TW200303316A - Substituted indolizine-like compounds and methods of use - Google Patents

Abstract

Selected novel substituted indolizine-like compounds are effective for treatment of diseases, such as TNF- α, IL- l β, IL-6 and/or IL-8 mediated diseases, and other maladies, such as cancer, pain and diabetes. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for treatment of diseases and other maladies or conditions involving inflammation, cancer, pain, diabetes and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

Description

200303316

说明 Description of the invention (the description of the invention should state: the technical field, prior art, content, implementation, and drawings of the invention are briefly explained) This application claims U.S. Provisional Application No. 60 filed on January 16, 2001 / 332,447, the content of which has been fully incorporated by reference. Previous invention The present invention includes a novel, substituted docolinol compound suitable for the treatment of vector-borne diseases such as: TNF-α, IL-Ιβ, IL-6 and / or IL-8, and others such as: Cancer, pain and diabetes. In particular, the compounds of the invention are useful for treating diseases or conditions involving inflammation. The invention also relates to intermediates and methods suitable for the manufacture of these compounds. Interleukin-1 (IL-I) and tumor necrosis factor alpha (TNF-α) are caused by a variety of cells (including monocytes and macrophages) in response to many types of inflammatory stimuli (such as lipopolysaccharide-LPS) or external Proinflammatory cytokines secreted by cellular stress (eg osmotic shock and peroxide) ^ When TNF-α and / or IL-1 levels are higher than the basal amount, they involve mediators or worsen a variety of diseases. ; Patzell's disease; osteoporosis · multiple myeloma: grape: meningitis; acute and chronic myelogenous leukemia; beta cell destruction in the viscera; osteoarthritis; rheumatoid spondylitis; gouty joint steam, inflammatory Bowel Diseases: Adult Respiratory Distress Syndrome (ARDS); Dry Diseases, Crohn's Disease; Allergic Rhinitis; Ulcerative Colitis · Allergic Reactions: Contact Dermatitis: Asthma—, »Reiter's Syndrome ): Type I and Type II diabetes; bone resorption disease; graft versus host response; reperfusion injury after ischemia; arteriosclerosis: brain trauma; multiple sclerosis; cerebral malaria; sepsis; sepsis ^ -6 · 200303316 Invention Description Continued (2) grams; toxic shock symptoms; fever; and myalgia due to infection. TNF-a also worsens HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, herpes virus (including HSV-1, HSV-2), and shingles. It has been pointed out in the literature that TNF-a plays a role in head trauma, stroke and ischemia. For example, in animal models of head trauma (rats), TNF-a levels in contused cerebral hemispheres increase (Shohami et al. J. Cereb. Blood Flow Metab. 14, 615 (1994)). In the ischemic rat model, the TNF-α mRNA content of TNF-α increases when the middle cerebral artery is blocked (Feurstein et al. Neurosci Lett 164, 125 (1993)). Administration of TNF-a in the cortex causes neutrophils to accumulate significantly in capillaries and attach to small blood vessels. TNF-a promotes the infiltration of other cytokines (IL-1β, IL-6) and other chemokines that promote neutrophil infiltration into the infarcted area (Feurstein, Stroke 25, 1481 (1994)). TNF-a also plays a role in type 2 diabetes (Endocrinol. 130, 43.52, 1994; and Endocrinol. 136, -1474-1481, 1995). TNF-a appears to promote the life cycle of certain viruses and related diseases. For example, TNF-a secreted by mononuclear leukocytes can induce an increase in the expression of HIV in chronically infected T-cell pure lines (Clouse et al. J. Immunol. 142, 431 (1989)). Lahdevirta et al. (Am. J. Med. 85, 289 (1988)) discuss the role of TNF-α in HIV-related cachexia and muscle degeneration. TNF-α is located upstream of a series of cytokines during inflammation. Therefore, an increase in TNF-α levels may cause other inflammatory and pro-inflammatory cytokines, such as IL-1, IL-6, and IL-8 levels to increase. When the IL-1 content is higher than the basal amount, it involves mediators or worsens a variety of diseases, including the description of the continuation 200303316 (3) Including: arthritis; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease Adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease: ulcerative colitis; allergic reactions; muscle degeneration, cachexia, Reiter 1 s syndrome; type I and type 2 diabetes Bone resorption disease; reperfusion injury after ischemia; atherosclerosis: brain trauma; multiple sclerosis; sepsis; septic shock; and toxic shock symptoms. IL-1 also affects viruses that are sensitive to TNF-α inhibition, such as HIV-1, HIV-2, and HIV-3. TNF-a and IL-1 appear to play a role in pancreatic beta cell destruction and diabetes. Pancreatic beta cells produce insulin, which helps regulate blood sugar homeostasis. The destruction of pancreatic beta cells is usually accompanied by type I diabetes. Patients with type II diabetes may have abnormal pancreatic β-cell function. Type II diabetes is characterized by functional resistance to insulin. In addition, type 2 diabetes is often accompanied by an increase in plasma glucagon content and increased glucose production in the liver. E Glucagon is a regulatory hormone that can attenuate the glucose production in the liver that is inhibited by tengrin. Glucagon receptors have been found to appear in liver, kidney, and adipose * tissues. "Therefore, tenglucagon antagonists are suitable for reducing blood glucose concentrations (WO 97/16442, the contents of which are fully incorporated herein by reference) in). By antagonizing the glucagon receptors, insulin resistance in the liver should be improved, thereby reducing glucose production and reducing glucose productivity in the liver. In animal-like rheumatoid arthritis models, multiple injections of IL-1-in the joints can cause acute destructive arthritis (Clinical Immunol Immunopathol. 55, 382 (1990)) by Chandrasekhar et al. 200303316 _ (4) Description of the invention In the study of sequel fluid cells, IIM is a more potent inducer of stromalysin than TNF-α (Firestei'n, Am. J. Pathol. 140, 1309 (1992)). At the local injection site, migration of neutrophils, lymphocytes, and monocytes has been observed. Migration is caused by the induction of chemokinins (eg, IL-8) and up-regulation of adhesion molecules (Dinarello, Eur · Cytokine Netw 5,517-531 (1994)). IL-1 also seems to play a role in promoting the life cycle of certain viruses. For example, cytokine induces an increase in HIV expression in chronically infected giant salamander cell lines. This response is related to the simultaneous selective increase in IL-1 production (Folks et al. J, Immunol. 136, 40 (1986)). Beutler et al. (J. Immunol. 135, 3969 (1985)) discuss the role of IL-1 in cachexia. Baracos et al. (New Eng. J. Med. 308, 553 (1983)) discuss the role of IL-1 in muscle degeneration. In the arthritis mode, both IL-1 and TNF-α induce synovial cells and parachondrial cells to produce collagenase and neutral protease, causing tissue destruction in the joints. In the arthritic model (collagen-induced arthritis (CIA) in rats and mice), TNF-a can be accelerated and the disease process worsened when TNF-a is administered intra-articularly before or after CIA induction ( Brahn et al.,

Lymphokine Cytokine Res. 11, 253 (1992); and Cooper, Clin Exp.

Immunol · 898, 244 (1992) "IL-8 has been involved in the aggravation and / or occurrence of many diseases. The process of infiltration of a large number of neutrophils into the inflammation site or injury site (eg, ischemia) is performed by IL-8. These diseases include, but are not limited to, the following: asthma, inflammatory bowel disease, psoriasis, adult respiratory distress syndrome, heart and kidney reperfusion injury, embolism and glomerulonephritis. IL-8 In addition to the chemotaxis effect of Lingzhong 200303316 (5) invention description, continuation white blood cells, IL-8 also has the ability to activate neutrophils. Therefore, reducing IL-8 content will reduce neutrophil diafiltration. Several methods are known to block the effects of TNF-α. One of these methods involves the use of soluble receptors for TNF-a (eg, TNFR-55 or TNFR-75), which have been shown to be effective against TNF-a in animal models. The efficacy of the vector-mediated disease. The second method is to use a monoclonal antibody against TNF-a, cA2, to neutralize TNF-a. This method has been shown to improve the number of swelling joints in the rheumatoid arthritis phase II human trial. (Feldmann et al., Immunological Reviews ρρ · 195-223 (1995)). These methods block the effect of TNF-α and IL-1 by chelating with protein or receptor antagonists. GB 2,306,108 (the contents of which have been cited by reference) The methods are fully incorporated herein) Explain that imidazole derivatives as Raf kinase antagonists are suitable for treating cancers mediated by Raf and Raf-induced proteins. Raf proteins are extracellular mitogenic stimulants (such as: PDGF, EGF, acid FGF, thrombin-, insulin, or endothelin) and kinases that are activated in response to tumor proteins (such as v-src, v-sis, and v-fms). Raf function is located in the signal transduction of cell membrane to nucleus. Downstream. The compound can act as a tumor lysing agent by antagonizing the Raf kinase. It has been pointed out in the literature that antisense constructs that reduce c-Raf content in cells and therefore reduce Raf activity can inhibit cavities in soft agar Fibroblast-like growth with little or no toxicity to the cells. This inhibition of growth in soft agar can highly predict its tumor reactivity in whole-animals. In addition, Raf antisense constructs Already moving Object. # Shows the effect of reducing tumor burden. Examples of cancers involving Raf kinase overexpression include brain cancer, laryngeal cancer, lung cancer, lymphatic cancer, urinary tract cancer and — -10- 200303316 _ 发明 Description of the invention continued on gastric cancer, including Uterine bladder lymphoma, lung adenocarcinoma, and small cell lung cancer. Other examples include cancers involving overexpression of Raf or Raf-activated oncogene upstream activators, including pancreatic and breast cancers. US 5,7 14,495 illustrates compounds of the formula

R4 wherein X, I, R2, R3, R4 and R5 are as defined above, which are suitable as melatonin receptor ligands. US 5,624,935 describes a compound of the formula wherein X may particularly represent optionally substituted imidazo [1,2-a] pyridine, and m, R, Y and Z are as defined above, which has hypoglycemic and anti-diabetic activity. W01 / 34603 illustrates compounds of the formula

