, wherein one or more NH groups The atom in the group can be placed by Rn And wherein the heterocyclic group is a 4- to 7-membered unsaturated or saturated carbocyclic ring, wherein 1 or 2 -CH 2 groups are independently of each other via NRN, hydrazine, &lt;(=〇), 161177.doc 10- 201249837 s, -S(=〇)- or -s(=0)2-substitution, and/or wherein i of the _CH groups are replaced by N; and wherein each aryl, heteroaryl or heterocyclic group may be optionally One or more substituents independently selected from LA are substituted; and RNT1 is selected from the group consisting of hydrazine, Cl. 6 alkyl, (: 3.6 cycloalkyl, Cw alkyl-c(=0)-, Cw alkyl- a group consisting of s(=〇)2, a heterocyclic group, an aryl group and a heteroaryl group RNT1-G1; wherein each alkyl group and cycloalkyl group may optionally be selected from F, OH, CN, independently of one or more Substituents of the group consisting of Cl-4 alkyl, Cl 4 alkyl·〇·, R 2N, Cw alkyl-s(=0) 2 —, c 3 6 cycloalkyl, heterocyclic, phenyl and heteroaryl Substituting; and wherein the heterocyclic group is optionally selected from F, independently of one or more

Substituted with a substituent of a Cl-4 alkyl group, an R'N, OH group, and a C.4 alkyl group; and wherein the heterocyclic group is a C4.7 cycloalkyl ring in which i or two _CH2_ groups are independently of each other NRN, 0, C (=0), s, s (=0) or s (=0) 2 substitution; and wherein the square group is phenyl or naphthyl; and wherein the heteroaryl group contains 1, 2 or 3 a 5- or 6-membered aromatic ring independently selected from the heteroatoms of N, hydrazine, and S, wherein the fluorene atom in one or more of the groups may be replaced by rn; and wherein the base and the chores may be visualized Substituted by one or more substituents A; and RN&quot; is selected from the group consisting of alkyl groups R&gt;-_G1; or 161177.doc -11. 201249837 rnt1 is linked to RNT2 to form an alkyl group selected from c3.5 a group of the group RNT1RNT2-G1; wherein one or two -CH2 groups are independently substituted with nrn, 〇, C(=0), S, s(=o) or S(=〇)2; And optionally substituted by one or more substituents independently selected from the group consisting of F, Cw alkyl, (Rn) 2N, OH and Ci_4 alkyl-hydrazine-; LA is selected from F, C, Br, CN, OH, N〇2, C&quot;院基-, Cw alkyl-〇-, (Rn)2N-C(=〇), (Rn)2N- and Cb4 alkyl-S (=0 a group of LA-G1, wherein each alkyl group may be optionally substituted with one or more substituents independently selected from the group consisting of F ' a, CN, OH, and Ci-3 alkyl-0-; a group selected from the group consisting of alkyl groups LP-G1 wherein the alkyl group may be substituted with one or more F atoms; and L is selected from And Cl-3&quot;* a group consisting of LQ-G1, wherein the alkyl group may be substituted by one or more F atoms; and R is selected from the group consisting of RC-G1: F, Cl, Br, I, CN, OH, N02, Cl_6 alkyl group, Cl 6 weak group _, Ci 6 fast group · c3.6 cyclodyl group 'C 6 alkyl 〇 、 _, c 3 6 cycloalkyl 〇 、, Cl. 6院-S-, HO-C(=〇)_, Ci.6 alkyl-0-C(=0)-, Ci-4 alkyl-C(=0)-, C3-6 cycloalkyl- C(=0)-, C].4 alkyl-s(=0)-,

Cw alkyl-S(=〇)2_, rntlRNT2N_, R&gt;mRNT2N_c(=〇)_, RNT, rNT2N-S(=〇)2_, Rnt1rnT2n_c(=〇) (rN)n, heterocyclic group, heterocyclic group · 〇·, aryl, aryl-hydrazine-, heteroaryl and heteroaryl wherein each alkyl, alkenyl, alkynyl and cycloalkyl group can be independently of one or more of the cases I61177.doc -12- 201249837 Substituents selected from the following groups are substituted: (3)^^(10)yl-monocycloalkyl, C,3 alkyl hydrazine, 〇_, R&gt;-RNT2N_, rNT1rNT2n c(=〇)·, Ci 4 alkyl-S (=〇)_, Ci_4 alkyl_s(=〇)2_, rNT1rNT2n_S(=0)2-, aryl, heteroaryl and heterocyclic; and wherein aryl represents phenyl or naphthyl; A heteroaryl group is a 5- or 6-membered aromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of ruthenium, osmium and S, wherein one or more of the NH groups may be optionally present. Substituted by a ruler; and wherein the %: group is a 4- to 7-membered unsaturated or saturated carbocyclic ring, wherein 1 or 2 of the -CH 2 groups are independently of each other via nrn, 〇, _c(=〇)_, s, -s(=o)- or -s(=o)2_substitution, and/or wherein the _CH group is replaced by N; and wherein each aryl, heteroaryl or heterocyclic group is The case is substituted by one or more substituents selected from each other independently of 1/; and X, X2, X3 are discretely selected from the group consisting of C(R2) and n, such that it consists of X1, X2 and X3 〇, 1 or 2 members of the group have the meaning of N; and R2 is selected from the group consisting of Η, F, C1, CN, OH, C. 4.4, (: 3.7 cyclization-, F2HC, F3C, a group of Cw alkyl·〇·, f2HC-0-, F3C-〇- and C3·7 cycloalkyl-〇-constituted r2_gi; and n is an integer selected from 〇, 1, 2, 3 or 4; Is an integer selected from 0, 1 or 2; includes any tautomers and stereoisomers thereof; 16U77.doc •13·201249837 or a salt thereof; or a solvate or hydrate thereof. The present invention relates to a process for the preparation of a compound of the formula j and a novel intermediate compound thereof in the process. Another aspect of the invention relates to a salt of the compound of the formula I according to the invention 'detailed' relating to its medicine In another aspect, the invention relates to a pharmaceutical composition comprising one or more of the compounds of the invention or one or more pharmaceutically acceptable salts thereof Optionally, one or more inert carriers and/or diluents are used. In another aspect, the invention relates to a disease or condition mediated by activation of the G protein-coupled receptor GpRU9 in a patient in need thereof. Method, the method characterized by administering to the patient a compound of formula j or a pharmaceutically acceptable salt thereof. According to another aspect of the present invention, there is provided a method of treating a metabolic disease or condition in a patient in need thereof, the method characterized by administering to the patient a compound of formula I or a pharmaceutically acceptable salt thereof. According to another aspect of the invention, there is provided the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in a method of treatment as described above and below. According to another aspect of the present invention, there is provided a compound for use in a method of treatment as described above and below, or a pharmaceutically acceptable salt thereof. In another aspect, the invention relates to a method of treating a disease or condition mediated by activation of the G protein-coupled receptor GPRi 19 in a patient. The method includes 161177.doc 201249837, steps. The patient is administered a therapeutically effective amount of a formula or a pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents in a therapeutically effective amount. In another aspect, the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with - or a plurality of other therapeutic agents, for use in the treatment of G protein-activated receptor GPR119 The disease or condition mediated. In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, optionally with one or more inert carriers, and / or thinner. Other aspects of the invention will be apparent to those skilled in the art from the description and the <RTIgt; [Embodiment] Unless otherwise stated, groups, residues and substituents, especially A,

Ri, R2, T, RN, RNT, rNT2, la, LP, lQ, rC, χΐ x, x, n, m are as defined above and below. If a residue, substituent or group occurs several times in a compound, such as rn 'La 'Lp or lq, they may have the same or different meanings. Some of the preferred meanings of the individual groups and substituents of the compounds of the invention are provided below. Either or each of these definitions can be combined with each other. R1: R]-G1: The group R1 is preferably selected from the group R^-G1 as defined above and below. R]-G2: 161177.doc 15 201249837 According to one embodiment, the group R, consists of: 2 or 3 independently selected from the group consisting of: a free heterocyclic ring and a coffee atom 0, s The 5-membered ring of a hetero atom may be circulated with the 5 and 6 hetero-cylinder rings, and the second Han &amp; member hetero-group ring condenses, 5 or 6 members of the unsaturated or aromatic ring with the first ring 1 or 2 of the heteroatoms 3 from N, 〇 and S are selected independently of each other, and N is in the second ring, and 1 or 2 -CH2_ groups may be used as the case. ^ (1 0)- or -s(=o)2-substitution; and wherein in the heteroaromatic ring and/or the _^ Μ/δ _ brother-ring, the ruthenium atom in one or more NH groups may be regarded as the case Substituting rN; and wherein the heteroaromatic ring and/or the parent of the -^, a ring may be substituted independently of each other by one or two substituents selected from LA; Aromatic ring or second ring may be subject to a group

Re replaced. R - G2a : According to one embodiment, the group R1 is selected from the group consisting of 2 or 3 of 5 heteroatoms independently selected from N, 0 and S: a family ring and a 1 Or a 6-membered heteroaromatic ring of a coffee atom; a W substitution; and a helium atom in the NH group is visible. The heteroaromatic % may optionally be substituted by one or two substituents selected from the group consisting of: wherein the heteroaromatic ring is optionally c RJ-G3: according to the embodiment - the group is selected from the group consisting of Group 仏vJ J * 161177.doc 16· V 0, 201249837 N- .rn

N IT

N

弋),·~〇.·〇

N

And 4: o * &lt;?〇, * cut 1 · N fly where RN is as defined above and below; and wherein each ring may be substituted by a substituent LA as appropriate and each group may optionally undergo a substituent Re replaced. R. -G3a · According to one embodiment, the group R1 is selected from the group Ri_G3a consisting of:

V IV Λ?ν

,s'V rn\ N- N-

N

V S-

N N, N, Ν' s-

N

N

N Γ N-

N

N- S

The substituent LA and a substituent RC are as defined above, wherein R is as defined above and below; and wherein each group is optionally subjected to _161177.doc -17·201249837 generation. R1-G4: In another embodiment, the group R1 is selected from the group consisting of *-V·*~Vs]. Ν=/^Ν=&quot;/ -7, and Ν, R1 - G4, each of which The ring may be optionally substituted with a substituent LA and a substituent Rc. R1-G4a: In the case of the work, the 'group Rl' is selected from N: V V N = 0 ^ *-ΓΝ Ν = /

And Ν = / group ruler - (} 4 &amp;, wherein each ring can be replaced by a substituent Rc as appropriate. R] _G5 : N, 〇 Nc

〇, N

In another embodiment, the group R1 is selected from

Group R R-G5, in which each ring can be replaced by a J

Re replaced.

Rn

Rn-G1 : Group! Preferably, it is selected from the group RN_G1 as defined above and below. Rn-G2: In another embodiment, the group '1' is selected from the group consisting of ruthenium, osmium, ethyl, isopropyl, decylcarbonyl and methanesulfonyl.

Rn-G3: In another embodiment, the group rN is selected from the group consisting of ruthenium, osmium, methylcarbonyl 161177.doc •18·201249837 and the group RN-G3. RN-G4: In another embodiment, the group RN is selected from the group consisting of 11 and C! 3 alkyl groups RN-G4. RN-G4a: In another embodiment, the group RN is selected from the group consisting of ruthenium and osmium groups RN-G4a. RN-G4b: In another embodiment, the 'group RN' is selected from the group consisting of Η-RN4. A: A-G1 group A is preferably selected from group VIII-(1) as defined above and below. A-G2: In one embodiment, the group A is selected from the group a_g2 consisting of: a phenyl ring, a 6-membered heteroaromatic ring containing 1 or 2 atoms, and a containing 2 or 3 independently selected from N a 5-membered heteroaromatic ring of a hetero atom of S; and the "middle-ring" may be condensed with the phenyl ring or the (tetra) family ring, which may be a 5- or 6-membered unsaturated or aromatic ring in the basin, and The condition contains _ = 立: selected from Ν, a hetero atom, and wherein the bicyclic two group can be replaced by 鲁^-s(-o)- or _s(=0)2•; The heteroaromatic ring and/or the second ring of the ruthenium atom may be replaced by RN according to the situation] * Multiple NH groups make it possible for the stupid base ring and the heteroaromatic ring armor to be one I6M77.doc • 19-201249837 are substituted independently of one another or a plurality of substituents selected from the group consisting of; and such that the phenyl ring, heteroaromatic ring or second ring is optionally substituted by the group τ; and the group A G2 is - Step by, 2,3,6_tetraammine n is composed of biting ice base, wherein the NR group is replaced by C 丨 基 § (=〇) 2_. A · G 2 a · In another embodiment In the group A, the group A is selected from the group consisting of A_G2a: a phenyl ring, containing a 6-membered heteroaromatic ring and a 5-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from N, hydrazine and s; wherein the phenyl ring or heteroaromatic ring-through group a τ substitution, and wherein the phenyl ring and the heteroaromatic ring are optionally substituted with one or more substituents independently selected from each other; wherein in the heteroaromatic ring, (10) of one or more groups Sub-visible MRN substitution. A-G2b: In another embodiment, the group A is selected from the group consisting of a phenyl ring and a 5-member hetero atom containing N, 〇 or 5 independently of each other. a group consisting of a group of rings A-G2b; and wherein the second ring is condensed with the phenyl ring or heteroaromatic ring, wherein the second ring of shai is a 5- or 6-membered unsaturated or aromatic ring, and may be contained in the case of production. 1 or 2 heteroatoms independently selected from N, 〇 and 3, and wherein in the second ring, i or 2 _CH2_* groups may optionally be _N(rN)·, -C(=0 - ' -s(=0)- or _s(=0)2-substitution; and wherein in the heteroaromatic ring and/or the second ring, one of the one or more NH groups may be ascertained Replaced by RN; and 161177.doc • 20· 201249837 where the phenyl ring, miscellaneous Each of the family ring and the second ring may be optionally substituted with one or more substituents independently selected from LA; and wherein the phenyl ring, heteroaromatic ring or second ring may optionally be via the group τ Substituted. A-G2c: In another embodiment, the group A is selected from the group consisting of ά1,2,3,6_four gas 〇 _4_ group consisting of group A_G2c, wherein the ΝΗ group is passed through ^· Alkyl (7) 2 is substituted. A-G3: In one embodiment, the group octa is selected from the group consisting of phenyl groups. a group A_G3 consisting of a pyridyl group, a pyrazinyl group, a pyrazinyl group, a pyrimidinyl group, an isoxazolyl group, an oxazolyl group, an oxadiazolyl group, an imidazolyl group, a pyrazolyl group, a thienyl group, and a thiazolyl ring, and wherein The second ring may be condensed with the cyclic groups, wherein the second ring is selected from the group consisting of cyclopentene, cycloheximide, diclofenac, tetrahydropyridine, tetrahydrochloridazine, dihydrogen Pyridazine, dihydrofuran, dihydropiperone, [1,3]dioxol, dihydrodioxane, dihydrogenate, dihydropyrazine, dihydropyridazine, benzene, Pyridine, pyrimidine, pyrazine, pyridazine, vaginal and thiazole, in which the second ring,! Or 2 _CH2_ groups may be optionally 蛵·(:(=〇)-substitution, and wherein H in the cyclic group and/or the second ring, or a plurality of ΝΗ· groups The atoms may be replaced by a substituent RN independently of one another; wherein each of the above rings may be optionally substituted with one or more substituents independently selected from [A; and wherein the cyclic group or the second ring may be via a group τ Substituted; and 161177.doc -21 - 201249837 Group A G3 progress / cover tetrahydrobite _4 · base, in which the centipede of the centipede is replaced by Cu-based _s (= 〇) 2_. A-G3a In one embodiment, the 'group A' is selected from the group consisting of phenyl and selected from pyridyl, pyridyl, arginyl, sulfhydryl, sulfhydryl, oxazyl, chetridyl, and taste. a group of A G3a consisting of a heteroaromatic carbocyclic ring of the base ring, wherein the phenyl group and the heteroaromatic ring are optionally selected from each other independently or independently of each other. a substituent substituted with LA&gt; π &amp; * &amp; and wherein the phenyl or heteroaromatic ring is substituted by a group T. A-G3b: In one embodiment 'group A is selected from phenyl and selected Tons of bite base, pyridazine , Jian. Qin group m, different. oxa thiol, ^ sitky ... oxadiazide, pyrazolyl, thienyl and thiazolyl ring heteroaromatic ring group A G3b and the second ring Condensation with the phenyl or heteroaromatic ring, wherein the second ring is selected from the group consisting of cyclopentene, cyclohexene, diazo, hydrazine, hydrogen, 0. Hydrogen oxazine, dihydrogenate, dinitrogen british [1,3]-oxocyclopentadiene, dioxane dioxane, two gas taunting hydrogen than Qin, monohydropyridazine, benzene, Pyridine, pyrimidine, pyrazine, Jian Qin heart sitting and plug. Sitting 'in which in the second ring, 1 or 2 -CH2 · group. Visual It HC Di) _ replacement 'and in which the heteroaromatic The ruthenium atoms in the ring and, or in the second %, or in the ΝΗ··· group may be replaced by a substitution *RN independently of each other; 袁 each of which may optionally be selected from one another by one or more Substituent substitution; and I61177.doc • 22-201249837 wherein the phenyl ring, heteroaromatic ring or: ring may optionally be via the group 0 A-G3c: In another embodiment, the group A is selected from i, 2, 3, 6_ tetrachloro. The group A-G3C consisting of ~-based groups, in which the NH group is replaced by _C|3.

A-G3d I In another embodiment the 'group filaments are selected from the group consisting of four gases. Group A-G3c consisting of a bite group of 4, wherein MCH3_s(=〇)2 of the oxime group is substituted. A-G4: The material is in one shot, and the group A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, oxazolyl, imidazolyl , pyrazolyl, thienyl, thiazolyl, triazolo[l,5-a]acridinyl, benzoxazolyl, benzothiazolyl, indanyl-ketone, fluorenyl, 2, 3-dihydroindenyl, quinoxalinyl, quinolyl, 3-pyrimazolin-4-one, 2,3-dihydrobenzo[M]dioxenyl, 3,4 • Dihydro _ 1H-2-oxa _4a,9-diazaindole, isoindole q, 〗 〖dione, I 〗 Dihydroindol-2-one, 1 Η carbazole a base, a nodule, a 2_sideoxy-2,3-dihydrooxazolo[4,5-b]pyridinyl and an isoxazolo[5,4-b]pyridinyl group, wherein among the above groups, The H atoms in the one or more -NH- groups may, as such, be replaced independently of one another by the substituent rn, and wherein each ring may be optionally substituted by the group τ and optionally selected from one or more independently of one another by one or more a substituent substituted; and the group A-G4 is additionally composed of a 1,2,3,6-tetrahydropyridine-4-yl group, wherein the oxime of the NH group is substituted by Ci-3 alkyl-S(=0)2-, Preferred by ch3-S (=0)2-Replacement. 16U77.doc -23· 201249837 A-G5: In another embodiment _, the group money is selected from the group consisting of A_G5. *-〇

each

and

In the NW group of N- 0\.3-alkyl, the atom in the .NH_ group may be substituted, wherein each aromatic group and heteroaromatic group are not substituted by the group T or substituted by the group T. And each aromatic ring and heteroaromatic ring may be optionally substituted with one or two substituents independently selected from LA, and wherein the groups D and LA are as defined above and below. A-G5a: In another embodiment, the group A is selected from the group consisting of A_G5a: *Ό*-〇Ά W and v_y 0 , wherein the phenyl group mentioned above is burned by a Ci-3 Substituting -S(=0)2-, Cu-mercapto-S(=〇)2-CH2- or -(CO)-NRnt丨RNT2 substituted; wherein RNT1 and RNT2 are as defined above and below; RNT1 is preferred It is a C丨_6 alkyl or tetrahydropyranyl group; in the oxime, the alkyl group may optionally be passed through a CN, OH, OCH3, tetrahydrogen. Oryrazolyl, oxazolyl, [1,4]-dioxanyl or "pyridyl" taken 161177.doc -24- 201249837; and R" is H or methyl, in particular, RNT2 H; or ^" and RNT2 together with the N atom to which they are attached form an azetidinyl group, a pyridyl group, a piperidinyl group or a morpholinyl group; wherein azacyclobutyl, pyrrolidinyl and piperidinyl Each of these may optionally be substituted with one or two substituents independently selected from the group consisting of F, OH, CH3 and -〇ch3. A-G5b: In another embodiment, the group A is selected from the group A-G5a wherein the phenyl group is substituted at the 4-position. A-G6: In another embodiment, the group A is selected from the group consisting of: A-G6:

161177.doc -25- 201249837

A-G6a: In another embodiment, the group A is selected from the group consisting of the following groups A-G6a:

F

161177.doc •26- 201249837

A-G6b: In another embodiment, the group A is selected from the group consisting of: A-G6b:

161 - - -27 -27 -27 -27 -27 Group T-G2: F, Cl, Br, CN, OH, Ν〇2, ke-, Ci-4 烧基_〇_, CU4 burnt base-0-C(=0)-, Cw yard base-C (=0)- 'C1.4 alkyl-S(=0), Ci.4 alkyl-S(=0)2, c丨.4 alkyl-S(=0)2-C丨·4 alkane base-,! ^1'1!^1'2]^- c(=0)-, RNT1RNT2N_s(=〇)2_, Cl-4 alkyl-S(=0)2-(Rn)N-, RNT1RNT2N, Rnt1RNT2N_C(= 0) _Ci.4alkyl-, wherein each alkyl group may be optionally substituted with one or more substituents independently selected from the group consisting of F, C, CN, OH, aryl, heteroaryl and heterocyclic; The aryl group is selected from the group consisting of a bite base, a mouth bite base, a serotonin group, and a beta base group. a group consisting of tb succinyl, imidazolyl, triazolyl and tetrazolyl; and wherein the heterocyclic group is azetidinyl. a singly or a sulphonyl group, wherein the _CH2. group may be optionally substituted with a group selected from the group consisting of _c (7)· and -S(-〇)2. The group may be optionally substituted with one or more substituents independently selected from the group consisting of Cl_3.alkyl; and the phenyl and heteroaryl groups in A may optionally be substituted with one or more substituents L independently of one another. T-G3: According to another embodiment, the group τ is selected from the group consisting of J 2 pit-S(-0)2, 161177.doc -28-201249837 S(=0)2-, RNT1RNT2N-C (=0 -, (: 4 alkyl-S(=0)2-(Rn)N- and rnt丨rNT2n-. T-G4: According to another embodiment, the group τ is selected from the group consisting of: T_ G4 : Ci.4 alkyl-S(=〇)2-CH2-, c 4 alkyl-S(=0)2 and RNT1RNT2N-c(=o)-. An example of the group T-G4 is CH3-S (=0)2-CH2- and CH3-S(=0)2_. rnt,

Rnt1-G1: RNT1 is preferably selected from the group ^^-(1) as defined above and below. RNT1-G2: In another embodiment, RNT1 is selected from the group consisting of ruthenium, Cw alkyl, C3-6 cycloalkyl, tetrahydropyranyl group RNT1_G2, wherein each alkyl group and cycloalkyl group may be subjected to one Substituting substituents of a group consisting of F, CH3, OH, Cu alkyl-0-, (Rn) 2N, CN, tetrahydrofuranyl, 1,4-dioxenyl, oxazolyl and pyridyl groups . RNT1-G3: In another embodiment, RNT1 is selected from the group consisting of Η, C _4 alkyl and C 3-6 cycloalkyl, RNT1-G3; wherein each alkyl and cycloalkyl may be one or two The substituents are independently selected from the group consisting of F, CH3, 011 and C!.3 alkyl groups. RNT1-G4: In another embodiment, 'RNT1 is selected from the group consisting of 11 and c _4 alkyl groups 161177.doc • 29- 201249837 RNT1-G4; wherein each of the alkyl groups and the ring-burning group may be selected from F, CH3, 011 and (21.3 substituents of the group of ketone-oxime-compositions. rNT2 rNT2-gi: RNT2 is preferably selected from the group RNT2_G1 as defined above and below. RNT2-G2: in another In an embodiment, RNT2 is selected from the group consisting of 11 and C--3 alkyl groups RNT2-G2. RNT2-G3: In another embodiment 'RNT2 is selected from the group consisting of ruthenium and methyl groups rNT2 __ RNT2-G4 In another embodiment 'RNT2 is selected from the group consisting of ΗRNT2-G4. j^NT1j^NT2 RNT1RNT2_G1. According to one embodiment, the group RNT1 is linked to rNT2 and forms a group selected from the group defined above and below a group of rnt丨RNT2-G1. rnt, rnt2_G2. According to another embodiment, the group RNT1 is linked to rNT2 and, together with the 1 atom to which it is attached, forms a group selected from the group consisting of Rnt1rnt2_G2: nitrogen heterocycle Butyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, piperazine·2·keto, N_Cl·3 alkylpiperazinyl , N_Ci_3 alkyl piperazine 2 -keto and Ν-β, ·3 alkyl-C(=0))-piperazinyl, these groups may be 161177.doc -30· 201249837 as many times Substituted independently of each other, a substituent selected from the group consisting of F, HO, Cm alkyl, c--3 alkyl-fluorene-, and (Rn)2N. RNT1RNT2.G3. According to another embodiment, the group 1^1'1 is bonded to 1^1'2, and together with the N atom to which it is attached, forms a group selected from the group consisting of rNT丨rNT2_G3, a nitrogen heterocycle Butyl, pyrrolidinyl, piperidinyl and morpholinyl, each of which may be optionally substituted by one or two substituents independently selected from the group consisting of F, CH3 and CHs-O.