Y

Q, W, X, Xι, Y, and Z are as defined above, which can bind to the benzodiazepine position of the GABAa-receptor. WO 01/34605 describes substituted 2-aryl-3- (heteroaryl) -imidazo 200303316-(7) Description of the invention Continued [1,2-a] Pyrimidine compounds, which are suitable for inhibiting inflammatory cytokines It produces, specifically, TNF-tf and IL-Ιβ, and is used to treat p38-mediated diseases such as inflammation, and so on. WO 00/3 1065 (the content of which is fully incorporated herein by reference) describes substituted heterocyclic compounds that are suitable for inhibiting cytokine production, such as TNF, IL-1, IL-6 and / or IL-8. WO 01/00208 (the content of which is fully incorporated herein by reference) describes a substituted p-pyridone compound, which is suitable for inhibiting cytokine production, such as: TNF, [L- 丨, IL-6 and / Or IL-8. WO 01/42241 (the content of which is fully incorporated herein by reference) describes substituted Tahu compounds which are suitable for inhibiting cytokine production, such as: TNF, IL-1, IL-6 and / or IL- 8. US 6,096,753 (the content of which is fully incorporated herein by reference) describes substituted pyrimidinone and pyridone compounds and compositions, which are suitable for the prevention and treatment of diseases such as: TNF-α, IL-Ιβ, IL -6 and / or IL-8-mediated diseases, and other conditions such as pain and diabetes, and explain how to make these compounds. SUMMARY OF THE INVENTION Brief description of the present invention The present invention includes a class of agents suitable for treating diseases such as TNF-a, IL-Ιβ, IL-6 and / or IL-8 and other diseases such as pain, cancer and diabetes. Novel compounds. In particular, the compounds of the present invention are useful for treating diseases or conditions involving inflammation. Therefore, the present invention also includes pharmaceutical compositions containing the compound, and use of the compounds and compositions of the present invention to treat TNF-a 200303316. Description of the Invention Continued ⑻, IL-1β, IL-6 and / or IL-8 disease, such as : Methods for diseases such as inflammation, pain, and diabetes, and intermediates and methods for preparing the compounds of the present invention. The compound of the present invention is represented by the following structural formula or a pharmaceutically acceptable salt thereof

R R

Where 1 ;, 乂, 以, 乂, 111, 1111, and 1112 are defined below. The foregoing merely outlines certain aspects of the invention and should not be construed as limiting the invention in any way. The contents of all patents, patent applications, and other documents excerpted herein have been fully incorporated by reference. Embodiment Detailed description of the present invention According to the present invention, a compound of the following formula is provided:

Or a pharmaceutically acceptable salt thereof, wherein X is C-R2 or N; U, V, and W are independently C-R6 or N, but the limitation is that when U is N..., 11 V is C-R6; where each R6 is independently hydrogen, halo, halo, oxy, thio, -13 200303316 (9) Description of the invention continued on halo, halo, meridian or cyano ; Preferably each R6 is independently hydrogen, halo, XVC4 alkyl, Ci-CU alkoxy, CrC4 alkylthio, CVC4 haloalkyl containing 1 to 3 halo groups, and 1 to 3 halo groups (VC4 haloalkoxy, hydroxyλ or cyano; more preferably, each R6 is independently hydrogen, C, C4 alkyl, CrC4 alkoxy, -CF3, -OCFpt hydroxyl; most preferably each is 116 independently Is hydrogen, methyl, methoxy, -CF3, -OCFpt hydroxyl; and R2 are independently -ZY or -Y; but the limitation is that ^ and R2 are aryl, heteroaryl, cycloalkyl and The total number of heterocyclic groups is 0-3; preferably, 1 ^ is -ZY or -Y; but the limitation is that the total number of aryl, heteroaryl, cycloalkyl and heterocyclic groups in Ri is 0- 2; and preferably, R2 is hydrogen, CVC4 alkyl, halo, cyano, hydroxyl, (^-(: 4 alkoxy CrCz haloalkoxy group containing 1 to 3 halo groups, CrC # alkylthio group, amine group, C "C4 alkylamino group, di- (C" C4 alkyl) amino group or containing 1 to 3 halogen groups C "C2 haloalkyl; more preferably, R2 is hydrogen, CVC4 alkyl, halo, cyano, -hydroxy, Ci-G alkoxy, trifluoromethoxy, or trifluoromethyl; more preferred , R2 is hydrogen, C2 alkyl, halo, cyano, hydroxy, crc2 alkoxy, trifluoromethoxy or trifluoromethyl; more preferably, r2 is hydrogen, methyl, halo, cyano · Group, hydroxy, methoxy, trifluoromethoxy or trifluoromethyl; best, R2 is hydrogen; each Z is independently (1) alkyl, alkenyl or alkynyl, which may The following substituents replace (a) 1-3 * of the following substituents: amine, alkylamino, dialkylamino, alkylamino, alkyl. Oxycarbonylamino, sulfamoylamino, hydroxyl, alkoxy Group, alkylthio group or functional group 1 and (b) 1-2 of the following substituents: heterocyclyl, aryl, or heteroaryl; or -14 200303316 Description of the Invention Continued (ίο) (2) Heterocyclyl , Aryl or heteroaryl; wherein heterocycle 1 may be substituted with 1-3 of the following substituents as required: amine, alkane Base, dialkylamino, alkylamino, alkoxycarbonylamino, alkanesulfonamido, hydroxyl, alkoxy, alkylthio, alkyl, aralkyl, heteroaralkyl, or haloalkyl; And aryl and heteroaryl can be optionally substituted with 1-3 of the following substituents: amine, alkylamino, dialkylamino, alkylamido, alkoxycarbonylamino, continuous amino, and , Oxy, thio, thio, phenyl, dentyl, pit, or halide; preferably, each Z is independently (1) Ci-Cs alkyl, c2-c8 · shoe, or c2- c8 alkynyl, which may optionally be substituted with the following substituents (a) 1-3 amines, CrC * alkylamino, di- (CrC4 alkyl) amino, CVC5 alkylamino, (CrC4 alkoxy) Carboxamide, CKC4 alkylsulfonamido, hydroxyl, C, C4 alkoxy, C-C4 alkylthio or halo, and (b) 1-2 of the following substituents: heterocyclyl, aryl or Heteroaryl; or (2) heterocyclyl, aryl, or heteroaryl; where heterocyclyl can be optionally substituted with 1-3 of the following substituents: amine, CrC4 alkylamino, di- (CrC4 alkyl) Amine group, CrC5 alkylamino group, (CVC4 alkoxy) carbonylamino group, CrC4 alkylsulfonamido group, hydroxyl group C, C4 alkoxy, C, C4 alkylthio, (VC4 alkyl, aryl-C, C4 alkyl, heteroaryl-CrC4 alkyl, or C, C4 haloalkyl And aryl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine, CkC4 alkylamino, di- (CVC4 alkyl) amino, C "C5 alkylamino, CVC4 alkyl (Oxy) carbonylamino, CrC4 alkylsulfonamido, hydroxyl, CVC4 alkoxy, C "C4 alkylthio, cyano, halo, CVC4 alkyl or Ci-C # halo with 1-3 halo groups Alkyl; _ 15- 200303316-(il) The description of the invention is better, each Z is independently (1) c "c8 alkyl or c2-c8 alkenyl, which may be substituted with the following substituents if necessary: (a ) 1-3 of the following substituents: amine, Ci-C * alkylamino, di- (CrC4 alkyl) amino, CVC5 alkylamino, (CrC4 alkoxy) carbonylamino, hydroxyl, C " C4 alkoxy, CrC4 alkylthio or halo, and (b) U2 of the following substituents: heterocyclyl, aryl or heteroaryl; or (2) heterocyclyl, aryl or heteroaryl; where The heterocyclic group may be optionally substituted with 1-3 of the following substituents: amine, Ci-Cj alkylamino, di- (C "C4 alkyl) amino, CVC5 alkylamino, (CrC4 alkoxy) carbonylamino, hydroxyl, CrC4 alkoxy, CVC4 alkylthio, CrC4 alkyl, aryl-Ci-C4 alkyl, heteroaryl-CVC4 alkyl or containing CrC2 haloyl groups of 1-3 halo groups; and aryl and heteroaryl groups can be optionally substituted with 1-3 of the following substituents: amine, CnCU alkylamino, di- (CVC4 alkyl) amino, CrC5 Alkylamino, (C "C4 alkoxy) carbonylamino, hydroxyl, CVC4 alkoxy, (VC4-alkylthio, cyano, halo, C" C4 alkyl or 1-3 halo groups (^-(: 2 haloalkyl; more preferably, each Z is independently (1) CrG alkyl or C2-C5 · alkenyl, which may be substituted with the following substituents as required: (a) 1-3 The following substituents: amine, di- (CVC2 alkyl) amino, CVCs alkylamino,. (CVC4 alkoxy) carbonylamino, hydroxyl, Ci-C: alkoxy, (: "(: 2 Alkylthio or halide, and (b) 1-2 of the following substituents: heterocyclyl, aryl, or heteroaryl; or (2) heterocyclyl, aryl, or heteroaryl; where heterocyclyl is visible Need to be substituted with 1-3 of the following substituents: amine, di-16- 200303316-(12) Description of the Invention Continued-(C "C2 alkyl" , C, C5 alkylamino, (C | -C4 alkoxy) carbonylamino, hydroxyl, C |: C4 alkoxy, CVC4 alkylthio, Ci-C # alkyl, aryl-CVC4 alkyl , Heteroaryl-c "c4 alkyl or trifluoromethyl; and aryl and heteroaryl can be optionally substituted with 1-3 of the following substituents: amino, di- (CrC2 alkyl) amino, CkC5 alkyl Fluorenylamino, (CrCU alkoxy) carbonylamino, hydroxyl, CrC4 alkoxy, (^ -0: 4 alkylthio, cyano, halo, CVC4 alkyl, or trifluoromethyl; more preferably, Each Z is independently (1) CrC # alkyl or c2-c5 alkenyl, which may be substituted with the following substituents as required: (a) 1-3 of the following substituents: amino, dialkyl) amino, (C "C4 alkoxy) carbonylamino, hydroxyl, oxy, CnC2 alkylthio or halo, and (b) 1-2 of the following substituents: heterocyclyl, aryl or heteroaryl; or ( 2) Heterocyclyl, aryl or heteroaryl; wherein heterocyclyl may optionally be substituted with 1-2 of the following substituents: (^-(^ alkyl-, aryl-C, C2 alkyl or heteroaryl) -Ci-C2 alkyl; and wherein aryl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine, dialkyl) amine Group, acetamido group, (CrCU alkoxy) carbonylamino group, hydroxyl group, (^ (: 2 alkoxy group, C, C2 alkylthio group, cyano group, halo group, CrC4 alkyl group, or trifluoromethyl group) ; More preferably, each Z is independently (1) CVC4 alkane, which may be substituted with the following substituents as required: (a) 1-2 of the following substituents: amine, di- (Ci-C2 alkyl) amine Group, hydroxyl group, CVC2 alkoxy- group or CVC2 alkylthio group, and (b) heterocyclic group or aryl group; or ^ (2) heterocyclic group, which may be optionally substituted with 1-2 of the following substituents: CrG Alkyl, aryl-C, C2 alkyl, or heteroaryl-Ci-C2 alkyl; -17 · 200303316-(13) Description of the invention continued page where aryl and heteroaryl are optionally substituted with 1-2 of the following Group substitution: amino, di- (K2 alkyl) amino, hydroxyl, (^-(: 2 alkoxy, CrC2 alkylthio, cyano, halo, CrC2 alkyl, or trifluoromethyl); better Wherein, each Z is independently (1) CrC4 alkyl ', which may be optionally substituted with the following substituents: (a) 1-2 of the following substituents: amino, dimethylamino, hydroxyl or methoxy, and ( b) a heterocyclic group or a phenyl group; or (2) a heterocyclic group; To be substituted with 1-2 of the following substituents: CkC4 alkyl® or stupid methyl; where phenyl is optionally substituted with 1-2 of the following substituents: amino, di- (C "C2 alkyl) amino, A hydroxy group, an oxy group, a CrC2 alkylthio group, a cyano group, a halo group, a CnC2 alkyl group, or a trifluoromethyl group; or more preferably, each Z is independently (1) a CrQ alkyl group or a C2-C5 alkenyl group, which Optionally substituted with the following substituents: (a) 1-2 of the following substituents: amine group, di- (C "C2 alkyl) amino group, hydroxyl or CrC2 alkoxy group, and (b) heterocyclic group, Aryl or heteroaryl; or (2) heterocyclyl, aryl or heteroaryl; Φ where the heterocyclyl is optionally substituted with 1-2 of the following substituents: amine, di-((VC2 alkyl) Amine, hydroxy, (: 1 < 2 alkoxy, C, C4 alkyl or trifluoromethyl; where aryl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine, di- ( Ci-Cz alkyl) amino, acetamido, hydroxyl, 0: 1-(: 2alkoxy, halo, C1-C2 alkyl, or trimethyl group; each Y is independently ( 1) Hydrogen radical, -18- 200303316 __ (14) Description of the invention continued (2) Drawing base or nitro group; (3 ) -C (O) -R: 20, -C (O) -OR2 |, -C (0) -NR5R2l or-(:( Νί15) -ΝΙ15 [121 group; (4) -OR ", -〇- C (0) -R2 |, -0-C (0) -NR5R2l or -OC (O) -NR22-S (O) 2-R20, (5) -SR21, -S (〇) -R2〇, -S (O) 2-R20, -S (0) 2 * NR5R21, -S (0) 2-NR22-C (0) -R21, -S (〇) 2-NR22-C (O) -OR20 or -S (0) 2-NR22-C (0) -NR5R2i group; or (6) -NR5R2 丨, -nr22-c (o) -r2 丨, -nr22-c (o) -or20, -nr22-c (o) -nr5r21, -NR22-C (NR5) -NR $ R2i, -NR22-S (O) 2-R20, or -NR22 ** S (0) 2-NR5R2i group; preferably, each Y is independent (1) Ar or halo; (2) -C (0) -R2〇, -C (0) -0R21, -C (0) -NR5R2l or -C (NR5) -NR5R2I group; (3)- OR21, -〇-C (0) -R2i or -0-C (0) -NR5R2i group: (4) -SR21, -S (〇) -R2〇, -S (0) 2-R2〇 or -S (0) 2eNR; 5R2i group, or (5) -nr5r21, -nr22-c (o) -r21, -NR22-C (O) -OR20, or -nr22-c (o) or N H1 group, more preferably , Each Y is independently (1) hydrogen group; (2) -C (0) -R2〇 or -C (0) -NR5R2 | group; (3) -〇R ″, -SR2l, · 5 (0) -K2〇, -S (0) 2-R2〇 or -S (〇) 2-NR5R21 group: or (4) -NR5R21 or -NR «2:!-C (0) -R2i group, more preferably, Each Y is independently hydrogen, -OR2 1, -SR21, -S (0) -R2. , -S (O) 2-R20 or -NR5R21 group, the best, each Y is independently hydrogen, -ORn, -SR21 or -NR5R2i group; 200303316 Description of the invention continued (15) Each R5 is independently (1 ) Hydrogen group; '(2) Alkyl, alkenyl or alkynyl, which may be substituted with 1 to 3 of the following substituents as needed: amine, amine, diamine, mesyl, oxy, tiger Thio, -s03h or halo; or (3) aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocycloalkyl, cycloalkyl or cycloalkylalkyl, Wherein aryl, heteroaryl, heterocyclyl and cycloalkyl can be optionally substituted with 1-3 of the following substituents: amino, alkylamino, dialkylamino, hydroxyl, alkoxy, alkylthio, alkyl Or alkynyl; preferably, each R5 is independently (1) hydrogen; (2) CrCs alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, optionally substituted with 1-3 of the following Group substitution: amine, CrG alkylamino, di- (Ct-G alkyl) amino, hydroxyl, CVC4 alkoxy, CrG alkylthio, -S03H or halo; or · (3) aryl, hetero Aryl, aryl-CrCV alkyl, heteroaryl-CrCV alkyl, heterocyclyl, heterocyclyl- (VC4-alkyl, : 3 - (: 8 cycloalkyl or C3-C8- cycloalkyl group

Alkyl, in which aryl, heteroaryl, heterocyclyl and cycloalkyl are optionally substituted with U3 of the following substituents: amino, (VC4 alkylamino, dialkyl) amino, hydroxyl, CKC4 alkoxy , CrC4 alkylthio, (VC4 alkyl or halogen 'pit containing 1-3 string groups; more preferably, each R5 is independently (1) hydrogen; (2) CrC4 alkyl or C2-C5 olefin Group, which may be substituted with 1-3 of the following substituents as necessary: amine group, di- (CVC4-alkyl) amino group, hydroxyl group, C "C4 alkoxy group · 20 · 200303316 Description of the invention continued on (16), cnc4 Alkylthio, -so3h or halo; or (3) phenyl-C ^ C2-alkyl, heteroaryl-CrC2-alkyl, heterocyclyl-CrC2-alkyl or C3-C6-cycloalkyl- (VC2-alkyl, where cycloalkyl, phenyl, heterocyclyl, and heteroaryl are optionally substituted with 1-3 of the following substituents: amino, di- (Ci-CV alkyl) amino, hydroxyl, Ci-C * alkoxy, Ci-q alkylthio, crc4 alkyl or Ci-Cz haloalkyl containing 1-3 halo groups; more preferably, each R5 is independently (1) a hydrogen group; ( 2) Alkyl group, which may be substituted by 1-3 following substituents as needed: amine group, di-((VCV alkyl) amino group, hydroxyl group, CrC2 alkane Oxy, CrC2 alkylthio or drawing group; or (3) phenyl-C | -C2-alkyl, heteroarylalkyl, heterocyclyl-C | -C2-alkyl or C3-C6 cycloalkyl -CrC2-alkyl, in which phenyl, heteroaryl, heterocyclyl and cycloalkyl are optionally substituted with N3 of the following substituents: amine, di- (CrC2 alkyl) amino, hydroxyl, CrCz alkoxy Group, Ci-C: alkylthio group, CrCU alkyl group, or trifluoromethyl group; more preferably, each R5 is independently fluorenyl group; (2) Ci-G alkyl group, which may be subjected to 1-3 halogens as required Or (3) phenyl-C,-. C2-alkyl or heteroarylalkyl, where phenyl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine, dimethylamine Group, hydroxy group, methoxy group, methylthio group, methyl group or trifluoromethyl group; most preferably, each R5 is hydrogen or f group; each R2 is independently • 21-200303316 (17) LI 一 ^- (υ alkyl, alkenyl, or alkynyl, which may be substituted with the following substituents as necessary * (a) U amine 1, alkylamine, dialkylamino, alkylamino, alkoxycarboxamine, N -(Alkoxycarbonyl) -N- (· Tigeryl) amino, aminocarbonyl, alkanesulfonylamino, hydroxyl, alkoxy, alkylthio, alkyl Sulfonyl, alkanesulfonyl or cyano, and (b) aralkyloxy, aralkylthio, aralkylsulfonyl, cycloheptyl, heterocyclyl, aryl, or heteroaryl, of which aryl , Heteroaryl, Heterocyclyl and Cyclopentyl can be substituted with N3 of the following substituents as needed. Amine, Alkylamino, Dialkylamine, Alkylamino, Alkoxycarbonylamino, Alkylsulfonamide Base, sulfuryl, alkyl, alkoxy, alkylthio, alkanesulfinyl, alkanesulfonyl, halo, alkyl, or alkyl; (2) Heterocyclyl, which may be optionally substituted by 1 -3 substitutions of the following substituents: amino, alkylamino, dialkylamino, alkylamino, alkoxycarbonylamino, acetamino, amino, alkyl, thio, thio, etc. Or alkynyl: or (3) aryl or heteroaryl, which may be substituted with 1-3 of the following substituents as needed: amino, alkylamino, dialkylamino, alkylamino, alkoxy Carboxamido, Carboxamido, Alkoxycarbonyl, Hydroxyl, Alkoxy, Alkylthio, Gaso, Halo, Azido, Gauge or Halo, more preferably, each R2 () respectively Independently (1) CrC8 alkyl, C2-C8 alkyl or CVC: 8 alkynyl To be substituted by the following substituents: (a) 1-3 amine groups, CVC4 alkylamino groups, di- (C ^ C4 alkyl) amino groups, CrC5 alkylamino groups, (c "c4 alkoxy) bromine Group, Ne ((ci-C4 ^ oxy) carbonyl) -N-((VC4 alkyl) amino group, aminocarbonylamino group, C "C4 sulfonamido-yl group, hydroxyl group, C" C4 alkoxy group, 〇 "(: 4 alkylthio, divinyl, CrCA sulfonyl or halo 'and (b) aryl-CVC4 ·· tigeroxy, aryl 200303316 Description of the invention continuation ⑽ -CVCV alkylthio, Aryl · CrCf alkylsulfonyl, c3-c8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, among which aryl, heteroaryl, heterocyclyl, and cycloalkyl can be passed through i-3 as needed Substituent substitution: amine, CrC4 alkylamino, di- (crc4 alkyl) amino, crc5 alkylamino, (crc4 alkoxy) carbonylamino, (: rC4 alkylsulfonamido, CrC5 alkylsulfo Hydroxy, CVC4 alkoxy, Ci-C4 thio, Ci-C4 fluorenyl, CrC4 fluorenyl, halo, C1-C4 pit or C1-C4 halide with U halo groups (2) heterocyclyl, which may be optionally substituted with 1-3 of the following substituents: amine