La: la-gi: The group LA is preferably selected from the group la_gi as defined above and below. La-G2: In another embodiment, the group La is selected from the group consisting of la_G2: F, Cl, Br, cn, OH, C, -3 alkyl-, C-3 alkyl-〇- , H2N_, C!·3 alkyl_NHj(Ci 3 alkyl) 2n_, wherein the c _3 alkyl _ and

The Cw-based 〇-yl group may optionally be substituted with one or more F atoms.

La-G3: In another embodiment, the group LA is selected from the group la_g3 consisting of F, Cl, C_4 alkyl- and CF3.

Rc : RC-G1 : The group Rc is preferably selected from the group RC-G1 as defined above and below. Rc-G2: According to one embodiment, the group rc is selected from the group consisting of Rc-161177.doc 31 201249837 G2 : F, C Br Br, I, CN, OH, Cw alkyl-, Cw--- C,-6 alkynyl-, C3.6 cycloalkyl, Cw alkyl-O-, C3.6 cycloalkyl-hydrazine-, CN6 alkyl-S-, Cw alkyl-〇-C (=0) -, C, .4 alkyl-S(=0)-, Cm alkyl-

5(=0)-(:,.4 alkyl-, (:丨.4 alkyl-S(=0)2-, Cm alkyl.-SpOh-CM alkyl_, RNT1RNT2N-, rnt丨rNT2n- C丨.3 alkyl_, rnt^ΝΤ2ν-c(=0)-, rNT1rnt2n s(=〇)2_, rNT1rNT2n s( = 〇)2_Ci 4 alkyl group _, RMT1rNT2nc( = 〇)cb*alkyl· , heterocyclylheterocyclyl-hydrazine, phenyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally selected from F, C, CN, OH, independently of one or more Substituted with a substituent of C丨-3 alkyl, C3.6 cycloalkyl, C..3 alkyl-fluorene, phenyl, heteroaryl and heterocyclic; and wherein the heteroaryl is selected from pyridyl a pyrimidine group, a pyridazinyl group, a pyridyl group, a rhodium group, a group consisting of a sedentyl group, an imidazolyl group, a thiazolyl group, and a thienyl group; and wherein the heterocyclic group is selected from pyrrolidine-2-keto group, piperidine_2 a group consisting of a keto group, a piperazin-2-one group, a morpholinyl group, a morpholine-3-yl group, an oxetanyl group, a tetrahydrofuranyl group and a tetrahydropyranyl group, each group being optionally subjected to one or Two substituents independently selected from the group consisting of CN3 alkyl; and wherein the phenyl and heteroaryl are optionally substituted one or more independently of each other ! / Replace "

Rc-G3: According to one embodiment, the group Rc is selected from the group consisting of rC·G3 F Cl, CN, Cu, and C3_6 cyclodecyl, cN6 alkyl 〇, C3.6 cycloalkyl ·〇_, Cl.4 alkyl_S(=0)_, Cn4 alkyl_s(=〇)2, RNT1RNT2N-, R_rNt2n_c]3 alkyl, rNT1rNT2n c(=〇), I61177.doc -32- 201249837 rNT1rNT2n R alkyl-, heterocyclic, heterocyclic-fluorene-, phenyl, and hetero-ruthenium, arylene, wherein each alkyl group and cycloalkyl group may be independently of one or more human y W The feed is desirably substituted with a substituent selected from the group consisting of F, H3C_, H3C_〇, phenyl and heterocyclic groups; and wherein the heteroaryl group is selected from the group consisting of (8) silk, (tetra), and a base. a group consisting of a conjugate group and a phenoxy group; and wherein the heterocyclic group is selected from the group consisting of oxetanyl and tetrahydro. A group consisting of a bromo group and a tetrazolidine group, each group being optionally substituted by one or two groups; and wherein the phenyl group and the heteroaryl group may be optionally substituted with a substituent y.

Rc-G4: According to another embodiment, the group 1 is selected from the group consisting of F, c, Cm alkyl, F3C, CM cycloalkyl, phenyl, wherein the phenyl ring is F C1, CH3, CF3 or OCH3 is monosubstituted and the cycloalkyl group may be monosubstituted by CH3.

Rc-G4a: According to another embodiment, the group RC is selected from the group consisting of F, a, Cn4 alkyl, F3C- and cycloalkyl, Rc-G4a, wherein the cycloalkyl group may be monosubstituted by CH3. RC-G4b: According to another embodiment, the group rC is selected from the group consisting of ρ, ci, C.4 alkyl, F3C. and cyclopropyl, wherein the cyclopropyl group can be monosubstituted by CH3. RC-G4c: 161177.doc • 33- 201249837 According to another embodiment, the group Rc is selected from the group consisting of F, Cl, Cl-4, f/-, c; 3-4 cycloalkyl and c, .3 A group of alkyl-hydrazine-compositions|1&lt;:_(343, wherein the cycloalkyl group may be monosubstituted by CH3.

Rc-G5: According to another embodiment, the group Rc is selected from the group consisting of *Ci*alkyl, F3c_, cyclopropyl, cyclobutyl and phenyl groups Rc_G5, wherein the phenyl ring can be F, C CH3, CF3 or 〇CH3 is monosubstituted.

Rc-G5a: According to another embodiment, the group RC is selected from the group consisting of iC|-4 alkyl and F3C_ group Rc-G5a. Preferred examples of the group Rc-G5a are ethyl, n-propyl and isopropyl.

Rc-G5b: According to another embodiment, the group! ^ is selected from the group consisting of C!3 alkyl, FA- and H3C-0-, Rc-G5a. X1 ' X2 ' X3 X-G1 :

The groups X1, X2, X3 are preferably white as if they are a group X-G1 as defined above and below. X-G2: In another embodiment, the group X1, group X-G2. X-G3: In another embodiment, the group X1, the group X-G3, such that it is composed of X, χ2, and X3 is selected from C(R2)'2, and the X3 is selected from N and C. The group of the group consisting of (R2) group X3 is 161177.doc -34 · 201249837 The member has the meaning of N, and the other members of the group have the meaning of C(R2). X-G4: In another embodiment, the groups χΐ, X2, X3 are selected from the group consisting of N and C(R2), X-G4, such that members of the group consisting of χ&gt;, X2 and X3 have Ν Meaning, and other members of the group have the meaning of c(r2). X-G4a: In another embodiment, χΐ, X2 and X3 are selected from the group consisting of x_G4a: X1 and X3 are each C(R2); and X has the meaning of N. X-G5: In another embodiment, the 'groups X1, X2, X3 are selected from the group X-G5 consisting of ruthenium and C(R2) such that two members of the group consisting of X1, X2 and X3 have N means 'and another member of the group has a ruler 2' meaning. R2 R2-G1: The group R2 is preferably selected from the group r2_G1 as defined above and below. R2-G2: In another embodiment, the group R2 is selected from the group consisting of Η, F, CN, OH, H3c-, F2HC, F3C, h3c_o-, f2hc-o-, and f3c-o-, R2-G2 〇R2-G3: In another embodiment, the group R2 is selected from the group consisting of H, F and H3C- R2-G3 〇 161177.doc • 35· 201249837 R2 G4 : In another embodiment, the group R2 is selected from the group consisting of H-group R2-G4.

Lp : LP-G1 : The group L is preferably selected from the group lp_Gi as defined above and below. Lp-G2: In another embodiment the 'group lp' is selected from the group consisting of F and methyl group Lp_G2.

Lq :

Lq-G1: The group LQ is preferably selected from the group LQ_G1 as defined above and below. Lq-G2: In another embodiment, the group 1 is selected from the group consisting of F and fluorenyl groups 1^-G2 〇 η : The index η is an integer selected from 0, 1, 2, 3 or 4. According to one embodiment, the index η is 0, 1 or 2, in particular 0 or 1. According to another embodiment, the index η is zero. m · The index m is an integer selected from 0, 1 or 2. According to one embodiment, the index m is 0, 1 or 2, in particular 〇 or 1. According to another embodiment, the index m is one. According to another embodiment, the index m is 0 » using the general formula (1.1) to the general formula (1.7) to describe the following preferred embodiment of the compound of formula I 161177.doc • 36·201249837, which encompasses any tautomer thereof and Stereoisomers, solvates, hydrates and salts, especially pharmaceutically acceptable salts thereof.

161177.doc •37· 201249837

(1.7) wherein in each of the above formulas (Ι·1) to (1.7), the τ groups R1, Lp, LQ, η, m and A are as defined above and below. The compound of formula I is described by the general formula (IR) and formula (IS). <Other preferred embodiments' encompass any tautomer thereof and stereoisomers, solvates, hydrates and salts thereof. Especially its pharmaceutically acceptable sleep

G.XSJ Han Ba (l.bj armor armor in the above., ^ claws ~ 乂 ^ 乂 ^ ^ and eight systems as defined above and below. Examples of preferred sub-embodiments according to the present invention are set forth in the following table Each substituent of the formula is defined according to the definitions described above and all other substituents of formula I are defined according to the definitions described above and

161177.doc -38 · 201249837 Example R1-A- E-5 I RJ-G2 A-G5 E-6 IR R'-Gl A-Gl E-7 IR R, G2 A-G2a E-8 IR Rl -G2 A-G2b E-9 IR R*-G2 A-G4 E-10 IR R!-G2 A-G5 E-ll IS R^Gl A-Gl E-12 IS R*-G2 A-G2a E- 13 IS R*-G2 A-G2b E-14 IS Rl-G2 A-G4 E-15 IS Rl-G2 A-G5 E-16 1.1 R*-G1 A-Gl E-17 1.1 R, G2 A-G2a E-18 1.1 Rl-G2 A-G2b E-19 1.1 RJ-G2 A-G4 E-20 1.1 RLG2 A-G5 E-21 1.2 R, G1 A-Gl E-22 1.2 R^GZ A-G2a E- 23 1.2 R*-G2 A-G2b E-24 1.2 R, G2 A-G4 E-25 1.2 R!-G2 A-G5 E-26 1.3 r!-gi A-Gl E-27 1.3 Ri-G] A -G2a E-28 1.3 ^-02 A-G2b E-29 1.3 R*-G2 A-G4 E-30 1.3 R1^ A-G5 E-31 1.4 R*-G1 A-Gl E-32 1.4 R^GZ A-G2a E-33 1.4 R!-G2 A-G2b E-34 1.4 R*-G2 A-G4 E-35 1.4 R*-G2 A-G5 E-36 1.5 R'-Gl A-Gl E-37 1.5 R*-G2 A-G2a 161177.doc •39- 201249837 Example R1- ------------- A. E-38 1.5 R'-G2 - —----- ^ A-〇7K E-39 1.5 R'-G2 E-40 1.5 R*-G2 E-41 1.6 R*-G1 Α-Γίΐ E-42 1.6 R,-G2 E-43 1.6 R, G2 __—- A-G7K E-44 1.6 R, G2 A-Gd E-45 1.6 R*-G2 E-46 1 .7 R*-G1 ___________ A-fii E-47 1.7 R'-G2 --——Hi__— E-48 1.7 R*-G2 —4____ E-49 1.7 R*-G2 A-C4 E-50 1.7 R *-G2 a-gs is preferably a compound of the formula i wherein: X1 is CH; X2 is CH or N; X3 is CH;

Rl is selected from the group consisting of:

Wherein each ring may be replaced by a F and/or a substituent rC, optionally selected from the group consisting of F, C1, ci-4 alkyl, F3C- and cyclopropyl; wherein the cyclopropyl group may be monosubstituted by CH3 ; A is selected from the group consisting of:

16U77.doc •40- 201249837

Bu is ch3; η is 0; m is Ο or 1; and a pharmaceutically acceptable salt thereof. More preferably, the compound of formula i, wherein: X1 is CH; X2 is N; X3 is CH; and R1 is selected from the group consisting of:

, Ν, V

Ν

And

N , S , N= wherein each ring may be optionally substituted by a F and/or a substituent Rc; the group selected from the group consisting of F, C, Ci-4 alkyl, F3C- and cyclopropyl; The group may be monosubstituted by CH3; the A group is selected from the group consisting of:

η is 〇; m is 〇 or 1; and particularly preferred compounds among its pharmaceutically acceptable salt salts, including tautomerism thereof, or any solvate thereof or hydrated and stereoisomers thereof, The following compounds are mentioned in the experimental section below as the actual gamification of the present invention. I6I177.doc • 42- 201249837 Example structure

161177.doc •43- 201249837

161177.doc 44 · 201249837

It includes any tautomers and stereoisomers thereof, or a salt thereof, or a solvate or hydrate thereof. The compounds of the present invention and intermediates thereof can be obtained by synthetic methods known to those skilled in the art and described in the organic synthesis literature of 161177.doc-45·201249837. These compounds are preferably obtained in a similar manner to the preparation methods described more fully below, as described in the experimental section. In some cases, the order in which the reaction process is performed can be changed. Variations in such reactions known to those skilled in the art but not described in detail herein may also be used. The general method of preparing the compounds of the present invention will be apparent upon a study of the following procedures by those skilled in the art. The starting compound can be purchased from the market' or can be prepared by the literature or by the methods described herein or can be prepared in a similar or similar manner. Any corresponding functional group in the compound can be protected using conventional protecting groups prior to carrying out the reaction. These protecting groups can be re-cleaved at a suitable stage within the reaction sequence using methods familiar to those skilled in the art. Compound I of the present invention can be obtained using the synthetic route outlined in Scheme 1; R1, Lp, η, X1, X2, χ3 and a have the meanings as defined above and below. Starting from compound 1, the target compound is obtained after partial reduction of benzofuran. It is preferred to carry out the reaction in the presence of a hydrogen atom as a reducing agent in the presence of a transition metal catalyst. Suitable transition metals can be derived from Ni, Pd, Pt, Ir and Rh, such as Raney nickel, palladium/carbon, platinum/carbon '铑/carbon, Pt〇2 and Rh2〇3. The reduction is preferably carried out in tetrahydrofuran, propylene glycol, ethyl acetate, an alcohol (e.g., methanol, ethanol or isopropanol), acetic acid or a mixture thereof under a hydrogen pressure of from 1 bar to 1 bar, at a temperature of from 12 Torr to 12 Torr. Let's go under your arm. Alternatively, tannic acid or a formate may be used instead of hydrogen as a reducing agent. Reduction can also be achieved by using Shi Xi or sodium amalgam as a reducing agent. For example, 'the reduction using decane is at -2 (rc to l2〇〇c, using triethyl 161177.doc -46-201249837 decane and trifluoro in di-methane, tri-methane, acetonitrile, mixtures thereof) It is carried out with acetic acid or in the absence of a solvent in trifluoroacetic acid. Naxizi is usually used in the form of sodium hydroxide or aqueous solution of sodium hydrogencarbonate.

Compound 1 may in turn be obtained from Compound 4 having two replaceable halogen or pseudohalogen groups, as described in Scheme 2; R1, LP, η, X1, χ2, X3 and A have as defined above and below The meaning. Depending on the reactivity of the two carbon atoms bearing a halogen or a pseudodentin group, the two coupling partners 6 and 5 are introduced in the order indicated at the top or bottom of the scheme. Preferably, the two residues are linked via a transition metal catalyzed reaction, preferably mediated by palladium, nickel, steel or iron species. The active catalyst may be derived from an elemental form of a transition metal such as palladium on carbon or a nanoparticle of iron or palladium; or a salt of a transition metal such as fluoride, vapor, bromide, acetate, triflate Or a trifluoroacetate salt, preferably with a ligand such as a phosphine such as tri-tert-butylphosphine, trimethylhexylphosphine, optionally substituted bicyclohexylphosphine, optionally substituted biphenyl Combination of tert-butylphosphine '(diphenylphosphino)ferrocene, triphenylphosphine, trif-phenylphosphine or tri-c-propylphosphine; sub-disc, U-disubstituted taste (iv) carbon dilute, diphenyl Sub; = ketone, propyl or nitrile. Good for eight, _, trifluoro, 酉 vinegar, _ zinc, or _ magnesium, and block hydrocarbon 5 is preferably used as it is or B 161177.doc •47· 201249837 ^ 视 nucleophile Preferably, the reaction is preferably at (10). c in benzene, toluene, ether 'tetrahydrofuran,〗 〖, 2-dimethoxyethane,], 4-dioxane, N,N-dimethylformamide, N,N_:methylacetamide, &amp;methylpyrrolidone' alcohol, water or a mixture thereof. Additives, such as toothed salts (such as gasification, potassium fluoride, tetrabutyl fluoride), gas oxide sources (such as potassium hydroxide, potassium carbonate), amines (such as triethylamine, diisopropyl) a base amine and ethyl diisopropylamine), a silver salt (such as silver oxide or silver triflate) and/or a copper salt (such as copper iodide or copper chloride or thiophene-2-formic acid), possibly for the reaction It is beneficial or even necessary. The conditions in which the alkyne 5 is coupled to one of the electrophilic agents 2 or 4 can also cause subsequent cyclization, and thus benzofuran is obtained. For example, 5' can be directly obtained from Pd(PPh3)2Cl2, CuI and triethylamine in N,N-dimethylformamide at 20 C to 140 °C. If an intermediate alkyne is obtained, then benzofuran can be formed in a separate step using, for example, BwNF in tetrahydrofuran at 5 (rc to 7〇t: ; NaOH in aqueous solution at ambient temperature; Cul or CuCN NEt3, depending on the situation, in the Ν, Ν 曱 甲 甲 甲 ' 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 A 在 在 在 在 在 A 在 在 A 在 A A 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在CH2C12), Pd (such as PdCl2) or other transition metals (such as Rh). It is also possible to assemble a stupid and furan according to the following conformation: oxygen to be cyclized (oxygen on a carbon atom adjacent to a carbon atom bearing an alkyne group) The indole amine group embedded in the azaheterocyclic group is limited in that the other groups on the indoleamine N are cleaved under the reaction conditions (see, for example, 2007, 3117). The reaction partner (reactive carbon) The reactivity is reversible, that is, compound 2, compound 3 and compound 4 are nucleophiles with hydrazine, and compounds 5 and 161177.doc • 48· 201249837 compound 6 is an electrophile with Hal1 or Hal2. Thus the same product is obtained under the same or phase &amp; conditions.

R1· = R1, a protecting group such as -C〇20u = dentate or pseudo-dentin, such as Cl. Br, 丨, OSOzcf3. 〇S02Me. 〇s〇, aryl Μ = metal residue 'eg Β (ΟΗ&gt; 2· Βπ ZnC丨, 另一 叻 另一 Another suitable way to synthesize the compound of the present invention is to use benzofuran derivative 7 as a starting material (Scheme 3); R1, lp, η, X1, X2, X3 and a have The meanings as defined above and below. Preferably, compound 7 is combined with piperidine u by a transition metal catalyzed process as described above for Scheme 2. The reactivity of the 2 position of benzofuran 7 determines the piperidine Coupling reaction. The benzofuran with Cl, Br or I at the 2-position is preferably combined with a Z-type tetrahydropyridine such as b(〇h)2, B(0CMe2CMe20) or BF3K. Reversing the reactivity of 7. (ie, 7 is a nucleophilic partner with μ, such as b(〇h) 2 or 161177.doc -49 - 201249837 B (0CMe2CMe20)) requires a piperidine with opposite reactivity, ie with for example OS Z2CF3 or C1 Z-type tetrahydropyridinium. In addition, piperidine-4- can be used in a solvent such as 1,4-dioxalate using anthraquinone, a test such as LiOtBu, and a Pd catalyst. ketone (Z = 0) coupled with electrophilic benzofuran 7 (Y = C1, Br, I) (see for example C/ie/w. five wr. «/. 2008, to 4792-5; and Org. Le&quot; 2010, 4〇42_5; and references cited therein). Other double bonds present in the product due to the use of tetrahydropyridine can be reduced with benzofuran in the next reaction step, as described above with respect to Scheme 1. Halogenating compound 9 with Cl, Br or I to obtain compound j 〇. Gasification is carried out, for example, with N-gas, sulfonium imine, gas or sulfonium. N-chlorobutadiene imide is preferred. In the presence of a Lewis acid (eg ZrCl44HC1), it is used in dioxane, acetonitrile, N,N-didecylguanamine, decyl alcohol, water or acetic acid, preferably gas or chloroform or Used in acetic acid, and sulphur sulphur is used in di-methane and tri-gas methane. It is preferred to use bromine or 1 bromodiimide in a gas, acetonitrile or acetic acid, optionally in the presence of a Lewis acid. In this case, bromination can be achieved by, for example, iodine combined with silver nitrate, iodine in sulfuric acid, and ice iodobutane diimine in combination with indium triflate, Acetic acid or - in the gas burning vaporized Wo Yue moth finishing step of introducing Scheme 3, i.e., the transition metal catalyzed coupling of 6 and 10, similar to the above procedures can be used to carry out processes 3 embodiment.