, CkQ alkylamino, di- (Ci-C4 alkyl) amino, CrC5 alkylamido, (CrC4 alkoxy) carbonylamino, CrC4 alkylsulfonamido, hydroxyl, CrC * alkoxy, C "C4 alkylthio, alkyl or C1-3 haloalkyl" C4 haloalkyl; or (3) aryl or heteroaryl, optionally substituted with 1-3 of the following substituents: amino , CrC4 alkylamino, di- (CrC4 alkyl) amino, CrC5 alkylamido, (<:!-(: 4 alkoxy) carbonylamino, C4C4 alkylsulfonamido, (CrC4 Alkoxy > Carboxyl, mesityl, C 「C4 烧 oxy, C1-C4 烧 thio, cyano, halo, azide, C「 C4 alkyl or CnCU halide containing 1-3 halo alkyl:

More preferably, each R20 is independently (1) a C8 alkyl group or a C2-C5 alkenyl group, which may be optionally substituted with the following substituents ... (a) 1.3 or less of the following substituents ... an amino group, CVC4 Burnt amine, di- (C "C4 · Tigeryl) amino, C" C5 alkylamino, (C "C4 alkoxy) carbonylamino, N-((C" C4 alkoxy) carbonyl) -N- (C "C4 alkyl) amino, aminocarbonylamino, hydroxyl, C" C4 alkoxy, (VC * alkylthio), C "C4 alkylsulfinyl, C" C4 alkylsulfonyl -Or halo, and (b) aryl- (VC4-alkoxy, aryl-CVC4-alkylthio, aryl-CrC4-alkylsulfonyl, C3-C6 cycloalkyl, heterocyclyl, aromatic Or Heteroaryl • 23 200303316 _ (19) Description of the invention continued, where cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with N3 of the following substituents: amine, Ci-C * Alkylamino, di- (CVC4 alkyl) amino, CVC; alkylamine, (CrC4 alkoxy) carbonylamino, CVC4 alkylsulfonylamine, methyl, Ct-Cs alkylamino, hydroxyl, CVC4 Alkoxy, CrC4 alkylthio, halo, C "C4 alkyl or one containing 1-3 halo (" 0: 2 haloalkyl; (2) heterocyclic group, which may be The following substituents are substituted: amine, di-((VC4 alkyl) amino, (CVC4 alkoxy) carbonylamino, hydroxyl, CrC4 alkoxy, (VC4 alkylthio or CrCU alkyl); or (3) Aryl or heteroaryl, optionally substituted with 1-2 of the following substituents: ® Amine, Ci-C4 alkylamino, di- (CrQ alkyl) amino, acetamido, (CrC4 alkoxy Group) carbonylamino, CrC4 alkylsulfonamido, (Ci-C * alkoxy) carbonyl, hydroxyl, CrC4 alkoxy, C "C4 alkylthio, cyano, halo, azide, C" C4 alkyl or trifluoromethyl; more preferably, each R2 () is independently (1) CrC8 alkyl, which may be substituted with the following substituents as required: (a) 1-3 of the following substituents: amine, CrC4 alkylamino, di-((^-(^ alkyl) amino, alkylamine, (CrC4alkoxy) carbonyl), N-((C "C4alkoxy) carbonyl) ® alkyl ) Amino group, aminocarbonylamino group, hydroxyl group, (: 丨-(: 4alkoxy group, CrC4 alkylthio group, CkC4 alkylsulfinamilide group, CVC4 alkylsulfonium group or halogen group, and (b) C3-C6 Cycloalkane, heterocyclyl, aryl, or heteroaryl, of which cycloalkyl, heterocyclyl, aryl, and heteroaryl are available upon request Substituted by 1-2 of the following substituents: amine, di- (C "C4 alkyl) amino, CfCs alkylamino, (Ci-C * alkoxy) carbonylamino-, CVC4 alkylsulfonamide Group, hydroxyl, C4C4alkoxy, CkQ alkylthio, halo, CVC4 alkyl, or trifluoromethyl: • 24-200303316 Description of the Invention Continued (20) (2) Heterocyclyl, which may 1-2 of the following substituents: hydroxy, alkoxy ', CrC4 alkylthio or alkyl; or (3) aryl or heteroaryl, which may be substituted with 1-2 of the following substituents as necessary: amine C, C4 alkylamino, di- (CrCU alkyl) amino, (CrC4 alkoxy) carbonyl, hydroxyl, C | -C4 alkoxy, CVC4 alkylthio, cyano, halo, azide , C "C4 alkyl or trifluoromethyl; more preferably, each R2G is independently (1) CrC6 alkyl, which may be substituted with the following substituents as required: (a) 1-3 of the following substituents: amino , Methylamino, dimethylamino, third butoxycarbonylamino, N-((third butoxy) carbonyl) -N- (methyl) amino, aminocarbonylamino, hydroxyl, butoxy , Methoxy, butylthio, methylthio, methylsulfinyl, mesylsulfonyl, or selfyl And (b) C5-C6 cycloalkyl, heterocyclyl, phenyl or heteroaryl, which may be substituted with 1-2 of the following substituents as necessary: amino, dimethylamino, acetamido, hydroxy, Methoxy, methylthio, halo, methyl, or trifluoromethyl;-(2) heterocyclyl, which may be optionally substituted with 1-2 of the following substituents: hydroxyl or (: "04 alkyl; or (3) aryl or heteroaryl, which may be substituted with 1-2 of the following substituents as necessary: amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl, or trifluoromethyl Group: More preferably, R2q is independently (1) a CrG alkyl group, which may be substituted with the following substituents as required: (a) 1-3 of the following substituents: amine, methylamino, dimethylamino, Tertiary butoxycarbonylamino, N-((third butoxy) carbonyl (methyl) amino, aminocarbonylamino, hydroxyl, butoxy, methoxy, butylthio, methylthio, methyl 25-200303316 (21) Description of the Invention Continued or halo, and (b) C5-C6 cycloalkyl, heterocyclyl, phenyl, or heteroaryl, which may Ί-2 substitutions of the following substituents: amino, dimethylamino Acetylamino, hydroxy, methoxy, methylthio, halo, methyl, or trifluoromethyl: (2) heterocyclyl; or (3) aryl or heteroaryl, which may be optionally treated with 1- Substitution with 2 of the following substituents: amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl, or trifluoro 1f; more preferably, each R20 is independently (1) C "C6 alkyl, optionally substituted with the following substituents: (a) 1-3 of the following substituents: amine, methylamino, dimethylamino or hydroxyl, and (b) phenyl or heteroaryl, It may be optionally substituted with 1-2 of the following substituents: amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl, or trifluoromethyl; (2) a heterocyclic group; or (3) aryl or heteroaryl, which may be substituted with 1-2 of the following substituents as necessary: amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl, or trifluoromethyl The best; each R20 is independently (1) Ci-G alkyl, which may be substituted with 1-2 of the following substituents as needed: amine, (^-(: 2 alkylamino, di- (C, -C2 alkyl) amino, hydroxy or <^-(: 2 alkoxy; or (2) Trifluoromethyl; each R21 is independently hydrogen or R20; each R22 is independently (1) hydrogen group; 200303316 description of the invention continued (22) (2) alkyl group, which may be substituted with the following substituents as required: heterocyclic Aryl, aryl, or heteroaryl ', where heterocyclyl, aryl, or heteroaryl is optionally 1-3

The following substituents are substituted: amine, alkylamino, dialkylamino, alkylamino, oxamino, amine, amine, alkoxy, thio, sulfonyl , A si group, a cyano group, a cyano group, a dentyl group, a thio group, or a fluorenyl group; or (3) a heterocyclic group, an aryl group, or a heteroaryl group, which may be substituted with 1-3 of the following substituents as necessary: amine group, Alkylamino, dialkylamino, alkylamido, alkoxycarbonylamino, calcined amino, meridian, oxyoxy, thiosulfan, ketosulfenyl, alkylsulfonyl, cyano , Halo, alkyl, or haloalkyl; Preferably, each R22 is independently (1) hydrogen;

(2) Alkyl, optionally substituted with the following substituents: heterocyclyl, aryl, or heteroaryl, where aryl, heteroaryl, and heterocyclyl are optionally substituted with 1-3 of the following substituents: amine Group, CrCU alkylamino group, di- (C "C4 alkyl) -amino group, (:!-(: 5 alkylamino group, (Ci-C # alkoxy) carbonylamino group, alkylsulfonylamino group, Hydroxyl, CfCe alkoxy, CrC4 alkylthio, CVC4 alkylsulfinyl, C4 alkylsulfonyl, cyano, halo, (VC4 alkyl or CVCU haloalkyl containing 1-3 halo groups ; Or (3) heterocyclyl, aryl, or heteroaryl, which may be substituted with 1-3 of the following substituents as needed, cross-group, (: κ (: 4 alkylamino, di- (CVC4 alkyl) Amine group, CrCs alkylamino group, (CnC4 alkoxy) carbonylamino group, C / C4 alkylsulfonylamino group, hydroxyl group, Ci-Ca alkyloxy group, C1-C4 · pit sulfur group, C1-C4 alkylene group Trans-Si group, C1-C4 alkyl-sulfofluorenyl group, cyano group, halo group, C "C4 alkyl group or haloalkyl group containing 1-3 halo groups; -27 · 200303316 __ (23) Description of the invention continued on more Preferably, each R22 is independently fluorenyl: or (2) Ci-C4 alkyl, which may be substituted with the following substituents as necessary: phenyl Heteroaryl, where phenyl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine, di- (C "C2 alkyl) amino, CVCs alkylamino, (CrC4 alkyl'oxy ) Carboxamido, hydroxyl, CrC4 alkoxy, CVC4 alkylthio, cyano, halo, C! -C4 alkyl or C "C2 haloalkyl containing 1-3 halo groups; the best, each R22 is independently hydrogen or CrC4 alkyl;

Rn is aryl or heteroaryl, and Rn is &quot; N &quot; -heteroaryl, in which aryl, hetero · aryl and "N" -heteroaryl are optionally substituted with 1-3 of the following substituents R R ; o; (2) painting or cyano: (3) -C (O) -R30, -C (0) -0R29, -C (0) -NR3 丨 R32 or -C (NR31) -NR3 丨 R32 (4) -OR29, · 〇-〇 (0) -Κ »29, -〇-C (0) -NR3iR32 or -〇-C (0) -NR33-S (0); 2-R3〇 '( 5) -SR29 '* S (0) -R3〇' &quot; S (0) 2eR3〇 '* S (Ο) 2 * N R3 i R3 2' -S (0) 2 * NR33-c (〇)- r30, -s (o) 2-nr33-c (o) -or30 or -s (o) 2-nr33-c (o) -nr31r32; or (6) -NR3 丨 R32, -NR33-C (0) -R29, -NR3: rC (O) -OR30, -NR33-C (0)-· NR31R32 '-NR33-C (NR3i) -NR3iR32' -NR33-S (0) 2-R3〇 ^ -NR33-S (0) 2-NR31R32; but its limited release is that the total number of aryl, heteroaryl, cycloalkyl, and heterocyclic substituents on each of Rh and R12 is (M; · Preferably, Rn is aryl or Heteroaryl, in which aryl and heteroaryl can be optionally replaced by -2 R30 with i-2 of the following substituents; -28- 200303316 (24) Description of the invention continued (2) halo or cyano; (3 ) -c (o) -r30, -c (o) -or29, -c (o) -nr31r32 or -C (NR31) -NR3lR32; or ( 4) -OR29 '-SR29, -S (0) -R: j〇, -S (O) 2_R30, -S (0) 2-NR3iR32, -NR33-S (O) 2-R30, -NR3 | R32 Or -nr33-c (o) -r29; more preferably,! Is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with 1-2 of the following substituents (1) R4〇; (2 ) Halo or cyano; or (3) -C (0) -NR41R42 'OR39' -SR39, -S (0) -R40, -S (0) 2-R40, -S (〇) 2-NR41R42, -NR41R42 or -NR3: rC (0) -R39; more preferably, Rh is aryl or heteroaryl, which may be substituted with 1-2 of the following substituents as required: (1) R4Q; (2) i group or Cyano; (3) -C (0) -NR41R42, -OR39, -SR39, -S (O) -R40, -S (O) 2-R40, -S (0) 2 ** NR4lR42, -NR4lR42 or '-NR} 3-C (0) -R39, and the best, Rn is phenyl, phenyl, thio, thiophene, benzofuranyl, or benzothienyl. Substituent substitution: Φ methyl, amino, dimethylamino, acetamido, hydroxy, functional, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminecarbonyl , Methyl or trifluoromethane; or, preferably, when Rn is heteroaryl, heteroaryl is not heteroaryl; Or, R12 is "N &quot; -heteroaryl, which may be substituted with 1-2 of the following substituents as needed. 29- 200303316 _ (25) Description of the invention continued (2) halo or cyano; (3) -C (0) -R3〇, -C (0) -0R29, -C (0) -NR3iR324 -C (NR3i), NR3iR: 52: or (4) -〇R29 '-SR29' -S (0) -R3 〇 '-S (0) 2-R3〇' -S (0) 2-NR31R32 '-NR33-S (O) 2-R30, -NR3 丨 R32 or -NR33-C (0) -R29; Better , Rl2 is &quot; N, heteroaryl, which may be substituted with 1-2 of the following substituents as required: (1) R3G; (2) self- or cyano; or (3) -C (0) -NR4lR42, OR39, -SR39, -NR41R42 or -NR; J3-C (0) -R39, more preferably, R12 is 4-pyridyl, 4-pyrimidinyl, 4-quinolinyl, 7-imidazo [4,5 -bp than pyridyl, 8-juvenyl, 6- (1Η) -purin or 4-imidazolyl, which may be substituted with the following substituents as necessary: amine, diamido, acetamido, hydroxy , Halo, cyano, methoxy, methyl or trifluoromethyl; and most preferably, Ri2 is 4-pyridyl or 4-pyrimidinyl, which may be substituted with the following substituents as necessary: amine, dimethyl Amino, acetamido, hydroxy, halide, cyano, methoxy, methyl or Fluoromethyl; or more preferably, 12 is 17-pyridyl or ° * pyridyl, which may optionally be substituted with 1-2 R; 0; (2) halo; (3) -C (O) -R? 0, -C (0) -0R29, -C (0) -NR3lR324 -C (NR3l) -NR3lR32: or (4) -OR29, -SR29, -S (0) -R3〇, -S (0) 2-R3〇, -S (0) 2-NR3lR32, -NR33-S (〇) 2-R30, -NR31R32 or -NR33-C (0) -R29; and the best, R12 is Pyridyl or pyrimidinyl, which may be substituted with 1-2 of the following 200303316 description of the invention (2) Substituents (1) Rso; 1 (2) Halo; (3) -C (0) -NR31R32 or- C (NR31) -NR3iR32; or (4) -〇R29, -S (〇) 2-NR3lR32, -NR33-S (O) 2-R30, * NR3lR32 or -NR ;;-c (o) -nr29; Each Rw is independently (1) an alkyl group, an alkenyl group or an alkynyl group, which may be optionally substituted with the following substituents: (a) 1-3 of the following substituents: -NR31R32, hydroxyl, alkoxy, alkylthio, Alkanesulfenyl, alksulfenyl, cyano, or halo, and (b) aralkyloxy, aralkylthio, aralkylsulfonyl, heterocyclyl, aryl, or heteroaryl, wherein hetero Cyclic, aryl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine , Alkylamino, Dialkylamino, Alkylamino, Alkoxycarbonylamino, Alkylsulfonamido, Warpyl, Burntoxy, Ammoniumthio, Pyridyl, Pyridyl, Cyanide (2) Heterocyclic group, which may be substituted with 1 to 3 of the following substituents as needed: amino, alkylamino, dialkylamino, alkylamino, alkyl Oxycarbonylamino group, alkanesulfonylamino group Φ, hydroxyl group, alkoxy group, alkylthio group, cyano group, alkyl group, or functional alkyl group; or (3) aryl group or heteroaryl group, which may be subjected to 1-3 if necessary Substitute the following substituents: amine, amine, diamine, diamine, diamino, amine, hydroxyl, alkoxy, alkylthio, cyano, Group, alkyl group, or i, alkyl group: 'Preferably, each R30 is independently (1) c "c4 alkyl, c2-c4 alkenyl, or c2-c4 alkynyl, which may be optionally passed through 200303316 Invention description continued (27)