161177.doc •50· 201249837

9 R = R1 'protecting group, for example -C&lt;VBu Hal = CL Br, I M=metal residue, for example

Halogenated (LP) „

A LP)nx/ ^?CMe2CMe2〇). BF3K, ZnCI/Br/l, MgCI/Br/l == for example Hal, 〇S〇2CF3, 〇S〇2Me, 0S02Ph, Μ, HZ = eg Hal, 〇S02CF3 , M, =〇-----Single or double bond Scheme 4 shows another way of synthesizing a compound of the invention; Ri, Lp, LQ, η, X1, χ2, χ3 and A have the same as defined above and below The meaning. This sequence begins with the reduction of the ketone 12 to obtain the alcohol. The reduction is preferably carried out using a complex metal hydride such as sodium borohydride, lithium borohydride, lithium triethylphosphonium hydride, diisobutylaluminum hydride or lithium aluminum hydride. . Sodium borohydride is usually used in the form of an aqueous solution or an alcohol solution at -20 ° C to 100 ° C, while other reagents are preferably at -8 (TC to 6 〇 t in dioxane, hydrazine, 2 _ 2 gas B Alkane, hexane, B. ' 1,4- 嗯 烧, tetrahydrofurfuran, N-fluorenyl. It can also be used to obtain only one type of anomeric than acetophenone, benzene, toluene or a mixture thereof. The stereoselective mode of the structure is carried out using, for example, the conditions of c〇rey_ Bakshi-Shibata (CBS) reduction (also known as reduction of c〇rey_ Itsuno). The leaving group LG is intramolecularly substituted to obtain the target compound Γ. When LG is equal to F, S02CM alkyl, S02-aryl or Ν〇2, the reaction is preferably at 20 ° C to 200 ° C in the presence of In the case of, for example, NaH, CaH2, BuLi, KOtBu or K0H), in the form of benzene, tetrahydrofuran, hydrazine, dioxane, N,N-didecyl decylamine, N, quinone decylamine, N _Methylpyridyl = 161177.doc 201249837 Gingerone or a mixture thereof. When LG is Cl, Br, I, the reaction is preferably in the presence of a transition metal catalyst such as Pd or Cu. Carried out under Scheme 4 Rr-N ^ ~ 12 f reductive [Lambda] 1 R1-N · L 13 is factory Rl

LG = leaving group 'eg F ' Cl, Br, I, OS02CM alkyl, S02-aryl, N02 Rz = A or a group which allows introduction of A, for example, R1' = R1 'protecting group as described above, For example -CO/Bu L. · = L. , Η may also be formed from a compound 13 having another hydroxyl group on the aromatic ring to form a dihydrofuran ring. The intramolecular substitution of an aliphatic oxime group with an aromatic oxime group can be carried out using a phosphine and an azodicarboxylate or a guanamine in tetrahydrofuran, M-dioxane, diethyl ether at -300 ° C to 100 ° C. It is achieved in toluene, benzene'dioxane or a mixture thereof (Mitsunobu reaction). Triphenylphosphine or tributylphosphine with dimethyl azodicarboxylate, diethyl azodicarboxylate, isopropyl succinic acid monoisopropyl sulfonium, acesulfonic acid di-(4- gas benzoic acid) , diazoacetic acid azoacetate, ditributyl azodicarboxylate, bis(dimethylammonium) azodicarboxylate, az〇dicarboxylic acid dipiperidide or The combination of az〇dicarb〇Xylic acid dimorpholide is a common combination for this transformation. Alternatively, the aliphatic 〇H group can be converted to a leaving group such as Cl, Br, I, 〇S〇2CH3 and 0S02Ph, and I61177.doc -52-201249837 is replaced with an aromatic hydrazine under the test conditions. Suitable tests are, for example, carbonates (for example, Cs2C〇3 and K2C〇3), hydrides (such as NaH), alcoholates (such as NaOMe and KCVBu), hydroxides (such as KOH and NaOH), and such tests are preferred. Toluene, tetrahydrofuran, hydrazine, hydrazine-dimethylformamide, hydrazine, hydrazine-dimercaptoacetamide, hydrazine-methylpyrrolidone, dimethyl sulfoxide, ethanol, water, and mixtures thereof are employed. The reaction may be such that the aliphatic hydroxy group is substituted with a completely inverted configuration to obtain an enantiomerically enriched product or a pure product, which is limited to the use of enantiomerically enriched starting compounds or pure starting compounds. . Process 5

R1· = R1, protecting group, eg -C02*Bu

Rz = A or a group that allows introduction of A, for example, intermediate 12 as described above can be obtained as depicted in Scheme 6; R1, Lp, LQ, n

Xi, X2, X3 and a have the meanings as defined above and below. The acid-reducing derivative 14 can be combined with an aromatic compound 15 having an anionic carbon center to form an intermediate 12' (pathway a.). Suitable carboxylic acid derivatives may be, for example, a diacid halide, a carboxylic acid ester, a carboxylic anhydride, and a decylamine carboxylic acid, and a suitable nucleophilic precursor 15 preferably has an electron withdrawing group (EwG) at the carbon center to further Easily producing a negative charge; preferably EWG is a carboxylate and a cyano group reaction is mediated by a base which removes the proton of compound 15 to produce an anion which in turn is added to the carboxylic acid functional group of 14 to obtain 12; The anion production step can be carried out in the presence of compound 14 or prior to the addition of compound 14 "Best test 161177.doc • 53· 201249837 is selected from the group consisting of alcoholates (such as KCVBu and NaOMe), amines (such as triethylamine and 1, 8-diazabicyclo[5.4.0]undec-7-ene), carbonates (eg €32 (:〇3 and K2C03), hydroxides (eg NaOH and KOH) and guanamines (eg LiN (eg LiN) SiMe3)2 and LiNiPr2), depending on their reactivity and compatibility, can be used in solvents such as toluene, tetrahydrofuran, 1,4-dioxane, N,N-dimercaptocaramine, N,N - used in dimercaptoacetamide, N-methylpyrrolidone, diterpenoid, ethanol or a mixture thereof. For example, Using KO, Bu or NaOEt as a base and using tetrahydrofuran, N-methylpyrrolidone or ethanol as solvent 'Compounds with ester functional group 140 = 0-(^-4 alkyl) and with cyano or ester Compounds 15 (EWG=CN or C(=0)0C丨.4 alkyl) are combined. The product 12 can be obtained by hydrolyzing an ester group or a cyano group followed by removal of the carboxyl group of the resulting carboxylic acid functional group. Conversion to intermediate 12 » can also remove EWG groups such as nitro or sulfonyl groups. The combination of compound 16 and compound 17 is another way of synthesizing intermediate 12 (pathway b.). Depending on the nature, the reaction is best carried out in the presence of a transition metal catalyst or in the absence of an additive. For example, it can be used at 60 ° C to 120 ° (:, using Pd catalyst (eg Pd (PPh3)) 4) and a base (for example, κ3Ρ04), a compound having lysine 16 (Μ=Β(ΟΗ) 2) and a compound having a carboxylic acid vaporized compound (X) in a solvent such as toluene or ι,4-dioxane =C1) Coupling. Compound 16 with M=Li or MgCl can be combined with electrophile 17 (X=N(〇Me)Me) with a carbenamide group. The reaction is usually at -70 °C. 40. (:, as the case may be in the presence of an additive such as CeCl3 'in tetrahydrofuran, 1,4-dioxane, diethyl ether, methyl bromide or a mixture thereof" by the presence of a transition metal (such as palladium / In the case of carbon) or hydrogenation 161177.doc -54 - 201249837 (eg [CuH(PPh3)]6), reduction of the double bond with hydrogen or phthalate to convert compound 12'' to intermediate 12 » Scheme 6

R1_ = R1 'protecting group, for example -C02»Bu Rz = A or a group allowing introduction of A, for example, as described above L〇· = H, L〇

EWG = Η or electron-withdrawing, such as COQ.4-alkyl, CN, S02CM-pile, N02 LG = leaving axe, such as F, Cl, Br, I, S02Cm-alkyl, SOr aryl, N 〇2 Μ = metal residue, such as b(〇H)2, BF3K, B(0CMe2CMe20&gt;, ZnCI/Br/丨, MgCI/Br/丨, CeCI2 X = leaving group, for example C OC^-pit , N(OMe)Me The general manner of linking the residue R1 to the N atom of the piperidine of the compound of the invention or its intermediate is outlined in Scheme 7; Ri, 1 and 11 have the meanings as defined above and below. The reaction can be carried out by a classical nucleophilic substitution on a heteroaromatic group with a leaving group such as F, c, Br, SC^Cm.alkyl, S〇2 aryl and N〇2. Grab: Machine ^ in the presence of a weak test (9) such as Na2C03, K2C03 or Cs2C03, pyridine, 4-diaminopyridine, triethylamine, ethyldiisopropylamine, i,8-diazabicyclo[5.4.0] In the case of deca-carbon·7_dilute, in the presence of indene, tetrahydrofuran, fluorene, U•dimethoxyethane, acetonitrile, fluorene-dimercaptocarboxamide, hydrazine, hydrazine · dimethyl acetamide, dimethyl (four), water, xiaoxiao, ethanol, isopropanol, dimethyl or 161177.doc -55- 201249837 mixture 'by conventional heating or microwave heating and the reaction was coupled with. Alternatively, piperidine 18 can be converted to the corresponding metal piperidide by removing the protons with a strong base (e.g., butyl, NaH or KH) prior to the addition of electrophile 19. In some cases, it may be advantageous or even necessary to use a transition metal as a coupling catalyst. The leaving group X in the compound 19 is preferably C1.

Br, I, 〇S〇2CH3, 〇S02-tolyl and 〇s〇2CF3. The reaction is preferably carried out using a transition metal-derived catalyst which is preferably based on copper or palladium. The catalyst may be in the form of an element of a transition metal (such as palladium/carbon or palladium nanoparticles) a salt of a transition metal (such as CuCM, CuBr, Cul, Cu(03SCF3)2'Cu(02CCH3)2, pdCl2, PdBr2, pd ( 〇2CCH3)2&amp;pd(〇2CCF3)2) or a transition metal complex (such as PL (dimethylenemethanol) 3), all of which may optionally be combined with other ligands, such as phosphines (eg Triphenylphosphine, trimethylphosphine, tris, cyclohexylphosphine, tri-tert-butylphosphine, u, bis(diphenylphosphino)ferrocene, optionally substituted biphenyl dibutylphosphine Or biphenyl dicyclohexylphosphine ' 2,2·-bis(diphenylphosphino), 1,3 disubstituted imidazole or imidazolium carbene, phosphite, 1,3-diketone, nitrile Or an olefin, preferably under (^ to 丨(10), in the presence of a base (such as Na〇/Bu, κο出u, i^iN(SiMe3)2, K2C〇3, Cs2C〇3 or “ο(d)) Toluene, benzene, tetrahydroanthracene. South, Μ_二 烧, Μ. dimethoxy ethane, N'N-dimethylformamide, N,N-dimercaptoacetamide, N_ Coupling reaction in thiopyrrolidone, di m iBu0H or mixtures thereof Should be - or 'as described in the experimental section, special (four) W, such as π, 2, 4] ^ [,,] - sit can be corresponding to the corresponding cyanamide of compound i 8 and the base I61177.doc • 56· 201249837 脎Or N-amine based lung combination.

Process 7

|«a«i

Rg=allow 1 to attach a residue or to lose a residue to obtain a group of a compound of the formula 例如 For example, refer to the above respective compounds X = leaving group 'e.g., F, a, Br, I, 〇S〇2CF3, 〇S02Cm The synthetic route exhibited by -alkyl, OS〇2-aryl, S02Cm-Hyun, and no2 ---= single or double bonds may depend on the use of the protecting group. For example, a potential reactive group (such as a hydroxyl group, a carbonyl group, a carboxyl group, an amine group, an alkylamino group or an imine group) may be protected by a conventional protecting group during the reaction, and then cleaved after the reaction. . Protecting groups suitable for the respective functional groups and their removal are well known to those skilled in the art and are described in the organic synthesis literature. The compounds of formula I can be resolved into their enantiomers and/or diastereomers as mentioned above. Thus, for example, a cis/trans mixture can be resolved into its cis isomer and trans isomer, and the racemic compound can be separated into its enantiomer. The cis/trans mixture can be resolved into its cis isomer and trans isomer by, for example, chromatography. The compound of the formula I in the form of a racemate can be separated into its enantiomers by the method known per se, and the mixture of diastereomers of the compound of the formula I can be used in the case of (iv) Different physicochemical properties can be resolved into their diastereomers by methods known per se (for example, chromatography and/or fractionation), and the compounds obtained from the latter are obtained as described above. It is referred to as an enantiomer by reference. 161177.doc •57· 201249837 preferably by chromatography on palm column chromatography or by crystallization from an optically active solvent or by formation of a salt or derivative (such as an ester or guanamine) with a racemic compound. The optically active substance reacts to resolve the racemate. The salt can be formed by enantiomeric pure acid (for basic compounds) and enantiomerically pure base (for acidic compounds). Diastereomeric derivatives may be formed by enantiomerically pure auxiliary compounds such as acids, activated derivatives thereof or alcohols. The diastereomeric mixture of the salt or derivative thus obtained can be separated by its different physicochemical properties (for example, solubility difference); it can be released from the pure diastereomeric salt or derivative by the action of a suitable reagent. Free enantiomer. The optically active acid commonly used for such purposes is, for example, D-form and L-form tartaric acid, benzhydryl tartaric acid, diterpene benzoic acid tartaric acid, malic acid, mandelic acid, 樟月b indeed, nooic acid, day Aspartic acid or qUinic acid. The optically active alcohol suitable as an auxiliary residue may be, for example, (+)-menthol or (_)-menthol, and the optically active thiol group in the amine can be, for example, (+)·menthyloxycarbonyl or (-). - a menthyloxy group. As mentioned above, the compounds of formula I can be converted into salts, especially into pharmaceutically acceptable salts for medical use. "Pharmaceutically acceptable salt" as used herein refers to a derivative of the disclosed compound wherein the parent compound is modified by making it an acidic or a test salt thereof. The compounds of the present invention may also be advantageously obtained by the methods described in the following examples, which may also be combined with methods known to those skilled in the art in accordance with the teachings. Terms and Definitions Terms not specifically defined herein shall be given to those skilled in the art from the teachings and the context of 161l77.doc-58-201249837. However, as used in the specification, the following terms have the meaning indicated and are in accordance with the following convention, unless otherwise stated. The terms "compound according to the invention", "compound of formula (1)", "compound of the invention" and the like mean a compound of formula (1) according to the invention, including tautomers, stereoisomers and mixtures thereof, and The salts thereof (especially the pharmaceutically acceptable salts thereof), and the solvates and hydrates thereof, include the tautomers, stereoisomers and solvates thereof and hydrates thereof. The term "treatment" encompasses prophylactic (i.e., preventative) therapeutic or therapeutic (i.e., curative and/or palliative) treatment. Thus, the term "treatment" encompasses the therapeutic treatment of a patient who has developed the condition, particularly in the form of a manifestation. Therapeutic treatment can be a symptomatic treatment aimed at alleviating the symptoms of sputum indications, or a treatment for the purpose of reversing or partially reversing the condition of the indication or suspending or slowing the progression of the disease. Thus, the compositions and methods of the present invention are useful, for example, in therapeutic treatments as well as in long-term therapies. In addition, the term "therapeutic" encompasses prophylactic treatment, i.e., treating a patient at risk of developing the above conditions, thereby reducing the risk. When the present invention refers to a patient in need of treatment, its mains, especially humans. One of the ritual illnesses or diseases or multiple symptoms or the term "therapeutically effective amount" means (1) treating or preventing a particular condition '(11) minus Is, improving or eliminating a particular disease or condition - or '4) preventing or delaying The amount of a compound of the invention for the onset of a particular disease or condition of a particular condition as described herein. 161177.doc -59-201249837:, unless otherwise indicated, otherwise the term "modulate" as used herein is used in conjunction with - or a plurality of compounds of the invention to activate the prion coupled receptor G-cut 9. Ε Unless otherwise indicated, the term "mediated" as used herein is used to treat (including) a particular disease or condition; (Η) to alleviate, ameliorate or treat a disease or condition - or multiple symptoms; Or (iv) prevent or delay the onset of a particular disease described herein or a homesickness. The term "substituted" as used herein, means that any or a plurality of hydrogens on a U, a group or a moiety are replaced by a group selected from the group indicated, with the proviso that it does not exceed the normal atom of the atom. The valence, and the substitution produces an acceptable stable compound. In the groups or moieties defined below, the number of carbon atoms is usually indicated before the group, for example, C!·6 alkyl means having! An alkyl group of up to 6 carbon atoms. In general, for a group containing two or more subgroups, the last listed subgroup is a group attachment point, for example, the substituent "aryl {^alkyl" means that the aryl group is bonded to the Cw alkane. The base-, cK3 alkyl group is bonded to the core or a group to which the substituent is attached. In the case where the compound of the present invention is described by chemical name and chemical formula, if there is any difference, the chemical formula shall prevail. The asterisk can be used in the subform to indicate a bond to a core molecule as defined. The atomic number of a substituent begins with the atom closest to the core or the group to which the substituent is attached. By way of example, the term "3-reactylpropyl" denotes the following substituent: 161177.doc -60- 201249837 1 3 wherein the carboxyl group is attached to the third carbon atom of the propyl group. The term Γι·methylpropyl-", "2,2-dimethylpropyl" or "cyclopropylmethyl" means the following groups:

1 2 CH3 3

The asterisk can be used in the subform to indicate the bond to the defined core molecule. In the definition of a group, the term "wherein X, oxime and 2 hydrazine are each replaced by a condition" and the like are indicated, each as a respective group or each as a part of a constituent group. Group X, each group γ and each group 2 may be as defined by substituted β, for example, "Rex represents hydrazine, Cw alkyl, C3.6 cycloalkyl, C3. 6 cycloalkyl-C!- a 3-alkyl or Cw alkyl group, wherein each alkyl group is optionally substituted by one or more Lex" or a similar definition thereof, in the above-mentioned groups comprising the term alkyl group, ie, in the group alkyl group, C3 · In each of the 6-rings, the bases, the C, the 3, and the 3, the alkyl group can be replaced by Lex as defined. Hereinafter, the term double ring includes a spiro ring. Unless otherwise stated, the specified chemical formula or name will encompass both tautomers and all stereoisomers, optical isomers, and geometric isomers (eg, enantiomers, non- Enantiomers, E/Z isomers, etc.) and racemates thereof, as well as mixtures of individual enantiomers, mixtures of diastereomers, or such isomers in varying proportions And a mixture of any of the above forms in the presence of an enantiomer, and a salt thereof 161177.doc 201249837 (including its pharmaceutically acceptable brain «») and its solvates (such as water) "including free compounds" Solvent (4) Sigma or a solvate of a salt of a compound. 0 "Pharmaceutically acceptable quinable ♦" This article is used to refer to the organization of human and private cheeks and animals in a reasonable medical judgment. Compounds, substances, compositions and/or dosage forms that are in contact without excessive toxicity, irritation, allergic reactions, or other problems, are commensurate with reasonable benefits/risk ratios. As used herein, "a pharmaceutically acceptable derivative of a tetraclic compound" wherein the parent compound is modified by making an acid salt or a test salt thereof. In addition to the above, other brewing #Bfi, Salts of Λ丨t_丹丹龀, for example salts suitable for the purification or isolation of the compounds of the invention (for example tris-acetate) also form part of the invention. 0 The term halogen generally denotes fluorine, gas, bromine and iodine. The term I cNn alkane Wherein 11 is an integer of 1 to 11, and when it is used alone or in combination with another group, it has 1 to 11 ([: atomic acyclic saturated branched chain or linear hydrocarbon group. For example, the term Cl 5-alkyl encompasses the group h3C... H3C-CH2-'H3C-CH2-CH2_, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH ( CH3)-CH2-, H3C-c(ch3)2-, h3c-ch2-ch2-ch2-ch2-, h3c-ch2-ch2-ch(ch3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-ch2-c(ch3)2-, h3c-c(ch3)2-ch2-, h3c-ch(ch3)-ch(ch3)- and h3c-ch2 -ch(ch2ch3)-. The term "Ch alkyl", where n is an integer from 1 to n, alone or in combination with another group of 16ll77.doc • 62· 201249837 H represents an acyclic straight or branched chain divalent alkyl group having 1 to n carbon atoms. For example, the term Cm alkyl includes -(CH2)-, -(ch2-ch2)-, -(ch (ch3))-, -(ch2-ch2-ch2)-, -(c(ch3)2)-, -(ch(ch2ch3))-, -(ch(ch3)-ch2)-, -(ch2- Ch(ch3))-, - (CH2-CH2-CH2-CH2)- &gt; -(CH2-CH2-CH(CH3))-, -(CH(CH3)-ch2-ch2)_, -(ch2- Ch(ch3)-ch2)_, -(ch2-c(ch3)2)_, -(c (ch3)2-ch2)·, -(CH(CH3)-CH(CH3))-, -(CH2 -CH(CH2CH3))-, -(ch(ch2ch3)-ch2)-, _(ch(ch2ch2ch3))-, -(chch(ch3)2)-, and -c(ch3)(ch2ch3)-. "C2-n-alkenyl" is used to mean a group having at least two carbon atoms as defined in the definition of "c丨n alkyl", wherein at least two of the carbon atoms of the group are bonded to each other via a double bond Knot. For example, the term C2 3 alkenyl includes -CH=CH2, -CH=CH-CH3, -ch2-ch=ch2. The term "〇2_„alkenyl group" is used to mean having at least two carbon atoms.

A group as defined in the definition of C alkyl, wherein at least two of the carbon atoms of the group are bonded to each other via a double bond. For example, the term C2_3 extended alkenyl includes -CH=CH_, CH=CH CH2·, CH2_CH=CH. "C2_n alkynyl" is used to mean a group gj' having at least two carbon atoms as defined by the definition of "c^ &amp; group", wherein the group is in the same carbon atom

161177.doc. For example, the term 'C2.3 alkynyl package, &amp;&quot; is used to mean a group having at least two carbon atoms as defined in the definition, wherein the g of the group is bonded to each other via a bond. . For example, the term -63 - 201249837 -CH2-OC- » C2-3 stretching alkynyl includes, alone or in combination with another group the term "c3n carbocyclyl" means a single having 3 to n c atoms A cyclic, bicyclic or tricyclic saturated or unsaturated hydrocarbon group. The hydrocarbon group is preferably non-aromatic. Preferably, the 3 to η C atoms form one or two rings. In the case of a double or triple ring system, the rings may be connected to each other via a single bond, or may be fused, or may form a spiro or bridged ring system. For example, the term C3.1() carbocyclyl includes Gw cycloalkyl, c3_iG cycloalkenyl, octahydrocyclopentadienyl, octahydrofluorenyl, decahydronaphthyl, indanyl, tetrahydronaphthalene base. The term C3-n carbocyclic group preferably denotes a cycloalkyl group, especially a C3_7 cycloalkyl group. The term "匸^cycloalkyl" as used alone or in combination with another group (wherein 11 is an integer from 4 to η) represents a cyclic saturated unbranched hydrocarbon group having 3 to 11 c atoms. The cyclic group may be monocyclic, bicyclic, tricyclic or material, and most preferably a single ring. Examples of such ring-based groups include cyclopropyl, cyclobutylcyclononylcyclohexyl, % heptyl, cyclooctyl, Cyclodecyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4 5]fluorenyl, norbornyl-reducing base-lowering hydroxy, etc., alone or in combination with another group The term "C3_3f alkenyl" (wherein 11 is an integer from 3 to η) denotes a non-branched hydrocarbon group having 3 to 11 (a ring-unsaturated but non-aromatic atom, at least two of which are carbon atoms) Bonded to each other via a double bond. For example, the term Cycycloalkenyl includes cyclopropenyl, cyclobutenyl, cyclopentane, cyclopentyl: dilute, cyclohexane, cyclohexane, cycloheptyl Cycloheptadienyl and cycloheptatrienyl. The term "aryl" as used herein, alone or in combination with another group, 161177.doc • 64· 201249837 not a carbon ring of 6 carbon atoms The aromatic monocyclic ring is based on a second 5 chang + called a six-step fused or non-I 6 member carbocyclic group, and the second carbocyclic group may be an aromatic saturated group, and the aryl group includes (but is not limited to) Phenyl, section Base, Section I - hydrazine: fluorenyl, phenanthryl, tetrahydronaphthyl and dihydronaphthyl. Separately or in combination with Mego: the term "aryl" as used herein preferably means stupid or Naphthyl, most preferably phenyl. "hetero" means a saturated or unsaturated monocyclic, bicyclic, or clothing containing one or more heteroatoms selected from N, hydrazine or a (Mr 0 1 or 2). The snail loop 'preferably a monocyclic, bicyclic or spiro ring system, which may be further: a phenyl group, alone or in combination with another group, a 5 hexyl group as used herein" is more preferred. Said to contain 1, 2, 3 or 4 heteroatoms selected from N, 〇 or S(〇)r(rG, 1 or 2) saturated or unsaturated (even more preferably full spear "mouth" single, double ring Or a spirocyclic ring system which may additionally have a number of groups. The term "heterocyclyl" is intended to include all possible isomeric forms. Examples of such groups include aziridine, oxiranyl, azetidinyl , oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, azepanyl, piperazinyl, morpholinyl, tetrahydrofuranone, tetrahydropiperidone, pyr Luo bite_base The term "heterocyclyl", "heterocyclyl", therefore, includes the following exemplary structures, which are not depicted as a group, since each form can be attached to any atom via a covalent bond. As long as the proper valence is maintained: 161177.doc -65· 201249837 Ο

161177.doc -66- 201249837

161177.doc -67- 201249837

The term "heterocyclic" means that the stomach contains a plurality of monocyclic apricot rings selected from the group consisting of N, 〇S(〇)r(r=〇, 1 or 2) (preferably Monocyclic or cyclic) ring systems wherein at least one of the heteroatoms is part of an aromatic J ring and wherein the ring system can have a carbonyl group. The term "heteroaryl" as used herein, alone or in combination with another - ^, is more preferably meant to contain 1, 2, 3 or 4 selected N, Ο or S (external (four), i or 2) A monocyclic or bicyclic ring system of an atom wherein at least one heteroatom is part of an aromatic ring and wherein the ring system has a number of groups. The term "miscellaneous / 1 π miscellaneous violence" includes all possible isoforms. Thus the term 'heteroaryl" includes the following exemplified structure as a group, since each form can be attached to any atom via a covalent bond, ^Illll77.doc -68 · 201249837 Maintain the appropriate valence: 6 ^ ό ό Ο °5°ό 6 Ο Ο Ο ύ ύ ύ Η

Many of the terms provided above may be repeated for use in the definition of a chemical formula or group and in each case independently of one another have one of the meanings provided above. Pharmacological activity The following assay can be used to demonstrate the activity of the compound of the invention. The compound of formula I according to the invention modulates the activity of the G protein-coupled receptor GPR119. The effect of these compounds on the activation of GPR119 and the stimulation of intracellular cAMP concentration was determined using an AlphaScreen cAMP assay kit manufactured by PerkinElmer (catalog number 6760625R). MIN6 cells were stably transfected with the expression vector of human GPR119 cDNA (Accession No. NP_848566) [Miyazaki J et al., Endocrinology. July 1990; 127(1): 126-32]. Min-6/hGPR119 cells were cultured in DMEM, 10% FBS, 50 μΜ β-mercaptoethanol, 0.3 mg/mL geneticin (Geniticin), 2 mM GlutaMAX at 37 ° C, 5% CO 2 . For analysis, cells were seeded in Optiplates (white, 384 well, 160 W-barcode, TC, sterile, capped, catalog number 6007688 (Perkin Elmer); 10000 cells/well; 50 μΐ). Next, the capped disks were incubated for 24 hours at 37 ° C / 5% CO 2 . After completely aspirating the medium from each well, 10 μΐ of the test compound was added using stimulation buffer (140 mM NaCl, 3.6 mM KC1, 0.5 mM NaH2P04, 0.5 mM MgS〇4, 1.5 mM CaCh, 1 mM mM Hepes, 5 mM NaHC03; pH). 7.4, 0.5 mM IBMX and 0.1% BSA, final DMSO concentration of 1%) diluted compound. After incubation for 45 minutes at room temperature (about 20 ° C), the cAMP concentration was determined using an AlphaScreen cAMP assay kit (catalog number 6760625R ' from PerkinElmer). Add 1 〇μΐBiotin-Camp (final concentration in lysis buffer (5 mM Hepes (pH 7.4), 0.1% BSA, 0.5% Tween) at 1 U per well) and 1 μμΐ^ bead solution ( The final concentration in the buffer was 161177.doc -70- 201249837 in the buffer was 1 U per well. The plates were incubated for an additional 2 hours at room temperature. The cAMP concentration was calculated from the Alpha Screen count using the cAMP standard curve. By analyzing E (: 5 g value and maximum value according to the positive control, data analysis using a suitable software (Graphpad Pdsm). The compound of the present invention increases the intracellular cAMP content by 3 to 5 times. The ECso value of the compound of the present invention is usually about 丨From nM to about 1 〇μΜ, preferably from 1 砸 to 2 _, preferably less than i μΜ, particularly preferably less than 500 η Μ, optimally less than 100 nM. The EC5 enthalpy of the compound of the invention is shown in the experimental part. The number of the example corresponds to the number of the compound in the table below.