Substituent substitution: (a) 1-3 of the following substituents: -NR31R32, hydroxy, CrCU alkoxy, alkylthio, Ci-CU alkylsulfinyl, Ci-C4 alkylsulfonyl, cyano or halogen And (b) aryl-CrC ^ alkoxy, aryl-CrC4-alkylthio, aryl-C ^ C ^ alkanesulfonyl, heterocyclyl, aryl or heteroaryl, wherein heterocyclic Aryl, aryl and heteroaryl can be substituted with 1-3 of the following substituents as required: amine, CrC4 alkylamino, di- (CrC4 alkyl) amino 'CrC5 alkylamino, (CrC4 alkoxy) Carboxamido, CVCU alkylsulfonamido, hydroxyl, CkC4 alkoxy, CrCU alkylthio, CrC4 alkylsulfinyl, CrQ alkylsulfonyl, cyano, halo, CnC4 alkyl or containing 1-3 CVC4 haloalkyl groups with two halo groups; (2) Heterocyclic groups, which may be substituted with 1-3 of the following substituents as needed: amine group, C4 alkylamino group, di- (CVC4 alkyl) amino group, CrC5 Alkylamino, (C "C4 alkoxy) carbonylamino, Ct-CU alkanesulfonamido, hydroxyl, CrC4 alkoxy, C" C4 alkylthio, cyano, C "C4 alkyl or containing CVC4 haloalkyl of 1-3 halo; or (3) aryl or heteroaryl, which may be substituted with 1-3 of the following substituents as required: Amino group, CVC4 alkylamino group, di- (CrC4 alkyl) amino group, CVC5 alkylamino group. (C "C4 alkoxy) carbonylamino group, (^ (4 alkylsulfonylamino group, hydroxyl group, CVC4 ® alkoxy, CVC4 alkylthio, cyano, halo, CpC4 alkyl or CVC4 haloalkyl containing 1-3 halo groups; more preferably, each R3G is independently (1) &lt;: " (: 4 alkyl or c2-c5 alkenyl, which may be optionally substituted with the following substituents: (a) B 3 of the following substituents: -NRhR32, hydroxyl, CnC4 alkoxy or halo., And (b) Heterocyclyl, aryl or heteroaryl, where heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine, alkane-32- 200303316 _ (28) Description of the invention continued page Amine, di- (CrG alkyl) amino, CnC5 alkylamino, (CrCU alkoxy) carbonylamino, 'CkC4 alkylsulfonamido, hydroxyl, CrC4 alkoxy, CrC4 alkylthio, C "C4 alkylsulfonyl, cyano, halo, CrC4 alkyl or CVC4 haloalkyl containing 1-3 halo groups; (2) Heterocyclic groups, which may be substituted with 1-3 of the following substituents as necessary: Amine group, CrC4 alkylamino group, di- (CrCU alkyl) amino group, CrC5 alkylamino group, (CrQ Alkoxy) carbonylamino, C "C4 alkylsulfonamido, hydroxyl, CkC4 alkoxy, C" C4 alkylthio, cyano, CrC4 alkyl, or CVC4 haloalkyl containing 1-3 halo groups ; Or (3) aryl or heteroaryl, which may be optionally substituted with 1-3 of the following substituents: amine, (^-(: 4 alkylamino, di- (CrC4 alkyl) amino, CVC5 alkyl Fluorenylamino, ((VC4 alkoxy) carbonylamino, Ci-C4 alkanesulfonylamino, hydroxyl, CrC4 alkoxy, CVC4 alkylthio, cyano, halo 'C, C4 alkyl or containing 1 -CVCU haloalkyl with 3 halo groups; more preferably, each R30 is independently (1) CrC # alkyl, which may be substituted with the following substituents as required: (a) 1-2 of the following substituents:- NR31R32, hydroxyl or CrC2 alkoxy, and (b) aryl or heteroaryl, where aryl and heteroaryl are optionally substituted with 1-2 of the following substituents. · Amine, C, C2 alkylamino, Di- (CrC2 alkyl) amino, CVC5 alkylamino, alkoxy) carbonylamino, CVC4 alkylsulfonamido, hydroxyl, CVC4 alkoxy, CrC # alkylthio, CVC4 alkylsulfonyl, Cyano, halo, CrG alkyl or trifluoromethyl; or (2) aryl or heteroaryl, visible To 1-2 by the following substituents: amino, C "C2 alkylamino, di - (CKC2 alkyl) amino, (:! -(: 5 Alkylamino group 200303316 _ (29) Description of the invention continued, (CrC4 alkoxy) carbonylamino group, C "C4 alkylsulfonamido group, hydroxyl group, CVC4 alkoxy group, C | -C4 alkylsulfide Group, Ci-CU alkylsulfonyl, cyano, halo, CrC4 alkyl or trifluoromethyl group; more preferably, each R3G is independently R40; each R29 is independently hydrogen group or R30; each R3l is Independently (1) a hydrogen group; (2) an alkyl group, which may be optionally substituted with the following substituents: a cycloalkyl group, an aryl group, a heterocyclic group, or a heteroaryl group, wherein the cycloalkyl group, the aryl group, the heterocyclic group and the Heteroaryl groups may be substituted with 1-3 of the following substituents as needed: amine, alkylamino, dialkylamino, calcined amine, oxocarbonylamino, δ hydrazone, meridian, oxy , Alkylthio, cyano, alkyl, or alkylene; or (3) aryl, heteroaryl, heterocyclyl, or cycloalkyl, optionally substituted with 1-3 of the following substituents: amine, Alkylamino, dialkylamino, alkylamido, -alkoxycarbonylamino, alkanesulfonamido, hydroxyl, alkoxy, alkylthio, cyano, alkyl, or oxyalkyl; preferred , Each R31 is independently (1) hydrogen group; (2) CrQ alkane , If necessary, it may be substituted by the following substituents: C3-C8 cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein cycloalkyl, aryl, heterocyclyl and heteroaryl may be substituted by 1-3 The following substituents are substituted: amine, Ci-C4 alkylamino, di- (C "C4 alkyl) amino, CpCs alkylamino, (C" C4 alkoxy) carbonylamino, (: "(: 4 Alkylsulfonamido, hydroxyl, (VC4 alkoxy, CkC * alkylthio, cyano, alkyl, or haloalkyl containing 1-3 halo groups; or 200303316 Description of the invention continued on (30) (3 ) Aryl, heteroaryl, heterocyclyl or C3-C8 cycloalkyl, which may be optionally substituted with 1-3 of the following 'substituents: amine, CVCU alkylamino, di- (CrC4 alkyl) amino , CVC5 alkylamino, ((^ (: 4 alkoxy) carbonylamino, CrC4 alkylsulfonamido, hydroxyl, (^ (: 4 alkoxy, CVC4 alkylthio, cyano, CVC4 alkyl Or a CrC4 haloalkyl group containing 1-3 halo groups; more preferably, each R3l is independently (1) a hydrogen group; or

(2) C "C4 alkyl, which may be substituted with the following substituents as needed: aryl or heteroaryl, where aryl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine, CrC * alkyl Amine, di- (CVC4 alkyl) amino, CrC5 alkylamino, alkoxy) carbonylamino, hydroxyl, CrC4 alkoxy, CrC4 alkylthio, cyano, (: 丨-(: 4 alkyl Or trifluoromethyl; more preferably, each R31 is independently R4i; best, each R3l is independently hydrogen or methyl; each R32 is independently (1) hydrogen;

(2) Alkyl, which may be substituted with the following substituents as needed: cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with 1- 3 of the following substituents: amine, alkylamino, dialkylamino, alkylamino, alkoxycarbonylamino'alkylsulfonamido, hydroxyl, alkoxy, alkylthio, cyano, alkyl Or haloalkyl; or (3) aryl, heteroaryl, heterocyclyl, or cycloalkyl, which may be optionally substituted with one to three of the following substituents: amino, alkylamino, dialkylamino, Alkylamino, alkoxycarbonylamino, alkanesulfonamido, hydroxyl, alkoxy, alkylthio, cyano • 35- 200303316 _ (3i) Description of the invention continued on page, alkyl or haloalkyl: Preferably, each R32 is independently: a hydrazone; (2) a CrC4 alkyl group, which may be substituted with the following substituents as required: C3-C8 cycloalkyl, aryl, heterocyclic or heteroaryl, in which the ring Alkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine, C, C4 alkylamino, di- (CrC4 alkyl) amino, CrC5 alkylamino (CrC4 alkoxy) carbonyl amine CrC4 alkylsulfonamido, hydroxyl, CVCU alkoxy, CrC4 alkylthio, cyano, Ci-C # alkyl or CrC4 haloalkyl containing 1-3 halo groups; or (3) aryl, Heteroaryl, heterocyclyl or C3-C8 cycloalkyl, optionally substituted with 1-3 of the following substituents: amine, (: "(: 4 alkylamino, di-((:" (: 4 Alkyl) amino, C, C5 alkylamino, (CrC4 alkoxy) carbonylamino, CVC4 alkylsulfonamido, hydroxyl, CrC4 alkoxy, (^-(: 4 alkylthio, cyano) , (^-(: 4 alkyl groups or CVC4 haloalkyl groups containing 1-3 halo groups; more preferably, each R32 is independently (1) hydrogen group; (2) CpCU alkyl group, which may be subjected to Substituent substitution: aryl or heteroaryl, where aryl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine, CVC4 alkylamino, di- (CrC * alkyl) amino, alkyl Fluorenylamino, ((νς4alkoxy) carbonylamino, hydroxyl, c "c4alkoxy, CVC4alkyl, or trifluoromethyl; or (3) aryl or heteroaryl, which may be treated as 3 of the following substituents: amino, CVC4 alkylamino, di- (c "c4 alkyl) amino, cnc5 alkylamino, cvc4 alkoxy) carbonylamino, hydroxy, alkoxy, CVC4 alkyl or -36- 200303316 Description of the invention continued (32) trifluoromethyl; more preferably, each R32 is independently (1) hydrogen; (2) C ^ C4 alkyl, optionally substituted with the following substituents: aryl or heteroaryl, where aryl and heteroaryl are optionally substituted with 1-2 of the following substituents. · Amine, Ci -C2 alkylamino, dialkyl) amino, CrC5 alkylamino, (CVC4 alkoxy) carbonylamino, hydroxyl, ("(: 2 alkoxy, CVC2 alkyl or trifluoromethyl: Or (3) aryl or heteroaryl, which may be substituted with 1-2 of the following substituents as needed: gastric amine, CVC2 alkylamino, di- (Ci-C2 alkyl) amino, 0 ^ (: 5 Alkylamino, (CVC4alkoxy) carbonylamino, hydroxyl, CrC2alkoxy, CrGalkyl or trifluoromethyl; more preferably, each R32 is independently R42; each R33 is independently (1) Hydrogen; or (2) alkyl, optionally substituted with the following substituents: heterocyclyl, aryl, or heteroaryl, where aryl, heterocyclyl, and heteroaryl are optionally substituted with 1-3 ® Substituent substitution: amine, amine, Dialkylamino group, roasted amino group, pitoxy group, siamino group, warp group, alkoxy group, pit group, cyano group, alkyl group or alkyl group: Preferably, each r33 (1) a hydrogen group; or (2) a C "C4 alkyl group, which may be optionally substituted with the following substituents: heterocyclyl, aryl, or heteroaryl, wherein aryl, heterocyclyl and Heteroaryl can be optionally substituted with 1-3 -37- 200303316 (33) Description of the invention continued on the following substituents: amine, (VC4 alkylamino, di- (c "c4 alkyl) amine, Cr'C5 Alkylamino, alkoxy) carbonylamino, CrC4 alkylsulfonamido, hydroxyl, CrC4 alkoxy, Ci-G alkylthio, cyano, CVC4 alkyl, or those containing 1-3 halo groups (^-(: 4-haloalkyl; more preferably, each R33 is independently hydrogen or (: 丨-(: 4-alkyl; best, each R33 is independently hydrogen or methyl; each R4 () is Independently (1) alkyl, which may be substituted with the following substituents as required. · Phenyl or heteroaryl, where phenyl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine, di Methylamino, acetamido, hydroxy, i-based, methoxy, Or trifluoromethyl; (2) trifluoromethyl: or (3) aryl or heteroaryl, optionally substituted with 1-3 of the following substituents: amino, dimethylamino, acetamido Group, hydroxy group, halo group, methoxy group, methyl group, or trifluoromethyl group; Preferably, each R4G is independently (1) C "C4 alkyl group, which may be substituted with a phenyl group as required, and the phenyl group may be Requires 1 to 3 substituents: amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl, or trifluoromethyl; (2) trifluoromethane; or (3) Aryl, which may be substituted with 1-3 of the following substituents as needed: amine, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl, or trifluoromethyl .. Each R39 is independently argon or R40; -38-200303316 Description of the invention continued (34) Each R41 is independently (1) hydrogen; or (2) alkyl, optionally substituted with the following substituents: benzene Or heteroaryl, in which benzyl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine, CrC2 alkylamino, dialkyl) amino, acetamido, hydroxyl, C 丨- C2 alkoxy, C2C2 alkylthio , Cyano, C2C2 alkyl or trifluoromethyl; preferably, each R4l is independently hydrogen or CkC4 alkyl; each R42 is independently fluorenyl; (2) substituted by aryl or heteroaryl C "C4 alkyl or CrQ alkyl, where aryl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine, dimethylamino, acetamido, hydroxyl, methoxy, methyl Or trifluoromethyl; or (3) aryl or heteroaryl, which may be optionally substituted with 1-3 of the following substituents:-amino, dimethylamino, acetamido, hydroxy, methoxy , Methyl or trifluoromethyl; and preferably, each R42 is independently hydrogen or CnCU alkyl. In another specific embodiment, W is N, V is N, and U is CR6 in the content related to any of the above and below specific embodiments. The other item is a specific embodiment. In the content related to any one of the foregoing and specific embodiments, W is N, V is CR6, and U is CR6. In another specific embodiment, in the content related to any of the above and below specific embodiments, X is N. Another specific embodiment is related to any one of the above-mentioned and the following specific embodiments: -39 «200303316 Description of the Invention Continued (35) Z is a heterocyclic group. In another specific embodiment, in the content related to any one of the above and below specific embodiments, Y is NR5R2 |. In another specific embodiment, in the content related to any one of the foregoing and specific embodiments, r5 is hydrogen. In another specific embodiment, in the content related to any of the foregoing and following specific embodiments, R5 is:

CVCs alkyl, C2-C8 fluorenyl, or &lt; 248 alkynyl, which can be optionally substituted with 1-3 of the following substituents: amino, CrC * alkylamino, di- (CrC4-alkyl) amino, Hydroxyl, CVC4 alkoxy, C "C4 alkylthio, -S03H4 halo; or aryl, heteroaryl, aryl-crc4-alkyl, heteroaryl-crc4-alkyl, heterocyclyl, heterocyclic -CrCV alkyl, alkyl, or c3-cv cycloalkyl-CrC4 • alkyl, of which aryl, heteroaryl, heterocyclyl, and cycloalkyl may be substituted with 1-3 of the following substituents as necessary: amine , CVC4 alkylamino, di- (CrCV-alkyl) amino, hydroxyl, CrG alkoxy, CrC4 alkylthio, CrC4 alkyl or C "C4 haloalkyl containing 1-3 halo groups.

In another specific embodiment, in the content related to any one of the above and below specific embodiments, each R20 is independently a Ct-Cs alkyl group, a C2-C8 alkenyl group, or C2-C8 alkynyl: amine, C "C4 alkylamino, di- (cvc4 alkyl.amino) amino, crc5 alkylamino, (c" c4 alkoxy) carbonylamino, N-((C "C4 alkoxy) carbonyl) -N- (C" C4 alkyl) amino, aminocarbonylamino, CrC4 alkylsulfonamido, hydroxyl, CrCU alkoxy, (: γ (: 4 alkylthio, CrC4 burned Si group, C1-C4 alkyl group or halo group. Another specific embodiment is related to any of the above and any of the following specific embodiments. • 40- 200303316 Description of the invention continued on (36) In the content, each R20 is independently an aryl-CrC ^ alkoxy group, an aryl-crc4-alkylthio group, an aryl-crc4-alkylsulfonyl group, a c3-c8 cycloalkyl group, a heterocyclic group, an aryl group, or Heteroaryl, where aryl, heteroaryl, heterocyclyl and cycloalkyl are optionally substituted with 1-3 of the following substituents: amine, CrC4 alkylamino, dialkyl) amino, C | -C5 Alkylamino, (CVC4alkoxy) carbonylamino, (VC4 alkylsulfonamido, CrC5 alkyl Fluorenyl, hydroxyl, CrC4 alkoxy, CVC4 alkylthio, CVC4 alkylsulfinylfluorenyl, CrC4 alkylsulfinyl, halo, CrC4 alkyl or C "C4 haloalkyl containing 1-3 halo groups.

In another specific embodiment, in the content related to any of the above and below specific embodiments, each R20 is independently a CrC8 alkyl group, a C2-C8 alkenyl group or a C2- C8 alkynyl: amine, CrC4 alkylamino,