161177.doc -71 . 201249837

Since the compound of the formula (i) of the present invention is capable of modulating the activity of the prion-coupling receptor GPRU9, particularly agonistic activity, the compound of the formula (1) of the present invention (including its corresponding salt) is theoretically suitable for the treatment of prion protein The coupling receptor GPR119 activation affects or all of the diseases or conditions mediated by activation of the G protein-coupled receptor GpRU9. Accordingly, the present invention is directed to compounds of formula (I) for use as a medicament. Furthermore, the present invention relates to the use of a compound of the formula (1) or a pharmaceutical composition of the present invention for use in the treatment and/or prevention of activation of the G protein-coupled receptor GPR119 in a patient, preferably a human. Disease or condition. In another aspect, the invention relates to a method of treating a disease or condition mediated by activation of the prion-coupling receptor GPR119 in a mammal, the method comprising administering to a patient in need of such treatment, preferably a human And a therapeutically effective amount of a compound or pharmaceutical composition of the invention. Diseases and conditions mediated by the agonist of the G protein-coupled receptor gpri 19 encompass metabolic diseases or conditions. According to one aspect, the compounds and pharmaceutical compositions of the invention are particularly useful for the treatment of diabetes (especially type 2 diabetes, type 2 diabetes), diabetic complications (such as retinopathy, nephropathy or neuropathy, diabetic foot, ulcers, large blood vessels) Lesions), metabolic acidosis or ketosis, reactive hypoglycemia, sputum sputum 'glucose metabolism disorder, insulin resistance, metabolism 161177.doc -72· 201249837 syndrome, dyslipidemia of different causes, atherosclerosis Sclerosing and related diseases, obesity, hypertension, chronic heart failure, edema, and hyperuricemia 0 The compounds and pharmaceutical compositions of the present invention are also useful for preventing cell degeneration, such as pancreatic beta cell apoptosis or necrosis. The compounds and pharmaceutical compositions of the invention are also useful for improving or restoring the function of pancreatic cells and increasing the number and size of pancreatic p cells. Thus, according to another aspect, the invention relates to a compound according to the invention [compounds and pharmaceutical compositions for preventing, delaying, slowing the progression of metabolic diseases and/or for treating metabolic diseases, in particular for improving Blood glucose control and/or beta cell function in patients. In another aspect, the invention relates to a compound of formula j of the invention and a pharmaceutical composition for preventing, delaying, slowing the progression of type 2 diabetes, overweight obesity, diabetic complications, and related pathological conditions and / or ... for type 2 diabetes, overweight, obesity, diabetic complications and related pathological conditions. Further, the compound &amp; pharmaceutical composition according to the present invention is suitable for the following therapeutic treatments: - for preventing, extending, licking, slowing the progression of metabolic diseases or treating metabolic disorders: diarrhea, type 2 diabetes, Insufficient tolerance of grape vines 'redemption' (five) blood sugar, hyperlipidemia, hypercholesterolemia, blood lipids and other syndromes X, pieces of birth, metabolic syndrome, obesity, hypertension, chronic systemic inflammation , retinotomy, ^, membranous lesions, neuropathy, nephropathy, atherosclerosis, endothelial dysfunction 戍 戍 相关 相关 ( ( ( ( ( ( ( ( 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 Inflammation or osteoarthritis); - used to improve glycemic control and / or reduce fasting blood glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbAlc; - used to prevent, delay, slow or reverse glucose damage, Tengdaosu resistance and/or metabolic syndrome progress to type 2 diabetes; - for preventing, delaying, or slowing the progression or treatment of a condition selected from diabetic complications or treatment selected from diabetes Symptoms or diseases, such as retinopathy, nephropathy or neuropathy, diabetic foot, ulcers or macrovascular disease; - for weight loss or prevention of weight gain or promotion of weight loss; - for the prevention or treatment of sputum beta cells Degrading and/or ameliorating and/or restoring the function of spleen p cells and/or restoring pancreatic insulin secretion; - for maintaining and/or improving insulin sensitivity and/or preventing or treating hyperinsulinemia and/or Insulin resistance. DETAILED DESCRIPTION OF THE INVENTION 'The compounds and pharmaceutical compositions according to the present invention are useful for the treatment of obesity, diabetes (including type 1 diabetes and type 2 diabetes, preferably type 2 saccharinosis) and/or diabetic complications (such as retinopathy), Nephropathy or neuropathy, diabetic foot, ulcer or macrovascular disease). The compounds of the invention are most particularly useful for the treatment of type 2 diabetes. The dose of the compound of the general formula (I) which can be administered per day is usually in the range of 0.001 mg to 10 mg per kg of body weight, for example, per kg of patient body weight 爪 1 pawl layer to 8 mg » each dosage unit should contain (U „^ to 1〇 〇〇mg, for example 〇5 〇^ to 500 mg 〇 The actual therapeutically effective amount or therapeutic dose will of course depend on factors known to those skilled in the art, such as the age and weight of the patient, and administration. Route and severity of disease. In any case, the compound or composition should be administered in a dosage and manner that allows for the delivery of a therapeutically effective amount according to the patient's unique condition. Oral, transdermal, inhalation, parenteral. Or a sublingual route for administration of a compound, composition, or any combination of one or more other therapeutic agents of the invention. In a possible administration method, it is preferred to administer the drug orally or intravenously. Formulations suitable for administration of a compound of formula (1), optionally in combination with one or more other therapeutic agents, and include, for example, tablets, pills, capsules, suppositories, buccal, sugar-soluble solutions, Poly, ugly, sachet, injection, inhalant, powder, etc. Preferably, it is an oral formulation, especially a solid form, such as a troche or a capsule. The pharmaceutically active compound is preferably present in an amount of oi% by weight of the entire composition. 99% by weight, for example, i% by weight to 70% by weight. Suitable lozenges can be prepared, for example, by mixing one or more compounds, known excipients (for example, inert diluents, carriers, disintegrating agents, adjuvants). Or a surfactant, a surfactant, a binder, and/or a lubricant. The tablet may also be composed of several layers. Those skilled in the art will be familiar with the specific excipients, carriers, and/or The diluent is preferably one which is suitable for the particular formulation and method of administration. The formulations or formulations of the present invention may be prepared, for example, by mixing or combining, using methods known per se and well known to those skilled in the art. - a compound of the invention or a compound of the invention: a pharmaceutically acceptable salt of the drug and / or a plurality of excipients, carriers and / or 161177.doc -75 · 201249837 combination therapy of the compound of the invention may further One or more, preferably a combination of other therapeutic agents. According to one embodiment, the other therapeutic agent is selected from the group consisting of treatments for the above mentioned diseases or conditions (especially associated with metabolic diseases or conditions, such as diabetes, obesity, diabetic complications) , a group of therapeutic agents suitable for the combination of sputum, especially including, for example, a therapeutic effect of a booster or an active substance for one of the indicated indications and/or a reduction of one or A therapeutic agent at a dose of a plurality of active substances. Accordingly, the compounds of the present invention may be combined with one or more other therapeutic agents selected from the group consisting of anti-diabetic agents, agents for treating overweight and/or obesity, and An agent for treating hypertension, heart failure, and/or atherosclerosis. Antidiabetic agents are, for example, diterpene biguanide, sulfonyl urea, nateglimde, repagininide, thiazolidinedione, PPAR-(ct, 丫 or ... 丫) agonist or modulation Agent, α-glucosidase inhibitor, DPPIV inhibitor, SG1T2 inhibitor, insulin and insulin analogue, GLP-1 and GLP-1 analogue or amyloid and amyloid analogue cyclodex, 11P - HSD inhibitor. Other suitable combinations are protein tyrosine phosphatase 1 inhibitors, substances that affect the production of glucose in the liver (such as glucose-6-phosphatase or fructose-丨, 6-bisphosphatase, glycogen phosphorylase) Inhibitors, glycosaminoglycan receptor antagonists and phosphoenol propionate buffer inhibitors, glycogen synthase kinase or pyruvate dehydrogenase, U antagonists, CCR-2 antagonists or glucose Kinase activator. One or more anti-monthly agents are also suitable as a combination conjugate 'such as HMG-coenzyme reductase inhibition 161177.doc -76- 201249837 agent, fibrates, nicotinic acid and its derivatives, ppAR-(a , γ or 〇 1 / 丫) agonist or regulator, ? ? Eight 11_5 agonists, eight-inhibitors or cholesterol absorption inhibitors, such as bile acid-binding substances, such as ileal bile acid delivery inhibitors, sputum inhibitors, or HDL-elevating compounds, such as CETP inhibitors or ABC 1 Conditioner. Therapeutic agents for treating overweight and/or obesity are, for example, cannabinoid 1 receptor antagonists, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists, β3· An agonist, leptin or leptin mimetic, 5HT2c receptor agonist. Therapeutic agents for the treatment of hypertension, chronic heart failure and/or atherosclerosis are, for example, sputum-sputum antagonists or ACE inhibitors, ECE inhibitors' diuretics, beta-blockers, Ca-antagonists' hubs. A functional antihypertensive agent, an alpha-2-adrenergic receptor antagonist, a neutral endopeptidase inhibitor, a platelet aggregation inhibitor, and other suitable agents or combinations thereof. Angiotensin A purine receptor antagonist is preferably used to treat or prevent hypertension and diabetes complications. The antagonist is usually combined with a diuretic such as hydrochlorothiazide. The dose of the combination conjugate mentioned above is usually 1/5 of the normal recommended minimum dose to 1/1 of the normal recommended dose. The compounds of the invention and/or pharmaceutical compositions comprising a compound of the invention, optionally in combination with one or more other therapeutic agents, are preferably administered in combination with exercise and/or diet. Thus, in another aspect, the invention relates to the use of a compound of the invention in combination with one or more other therapeutic agents as described above and below, 161177.doc-77-201249837 for use in the treatment of G Activation of the protein-coupled receptor GPR119 affects or is mediated by the activation of the G-protein-coupled receptor GPR119, particularly the diseases or conditions described above and below. In another aspect, the invention relates to a method of treating a disease or condition mediated by activation of a G protein-coupled genus GPR11 9 in a patient, the method comprising administering to a patient in need of the treatment, preferably a human A therapeutically effective amount of a compound or pharmaceutical composition of the invention in combination with a therapeutically effective amount of one or more other therapeutic agents as described above and below. Combinations of the compounds of the invention with other therapeutic agents can be used simultaneously or at the wrong time. The compound of the invention and one or more additional therapeutic agents may be present together in one formulation, such as a troche or capsule, or in the form of a so-called dispensing portion, respectively, in two identical or different formulations. Accordingly, in another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention and one or more additional therapeutic agents as described above and below, optionally with one or more inert carriers And / or thinner. Other features and advantages of the present invention will become apparent from the following detailed description. EXAMPLES The terms "ambient temperature" and "room temperature" are used interchangeably and mean a temperature of about 2 Torr. Introduction: In general, H_NMR and/or mass spectra of the prepared compounds are obtained. RHt was measured using a Merck silicone 60 F254 disk and 254 nm UV light. 161177.doc •78· 201249837 Compounds assigned to specific configurations at stereogenic centers are isolated as pure isomers. The configuration of the stereoisomeric center is arbitrarily specified. Any compound similar to a compound with any specified configuration gives a similar configuration. Analytical HPLC parameters for the characterization of the product (TFA for trifluoroacetic acid): Method 1 Columns Waters XBridge C18, 4.6 x 30 mm &gt; 3.5 μιη Method 2 Columns Waters XBridge Cl8, 4.6x30 mm &gt; 3.5 μηι Mobile Phase A : water +0.1% TFA B : sterol + 0.1% TFA mobile phase A: water + 0.1% TFA B : methanol time (min) A% B% time (min) A% B% 0.0 95 5 0.0 95 5 0.20 95 5 1.6 0 100 1.5 0 100 1.85 0 100 1.75 0 100 1.9 95 5 1.85 95 5 Flow rate 4.0 mL/min Flow rate 4.8 mL/min Wavelength UV 220 nm, 230 nm or 254 nm Wavelength UV 220 nm, 230 nm or 254 nm Method 3 Columns Waters XBridge Cl8, 4.6x30 mm, 3·5 μηι Method 4 Waters XBridge C18, 3χ30 mm j 2.5 μιη Mobile Phase A: Water + 0.1% TFA B: Sterol + 0.1% TFA A: Water + 0.1% TFA B: sterol time (min) A% B% time (min) A% B% 0.0 95 5 0.0 95 5 0.20 95 5 0.05 95 5 1.5 0 100 1.40 0 100 1.9 0 100 1.80 0 100 2.0 95 5 Flow rate 4.0 mL /min Flow rate 2.2 mL/min Wavelength UV 220 nm, 230 nm or 254 nm Wavelength UV 220 nm, 230 nm or 254 nm Method 5 Columns Waters XBridge C18, 4.6x30 mm » 3.5 Ηι Method 6 Columns Waters XBridge Cl8, 4.6x30 mm &gt; 3.5 μηι Mobile Phase A: Water + 0.1% TFA B : Sterols Mobile Phase A: Water + 0.1% HCOOH B: Methanol Time (min) A% B% Time (min) A% B% 0.0 95 5 0.0 95 5 1.6 0 100 1.15 95 5 1.85 0 100 1.7 0 100 1.9 95 5 2.25 0 100 Flow rate 4.0 mL/min Flow rate 4.0 mL/min Wavelength UV 220 nm, 230 nm or 254 Nm wavelength UV 220 nm, 230 nm or 254 nm 161177.doc •79· 201249837 Method 7 Columns Waters XBridge C18, 3x30 mm, 2.5 μιη Method 8 Columns Waters Sunfire Cl8, 3x30 mm » 2.5 μπι Mobile Phase A: Water + 0.1% ΝΗ4〇Η Β : sterol mobile phase A: water + 0.1% TFA B: sterol time (min) A% B% time (min) A% B% 0.0 95 5 0.00 95 5 0.05 95 5 1.25 95 5 1.40 0 100 1.70 0 100 1.80 0 100 1.75 0 100 1.90 0 100 Flow rate 2.2 mL/min Flow rate 1.8 mL/min Wavelength UV 220 nm, 230 nm or 254 nm Wavelength UV 220 nm, 230 nm or 254 nm Method 9 Column Waters Sunfire C18, 4.6x50 mm, 3.5 μηι Method 10 Column Waters Sunfire Cl8 5 4.6x30 mm, 3.5 μηι, 60〇C Mobile Phase A: Water + 0.1% TFA Β : Alcohol mobile phase A: water +0.1% HCOOH B: sterol time (min) A% B% time (min) A% B% 0.00 80 20 0.00 95 5 1.70 0 100 0.15 95 5 2.50 0 100 1.70 0 100 2.60 80 20 2.25 0 100 Flow rate 2.0 mL/min Flow rate 4.0 mL/min Wavelength DAD 210 nm to 500 nm Wavelength DAD 210 nm to 500 nm Intermediate 1 1-(4-Benzo-β-Cry-2-base-Brigade bite-1 -base)-2,2,2-three elephants-acetone

Trifluoroacetic anhydride (9.41 mL) was added dropwise to 4-benzofuran-2-yl-piperidine hydrochloride (8.00 g) and triethylamine (14.19 mL) in dioxane at 〇 °C. In a mixture of alkanes (80 mL). The mixture was allowed to warm to room temperature, washed with water and aq. NaH.sub.3, and dried (MgSO.sub. The crude product was used without further purification. LC (method 3): tR = 1.39 min; mass spectrum (ESI+): m/z = 298 [M+H]+. 161177.doc -80- 201249837 Intermediate 2 1·[4-(2,3-Dihydro-benzofuran-2yl)-piperidin-1-yl]-2,2,2-trifluoro-B ketone

1-(4-benzofuran-2-yl-piperidin-1-yl)-2,2,2-trifluoro-ethanone (11.50 g) at room temperature under a hydrogen atmosphere (3.5 bar) A mixture of 10% palladium on carbon (1·ΐ5 g), ethyl acetate (135 mL) and methanol (15 mL) was shaken for 24 hours. The catalyst was then isolated by filtration and the filtrate was concentrated to give an oil, which was taken to the next reaction without further purification. LC (Method 2): tR=l.34 min 〇Intermediate 3 l-[4-(5-Bromo-2,3-dihydrobenzofuran-2-yl)-piperidine-4-yl]_2 2 2_ Trifluoro-acetamidine

The title compound was prepared according to a procedure similar to that described for the intermediate 1 to be benzofos- -2- yl). LC (Method 2). (ESI+): m/z = 378 [M+H]+. LC (Method 2): difluoro-ethanone and N-bromo-butane 2): tR = 1.47 min; mass spectrum intermediate 4 4-[5-(4-methanesulfonyl-phenyl)_2,3_ Dihydro-benzofuran-2-yl]- 161177.doc • 81 - 201249837

To l-[4-(5-invalid-2,3·dihydro.benzoheptan-2-yl)·Broader] base]_2,2 2_trifluoroacetone (2.5〇g) and 4_ 2 NaNa2C〇3 Aqueous Solution (8.26 mL) was added to a mixture of (decanesulfonyl) phenyl g-ponic acid (1·45 g) in N,N-dimethyl decylamine (25 mL). Bubbling with argon for 1 minute and adding Pdci2 [i, ii-bis(diphenylphosphino)-ferrocene]*CH2Ci2 complex mg) was also mixed at 9 ° C overnight. Cooled to room After warming, water (50 mL) and ethyl acetate (1 mL) were added and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with water and brine, dried (M.sub.4) and evaporated. The residue was chromatographed under the reaction conditions, so the residue was chromatographed on EtOAc (methanol / EtOAc / EtOAc / EtOAc / 1) : tR = 0 0 min; mass spectrum (ESI+): m/z = 358 [M+H] + Intermediate 5 4-[5-(4-Methanesulfonyl-phenyl)_2,3_2 Hydrogen-benzofuran_2_piperidine-1-carbonitrile

Ethyl diisopropylamine (0.96 mL) and bromine nitrile (175 mg) were added to 4-[5-(4-methanesulfonyl-phenyl)_23-dihydro-benzofuran-2-yl]- Piperidine (400 mg) in dihydromethane (1 mL) and tetrahydrofuran (1 mL), 16 U 77.doc • 82· 201249837 and stirred the reaction mixture overnight at ambient temperature, adding dichloromethane and The organic phase was separated by water and washed with water, aq. The solvent was evaporated and the residue was triturated with diethyl ether to afford a pale brown solid. Since this material still contained ethyl diisopropylamine hydrochloride, ethyl acetate and water were added. The organic phase was separated, dried over EtOAc EtOAc The residue was triturated with EtOAc (EtOAc)EtOAc. Intermediate 6 4 (5-gas · astringent and [2,3-c] "bite -2 · base" - silver bite _ι_carboxylic acid third vinegar

Copper iodide (1) (25 mg) and bis-(triphenylphosphine) palladium (11) (30 mg) were added to N,N-dimethylformamide under argon atmosphere ( Add 3 parts of diethylamine (110 μι) to the room

LC (method 2): tR = 1.40 min; :tR = 1.40 min; <RTI ID=0.0></RTI> </RTI> <RTIgt; Gas 4-iodo-pyridin-3-ol (200 mg). The resulting mixture was stirred under warm for 1 hour. Driving acid tert-butyl ester (175 mg) in N,N-di intermediate 7

Pyridin-1·t-butyl formate 161177.doc •83- 201249837

4-(5-Angfu. Nanhe [2,3-c]π ratio bit-2-yl)-0 bottom bite-1-carboxylic acid tert-butyl ester (390 mg), 4-(methanesulfonyl) a mixture of phenyl acid (350 mg), aqueous Na2C03 (2 Μ; 1.50 mL) and dioxane (1 〇 mL) was bubbled with argon for 10 minutes and Pd(PPh3)4 (l〇〇mg) was added. . The resulting mixture was heated to 170 ° C ' in a microwave oven until the conversion was complete. The reaction mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over a pad of EtOAc and evaporated. The residue was chromatographed eluted eluted elut elut elut elut elut elut elut elut elut M+H]+. Intermediate 8 4·[5-(4-methanesulfonyl-phenyl)_2,3-dihydro-indole[2,3_c]b ratio bite-2 base]-piperidine-1-carboxylic acid Tributyl y-

Oscillating 4_[5_(4_nonanesulfonyl-phenyl)-furo[2,3-c]pyridine_2-yl]-piperidine- under a hydrogen atmosphere (5 bar) at 50 °C A mixture of 1-butylic acid tert-butyl ester (155 mg), acetic acid (4.0 mL) and 1 〇〇/0 palladium/carbon (4 〇 mg) in methanol (1 mL). The catalyst was filtered off and the filtrate was concentrated in vacuo to afford title compound. LC (Method 5): m.p. = 1.32 min; 161177.doc -84- 201249837 Intermediate 9 5-(4-Methanesulfonyl-stupyl)_2_Bistidin-4-yl-2,3-dihydro-furo[2,3-e]acridine

4-[5-(4-decanesulfonyl-phenyl)·2,3-dihydro-furo[2,3-c]D is bitten at the bottom of the base - A mixture of 1-carboxylic acid terpene vinegar (190 mg) and trifluoroacetic acid (0.40 mL) in dioxane (3 mL) was stirred for 2 hr. The reaction mixture was diluted with dichloromethane and washed with aqueous Na.sub.2CO.sub.3. The aqueous phase was extracted with EtOAc (EtOAc). LC (Method 5): m.p. Intermediate 10 4-[5_(4_methanesulfonyl-phenyl)_2,3_dihydro-furan [2,3_c]pyridine _ 2 -yl]-Broad bit _ 1 _ carbonitrile

Like a procedure, consisting of 5-(4-methanesulfonyl) and [2,3-c]n-pyridinium and bromonitrile • tR=0.9l min; mass spectrometry (ESI+): as described in relation to intermediate 5 The title compound was prepared in the same manner as the phenyl group. LC (Method 5): tF m/z = 384 [M+H]+. 161177.doc -85- 201249837 Intermediate 11 N-Hydroxy-4-[5-(4-methanesulfonyl-phenyl)_23_dihydrofuran [2 3 c]&quot;Bite-2-yl Bu travel bite _ι_甲脉

4-[5-(4-Methanesulfonyl-phenyl)_2,3-dihydro-furazolo[2,3-c] «Bist-2-yl]-piperidine-1 under reflux A mixture of -carbonitrile (75 mg), hydroxylamine hydrochloride (5 mg), potassium carbonate (70 mg), ethanol (1 mL) and water (15 mL) The reaction mixture was concentrated in vacuo and purified eluting elut elut elut elut Lc (method 5): t~0.65 min; mass spectrum (ESI+): m/z = 417 [M+H]+. Intermediate 12 4-[2-(5-漠-2-气-吼咬-4-yl) ethyl kebb brittle bit _ι_carboxylic acid = butyl ester

Add a solution of bis(trimethylsulfonylalkyl)amine lithium (1,0 Torr in tetrahydrofuran; n.00 mL) to tetrahydrofuran (15 mL) at -40 °C under argon. In the 5·bromo-2-propane-4-mercaptopyridine (950 mg). The mixture was stirred at -35 C to -45 C for 2 hours. Then, Niobium-1,4-dicarboxylic acid 1-t-butyl vinegar 4-ethyl ester (1.33 g) dissolved in tetrahydrofuran (15 mL) was added. The reaction mixture was allowed to warm to room temperature over 1 hour. Add cold water 161177.doc • 86 · 201249837 and extract the mixture with ethyl acetate. The combined extracts were washed with brine, dried EtOAc sol The residue was chromatographed on EtOAc (EtOAc:EtOAc:EtOAc (Method 5 broad tR = 1.43 min; mass spectrum (ESI+): m/z = 417, 419 [m+h]+. Intermediate 13 4-[2-(5-bromo-2- s-pyridyl-4-yl) ) hydroxyl-ethyl] piperidine q-butyl butyrate

Sodium borohydride (240 mg) was added to 4-[2-(5-bromo-2-a-pyridin-4-yl)-ethenyl]tributyl-1-butyrate (165 g) In an ice-cooled solution in a mixture of tetrahydrofuran (40 mL) and water (10 mL). The resulting mixture was stirred for 0.5 hours. 2 N citric acid was added and the mixture was extracted with ethyl acetate. The combined extracts were washed with aq. EtOAc (EtOAc) LC (Method 5): m.p. Intermediate 14 4-(5-Gas-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester

161177.doc -87 - 201249837 4-[2-(5-Bromo-2-carbopyridine-4-yl)-1-hydroxy-ethyl]-piperidine-i-carboxylic acid tert-butyl ester (11.60 g) , palladium acetate (5 〇〇 mg), racemic 2 _(di-tert-butylphosphino)-1,1'-binaphthyl (1.00 g) and carbonic acid planing (14.00 g) in benzene (150 mL) The mixture was placed at 11 Torr under an argon atmosphere. Heat in an oil bath for 5 hours. After cooling to room temperature, ethyl acetate and water were added and the organic layer was separated, washed with brine < The residue was chromatographed eluted eluted elut elut elut elut elut elut elut elut elut M+H]+. Intermediate 15 4-[5-(4-methanesulfonylmethyl-phenyl)_23-dihydro-furan[23_c] &quot;pyridyl]-piperidine-1-carboxylic acid tert-butyl ester y-

0 by 4-(5-gas-2,3-dihydrofuro[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid according to procedures similar to those described for intermediate 7 The title compound was prepared from tributyl ester and [4-[(sulfonyl)methyl]phenyl]-acid. LC (Method 6): m.p. Intermediate 16 5-(4-methanesulfonylmethyl-phenyl)_2-piperidine-4-yl-2,3-dihydrofuran and [2,3-c] bite 161177.doc -88- 201249837

According to a procedure similar to that described for Intermediate 9, 4-[5_(4_methylpyrenemethyl-phenyl)-2,3-dihydro-indolo[2,3-〇]° The title compound was prepared by biting the base of the base. LC (Method 6): m.p. Intermediate 17 4_[5_(4_methanesulfonylmethyl-phenyl)_2,3_dihydrofuran [2,3&lt;] 0 to bite-2-yl]-nitopic bite_1_carbonitrile

According to the trampoline sequence similar to that described for Intermediate 5, 5-(4-methanesulfonylmethyl 4-yl)·2·Μ·4·yl·2'3·: hydrogen , 3 external ratio biting and desert nitrile to prepare the title compound. LC (method + 10,000 deg6) · tR = 1 u as (ESI+): m/z = 398 [M+H]+. ,, aJ 1 8 N_hydroxy-4-[5·(4·methanesulfonylaminol

[2,3-c]pyridin-2-ylpiperidinecarboxamidine H,N

Stupid base)-2,3-dihydro-ββ

HO-N is in the order of a spear similar to that described for Intermediate 1 1 by 4-C5-M-methylglycosyl-phenyl)-2,3-dihydro-furan r) 1 1 1 τ ^ s L,3,c]pyridin-2-yl]-piperidine-1-161177.doc.89·201249837 The title compound was prepared from the carbonitrile and hydroxylamine hydrochloride. LC (Method 5): m.p. Intermediate 19 4-[5-(1-methyl succinctyl-1,2,3,6-tetrahydro-ringing _4_yl)_2,3_diazo _ bite and 丨2,3- c]°ifc bite-2-kib brigade bite••t-butyl formate

According to a procedure similar to that described for Intermediate 7, from 4_(5_gas_2,3_dihydro-.folmo[2,3-c]. than bit-2-yl)-〇辰 bite_ Iv_T-butyl formate and hydrazine (sulfonyl)-4-(4,4,5,5-tetramethyl·1,3,2-dioxaborene _2·yl^^^tetrahydrogen The title compound was prepared according to pyridine. LC (Method 5): tR=i.i2 min; MS (ESI+): m/z=464 [M+H]+ » Intermediate 20 5-(1-A) -1,2,3,6-tetrahydro-bite _4_yl)_2-Bourse _4-yl_ 2,3-dihydro-furo[2,3-c]pyridine

According to a procedure similar to that described for Intermediate 9, 4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-D is -4-yl)-2,3- The title compound was prepared by the dihydrofol[2,3-indole]pyridine-2-yl]-piperidine-1-carboxylic acid tert-butyl ester. LC (Method 5): tR = 0.44 min; Mass (ESI+): m/z = 364 [Μ+Η]+. I61177.doc 90· 201249837 Intermediate 21 4-[5-(1-甲烧&gt;^牛基-1,2,3,6-tetrazole-0 to bit-4-yl)-2,3-di Nitrogen - 0 Fu and [2,3-&lt;!] 11 than bite-2-yl]-Brigade bite-1-曱 guess

According to a procedure similar to that described for Intermediate 5, 5-(1-decanesulfonyl-1,2,3,6-tetra-rat-ratio. The title compound was prepared from 4-yl-2,3-diaza-phlo-[2,3-c]pyridine and bromonitrile. LC (Method 5): m.p. Intermediate 22 4-[5-(2-Fluoro-4-methanesulfonylnonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridine-2-yl]-peri Pyridin-1-carboxylic acid tert-butyl ester

According to a procedure similar to that described for Intermediate 7, from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-decanoic acid Preparation of the title of the third butyl ester and 2-(2-fluoro-4-methanesulfonylmethyl-phenyl)-4,4,5,5-tetradecyl-[1,3,2]dioxaboron Compound. LC (Method 6): m.p. Intermediate 23 5-(2- gas-4-methyl-branched fluorenyl-phenyl)-2-slightly -4-yl-2,3-diaza-161177.doc -91 - 201249837 furan[ 2,3-c]n ratio

According to a procedure similar to that described for Intermediate 9, 4_[5_(2_Fluor_4•methythroxyl-methyl-phenyl)-2,3-dihydro·Ban and [2,3_c] The title compound was prepared from n-butanol]-carboxylic acid terpene vinegar. LC (Method 6): m.p. Interstitial 24 4-[5-(2-fluoro-4-methanesulfonylmethyl-phenyl) 2,3-dihydrofuro[2,3-c]0-biti-2-yl]- Travel • carbonitrile ΝΞ-Ν

According to a procedure similar to that described for Intermediate 5, from 5-(2-fluoro-4-cyclodecanesulfonylmethyl-phenyl)-2.piperidin-4-yldihydro-furo[2,3_c] = pyridine and bromonitrile to prepare the title compound. LC (Method 6): tR = 1.21 min; mp. (ESI): m/z = 416 [M+H]+. Intermediate 25 N-hydroxy_4·[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridinyl-4-yl)-2,3-dihydro-furo[2, 3-c]pyridylpiperidine

161l77.doc •92 201249837 In accordance with (iv) a similar procedure as described in Intermediate 11, by 4.[5-(1-methylpyrene), 2,3,6·tetrahydrogen H4·yl)_2,3_ The title compound was prepared from dihydro-decamper [2,3 々 咬 基 基 基 基 。 卜 卜 卜 及 及LC (Method 5): m.p. Intermediate 26 4-[5-(2-Fluoro-4-methylsulfonylsulfanyl-l-phenyl) 2,3-dihydrocarba-[2,3-c]pyridin-2-yl]-N_ Hydroxy-piperidine·1 formazan

According to a procedure similar to that described for intermediate 11, from 4_[5_(2_fluoro_4_methane sulfomethyl-phenyl)-2,3-dihydrofuro[2,3c]pyridine_2 The title compound is prepared from the base of the piperidinium-1-carbonitrile and hydroxylamine hydrochloride. LC (Method 6): m.p. Intermediate 27 4-[2-(5-Bromo-2-a)pyridin-4-yl)-1-hydroxymethyl-hexyl]piperidine-1-carboxylic acid tert-butyl ester

4-[2-(5-Bromo-2-chloro-11-Butyl-4-yl)-ethlyl]-π bottom bite_3·butyl citrate (9.80 g) in tetrahydrofuran (6 mL) The solution was added dropwise to an ice-cold solution of methylmagnesium bromide (1.4 Μ in toluene/tetrahydrofuran 75:25, 74 mL). The reaction mixture was stirred for 30 minutes, warmed to room temperature and mixed with 161 177.doc •93·201249837 hours. The mixture was poured into aqueous NH.sub.4CI and extracted with ethyl acetate. The combined extracts were dried over MgSO4 and concentrated in vacuo. Toluene was added to the residue and evaporated several times. Since the residue still contained a large amount of starting material, it was again treated with Grignard reagent according to the procedure described above. The crude product was purified by preparative EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: LC (method 4): tR = 1.33 min; mass spectrum (ESI+): m/z = 433, 435 [M+H]+. Intermediate 28 4-(5-Gas-2-methyl-2,3·dihydro-furo[2,3-c]pyridine·2-yl)-piperidine·1-carboxylic acid tert-butyl ester

According to a procedure similar to that described for intermediate 14, 4_[2_(5_bromo-2. gas-pyridin-4-yl)-1-hydroxy-1-indolyl-ethyl]-piperidine 4•曱The title compound was prepared from the acid tert-butyl ester. LC (method 4): tR=i 29 min; mass spectrum (ESI+): m/z=353 [M+H]+ ° Intermediate 29 and Intermediate 3〇(5)-4·(5_气-2_ Methyl-2,3-dihydro-furo[23c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and (and)-4-(5-phenoxy-2-methyl-2, 3·Dihydro-furo[2,3-c]pyridin-2-yl)-piperidinecarboxylic acid tert-butyl ester 16M77.doc -94· 201249837

The racemic intermediate 28 is subjected to a palm phase SFC (column: Daicel IC '250x20 mm; mobile phase: sterol/supercritical carbon dioxide containing 〇.2 ° / 〇 diethylamine 25:75; flow rate 60 ml / Min) 'The title compound was obtained as a separate fraction. The configuration of the stereogenic center is arbitrarily specified; the residence time on the palm phase SFC (Daicel 1C, 250x4.6 mm; mobile phase: methanol with 0.2% diethylamine/supercritical carbon dioxide 25:75; flow rate 4 ml/min): Intermediate 29: tR = 3.77 min; Intermediate 30: tR = 4.42 min. Intermediate 31 〇S)-4-[5-(4-methanesulfonyl-phenyl)-2-methyl-2,3-dihydro-trinop[2,3-c]pyridine-2- Base]-piperidine_1_carboxylic acid third butyl

Followed by a procedure similar to that described for Intermediate 7, by ($)_4_(5 gas 2 methyl-2,3-dihydrocing and [2,3-c]acridinyl) : butyl ester (intermediate 29; configuration of the stereoisomerization center arbitrarily designated) and 4 alkylsulfonyl) phenyl δ-acid to prepare the title compound. LC (method 4) . 曱 min ; mass spectrum (esi+): m/z = 473 [M+H]+. Intermediate 32 ($)-5-(4-methanesulfonyl-phenyl)_2_methyl_2_piperidine-4-yl·2 3 monohydro-indole and [2,3-c]》ifc唆161177.doc .95· 201249837

By &lt;S)-4-[5-(4-methane % aryl-benzyl)-2-methyl-2,3-dihydro, as described in relation to Intermediate 9, The ####################################################################################### LCi square 沣 7, H 7): tR = 0.63 min; mass spectrum (ESI+): m/z = 373 [M+H]+. Intermediate 33 Hydrogen-bite-and-(5)-4-(5-(4-methanesulfonyl-phenyl)_2-methyl_2 3_ [2,3-c]nt bit-2-keb brig唆_ι_carbonitrile

According to a procedure similar to that described for Intermediate 5, from (5&gt;5_(4_甲烧烧基-phenyl)-2-methyl-2-Bent-4-yl-2,3-dihydro The title compound was prepared by the preparation of the title compound of the [2,3-c]0-pyridinium (intermediate 32; the configuration of the stereoisomerization center) and bromonitrile. LC (Method 4): tR=0.87 min; ESI+): m/z=398 [M+H]+ 〇Intermediate 34 and intermediate 35 (and)-4-(5-Gas-2,3-dihydro-furo[2,3-c]&quot ; bite-2-yl)-bite-1-carboxylic acid tert-butyl ester and hydrazine S&gt; 4-(5-gas_2,3-dihydro-furo[2,3-c]pyridine-2- Base)-t-pyridine-1-carboxylic acid tert-butyl ester I6I177.doc -96· 201249837

The racemic intermediate was subjected to a palmitic phase SFC (column: Daicel Ic, 250 x 20 mm; mobile phase: ethanol containing 2% diethylamine/supercritical carbon dioxide 25:75; flow rate 50 ml/min), The title compound was obtained as a separate fraction. The configuration of the stereogenic center is arbitrarily specified; the residence time on the palm phase SFc (Daicel 1C, 250x4.6 mm; mobile phase: ethanol with 0.2% diethylamine/supercritical carbon dioxide 25:75; flow rate) 4 ml/min): Intermediate 34: tR = 1.64 min; Intermediate 35: tR = 1.91 min 〇 Intermediate 36 〇S) -4-[5-(l-methanesulfonyl 4,2,3,6 -tetrahydro-pyridine-4-yl)_2,3_diaza-bite and [2,3-c]e than bit-2-yl]-bred bitillary formic acid tert-butyl vinegar

According to a procedure similar to that described for Intermediate 7, from (iS)_4_(5_gas_2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-i_ Tert-butyl citrate (intermediate 35, configuration of stereoisomerization center arbitrarily specified) and 丨·(曱 醯 醯)_4·(4,4,5,5-tetra-T-h-ah The title compound was prepared as the title compound. LC (method 5): tR=i.10 min; mass spectrum (ESI+): m/z = 464 [M+H]+ 161177.doc • 97· 201249837 Intermediate 3 7 yl-2,3-dihydro-furo[23弋pyridine 0)-5-(1-methanesulfonyltetraamine-β than -4-yl)-2·Brigade bite - 4-

According to the procedure similar to that of the class of the intermediates mentioned in the article 9, by (s) _4_[5_(b), the base is -1,2,3,6-tetrahydro-. , 疋一基)·2,3·Dihydro-furo[2,3-c]pyridine·2-yl]•piperidine·ι_carboxylic acid 篦=Di-Di Sa (Intermediate 36, Stereoisomeric Center The configuration is arbitrarily specified.) The fee is borrowed > μ a ~ 疋 J table prepared for the compound. LC (Method 5): tR = 0.44 min; Mass (ESI+): m/z = 364 [M+Hp Intermediate 38 (/?)-4-[5·(ι_methanesulfonic acid hm tetrahydroacridine _4·基)-2,3•二It Fuchuan and [2,3-c] ton 唆-2-yl]-Brigade bitillary formate

According to a procedure similar to that described for Intermediate 7, (Λ··································· Pyridinium-hydrazine-tert-butylate (the configuration of the intermediate 34' stereoisomerization center is arbitrarily specified) and ι·(methylsulfonyl)-4-(4,4,5,5-tetramethyl- Preparation of the title compound, LC, m.p. =464 [M+H]+. 161177.doc -98- 201249837 Intermediate 39 (and) 5 (1 A burning base -1,2,3,6-four gas - blowing bit-4-yl)-2-Brigade bite 4-base- 2,3-dihydro-furo[2,3-c]pyridine

According to a procedure similar to that described for Intermediate 9, from (i?)-4-[5-(l-methanesulfonyl-1,2,3,6-tetra-argon-pyridine-4-yl)-2 , 3-dihydro-furo[2,3-c]. The title compound was prepared in the same manner as the tert-butyl-2-yl]- acyl-indole-carboxylic acid tert-butyl ester (Intermediate 38, configuration of the stereoisomer center). LC (method 5): tR = 0.44 min; mass (esi+): m/z = 364 [M+H]+. Intermediate 40 (S)-4-[5-(i_methanesulfonyl_1 2 3 6_tetrahydro-pyridine-4-ylmethyl 2,3-dihydro-furo[2,3-c] Pyridin-2-yl]-piperidine-1-carboxamidine tert-butyl ester

According to a procedure similar to that described for Intermediate 7, from ($)-4-(5-methylmethyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-per Dibutyl -1-carboxylic acid (intermediate 29; configuration of the stereoisomerization center is arbitrarily specified) and u (methylsulfonyl)_4-(4,4,5,5-tetramethyl-1, The title compound was prepared from 3,2-dioxaboron-2-yl)tetrahydropyridine. LC (method sentence: tR=1.〇2 min; mass containing general (ESI) ·· m/z=478 [M+H]. 161l77.doc •99· 201249837 Intermediate 41 (7)·5-0-甲烧牛-基-1,2,3,6_tetrahydro^4_yl)2_methyl_2 Ninjabit-4-yl-2,3-dihydro-cough and [23 Chinese 唆

According to the similarity with the description of the intermediate matter 9, only in order, by (Fantasy 4 [5 (11 calcined base · 1,2,3,6-tetrahydro-° ratio. 00 丞)-2-methyl-2,3_dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1·decanoic acid _ ninth dibutyl ester (intermediate) 40; The configuration of the stereoisomerization center was arbitrarily assigned to prepare the title compound. a (Method 7): tR = 〇.48 min; mass spectrum (ESI+): m/z = 378 [M+H]+. Intermediate 42 (7)冬丨5-(1_甲炫罐粉基十2^-tetrahydro"bit than -4_ base)·2_methyl-2,3-dihydro-furo[2'3-c]pyridine_ 2_base] piperidine

According to a procedure similar to that described for Intermediate 5, by (幻_5(1 methanesulfonyl-1,2,3,6-tetrahydropyridin-4-yl)_2-methyl_2-piperidine_ 4-Based 2,3·dihydro-furo[2'3_c]pyridine (Intermediate 41; configuration of stereoisomerization center arbitrarily specified) and the preparation of the title compound from the carbonitrile. LC (Method 4): tR=0 · 68 min; mass spectroscopy (ESI+): m/z = 403 [M+H]+. Intermediate 43 (M-hydroxy-4-[5-(l-methanesulfonyltetrahydro-pyridine-4- 161l77.doc) •100· 201249837 bite-2-yl]-bred bite-1-mercapto)-2-methyl-2,3-dihydro-furan oxime 2,3 &lt;;]pyridyl

, ~ (4) lack of procedures, from (δ)-4·[5 · alkanoyl-1,2,3,6-tetrahydropyridine-decyl r9 . -, LZ methyl-2,3-monohydrogen - furan and bite 2 - yl) - bottom bite - 1 - carbonitrile (intermediate 42; configuration of the stereoisomer center is optionally reduced) and the title compound is prepared from the amine hydrochloride. Lc (method 4): tR = 0.46 min; mass spectrum (10) 1+): [_]+. Intermediate 44 A burned base · ^ 3 + tetrahydrobite · 4 · base) 2 3 dihydro-bite and [2,3_中比pyridine-2 · base]_Brigade bite small carbonitrile Ν = —Ν

According to a procedure similar to that described for Intermediate 5, (8)_5_((2,3,6·tetrahydrogen) 4,4,4,2,2,2,2,2, Nanhe [2,3 external (intermediate 39, configuration of stereoisomerization center) and the preparation of the title compound eLC (method Ο,·-:he spectrum (ESI). m/z= 389 [M+H]+. Intermediate 45 via thiol hydrazino-1,2,3,6-tetrahydro-indole _4_yl) 2,3-hydrogen-furan hydrazine 2 3 c] Pyridine·2·yl] piperidine small formazan 161177.doc 201249837

According to a procedure similar to that of Intermediate 34, by W-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyrobitole_4_storm&gt; 2,3-Dihydro-furo[2,3-c 0-biti-2-yl]-〇chen bite-1-carbonitrile (Zhongmen Dingbo (〒物44, stereoisomerization center configuration) The title compound was prepared arbitrarily and by amine hydrochloride. Μ(Method 6) ^ tR=〇_75 min; mass spectrum (ESI+): m/z=422 [m++. Intermediate 46 Mb tetrahydro-吼 bit _4 base) 23 hydrogen-furan oxime 2,3-c]pyridine_2-piperidine carbonitrile

According to a procedure similar to that described for Intermediate 5, by (幻_5_(丨_methanesulfonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-piperidine-4- Base-2,3-dihydrofuran[2,3-c]pyridine (arrangement of the intermediate 37' stereoisomerization center) and the preparation of the title compound in the form of a nitrile. LC (Method 6): tR= 1.02 min; mass spectroscopy (ESI+): m/z = 389 [M+H]+. Intermediate 47. ???-[5-(1-methyl-decyl-decyl-1,2,3,6-tetrahydrol Bite _4_ base)-2,3-dihydro-oxime and [2,3-c]0 than bite-2-yl]-Brigade bite·ι_甲脉161177.doc -102· 201249837

4_yl)-2,3-dihydro-furo[2,3-c] oxime 46' stereoisomeric center configuration according to a procedure similar to that described for intermediate 11 ·1,2 , 3,6-tetrahydropyrimidinyl) 2 3 pyridyl 2,yl]piperidin-1-carbonitrile (Intermediate 46, arbitrarily designated) and hydroxylamine hydrochloride The title compound was prepared. LC (Method 6) tR_〇.75 min, mass s 醤 (ESI): ni/z=422 [M+HJ+. Interstitial 4 8 4-(5-bromo-2,3-dihydrobenzoyl-2-yl)piperidine

Potassium carbonate (10.17 g) was added to ι·μ-(5-bromo-2,3-dihydrobenzofuran-2-yl)-bottom-l-yl]-2,2,2-three An ice-cold mixture of fluoro-ethanone (4.64 g), decyl alcohol (120 mL) and water (30 mL). The reaction mixture was stirred overnight at room temperature. Brine (150 mL) was added and the mixture was extracted with di-methane. The combined organic phases were dried with MgSO4 and concentrated in vacuo. The crude product was used in the next step without further purification. &lt;RTI ID=0.0&gt;&gt;&gt; Intermediate 49 4-(5-Bromo-2,3-dihydro-benzofuran-2yl)-piperidine-1-carboxylic acid tert-butyl ester

4-(5-Bromo-2,3-dihydro-benzofuran-2-yl)-piperidine (2.37 161I77.doc -103· 201249837 g) and dibutyl carbonate-second butyl hydrazine at room temperature ( 1.83 g) A mixture of tetrahydrofurfuryl domains (25 mL) was mixed for 4 hours. The solvent was evaporated in vacuo and EtOAcqqqqqq Tlc: rf = 0.40 (Shixi gum 'cyclohexanol / acetic acid) 4:1); mass spectrum (esI+): m/z = 382, 384 [M+H]+. Intermediate 50 4-(2-Big bit-4-yl-2,3-dihydro-benzo[beta]#5_yl)-benzoic acid methyl vinegar

To 4-(5-bromo-2,3-dihydro-benzo-hydrazin-2-yl)-11, the bottom of the 11th _1_decanoic acid, the third butyl s (1.00 g) and 4- (methoxy) To a mixture of hydrazine, hydrazine-dimethyl decyl decylamine (50 mL) was added 2 μl aqueous Na 2 CO 3 (3.27 mL). The mixture was bubbled with argon for 1 minute, and PdCl 2 [l,l-bis(diphenylphosphino)-ferrocene]*CH 2 ci 2 complex (213 mg) was added »the mixture was stirred at 90 ° C. hour. After cooling to room temperature, water (50 mL) and ethyl acetate (1 mL) The organic phase was washed with water and brine, dried over MgSO 4 and evaporated. The residue was mixed with trifluoroacetic acid (1.4 mL), dichloromethane (4 mL) and water (0.15 m.L) and stirred for 3 hours. The solvent was evaporated and the residue was combined with diethyl ether. The title compound was obtained as a trifluoroacetate salt by filtration. LC (method 8): m.p.: s. Intermediate 51 4-{2-[1·(5-ethyl-pyrimidin-2-yl)-piperidine-4-yl]_2,3 dihydrobenzofuran 161l77.doc •104· 201249837 -5-5- Benzoic acid

Add ethyl diisopropylamine (1.38 mL) and 2-gas-5-ethylpyrimidine (380 μ!〇 to 4-(2-0-pyridin-4-yl-2,3-dihydro-benzopyrene) To a solution of decyl benzoate (0-90 g) in tetrahydrofuran (20 mL), and the reaction mixture was heated to reflux for 48 hours. The solvent was evaporated after cooling to room temperature. Dichloromethane and water were separated, and the aqueous phase was separated and extracted with a gas chamber. The combined organic phases were dried over MgSCU and evaporated. The residue was combined with methanol (2 mL) and 1 NaOH aqueous solution (6.67 mL) Mixing. The reaction mixture was stirred for 12 hours at 55. The solvent was evaporated after cooling to room temperature. Dioxane and water were added; the organic phase was separated and extracted with water. Adjust to pH 2. The title compound was collected by filtration and dried under vacuum (ESI+): 50 &lt;0&gt;C&quot; LC (Method 8): tR = 156 min m/z = 430 [M+H]+. -ethyl-2-{4-[5-(4-methanesulfonyl-phenyl)·2 3 ·dihydrobenzofuran-2-yl]-piperidin-1-ylpyrimidinium

Ethyl diisopropylamine (50 and 2·gas ethylpyrimidine (17 μΐ〇 added 161177.doc. ιη&lt; _ 201249837 to 4-[5-(4-甲烧醯基-phenyl)-2,3 - dihydro-stupyl-pyrene-2-yl]-Nionyl (50 mg) in a solution of N,N-dimethylformamide (1 mL), and stirred at 12 (TC) After cooling to room temperature overnight, di-methane and water were added. The aqueous phase was separated and extracted with dioxane. The combined organic phases were washed with water, 10% NH^Cl solution and brine, and dried over MgSO. The residue was triturated with EtOAc (EtOAc)EtOAc. Base-[1,2,4]oxadiazol-5-yl)-4-[5-(4-methanesulfonylphenyl)_2,3-dihydro-benzo-c-but-2-yl] - bite

The solution of zinc sulfide in tetrahydrofuran (0.78 mL) was diluted with tetrahydrofuran (5 mL), and added dropwise to the base-isobutylformamidine (40 mg) and 4·[5-(4) at room temperature. - methanesulfonyl-phenyl). 2,3-dihydro-benzofuran-2-yl]-piperidine-1-carbonitrile (100 mg) in EtOAc (5 mL). The reaction mixture was stirred at 50 ° C for 4 hours and cooled to room temperature. The precipitate was taken and heated to l ° ° C for 2 hours in a mixture of ethanol (5 mL) and glacial acetic acid (2.5 mL). The solvent was evaporated and the residue was combined with dioxane and &lt The organic phase was washed with brine, dried over EtOAc EtOAc The residue was triturated with ether to give the title compound. LC (Method 2): m.p. 161177.doc •106· 201249837 Example 3 Bu (3-cyclopropyl-[1,2,4]oxadiazol-yl)_4-[5-(4·甲烧烧基·phenyl)-2, 3-dihydro- benzofurfural_2_yl]-bristidine

.0 is similar to that described in Example 2, 4 #友#, 爻 program, from 4_[5-(4-methanesulfonyl-yl)-2,3-one mouse-benz.夫°^_2 ·Λι 唧2_yl]-piperidine-1-carbonitrile and N_hydroxy-ring

Propane formazan to prepare the title compound. L (Method 2) . tR = l. 〇 8 min ; mass spectrum (ESI): m/z = 466 [M+H] + 〇 Example 4 Christine) 2,3-hydrobenzofuran-2-yl]- 1-(3-propyl-[1,2,4] chewing diterpene _5_ kibidine

4-[5-(4-Methanesulfonylphenyl) N- according to a procedure similar to that described in Example 2, from 4_[5_(4•甲院项基_phenyl)-2'3_ The title compound was prepared from dihydro-benzo benzophenan-2-yl]" 底心·甲猜缘基丁曱脒. LC (Method 2): tR=1.4Q 质质(ESI+) : m/z=468 [M+H]+ 〇Example 5 2-[l-(5-ethyl shouting_2_base)_旅唆_4·基]·5(4甲烧烧基·phenyl)-2, 3-dihydro-furo[2,3-cl pyridine 161177.doc 201249837

According to the furnace skin similar to that described in Example 1, c β is only in a private order, consisting of 5-(4-methanesulfonyl-phenyl)-2-0 base 0--4-yl- 2,3- The title compound was prepared by dihydro-t-'name 1 夭 夭 并 and [2,3-c]pyridine and 2- gas-5-ethyl. L cv ·#τ, t e, (method 5): tR=1.14 min; mass spectrum (ESI+) ·· m/z=465 [M+H]+. Example 6 2-[l-(3-Isopropyl-[1,2,4]heptanesulfonyl-phenyl)_2,3-oxadiazol-5-yl)-piperidin-4-yl]-5 -(4-Dihydrogen·Scream and 丨2,3-c]° than bite

According to a procedure similar to that described in Example 2, 4-[5_(4_甲烧罐粉基·phenyl) 2,3-hydrofuran [2,3_c]n-pyridyl] The title compound was prepared from the carbonitrile and N- s-isobutyl hydrazide. lc (method 5): tR = 1 15 min; mass spectrum (ESI+): m/z = 469 [M+H]+. Hyun item brewing base - stupid base) 2• mouth (3·propyl _ mouth, 24] 嗔 two saliva _5_ base) brigade bite 4 base b 2,3_ two gas-bite and [2,3-c] «Biidine

According to a procedure similar to that described in Example 2, 4 4 4•甲烧瓣161177.doc 201249837 phenyl)-2,3-dihydrofolino[2,3-c]°biti-2-yl The title compound ❶LC (Method 5): m.p. Example 8 2-[1-(5-Isopropyl-[1,2,4]noisem--3-yl)-Blanch-4-yl]-5-(4-methanesulfonyl-phenyl )-2,3-dihydro-furo[2,3-c]pyridine

N-Hydroxy-4-[5-(4-nonanesulfonyl-phenyl)_2,3·dihydro-furo[2,3-c]pyridin-2-yl]-peripherate at room temperature A mixture of pyridine hydrazine (45 mg), isobutyl hydrazine (12 μ! hydrazine and triethylamine (50 μί) in tetrahydrofuran (5 mL) was stirred for 3 hrs, then heated to 80. The mixture was stirred for 5 hours. The mixture was heated at rt. EtOAc (EtOAc m. Washed with diethyl ether and dried to give the title compound, m., m, m, m. Phenyl)_2-[1_(5propyl-丨^oxadiazole·3_yl)-piperidin-4-yl]-2,3-dihydro-furo[2,3-C]pyridine

161177.doc -109- 201249837 by N-hydroxy-4-[5-(4.methanesulfonyl-phenyl)-2,3-di-ar-furan [further] according to procedures similar to those described in Example 8. The title compound was prepared from 2,3-cp-pyridin-2-yl]-niobium and butyl sulfonium. LC (Method 5): m.p. Example 10 5-(4-Methanesulfonyl-phenyl)-2-[l-(5-methyl-pyridazin-2-yl)-has__4yl]-2,3-dihydro-furan And 丨 2, 3 〇 咐 (bite

5-(4-decanesulfonyl-phenyl)-2-piperidine-4-yl-2,3-dihydrofol[2,3-c]° ratio bite (50) in a microwave oven Mg), 2-gas-5-fluorenyl D ratio. A mixture of Qin (3 mg) and cesium carbonate (91 mg) in diterpenoid (1 mL) was heated to 150 °C. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel (ethyl acetate / methanol: 98:2 - 97:3). The crude product was triturated with a small amount of methanol and the precipitate was filtered, washed with diethyl ether and dried to give the title compound. LC (Method 5): m.p. Example 11 2-[1·(5-Ethyl-pyridazine-2-yl)-piperidin-4-yl]-5-(4-methanesulfonyl-phenyl)-2,3-dihydro- Furo[2,3-c]pyridine 16II77.doc •110- 201249837

According to the procedure similar to the 龆 handle + ^ 龆 described in the example ίο, by 5_(4_nonanesulfonyl)

Phenyl)-2-indolyl-4-yl-2,3--anhydro n+ A ' 虱·furo[2,3-c]pyridine and 2-bromo·5-ethylpyrazine The title compound was prepared from Ν·曱曱曱曱醯 face + toluene. LC (method 5): tR = 1 · 25 min; mass spectrum (EST+, . / + 曰, ). m/z = 465 [M+H]. Example 12 2 [1 (5-Ethyl-pyrimidin-2-yl)piperidinyl] _5_(4 methanesulfonylmethyl-phenyl)-2,3-dihydro-branching 丨2 3_c]吼Pyridine

According to a procedure similar to that described in Example 1, 5-(4-deoxasulfonylhydrazino-phenyl)-2-piperidine-4-yl-2,3-dihydro-furo[2, 3-c]pyridine and 2-gas-5-ethyl 0i bite gave the title compound. Lc (method 6): tR = 1.55 min; mass spectrum (ESI+): m/z = 479 [M+H]+. Example 13 2_[1-(3-isopropyl-H4)oxadiazole_5_yl)·piperidine-4-yl]_5_(4_甲院醯醯 methyl-phenyl)_2,3-二Hydrogen-furo[2,3-c]pyridine

According to a procedure similar to that described in Example 2, 4-[5-(4-methanesulfonyl 161177.doc -111 - 201249837 methyl-phenyl)·2,3-dihydro-furo[2 3_c The title compound was prepared by the procedure of tl.sub.2-yl-2-phenyl]-piperidine-i-carbonitrile and N-propanyl-isobutylformamide. LC (Method 6): m.p. Example 14 5-(4-Methanesulfonyl-phenyl)_2_[1(3-trifluoromethyloxadiazole-5-yl)-piperidin-4-yl]-2,3-dihydro-furan And [2,3-c]pyridine

According to a procedure similar to that described in Example 2, 4_[5_(4 methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine The title compound was prepared from 1-acetonitrile and 2'2,2-trifluorohydroxy-acetamidine. LC (Method 5): m.p. Example 15 5-(4-Methyl-branched-methyl-phenyl-propyl-propyl succinyl-5-yl)-piperidin-4·yl b 2,3-dihydrofuro[2 3 c]pyridine

According to a procedure similar to that described in Example 2, 4_[5_(4_methanesulfonylmethyl-phenyl)_2,3·dyne fuco[2,3-small ratio-2-yl] The title compound was prepared from m-carbonitrile and N.sub. Lc (method 6): w ^ min ; mass spectrum (ESI+): m/z ==483 [m+h]+. 161177.doc •112· 201249837 2-[l-(5-isopropyl-[1,2,4]histanesulfonylmethyl·phenylpoly 2 3 Example 16oxazol-3-yl)-piperidine 4-yl]-5-(4-methylhydro-furo[2,3-c]pyridine

According to the procedure described in Example 8, N-hydroxy-4-[5-(4-nonanesulfonylhydrazino-phenyl)_2 3 _ &amp; '- fluorene-furan The title compound was prepared by [2,3-c]pyridin-2-yl]-piperidine 1 formazan and isobutyl hydrazine. LC (Method 6): m.p. Example 17 5-(4-Methyl(tetra)indenylmethyl-phenyl]1 (5 propyl [(4) rabbit dis- 3 -yl)-Bacray-4-yl]-2,3-dihydro-indole And [2,3-c]nb pyridine

According to a procedure similar to that described in Example 8, N-hydroxymethanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]. The title compound was prepared by the use of pyridine, pyridine, and hydrazine. LC (Method 6): m.p. Example 18 2-[1-(5-Ethyl-pyrimidin-2-yl)-piperidine-4-yl]·5_(1_methanesulfonyl-1,2,3,6-tetrahydro-pyridine_ 4-yl)-2,3-dihydro-furo[2,3-c]pyridine 161177.doc 113 201249837

According to a procedure similar to that described in Example 1, 5_(1_甲烧烧-i,2,3,6_tetrahydro-end-4-yl)-2,4·yl-2,3 dihydrogen· The title compound was prepared by nucleating [2,3_c]pyridine and 2-hexane-5-ethylpyrimidine. Lc (method): tR=0.91 min; mass spectrum (ESI+): ^/2=470 [M+H]+. Example 19 5-(1-Axylation)-1,2,3,6-tetraindole Called 4苴, 风风-吹啶-4-yl)·2-[ΐ_(3-propyl_[1,2,4]嗔二吐-5-基)-派唆|丨基】·2 ,3-dihydro-furo[2,3-c]pyridine

LC (Method 5): tR = 1G2 min, · MS (+): m/z = 474 [M+H] Example 20 2-il-(3-isopropyl·丨1,2,4〗喵-地e ^ ^ oxazol-5-yl)-piperidine _4_yl]·5-(1-methylxanthene-1,2,3,6-tetrahydro-0^0^/||,,1 Milk% pyridine-4-yl)·2,3-dihydro-furo[2,3_c]pyridine 161177.doc -114· 201249837

According to the procedure similar to the one described in Example 2, 4-[5-(1-decanesulfonyl-1,2,3,6-tetrahydropyridin-4-yl, plant 2' The title compound was prepared from 3-dihydro-pyrano[2,3-c] ° ratio -2-yl]-piperidine-1-carbonitrile and N-hydroxymethane I-isobutyl hydrazine. (Method 5) . tR=l.〇2 min ; Mass Spectrum (ESI+): m/z=474 [M+H]. Example 21 MU-甲烧醢醢 methylphenyl)·2_[ι (3 Propyl]i 2 4]oxadiazol-5-yl)piperidinyl-4-yl]·2,3-dihydro-furo[He]pyridine

According to a procedure similar to that described in Example 2, 4_[5(2•fluoro-4-methylsulfonylmethyl-phenyl)-2,3-dihydrofuran[2,3_c]pyridine_2_ The title compound was prepared as the hydrazinonitrile and N-hydroxyisobutyl hydrazide. Lc (method 6): tR = 1.53 min; mass spectrum (ESI+): m/z = 501 [M+H]+. Example 22 2·[1·(5-isopropyl-[1,2,4]oxadiazole_3_yl)-piperidine-4-yl]-5-(1-methanesulfonyl-1, 2,3,6-tetrahydropyridine-4-yl)_2,3-dihydro-furo[2,3-c]indole

161177.doc • 115- 201249837 A procedure similar to that described in Example 8 was followed by 'N-carbyl-4-[5-(1-carbo-indole-1,2,3,6-tetrahydro-. Than 4-amino)-2,3-dihydro-indole[2,3-〇]. The title compound was prepared by substituting the chito-2-yl]-biten-1-carboxamidine and isobutyl brewing nitrogen. LC (Method 5): m.p. Example 23 5-(1-Alkyl-1,2,3,6-tetrazine-indenyl-4-yl)-2-[1-(5-propyl_[1,2,4 Oxadiazol-3-yl)-piperidin-4-yl]-2,3-dihydro-furo[2,3-c] bite

According to a procedure similar to that described in Example 8, from hydrazine-hydroxy-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3 -Dihydro-furo[2,3-c]acridin-2-yl]-piperidine-1-indole and butyl hydrazine to give the title compound. Lc (method 5): tR = 1.10 min; mass spectrum (ESI+): m/z = 474 [M+H]+. Example 24 5-(2-Fluoro-4-methanesulfonylmethyl-phenyl)_2_[1(5isopropylisooxadiazole_3_yl)-piperidine_4_yl b 2,3_ Dihydrofuro[2,3 c]pyridine

161177.doc -116· 201249837 tR-1.59 min, quality § Lu (ESI+): m/z=5〇i [m+H]+.

Example 2S 5-(2-Fluoro-4-methanesulfonylmethyl-phenyl) 2丨1 (5-propyl-[12 4]oxadiazol-3-yl)-piperidin-4-yl]_2 , 3_dihydrofuran [2,3 -c]n ratio bite

According to a procedure similar to that described in Example 8, 4_[5·(2_fluoro_4_nonanesulfonylfluorenyl-phenyl)-2,3-dihydrofuran[2,3 c The title compound was prepared from pyridin-2-yl]-indole-hydroxy-piperidine-1-carboxamidine and butyl hydrazine. LC (method 6): tR = 1.58 min; mass spectrum (ES): m/z = 5 〇 1 [Μ+Η]+. Example 26 〇S)-2-[l-(3-isopropyl-[ι,2,4]oxadiazole_5yl)piperidine-4-yl]-5 (4-methanesulfonyl-phenyl) _2_Methyl-2,3_dihydrofuro[2 3 c]e pyridine

According to a procedure similar to that described in Example 2, by (Fantasy_4_[5_(4_methanesulfonyl)]-2-methyl·2,3-dihydro-furo[2,3_c] The title compound was prepared as the title compound in the title compound: LC (method 4): tR = pyridine -2- pipiperidine-1- carbonitrile (intermediate 33; configuration of the stereoisomerization center arbitrarily specified) and N- mercapto-isobutylformamidine. I_i3 min, mass spectrum (ESI+): m/z = 483 [M+H]+. Example 27 (S)_(5_(4-曱 确 确 phenyl)-2-methyl-2-[l- (3-propyl-丨1,2,4] 161177.doc •117· 201249837 Dihydro-furo[2,3-c]pyridinium dipyridin-5-yl)-bunker·4-base]3

According to the procedure described in Example 2, it is also a procedure similar to that of [Phossin 4-[5-(4-methanesulfonyl-phenyl)-2-mercapto-2,3·-pain+ Mono-furo[2,3-c]pyridin-2-yl]-piperidin-1-indene nitrile (intermediate 33 · 'stereoisomeric ten-point configuration is arbitrarily specified) and N-hydroxy-butylformamidine The title compound was prepared as lc (Method: </RTI> </ </RTI> </RTI> </RTI> </RTI> </RTI> <RTIgt; 2·yl)·piperidine _4_ kib 5·(4·methanesulfonyl-phenyl)-2-methyl·2,3-dihydro-furo[2,3-c]pyridine

At 105. (: under 'in the presence of potassium carbonate, in the disulfoxide, ($)-5-(4-methylxanthene-phenyl)_2-methyl·2-0 base-based-2 , 3-dihydro·0fu and [2,3-c]pyridine (Intermediate 32; configuration of the stereoisomerization center arbitrarily specified) and 2-chloro-5-ethylmouth bite to prepare the title compound. LC (Method 4). tR=1.09 min; mass spectrum (ESI+) ·· m/z=479 [M+H]+ ° Example 29 〇S)-2_[l-(3-tert-butyl-丨I2,4 Oxadiazole _5_yl)-piperidine _4_ kib 5-(4-methyl succinyl-phenyl)_2·methyl-2,3·dihydro- 吱 并 [2,3 -c]°lb bite 161177.doc -118- 201249837

According to a procedure similar to that described in Example 2, ($)-4-1^-(4-methanesulfonyl-phenyl)_2-methyl-2,3-dihydrofu was shouted [2,3 -c]»Bit-2-yl]-0 bottom dec-1-carbonitrile (intermediate 3 3 ; configuration of stereoisomerization center arbitrarily specified) and N-hydroxy-2,2-didecyl - Propionate to prepare the title compound. LC (Method 4): m.p. Example 30 (*5)-2-[1-(5-ethyl-sound bite_2_base)_Break bite_4_base]_5_(1-methanesulfonyl-1,2,3,6- Tetrahydro-pyridine-4-yl)-2,3-dihydrofuran[2,3-c]pyridine

According to a procedure similar to that described in Example 1, (iS)_5_(1_methanesulfonyl-1,2,3,6-tetrahydro-pyridyl)_2-piperidine-4-yl-2,3 _Dihydro-furo[2'3-c]pyridine (Intermediate 37, configuration of the stereoisomerization center arbitrarily designated) and 2-chloro-5-ethylpyrimidine to prepare the title compound. LC (method 5): w min, mass (ESI+): m/z = 47 〇 [M+H]+. Example 31 (Λ)-2-[ΐ_(5-B;yl-1,2,3,6-tetrahydro-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-5-(1 -methanesulfonylpyridine_4-yl)_2,3-dihydro-furo[2,3-c]pyridine 161177.doc •119- 201249837

According to the procedure similar to that described in Example 1, (and)-5-(1-methanesulfonyl-1, Α·3,6·tetrahydro-pyridine_4_Γ9, 〇1 ^ The structure of the 39'-piperidin-4-yl-2,3-dihydro-furo-U-intermediate 39' stereoisomerization center * intended to specify) ^Ethyl (iv) to prepare the title compound. LC (square called W min * ^ s^(ESI+) : m/z=470 [M+H]+ 〇 Example 32 (4) servant burns the base. (8) 士四氢吼心心(6) ortho-methyl group) ·Brigade base ··2,3-dihydro-cough and [2,3♦ pyridine

According to the class described in Example 1, also ic, the negative procedure 'by ($)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-«» ratio bite:, 〇 ώ ^ ^ 疋4 yl)-2-piperidine-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 37, configuration of stereoisomeric centers) The title compound was prepared by substituting 2 genus-5-mercapto. Lc (Method 5): Seven 〇 84 min; Mass Spectrum (ESI+): m/z = 456 [m+h]+. Example 33 W-5-(l-甲烧烧醯基_1 2 3 6 tetrahydrobite-4·yl^methylH2-yl) slightly bite·4_yl]_2,3-dihydro-bite And [2,3_中比啶161177.doc -120. 201249837

Mercapto-1,2,3,6-tetrahydro-n is a bit like _4. γ一暴)·2-Piperidine _4_yl_2,3_two gas bite [2,3-c]pyridine (intermediate 39, 'and the configuration of the stereoisomeric center is arbitrary and 2- desert -5-decylpyrimidine preparation of indole compound LC (Method 5): tR = 〇 84 min, mass spectrum (ESI+): m/z = 456 [m+h] + 3 4 2 [1 (3 -Secondary butyl _[12 4] 喔二唾$基卜旅咬心基]$ &amp; 甲烧项醢基·^卜四氢-吨咬+幻^二氢-咬鸣鸣^ c]pyridine

According to the furnace skin similar to that described in Example 2, 1,2,3,6-tetrahydro-pyridin-4-yl)_2 3 - &amp; ^ Α procedure 'from 4-[5-(1-methane Sulfhydryl- 'monohydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-indene nitrile and N-hydroxy_22 _ Tian Yigong, △-methyl-propanthene preparation Title compound LC (Method 6): tR = l 51 m. mp. 2 min; mass spectrum (ESI+): m/z = 488 [M+H] + (5) -5 - (1) _ι 2,3 6 „„基四氢·pyridine_4基)·2_methyl_2 [1-(5-trifluoromethyl-pyrimidin-2-yl) piperidine_4·kib 2,3-dihydrofuran [2,3 call it bite

•12U 161177.doc 201249837

F at 105 °C, in the presence of carbonic acid unloading, in the dimethyl sulphate by (iS) - 5 - (1 _ A calcination thiol-1, 2, 3, 6-tetrahydro ratio bite _ 4_yl)_2_methyl-2-indolyl-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; configuration of stereoisomeric center The title compound was prepared by the designation of 2- gas-5-(trifluoromethyl)pyrimidine. LC (Method 4). m/z = 524 [M+H]+. Ethyl)4 bite_4 base]_s(i-methylsulfonyl-1,2,3,6·four H. mouth bite-4·yl)·2•methyl_23 diazide [2,3c] pyridine

In the case of long-term defeat, in (7)-5-(1-carboindole-"Μτ dm ^ ratio ° '4·yl)_2-methyl winter in dimethyl sulfoxide The structure of the base-2,3·dihydro-furo[2,3_c] is arbitrarily assigned) and 2 0, the stereoisomer [M+H] +. LC (method 4) 々 0.91 ^ The base is prepared by the title compound 1+., f spectrum (10) wide): m/z = 484 Example 37 • 4-yl)-2-methyl-2- (5-(1_甲炫确基基四氢) 1 bite 161177.doc •122· 201249837 [1-(5-trifluoromethyl-acridinyl)-piperidinyl j_2,3-dihydrofuro[2,3-c]nb bite

100S)-5-(l-methanesulfonyl-1,2,3,6-tetrahydro-pyridine_4_ in diterpenoids at 100 ° C in the presence of potassium carbonate )2)-2-methylpiperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; configuration of stereoisomeric centers are arbitrarily specified) and 2 • Chloro-5-(trifluoromethyl)pyridine The title compound was prepared. LC (Method 4): m.p. Example 38 〇S)-5-(l-methanesulfonyl-1,2,3,6-tetrahydropyridin-4-yl)_2-methyl_2_ [1-(5-trifluorodecyl)- Pyrazin-2-yl)-pyridinyl-4-yl b 2,3 dihydrofuran [2,3-c]nb

(5)-5-(1-decanesulfonyl-1,2,3,6-tetrahydro-pyridine-4 in diterpenoids at 100 ° C in the presence of potassium carbonate -yl)-2-methyl-2-piperidin-4-yl-2,3-dihydrofuro[2,3_c]pyridine (Intermediate 41; configuration of stereoisomeric centers are arbitrarily specified) and 2·Gas_5_(Trifluoromethylpyrazine to prepare the title compound. LC (Method 4): tR=i. 〇6 min; mass spectrum (ESI+): m/z=524 161177.doc -123- 201249837

S

II Ο Under reflux, 'N-hydroxy-4-[5-(l-methanesulfonyl-12,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furan[ A mixture of 2,3-c]pyridin-2-yl]piperidine_ι_ formazan (30 mg) and dimethylglycolic acid (30 μM) in methyl bromide (2 mL) was heated for 2 hours. The reaction mixture was concentrated in vacuo and chromatographed on EtOAc (EtOAc/EtOAc) The crude product was triturated with diethyl ether, filtered and dried to give the title compound. LC (Method 6): tR = 1.58 min; Mass (ESI+). m/z = 488 [M+H] + ° Example 40 ($)-5-(1-methanesulfonyl-1,2,3, 6-tetrahydro-pyridin-4-yl b-2-methyl-2 [1-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperidin-4-yl]·2,3 _ 二气咬咬[2,3-c]pyridine

At 10 (TC, in the presence of potassium carbonate 'in dimethyl sulphate; 6 in the wind by 161177.doc -124- 201249837 0S&gt; 5-(1-methanesulfonyl-1,2,3,6_ Tetrapyridin-4-yl-2,3-dihydro·bita and [2,3 bucket ratio: b pyridine-4·yl)·2-methyl 1 pipe center configuration is arbitrarily specified) and 2 spring 3 (Intermediate 41; stereoisomers of the title compound. LC (Method 4). t^5-(trifluoromethyl) °° custom m/z = 541 [M+Hr 〇 RM, 21 min; ESI+: Example 41 〇S)-5-(l-A-burning wall-[1-(5-methyl-pyrimidin-2-yl)-piperidine-4(4-)yl)_2_ Methyl·2_ Bu 2,3_dihydro-furo[2,3-c]pyridine

At 100 ° C, in the presence of potassium carbonate in the Qing - (10) brewing base cutting conditions, in the dimethyl subhard by the two [2'3 ° ° fixed (intermediate 4i; stereoisomerization center configuration The title compound was prepared by arbitrarily specifying) and 2 _淳$m, 昊~5-mercapto-pyrimidine. LC (Method 4) ·· tR=:〇81 n, mass spectrum (ESI+): m/z=47〇[M+H]+ 〇 Example 42 (S)-2-丨1-(3-isopropyl _ u,2,4] carbamide burning base-1,2,3,6-tetrahydro-ββ than bismuth-5-yl)_piperidine _4_yl]-5-(1-•4~ Base-2-methyl-2,3-dihydro-furan I61177.doc and [2,3-c]»« than bite-125· 201249837

According to the procedure of the thiol-1,2,3,6-four gas-«· bite-like procedure described in Example 2, from (iS)_4_[5-(1-methanesulfonyl-4-yl)-2 - mercapto-2,3-dihydro-furo[2,3 - c]. The bite is -2 - base] - the configuration of the sigma is arbitrarily specified) and the object. LC (Method 4): tR = 〇97 [M+H] + </RTI> </ RTI> carbonitrile (Intermediate 42; stereoisomery-based-isobutyl hydrazine preparation title compound min; mass spectrum (ESI+): m/z = 488 Example 43 (5:) 2 [1_(5_isopropyl-[12,4] noise 〇 )) slightly bite · 4 · base] _5 (Bao 炫 项 Item 2,3,6·tetrahydrogen Κ4. 基)_2 methyl H biting and [2,3-&lt;;] bite

〇According to the procedure described in Example 8, by (*S)-N-hydroxy-4-[5-(1- 甲烧烧基·1,2,3,6·Ε9氲_ A _4• base) winter methyl-2,3_two complex _. The title compound was prepared by the combination of keto[2'3c]pyridin-2-yl]-piperidine + formazan (intermediate; the configuration of the stereoisomer center is arbitrarily specified) and isobutyl sulfonium. Lc (method 4 broad tR=1.01 min; mass spectrum (ESI+): _=488 [m+h]+. Example 44 (R)-5-(l. A material-based base 12 2 3,6-tetrahydro (four) winter Base)··2]ι (5 propyl-[1'2'4] 嗯一峻-3-基)_嘛咬_4基】_2 3 Dihydrobite and [2,3 c] I61177.doc • 126- 201249837 pyridine

According to a procedure similar to that described in Example 39, from (Λ)·Ν·经基_4[5_(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridyl-4-yl)_2 , 3_Dihydro-furo[2'3-microbiti-2-yl]-densyl formamidine (Intermediate 45; the configuration of the stereoisomerization center is arbitrarily specified) and n-butyric anhydride to prepare the title compound. Lc (method 6) · tR-1.47 min, mass spectrum (ESI+): m/z = 474 [m+h]+. Example 45 (Exo 2-[1-(5-isopropyl-[H4]oxadiazole·3yl)·Bistidine 4yl]5 (1-methanesulfonyl-1,2,3,6-four Hydrogen-pyridine·4_yl)-2,3 dihydrofuro[2,3-c]nt bite

According to a procedure similar to that described in Example 39, from (Λ)_Νhydroxy_4_[5_(1-decaneindol-1,2,3,6-tetrahydro-pyridyl-4-yl)·2 , 3-Dihydro-furo[2,3-c]pyridin-2-yl]-piperidinium (Intermediate 45; configuration of the stereoisomer center is optionally specified) and isobutyric anhydride to prepare the title compound. LC (Method 6): m.p. = 1.47 min; Example 46 (S)-2-[l-(S-isopropyl 41241嗔二唾_3基)Brigade bite 5-(1-161177.doc -127- 201249837 Methanesulfonyl-1,2, 3,6-tetrahydro-bite-4-yl)-2,3-dihydrofuran [2,3- c]

桎, by (幻_N_hydroxy_4_[5_(1甲炫K醯基_1}2,3,6•tetrahydro)_2,3_dihydro- 咬 并 [2,3] bite 2 kibu. Bottom bite · i• formazan (intermediate; configuration of stereoisomerization center arbitrarily specified; 5 s butyl Α ι) and isobutyl amp; anhydride preparation title compound LC (method 6): tR =1.47min; ftf(Esr):m/z=474 [M+H]+〇Example 47 (Materials (1_甲烧冷酿基2, tetrahydrogen H4-group)_2_Methyl_2_ [ H5-propyl-like linings) _·4 bases] _2,3_diaza- koufu-[2,3-c]唆

According to a procedure similar to that described in Example 8, the external N-carboxyl sulfonyl-1,2,3,6-tetrahydroxidine, 4-yl)_2-methyl-2,3- The dinitrogen benzoate [2,3 々 咬 Μ Μ 派 派 派 派 派 派 派 中间 中间 中间 中间 中间 中间 中间 中间 中间 中间 中间 脒 脒 脒 脒 脒 脒 脒 标题 标题 标题 标题 标题 标题 标题LC (method 4): tn. OO min; mass _+): m/z = 488 [M+H]+. 161177.doc -128« 201249837 Example 48 5-(1-Methyl-organismyl-1,2,3,6-tetrahydro-tonate _4_yl)_2_methyl_2·[1_ (5_ Trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperidine-4-yl]·2,3·dihydrofuran shout [2,3-c]»

FN at 85 ° C in the presence of potassium carbonate, in the dimethyl sub-hard by 〇S &gt; 5- (l-methane fluorenyl-I, 2,3,6-tetraqi _. 4_yl)_2_methyl-2 piperidine_4_yl_2'3_dihydroindolyl[2'3_c]. The title compound was prepared for the specific ratio of the mouth (intermediate Ο; configuration of the stereoisomerization center) and 2_gas &amp; LC (Method 4): tR==〇 Q. R υ · 98 min ; mass spectrum (ESI+): m/z = 530 [M+H]+. (α-5-(ι-methanesulfonyl hydrazide, -tetraki-acridin-4-yl)-2-[l-(S-propyl-[',4]noise-sal-3-yl )-Niangxi _4_Kib 2,3-dihydro-furo[2,3-c] pyridine

According to the procedure described in Example 39 (1-decanesulfonyl-mb tetrahydro-pyridyl, by (phantom-N-hydroxy-4-[5·[2,3_c]° pyridine-2- ] 底 小 、 、 4 4 4 4 4 4 4 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 6) . tR=i.47 min; mass (ESI+). LC (method: m/z = 474 [M+H] +. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> oxadiazol-3-yl)-piperidin-4-yl]-5- , 2,3,6·tetrahydro-ton 唆•4-yl)-2,3-diaza-biting

According to a procedure similar to that described in Example 39, from (Λ)_Ν经基_4_[5_(1-methanesulfonyl-1,2,3,6-tetrahydropyridyl-4 base)_2,3_ Dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxamidine (Intermediate 45; configuration of stereoisomerization center arbitrarily specified) and preparation of dimercaptoacetic anhydride Compound. LC (Method 6). tR = 1.58 min; Mass (ESI+): m/z = 488 [M+H]+. Example 51 〇S)-2-[l-(5-t-butyl-[1,2,4]oxadiazole_3_yl)-piperidine _4_yl]·5· (1-A Hyun ·醯醯基-1,2,3,6-tetrahydropyridinyl·4·yl)_2,3 dihydrofuran [2,3-c]

According to a procedure similar to that described in Example 39, from (iS)_N_hydroxy_4_[5. (1-methanesulfonyl-1,2,3,6-tetra-ar-pyridin-4-yl)-2 , 3-dihydrofuran 161177.doc •130- 201249837 [2,3 - c] 0 ratio. The formula of -2 - base]-dchen bite 1 is arbitrarily specified) and three LC (method 6). tR=1.58 min; - formazan (intermediate 47; preparation of methyl acetic anhydride in stereoisomers) Compound 〇 〇 mass spectrometry (ESI+): m/z = 488 [M+H]+. Example 52 05)-5-(1-Methanesulfonyl-Xia 2^ _ A,2,3,6-tetrahydro- Pyridin-4-yl)-2-[1-(5-trifluoromethyl-indole)-pyrene·4 |, 疋4-yl]-2,3-dihydro-furo[2, 3-c]》lt pyridine

At 110C, in the presence of potassium carbonate, in the disulfoxide, (7)·5_(1_曱院 continued 醯基_1&gt;2,3,6 four gases than bite-4·base)_2· Slightly bite _4_yl_ 2,3-hydrogen-furo[2,3-c]pyridine (intermediate 37, configuration of stereoisomers is arbitrarily specified) and 2-gas-5-(trifluoro The title compound was prepared as a methyl pyrimidine. LC (Method 5): tR = 1.28 min; Mass (ESI+): m/z = 510 [M+H]+. Example 53 〇S)-5_(l-methanesulfonic acid-systemic tetrahydro-pyridine-cardioyl plant methyl·;^ [1-(5-methyl-pyrazin-2-yl)-piperidine _4_基]_2 3_Dihydro-furan[2 3_c] pyridine

At 125 °C, in the presence of potassium carbonate, (5)-5-(1-hypoxanthene-1,2,3,6-tetra-argon-.咬-4-yl)-2-mercapto-2-single 161177.doc • 131 - 201249837 pyridine-4-yl-2,3-hydrogen-furan[2 3 丄μ能#杯备此' bite (Intermediate 41; configuration of the stereoisomerization center you arbitrarily specified) and 2 ^ Toray 4, . ^ Wu-5-methylpyrazine to prepare the title compound min; mass spectrometry (ESI+): m/z = 470. LC (万法4) · tR=〇 84 [M+H]+. Example S4 (/0-5-(1-methanesulfonyl-12-^ X r ' ' '6·tetrahydro-perylpyridin-4-yl)-2-{l-[5-(1-A Base-cyclopropyl)-[1,2,4]oxo; 1^3-yl]-piperidin-4-yl}-2,3-dihydro•c]pyridine cough and U,夂r\

L is more than -4-yl) 2,3-dihydro-furo[2,3-C] ° than bite-2·yl]-σ bottom bite _ } _曱τ财, (intermediate 45; three-dimensional Group of centers

The title compound was prepared arbitrarily assigned to 丨-methyl I decyl-cyclopropanemethyl hydrazine. LC (Method 6). tR-1.53 min; Mass (ESI+): m/z = 486 [μ+η]+. Example 55 CS)-2-[i_(3-isopropyl)12,4]嗔二唾_5基卜旅咬_4_基】_5 (1_甲烧醯基_1,2,3,6 - four bites _4 base) 2,3 · dihydro cough and [2,3 · C] mouth bite

161177.doc •132· 0 201249837 by a procedure similar to that described in Example 2, by (magic _4_[5 (methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl) -2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-indenecarbonitrile (Intermediate 46; configuration of stereoisomeric centers are arbitrarily specified) and N- Hydroxy-isobutylformamidine Preparation of the title compound MH (Method 6): tj = 1.40 min; Mass (ESI+): m/z = 474 [M+H]+. - gas-pyrimidin-2-yl)-piperidinyl]-5-(4-methylpyridinyl-phenyl)-2-methyl-2,3-dihydrofuran[2,3-c Pyridine

CI at 105 ° C 'in the presence of potassium carbonate in dimethyl sulfoxide from (&lt;S)-5-(4-methanesulfonyl-phenyl)-2-mercapto-2-piperidin The title compound was prepared from the pyridin-4-yldihydro-furo[2,3-c]° pyridine (Intermediate 32; the configuration of the stereoisomerization center was optionally assigned) and 2,5·di-pyrimidine. LC (Method 6): m.p. Example 57 (5)-5-(1-Methanesulfonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-{1-[5-(1-methyl-cyclopropane Base)-[1,2,4]oxadiazol-3-yl-1-piperidin-4-ylindole-2,3-dihydro-furo[2,3-c]pyridine

161177.doc •133- 201249837 According to the procedure described in Example 8, 〇5)·Ν-hydroxy-4-[5-(l-甲炫续醯基,1,3,6- Tetrahydro-bipyridin-4-yl)_2,3-dihydro-furan |:2,3- c]0 is more than bite-2-yl]·o bottom bite-l-A fat 卞 (intermediate 4 7 The configuration of the stereoisomerization center is arbitrarily designated) and 1 _ 曱 base soil '% propane formazan to prepare the title compound. LC (method 6): tR = 1.53 min; &quot;&quot;&quot;&quot;&quot; Example 58 〇S&gt;2-[l-(5-gas-sounding base 卜 唆 唆 4 4 】 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _2,3 dihydrogenated and [2,3c] pyridine

At 105 C, in the presence of a carbonic acid clock, '(5)-5-(1-曱 绩 酿 -1,2,3,6-tetrahydro-0 ratio bite in dimethyl hydrazine - 4-yl)-2-methyl-2-0-bottom-4-yl-2,3-dihydro-β-pentano[2,3-c]° ratio biting (Intermediate 41; Stereoisomeric Center The configuration is arbitrarily assigned) and 2,5-di-pyrimidine to prepare the title compound. LC (Method 6): m.p. = 1.78 min; Example 59 (/?) -2-[1-(3-isopropyl-[1,2,4] 嗤二嗤-5-yl)- Niangbit-4-yl]-5_ (1-A burned horizontal Styrene-1,2,3,6-tetrahydrobit-4-yl)-2,3-dihydro-cough-[2,3-c]&quot;

161177.doc -134- 201249837 by (-?)_4_[5_( methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl) according to a procedure similar to that described in Example 2. -2,3-dihydro-furo[2,3-c]pyridine·2-yl]-piperidine _ _ carbonitrile (intermediate 44; configuration of stereoisomeric centers are arbitrarily specified) and N· The title compound was prepared via benzyl isobutyl hydrazine. LC (Method 6): m.p. = 1.40 min; Example 60 (4-{2-[l-(5-ethyl-pyrimidin-2-yl)-bunk-4-yl]-2,3-dihydrobenzoindole-5-yl}-benzene Base) _ linyl-ketone

White 4{2-[1-(5-ethyl-mouth bite_2-yl)-1» bottom bite 4-yl]-2,3-dihydro-benzofuran-5-ylbubenzoic acid ( 43 Diethyl isopropylamine (52 μΕ) and tetrafluoroboric acid 2_( 1H-benzodiazole·1-yl)-1,1 were added to the mixture of dimercaptomethylamine (1). 3,3 -tetradecylhydrazine (TBTU, 32 mg). After 1 minute, morpholine (11 mg) in hydrazine-dihydrazinamide (0.5 mL) was added. The mixture was stirred for 12 hours. Purification by preparative hplC (solvent: water (+0.1 〇/〇TFA)/methanol) gave the desired product. Ηριχ (method 9): tR = 1.95 min; mass (ESI+): m/z = 499 [M+H]+» The compound of the following formula (1-1) was prepared in a similar manner to that of Example 6, and the starting material used is shown in the title "SMi": 161177.doc • 135· 201249837 R Ο

(1-1) Example R SM 1 ESI-MS [m/z] [M+H]+ R, (HPLC) [min] (Method 6) 61 cX 1 * cX H 527 2.01 62 1 \ s〆* 1 \ Sr 501 1.98 63 K nh2 515 2.02 64 o H n 丫*HCI , nh2 510 1.92 65 f&lt;5f N •k F&lt;5F - B 505 2.05 I61177.doc 136- 201249837 66 OH Λ, ΟΗ Λ νη2 501 1.95 67 \ 4 1 , 〆 * Ν Η r 1 , νη2 468 1.91 68 ΟΗ 1 * ΟΗ 513 513 1.93 69 〇〆ό 1 * 6 Η 527 2.02 70 Η〇ν^ 0 * Η〇ν 0 Η 499 1.86 71 r 1 J 1 1 r 1 4 1 Η 482 1.92 72 Β νη2 513 1.99 161177.doc 137- 201249837

Example 79 (/?)-5-(1·methanesulfonyl-1,2,3,6·tetrahydro-pyridin-4-yl)-2-[l-(5-trifluoromethyl-pyrimidine- 2-yl)-piperidin-4-yl]-2,3-dihydro-furo[2,3-c]pyridine 161177.doc -138- 201249837

γ at 11〇C, α)-5-(1-methanesulfonyl-12,3,6-tetrahydro-pyridine)

39 'The configuration of the stereoisomerization center is arbitrarily specified; ιι 〇), 2-gas _5_ K2C03 (100 mg) and dimethyl hydrazine (1.5 After cooling to room temperature, add water and use hexafluoromethyl A mixture of -pyrimidine (76 mg), mL) was stirred for 3 hours. The resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na.sub.2) and concentrated. The residue was chromatographed on EtOAc (EtOAc:EtOAc:EtOAc Lc (method 5): tR = 1.32 min; mass spectrum (ESI+): m/z = 510 [M+H]+. Example 80 (^)-5-(1-methylxanthyl-1,2,3,6-tetrahydro-bito-4-yl)-2-[1-(5-trifluoromethyl-pyridyl) Pyrazin-2-yl)-piperidinyl]-2,3-dihydro-furo[2,3-c]»* pyridine

A procedure similar to that described in Example 79 was followed by '()-5-(1-methanesulfonyl-1,2,3,6-tetrahydrobile _4_yl)_2-piperidine-4- The base 2,3-dihydro-furo[2,3-c]pyridine (the configuration of the intermediate 39 'stereoisomer center is arbitrarily specified) and 2-chloro-5-trifluoromethyl group _. The title compound was prepared by the pyrazine. LC (Method 7): m.p. 161177.doc -139· 201249837 Example 81

Wl (1-methanesulfonic acid-!, 2,3,6·tetrahydro-hydroxylidine I base)·2· [2,3-c] bite

F

Ff according to the private order similar to that described in Example 79, by W-5-(l-甲后续.r?, yl)~2-piperidine-4-yl-2,3-dihydro -furo[2,3-c]pyridine (intermediate 39, configuration of stereogenic centers is arbitrary) and 2-gas _5_trifluoromethyl _[13 T .. ,] sedazole The title compound was prepared. LC (Method 7): tR = 1.46 min; m.p. (ESI): m/z = 516 [M+H]+. Example 82 (and)-4-[5·(1-methanesulfonyl 4 ^ , tetrahydro-pyridin-4-yl)-2,3-dihydro-indolo[2,3-c]pyridine- 2-based 1 s,-monofluoro*methyl-3,4,5,6-tetrahydro-2H-U, 2'] beta beta bite

According to the description of Example 79, fluorenyl-UU6-tetrahydro-. Than bite {base, #in order, from (8)-5-...a cans and simmers] (four) (intermediate 39, stand-up ^^·4·base·2,3·diazide-decandin) and 2-11· 5. The configuration of the three-discrete methyl · 2 structure center is the arbitrary reference to the title compound ❶ LC (method 161 161177.doc • 140· 201249837 7) : tR=l .63 n ' mass spectrum (ESI+) : m/z =509 [M+H]+. W-2-[K(S , Example 83 ^心四备2_基)_旅咬_4-基]Μ1·甲烧确醯-Pyridin-4-yl)-2,3-dihydro- Furan[2,3-c]pyridine

c'&lt;V〇醯基_1,2,3^ is a similar procedure, which is arbitrarily designated by the configuration of the 39' stereoisomeric center of the intermediates and 2,5-a pyrimidine The title compound was prepared. LC (Method 7): tj = 1. 63 min, MS (ESI+): m/z=476/478 (CI) [M+H]+ 〇 Example 84 (external 3'-fluoro-4-[ 5-(l-methanesulfonyl)^tetrahydrofluorinyl)·2,3·dihydro-furo[2,3-c]pyridine-2·yl b, _trifluoromethyl _ 3,4,5,6 tetrahydro-2H-[l,2,]bipyridine

According to a procedure similar to that described in Example 79, Μ)-5·(1·decanesulfonyl-1,2,3,6-tetrahydropyridinyl-4-yl)-2·l-pyridine-4 -Based-2,3_dihydro-trinop[2,3-c]pyridine (Intermediate 39, configuration of stereoisomerization center arbitrarily specified) and 2-bromofluorotrifluorofylpyridine to prepare the title compound . LC (Part-141. 161177.doc 201249837 Method 7): tR = 1.75 min; Mass (ESI+): m/z = 527 [M+H]+. Example 85 (π)-2-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl b-5-(4-methanesulfonyl-phenyl)-2,3-di Hydrogen-furoindole 2,3-c]pyridine

(i?)-5-(4-decanesulfonylphenyl)-2-piperidin-4-yl-2,3-dihydrofuran[2,3-indole at 120 °C ] &lt;pyridine {by cleavage of the amino decanoate group (according to the procedure similar to that described for Intermediate 9) 'from (/?)-4-[5-(4-decane fluorenyl-yl) -2,3 - monohydro-**fu 0 south and [2,3-(^]° than bit-2-yl]-slightly determined _1_decanoic acid tert-butyl ester, the compound is in accordance with A similar procedure as described for Intermediate 7 was synthesized from Intermediate 34 and 4-decanesulfonyl-phenyl-fatanoic acid, and the configuration of the stereoisomerization center was arbitrarily specified, · 110 mg}, 2·Ga·5· A mixture of ethyl ketone (52 μM, hydrazine, hydrazine-diisopropyl-ethylamine (0.18 mL) and hydrazine, hydrazine-dimercaptocarboxamide (2 mL) was stirred for 5 hours. After that, water was added and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried (NkSO4) and concentrated. EtOAc EtOAc EtOAc EtOAc Chromatography of the title compound mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

12,3,6-tetrazine-bite-4-yl)-2,3-dihydro-coughane[2,3 c]e-pyridyl I61177.doc -142- 201249837

Cl

1 ? λ - The procedure consists of ($)-5-(1-decanesulfonic acid -1,2,3,6 - four gas - η ratio bite _4 · meaning) 2 and [2,3-c Acridine (Intermediate 37, designated according to the configuration of the piperidin-4-yl-2,3-dihydro-furan stereoisomeric center as described in Example 79) and 2,5•dichloro (d) Preparation of the title compound. Lc (square: min; mass spectrum (ESr): m/z = 476/478 (ci) [M+H]+. . Example 87 (Λ)-2-[1-(5-gas-variable 唆_2_ 、,成成~4*))piperidin-4-yl]-5-(4-methanesulfonyl-phenyl)-2,3-dihydro-aspartate [2 3 cl acridine

According to a procedure similar to that described in Example 79, by (bucket 5_(4_methylform in fluorenyl-phenyl)-2-(tetra)-glycosyl] 2,3·dyne fuco[2,3♦ bite cleavage Amino decanoate group (according to the procedure similar to that described for Intermediate 9), from (and) o-(4·methyl hydrazino-phenyl)_2,3-dihydro-folph[2] , 3 piperidinyl 2-yl]-piperidine d-decanoic acid tert-butyl ester, which is further subjected to a procedure similar to that described in Intermediate 7, from intermediates 34 and 4 methanesulfonyl. Obtained with phenyl lysate, the configuration of the stereoisomerization center was arbitrarily designated 丨 and 2,5 _ chloropyrimidine to prepare the title compound. LC (Method 6): tR = 163 min; 噌 (ESI+): m/z = 471 /473 (Cl) [M+H]+. 161177.doc •143- 201249837

备备 I 52 Q W-2-[l-(5-|L.^^.2^ 1,2,3,6-tetrahydro-«» ratio bite_4_base-base]-5-(1 -methanesulfonyl)2_methyl-2,3-dihydro-furo[2,3 pyridine

CI

...,~~ 征 斤, 田(κ)_5·η 醯--1,2,3,6·tetrahydroκ4•基)~final 4_base_2,3 two continued and [2,3-small ratio Bite {by cleavage of urethane acetate (according to the procedure similar to that described for the intermediate South 9)' by 4-[5_(ι·methanesulfonyl-i,2,3,6-tetrahydropyridinium) -4·yl)-2-methyl-2,3-dihydrofuran[2,3_c]° is obtained by the third butyl ester of pyridine-2-yl]-piperidine-1-dicarboxylate, and the compound is again A procedure similar to that described for Intermediate 7, consisting of Intermediate 30 and 1-(Methanesulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)·1,2,3,6-tetrahydropyridinidine obtained the 'stereoisomeric center configuration system arbitrarily specified} and 2,5-dichloro shark bite to prepare the title compound. LC (Method 4): m.p. Example 89 (5&gt;2-[l-(5-cyclopropylH2.yl)-slightly biting base]·5_(4-methyl succinyl-phenyl)-2-methyl-2,3-di Hydrogen-callo[2,3-c]&quot;bipyridine 161177.doc -144· 201249837

According to a procedure similar to that described for you, I 7q π 4 Μ /, -, (5)-5-(4-曱石石黄湟土苯土) 2 pyridine 4_yl 2,3_ dihydrogen - cough reading and [2,3_c bupidine (intermediate 32, configuration of the stereoisomerization center arbitrarily designated) and 2-gas-5-cyclopropyl. Do not [C (method 4). tR = 0.95 min; mass spectrum (ESI). m/z = 496 [M+H]+. Example 90 w [ (= ^n2_基)-Brigade bite _4 base]-5 (4 A-burning base _ phenyl)-2,3-dihydro-furo[2,3 c]e pyridine

According to a procedure similar to that described in Example 79, from (7)-5-(4-methylpyrene)phenyl.定_4_基_2,3_Dihydrogen+南和[2,3_心咬{by cleavage of an amino citrate group (according to the procedure described in relation to the intermediate (4))曱 曱 醯 醯 苯基 ( ( ( ( ( ( ( ( ( ( ( 2 2 2 2 2 2 2 2 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基35 and 4 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Min ; mass spectroscopy (ESI+): m/z = 471 / 473 (CI) [M+H] + 161177.doc • 145 - 201249837 Example 91 (i?)-2-[l-(5-cyclopropyl- Pyrimidinylpiperidin-4-yl]-5-(1-methanesulfonyl)-2,3-dihydrofuran[2,3-c]pyridine

According to the procedure described in relation to Example 79, the type of the formula is as follows: (Λ)_5·(1_methane stone, the procedure of the formula -1,2,3,6-tetrazine-咐. Brewing base · i'2'3,6·tetrahydro _^·4_ base), 2_^_4_ base_2,3•diazepine[2,3-C]. The title compound was prepared by the bite (the configuration of the intermediate 39' stereoisomerization center was arbitrary) and the 2-gas-5-cyclopropyl-(iv). Lc (method 1): tR = 1,6 l min; mass spectrum (ES): m/z = 482 [M+H]+. Example 92 (and)-5-(1-methane wall-based 1,2,3,6-tetrahydron4-yl)_2-[1-(5-methoxy-pyrimidin-2-yl)-peripipeline Acridine_4-yl]_2, quinone dihydrofuran, furan oxime 2 3_c]pyridine

According to a procedure similar to that described in Example 79, from (i?)-5-(1-methylpropioninyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidine 4-yl-2,3-dihydro-furo[2,3-c] ° ratio. The title compound was prepared (Intermediate 39, configuration of the stereoisomerization center arbitrarily specified) and 2·gas-5-methoxy-pyrimidine. LC (Method 10): m.p. = 1.48 min; 16I177.doc -146· 201249837 Example 93 (i〇-2-[1-(5-cyclopropyl- 喷 _2_2_基)_旅咬_4_基]_5_(4甲烧烧-基-苯Base)·2,3-dihydrofol[2,3-c]&gt;

According to a procedure similar to that described in Example 79, (/?)-5_(4_甲基基基-基基基)-2-piperidine-4-yl-2,3-dihydro-furan[ 2,3-c] acridine {by cleavage of the amino decanoate group (according to the procedure similar to that described for Intermediate 9), from (/〇-4-[5-(4•methanesulfonyl) Obtained from phenyl) 2,3-dihydro-furo[2,3 c]pyridin-2-yl]-piperidine-1-furic acid tert-butyl ester, which is in turn similar to that described for Intermediate 7 The procedure was carried out from Intermediate 34 and 4·decanesulfonyl-phenyl benzoic acid. The configuration of the stereoisomerization center was arbitrarily designated as a title compound. LC (Method 1 〇): tR = 1% min; MS (ESI+): m/z = 477 [M+H]+. Example 94 (i?)-5-(4-methane dish base-stupid) _2_u (smethoxy-mouth _2 base) _ brigade-4-yl] _2,3-dihydrofuran [2 3 c] pyridine

The procedure is as follows: (i?)-5-(4-decanesulfonyl-hydrofuro[2,3-c]pyridine {by thiol-phenyl according to a procedure similar to that described in Example 79) -2-piperidin-4-yl-2,3-di- urgent 161177.doc •147- 201249837 cleavage of urethane acetate (according to the relevant intermediate 9 _ by W-4-[5-(4-A Hyun continued-branched-phenyl)_2,3_diaza^'debut-2-yl]-stolen bitter small formic acid terpene vinegar, the compound is again in accordance with the procedure described in the middle of the intermediate 7 , obtained by Shen 榀 榀 u &lt; '', Acupoints ^ by intermediate 34 and 4-decanesulfonyl phenyl phthalic acid, the configuration of the stereoisomerization center is arbitrarily specified} and 1 = 5-曱 oxygen The title compound was prepared by basal-pyrimidine. LC (Method 10 彳.+ '\^ re: iyj). tR=l &gt; 69 min; mass spectrum (ESI+): m/z=467 [M+H]+ The following compounds were prepared in a similar manner to the examples and other methods known in the literature.

Example 96

Example 97

161177.doc •148· 201249837 Example 98

Example 100

Example 102

161177.doc -149- 201249837 Example 103

Example 106

161177.doc -150- 201249837 Example 108 N - 〇\u /&gt; Example 109 N, 〇\ 161177.doc

Claims (1)

201249837 VII. Application for Patent Park: 1. A compound of formula I, Wherein R1 RNA is selected from the group r1_gi consisting of 5 or 6 member heteroaromatic rings independently of each other selected from N, 〇 and s; and wherein the second ring may be An aromatic ring condensation wherein the second ring is a 5- or 6-membered unsaturated or aromatic ring and may contain 1, 2 or 3 heteroatoms independently selected from N, 〇 and §, "中中在" In the first sentence, i or two _CHr groups can be seen as scales, -C (which, _s (which or state...where in the heteroaromatic ring and/or the second ring, or a plurality of NH groups) The H atom in the group may be replaced by RN as the case may be; wherein the heteroaromatic ring and/or the second ring are independently substituted with each other by - or a plurality of substituents selected from a wide range; Or the second ring may be optionally substituted by a group RC; independently selected from the group consisting of H, &amp; 炫, 基 〇)· and Cl·4 alkyl-s(=〇)2-, RN_G1; Free group consisting of A_G1: 1,2,3,6-tetrahydro in the N-substituted group _ () 2, I bite _4_ base ring, stupid base ring, and contain 1, 2 or 3 Independently selected from N, 〇 and 3 161l77.doc 2012 49837 of a hetero atom of 5 or 6 members of a heteroaromatic ring, and optionally condensed with the stupid base ring, the clothing and the mixed group ring, wherein the first »ca *1. /· e* . I _ '&quot;, S'6 member*saturated or aromatic ring, and may contain, 2 or 3 heteroatoms independently selected from N, 〇 and S, and wherein in the n second ring! or 2 An even-group may optionally be via N(R)-, ·(:(=〇)...s(which or _s(=• substitution; wherein in the heteroaromatic ring and/or the second ring, one Or the η atom of the plurality of NH groups may be optionally substituted; wherein the stupid ring, the heteroaromatic ring and/or the third ring are each independently substituted with one or more substituents selected from one another; The phenyl ring, heteroaromatic ring or second ring may be optionally substituted by a group T; τ is selected from the group T_G1 of the following composition: F, c, Br, I, CN, OH, N02, (:.6. Base —, Cu alkenyl-, C,-6 alkynyl —, q 6 cycloalkyl, C -6-alkyl-hydrazine-, (:3·6 cycloalkyl-〇_, Cl 6 alkyl _ S -, H0-C(=0)·, Cl-6 alkyl-〇-C(=〇)- 'Cl.4 alkyl-c(=0)-, c3.6 ring-base-c(=0 )-, c丨·4 alkane -s(=0)-, Ci-4 alkyl-8(=0)2-, 1^1'11^1'2]^-, 111'11'11^1'21^-C(=〇 ). RNT1RNT2N-s(=〇)2- ^ RNT1RNT2N-C(=0)-(Rn)N-, Heterocyclyl, Heterocyclyl-〇_, Aryl, Aryl-〇_, Heteroaryl And a heteroaryl-oxime wherein each alkyl, alkenyl, alkynyl and cycloalkenyl group may be optionally substituted with one or more substituents independently selected from the group consisting of F, C, CN, OH, Ci- 3 alkyl, C3-6 cycloalkyl, C 3 alkyl-fluorene-, RNnRNT2N_, 161177.doc -2- 201249837 , C1.4 alkyl-heteroaryl and hetero-RNT丨rNT2n-c (=〇) -, C丨-4 alkyl-s (which S(=〇)2-, Rn"Rnt2n_s(=〇)2 'aryl, ring group; wherein aryl represents phenyl or zeo; The H atom in one or more of the NH groups containing 5, 3 or 4 heteroatoms independently selected from N, fluorene and S, respectively, may be replaced by rN; Wherein the heterocyclic group is a 4- to 7-membered unsaturated or saturated carbocyclic ring, and the octyl or 2-CH2- group thereof is independently of each other via 1^^^, 〇, &lt;(=〇)_, s, - s (=〇)- or 奂, and/or wherein the HCH_ group is substituted by N; wherein each aryl, heteroaryl or The ring group may optionally be substituted by one or more substituents independently selected from La; R is selected from hydrazine, cN6 alkyl, c3.6 cycloalkyl, q 6 alkyl _ c( 〇)-, CN6 alkyl a group r_I gi consisting of _s(=〇)2, a heterocyclic group, an aryl group and a heteroaryl group; wherein each of the alkyl group and the cyclodextrin group may be independently selected from F, 〇H, CN by one or more , Cl 4 alkyl, Ci 4 alkyl 〇 R R 2 N Ci-4 alkyl-S (=0) 2, C 3-6 ring-based, heterocyclic ^ 'phenyl and heteroaryl group Substituent substituent; wherein the heterocyclic group may be optionally substituted with one or more substituents independently selected from the group consisting of F, ci-4 alkyl, Rn2n, OH and C _4 alkyl-fluorene; wherein the heterocyclic group is C4-7 cycloalkyl ring, wherein 1 or 2 -CH2- group 161177.doc 201249837 Groups are independently of each other via NRn, ο, c(=〇), s, S(=0) or S(= 〇)2 And wherein the aryl group is a phenyl or naphthyl group; wherein the heteroaryl group is a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, fluorene and S, wherein one or The ruthenium atom of a plurality of NH groups may be replaced by a case; wherein an aryl group and a heteroaryl group may be used as the case may be One or more substituents 1A are substituted; RNT2 is selected from the group consisting of alkyl groups: ^(1): or rNT, which is linked to rNT2 to form a group selected from the group consisting of CM alkyl groups RNT1RNT2-G1; Or the two -CH2 groups are replaced by nrn, 〇, C(=0), S, s(=o) or s(=o)2 independently of each other; and optionally, one or more independently of each other Substituted from F, C! · 4 alkyl, (Rn) 2N, (^ and 匚丨·*alkyl-〇-substituent; LA is selected from F, Cl, Br, CN ' OH, N02, ( ^ 4 院基_, C〗.4 alkyl-Ο-, (Rn) 2N-C (=0), (Rn) 2n_ and cN4 alkyl-S (=0) 2 _ group of LAr-Gl Wherein each of the substituents may be optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, CN, OH and C丨.3 alkyl-0-; Lp is selected from the group consisting of F and C丨·3 a group consisting of LP-G1, wherein the alkyl group may be substituted by one or more F atoms; and the LQ system is selected from the group consisting of F and C1-3 alkyl groups, wherein the thio group may pass one or more F atoms are substituted; 161177.doc -4- 201249837 Rc • « • * is selected from the group consisting of RC-G1: F, Cl, Br, I, CN, OH , N02, C, -6 alkyl-, 0-6 alkenyl-, CN6 alkynyl-, 匸3.6 carbyl, Ci-6 alkyl 〇, 〇3·6 cycloalkyl-〇-, Ci -6 alkyl-s-, H0-C(=0)-, C〗.6 alkyl-0-C(=〇)-, Cl.4 alkyl-c(=0)-, C3.6 ring Alkyl-c(=o)-, CU4 alkyl _s(=0)_, Cu alkyl-8(=〇)2-, 1^1'11^1'21&lt;[-, 111'11' 1尺町2]^_ c(=0)-, RNT1RNT2N-S(=0)2-, rnt1rNT2n-c(=o)-(Rn)N-, heterocyclic group, heterocyclic group-〇_, aromatic a aryl group, an aryl group, a heteroaryl group, and a heteroaryl group, wherein each alkyl group, alkenyl group, alkynyl group, and hexyl group can be optionally selected from one or more substituents independently of one another Substitution: F, Cl, CN, OH, c丨-3 fluorenyl, C3-6 cycloalkyl, c丨_3 alkyl-〇-, rNtirnt2n_, rnt1rNT2n_c(=o)_, C丨.4 alkyl- S(=0)-, Cl_4 alkyl_S(-0)2-, RrNT2n-S(=0)2-, aryl, heteroaryl and heterocyclic; wherein aryl represents phenyl or naphthyl Wherein the heteroaryl group is a 5- or 6-membered aromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, 0 and S, wherein one or more of the NH groups are halogen atoms Subject to rn substitution; wherein the heterocyclic group is 4 to 7 An unsaturated or saturated carbocyclic ring in which one or two -CH2 groups are independently substituted with each other&gt;], 〇, 'S, -S(=〇)· or -S(=0)2-, And/or one of the _CH_ groups is substituted by N; wherein each aryl, heteroaryl or heterocyclic group may be optionally substituted with one or more substituents selected from la independently of one or more of 161177.doc 201249837 x1; Χ2, f are independently selected from the group consisting of C(R2) and N, X-Gl such that 〇, i or 2 members of the group consisting of χΐ, X2 and X3 have the N meaning; R2 η is selected from H, Groups of F, C OH, Cl-4, C37 ring, F2hc, F3C, Ci4, 〇_, F2HC〇, F3C-O-, and C3.7 cycloalkyl 〇 R2_g1 ; is an integer selected from 0, 1, 2, 3 or 4; and m is an integer selected from hydrazine, 1 or 2; or a salt thereof. 2. The compound of claim 1, wherein R1 is selected from the group consisting of: a 5-membered heteroaromatic ring containing 2 or 3 heteroatoms independently selected from N, hydrazine, and s and containing 1 or a 6-member heteroaromatic ring of a coffee atom; and wherein the second ring may be condensed with the 5 member and 6M heteroaromatic ring, wherein the second ring is a 5- or 6-membered unsaturated or aromatic ring, and Containing a hetero atom independently selected from N, 〇, and S, and wherein in the second ring, a hydrazine or a holly ch2- group may optionally be via nn(rN)_, _c(=〇) or 〇 2_substitution; , in the heteroaromatic ring and/or in the second ring, or a ruthenium atom in a plurality of sensible groups may be replaced by rn; wherein the heterogeneous group % and/or the first The bicyclic rings are each independently substituted with one or two substituents selected from LA; wherein the heteroaromatic ring or the second ring may be optionally substituted by a group ^; wherein RN, LA and Rc are as claimed Defined in . The compound of claim 1 or 2, wherein the A is selected from the group consisting of 卩 161 177.doc 201249837 The group base ring '6 member heteroaromatic ring containing 1 or 2 N atoms, and containing L, two: Independently selected from N,. And a 5-membered heteroaryl of the hetero atom of s, wherein the phenyl ring or heteroaromatic ring is substituted with a group T, and wherein the present A-based and heteroaromatic ring are optionally independently of one or more Substituted from a substituent of L; % wherein in the heteroaromatic ring, - or a plurality of NH groups are optionally replaced by rn; ', wherein T, RN and La are as defined in claim i . 4. The compound of claim 1 or 2 wherein the eight groups are selected from the group consisting of a phenyl ring and a 5- or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms independently selected from N, 〇W. a group; and wherein: a ring: the ring with the phenyl ring or the heteroaromatic ring, wherein the second ring is a 5- or 6-membered unsaturated or aromatic ring, and optionally 1 or 2 independently of each other a hetero atom selected from the group consisting of ruthenium, osmium and S, wherein W2 _CH2_ groups in the first ring may be _n(rN)_-c(-o)-, _s(=〇)_ or Sho)" substitution; wherein in the heteroaromatic ring and / or the second ring, - or a plurality of ruthenium atoms in the bribe group may be replaced by rn; wherein the phenyl ring, the heteroaromatic ring and the Each of the bicyclic rings may be optionally substituted with one or more substituents selected from each other independently of 1/; wherein the phenyl ring, heteroaromatic ring or second ring may be optionally substituted with a group; and rn, T and 1/ as defined in claim 1. 5_A compound of claim 1 or 2, wherein ψ Δ Α Α Α is selected from the group consisting of 1, 2, 3, 6-tetrahydropyridin-4 , ψ#, τττ # m , the NH group in the ΗC i ·4 炫· I6ll77.doc 201249837 s (=〇)2-displacement 6. The compound of claim 1 or 2, wherein T is selected from CN, C|.4 alkyl _ S (= 〇) 2-CH2-, C, .4 alkyl·8(=〇)2, RNTIRNnN_s(=〇)2, R RNT2n-C(=0)-, cBu 4 alkyl-S(=0)2-(Rn)N- and RNT'RNT2 N-groups, of which, and are as defined in claim 1. 7. The compound of claim 1, wherein: X1 is CH; X2 is CH or N; X3 is CH; and R1 is selected from the group consisting of: RLG4a: /°'N s- N: '~〇 and each ring thereof may be substituted by a substituent RC; ^ is selected from the group consisting of F, Cl 'C丨·4 alkyl 'f3C_ and cyclopropyl group Rc-G4b, wherein the ring C The group may be monosubstituted by CH3; the A group is selected from the group consisting of A_G6a : F 161177.doc 201249837 L% CH3; n is 0; m is 0 or 1; and a pharmaceutically acceptable salt thereof. 8. The compound of claim 7, wherein: X1 is CH; X2 is N; 161177.doc • 9-201249837 X3 is CH; Ri is selected from the group consisting of: S- N=^/ N- Ν' an and medium = may be substituted by one or a substituent RC; = a group of free F, c, Cl. 4 alkyl, F3c_ and cyclopropyl, wherein the cyclopropyl group may be CH3 is monosubstituted; A is selected from the group consisting of: F . Yang η is 0; m is 0 or 1; and a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 8, which is in the form of a pharmaceutically acceptable salt. 10. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use in a method of treating diabetes, obesity or dyslipidemia. 11. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 8 or one or more pharmaceutically acceptable salts thereof, optionally 16ll77.doc • 10· 201249837 with one or more Inert carrier and / or diluent. 12. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 8 or one or more pharmaceutically acceptable salts thereof and one or more other therapeutic agents, In the case of one or more inert carriers and/or diluents. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for the manufacture of a disease or condition mediated by activation of the G protein-coupled receptor GPR1 I9 Drug. The use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of diabetes, obesity or dyslipidemia. 161177.doc 201249837 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 161177.doc