Di- (CVC4 alkyl) amino, crc5 alkylamino, (c "c4 alkoxy) carbonylamino, N-UCrCU alkoxy) carbonyl) -N- (CrC4alkyl) amino, aminecarbonyl Amine, CrC4 alkylsulfonamido, hydroxyl, C, C4 alkoxy, CrG alkylthio, CVCt alkylsulfinyl, CrCi alkylsulfonyl or halo; and R2O is also substituted with the following substituents: Aryl-CnC4 alkoxy, aryl- (VC4 alkylthio, aryl-C "C4 alkanesulfonyl, C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl, where aryl, Heteroaryl, heterocyclyl and cycloalkyl can be optionally substituted with 1 to 3 of the following substituents: amine, C "C4 alkylamino, di- (C" C4 alkyl) amino, Ci-Cs alkyl Amine group, ((^-(: 4 alkoxy) carbonylamino group, CVC4 alkanesulfonylamino group, CrCs alkanoyl group, hydroxyl group, CrG alkoxy group, CrCU alkylthio group, CVC4 alkanesulfinyl group, C "C4 alkylsulfonyl, halo, CVC4 alkyl, C1-C4 haloalkyl containing 1-3 halo groups. In another specific embodiment, the compound is selected from the group consisting of: ) I Description of the invention Continued on page 5- (3-Hexylprop-1-yl) amino-8- (4-gashexyl) -7- (4-sigma) -1, 2, 4 -Dijun [4,3-c] pyrimidine; 5- (3-phenylprop-1-yl) amino · 8- (3-tolyl) -7- (4-saidyl) -1, 2,4-triazolo [4,3-c] ^ dense, 5- (1-piperidyl) -8- (3-tolyl) -7- (2-chloro-4-pyridyl) -1,2,4-triazolo [4,3-c] ^ • Bite; 5- (3-phenylpropyl) amino-8- (3- (trifluoromethyl) phenyl)- 7- (4-pyridyl) -1,2, carditriazolo [4,3-c] pyrimidine; 5- (2 (S) -amino-3-hexylprop-1-yl) amino- 8- (3,4-Diazinonyl) -7- (4-Methylpyridyl) -1,2,4-triazolo [4,3-c] pyrimidine; 5- (piperidin-1- ) -8- (3- (trifluoromethyl) phenyl) · 7- (2- (2-phenylprop-2-yl) amino-4-pyridyl) -1,2,4-tri Azolo [4,3-c] pyrimidine: 5- (3,5-dimethylpiperin-1-yl) -8- (3- (trifluoromethyl) phenyl) -7- (2- ( l (S) -phenethyl) amino) -4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine; 5- (piperin-1-yl) -8- (3- (trifluoromethyl) phenyl) -7- (2- (l (S) -phenethyl) amino) -4pyridinyl) -1,2,4-triazolo [4 , 3-c] pyrimidine; 1- (8- (4-fluorophenyl) -7- (4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidin-5-yl ) Amino) -2 (S) -amino-3-phenylpropane; 2- (8 -(4-fluorophenyl) -7- (4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidin-5-yl) amino-2-phenylhydrazone; 5 -(2 (S) -amino-2-methyl-3-phenylpropanyl) amino-8- (3- (trifluoromethyl) phenylb 7- (cardio-pyridyl) -1 , 2,4-triazolo [4,3-c] pyrimidine; 5- (2,5-diazobicyclo [2.2.1] hept-2-yl) -8- (3- (trifluoromethyl) Phenyl) -7- (2- (l (S) -phenethyl) amino-4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine; -42- 200303316 DESCRIPTION OF THE INVENTION Continued (38) 5- (2 (S) -Amino-3-phenylprop-1-yl) amino-8- (2-fluorenyl) -7- (4-pyridyl) -1 , 2,4-triazolo [4,3-c] pyrimidine; 5- (3 (S) -benzyl-pipenyl) -8- (2-fluorenyl) -7- (4-pyridine Base) -1,2, the heart is stricken with [4,3-c] syndrome; 5- (2 (S) -amino-3 -benzyl-N-) amino-8- (3- -4-Gaspiyl) -7- (4-17pyridinyl) -1,2,4-triazolo [4,3-c] pyrimidine; 5- (2 (S) -pyrrolidinylmethyl) ) Amino-8- (2-fluorenyl) -7- (4-pyridyl) -1,2, carditriazolo [4,3-c] pyrimidine; 5- (1- (2-propyl) Say pyridin-2 (S) -ylmethyl) amino-8- (3,4-dichlorophenyl) -7 · (4 · pyridyl) -1,2,4-triazolo [4, 3-c] pyrimidine; 5- ( Phenyl) -8- (3- (trifluoromethyl) phenyl) -7- (2- (cyclopropyl) amino-4-pyridyl: M, 2,4-triazolo [4, 3-c] pyrimidine; 5- (1- (2-propyl) orallyl-3-yl) amino-8- (3,4 -.one-mouselyl) -7- (4-orbital Group) 5- (1- (2-propyl) pyrrolidin-2 (S) -ylmethyl) amino-8- (2 • fluorenyl) -7- (4-pyridyl) -1,2, 4-triazolo [4,3-c] pyrimidine; 2-methyl-N2- (8-fluoren-2-yl-7-pyridine-cardiyl- [1,2,4] triazolo [4, 3-c] pyrimidin-5-yl) -propane-1,2-diamine: N1-isopropyl-2-methyl-N2- (8-fluoren-2-yl-7-pyridin-4-yl- [1,2,4] triazolo [4,3-c] pyrimidine: 5-yl) -propane-1,2-diamine; N1-cyclopentyl-2-methyl-N2- (8- ^ 2-yl-7-supridin-4-yl- [1,2,4] triazolo [4,3-c] pyrimidin-5-yl) -propane-1,2-diamine; isopropyl -[1- (8-fluoren-2-yl-7-pyridin-4-yl- [1,2,4] triazolo [4,3-c] pyrimidin-5-yl) -pyrrolidine-2- Methylmethylbamine; 200303316 Description of the invention continued (39) [1- (N-Isopropyl-piperidin-2-yl) -1-methyl-ethyl]-(8-fluoren-2-yl-7 -Pyridin-4-yl- [1,2,4] triazolo [4,3-c] pyrimidin-5-yl) -amine; (4-methyl-piperidin-4-yl)-(8-荇 · 2 · 基 -7-. Bipyridin-4-yl- [1,2,4] triazolo · [4,3-c] pyrimidin-5-yl) -amine; (1-isopropyl-3-methyl-apex-3 -Based)-(8-nai-2-based-7-koubito-4-yl- [1,2,4] trituro [4,3-(:] ° 密 症 -5-based)- Amine; N2- [8- (3,4-dichloro-phenyl) -7 ^ pyridine · 4 · yl- [1,2,4] triazolo [4,3-c] pyrimidin-O-yl] -N1-isopropyl-2-methyl-propane-1,2-diamine; [8- (3,4-dichloro-phenyl) -7-pyridin-4-yl- [1,2,4 ] Triazolo [4,3-c] pyrimidin-5-wyl]-[1- (1-isopropyl-pyrrolidin-2-yl) -1-methyl-ethyl] -amine; [8 -(3,4-dichloro-phenyl) -7-pyridin-4-yl- [1,2,4] triazolo [4,3-c] pyrimidin 0-yl]-[1- (1- Isopropyl-piperidin-2-yl) -1-methyl · ethyl] -amine; [8- (3,4-dichloro-phenyl) -7-pyridin-4-yl- [1,2 , 4] triazolo [4,3-c] pyrimidin-5-yl]-(4 -fluorenyl-σagrobitan-4 -yl) -amine, [8- (3,4-dichloro-phenyl) ) -7-pyridin-4 · yl- [1,2,4] triazolo [4,3-c] pyrimidin-5-yl]-(1-isopropyl-3-methyl-piperidine-3 -Yl) -amine; isopropyl- [1- (8-fluoren-2-yl-7-pyridin-4-yl-imidazo [l, 2-c] pyrimidin-5-yl) -® pyrrolidine- 2-ylmethyl] -amine; {1- [8- (3,4 -digas-dongyl) -7-αbiyodo-4-yl-taste And [1,2-c] σ dense lake-5-yl] -pyrrolidin-2-ylmethylisopropyl-amine; Ν1-isopropyl-2-methyl-N2 · (8- ^- 2-yl-7-pyridin-4-yl-imidazo [l, 2-c] · ° Dense-5-yl) -propyl lake-1,2-diamine;, [1- (1-iso Propyl-pyrrolidin-2-yl) -1-methyl-ethyl]-(8-fluoren-2-yl-7-pyridin-4 -yl-sigma [1,2 -c] ° * Myodo-5 -yl) -amine, -44- 200303316 Description of the invention continued on (40) [1- (1-isopropyl-piperidin-2-yl) -1-methyl-ethyl]-(8 -Fluoren-2-yl-7-pyridin-4-yl-imidazo '[l, 2-c] pyrimidin 5-yl) -amine; (4-methyl-piperidin-4-yl)-(8 -Fluoren-2-yl-7 "bipyridin-4-yl-imidazo [l, 2-c] pyrimid-5-yl) -amine, (1-isopropyl-3-methyl-peak lake- 3-yl)-(8-naphthalenyl-2-yl-7-blown-4-yl-weijun and [1,2-c] Hepta-5-yl) -amine, N '[8- (3 , 4-Digas-Hexyl) -7-mouth ratio 0 ^ -4-yl-taste sigma [1,2-c] 0 Semen-5 -yl] -N1-isopropyl-2-methyl -Propane-1,2-diamine;

[8- (3,4-Digas-Hexyl) -7-αbiyodo-4 -yl-tamito [l, 2-c] 4-dian-5 -yl]-[1- (1-iso Propyl-pyrrolidin-2-ylmethyl-ethyl] -amine; [8- (3,4-dichloro-benzyl) -7-pyridin-4-yl-imidazo [l, 2-c] Pyrimidin-5-yl]-[1- (N isopropyl-pyridin-2-yl) -1 -methyl-ethyl] -amine; [8- (3,4-dichloro-phenyl)- 7-pyridin-4-yl-imidazo [l, 2-c] pyrimidin-5-yl]-(4-methyl-piperidin-4-yl) -amine; and [8- (3,4-bis (Chloro-phenyl) -7-pyridin-4-yl-imidazo [l, 2-c] pyrimidin-5-ylb (1-isopropyl-3-methyl-piperidin-3-yl) -amine ;

Or a pharmaceutically acceptable salt thereof. The invention may generally have several asymmetric centers, typically represented as a racemic mixture. The invention includes racemic mixtures, partially racemic mixtures, and separated enantiomers and diastereomers. The required compounds include the following:

N1-—N

R1 -45- 200303316 _ (4i) Description of the invention Continuation page where Rt, Rh and R12 are a combination shown in the following table: V1 R12 R1 Benzyl 4-rupridinyl 3-phenylpropylamine 3-fluorophenyl 4 -Lipidyl 3-phenylalanyl 4-fluorophenyl 4-phytyl 3-phenylalanyl 4-fluorophenyl 4-pyridyl 3-phenylalanyl 2-¾: yl 4-lipidyl 3-phenylalanyl 3 -Tolyl 4-, dense 3 · benzylamido 3-tolyl 4-pyridyl 3-benzylamido 3-CF3 "fluorenyl 4" than pyridyl 3-phenylalanyl 2-methyl than methyl 4-methyl Pyridinyl 3-phenylalanyl 3,4-dichlorophenyl 4-p-pyridinyl 3-phenylalanyl 3,4-xylyl 4 "Pyridinyl 3-phenylalanyl 2-thienyl 4 · pyrimidinyl 3 -Phenylalanyl 2-pyranyl 4-pyridyl 3-phenylalanyl 2-benzo4phenyl 4-pyryl 3-phenylalanyl 2-benzoanyl 4-nt pyridyl 3-phenylalanylphenyl 4 -Ordinyl 3-benzyl-1-oronidinyl 3-fluorophenyl 4-ntyl 3-benzyl-1 -17-pyridinyl 4-fluoro 4-Methylpyridyl 3-benzyl-1-pyrrolidinyl 1-fluorenyl 4, ° · melidinyl 2-benzyl Wintersyl 2-fluorenyl 4-pyrimidinyl 3- Benzyl-1-σ-pyridinyl. 3-CF3-phenyl 4-pyrimidinyl 3-benzyl-1 pyridyl 3,4-xylyl 4-pyrimidinyl 3-benzyl-1- Pyridyl 3-tolyl 4-pyridyl 3 reads Benzylmethyl • 1-Methylpyridyl 3-CF;-Benzyl 4-pyridyl 3-benzyl-1-Methylpyridyl 3,4 -Diyl 4-pyridyl 3-benzyl-1 pyridyl

• 46-200303316 Description of Invention Continued (42) 3,4-Xylyl 4-. Compared to the 2-benzyl-4-morphosome 2-4 phenone, 4 ·. Titanyl 3-benzyl-U piperidinyl 2-pyranyl 4-pyridyl 3-benzyl-U piperidinyl 2-benzo 4-phenyl 4-exocyano 3-benzyl -1-piperidinyl 2-benzofuranyl 4-kidodoyl 3-benzylpiperidinylphenyl 4-P than pyridinyl 3-benzyl-1-piperidinyl 3-fluorobenzyl 4 -External 1: 3-benzyl-1-piperidinyl 4-fluorophenyl 4-. Benzyl 3-benzyl-Upipenyl 3-tolyl 4-pyridyl 3-benzylpipenyl 3-CF3-phenyl 4 ·. Specific benzyl 3-benzyl-N piperidinyl 3-fluorophenyl 4-hexyl 3-benzyl-1-piperidinylbenzyl 4- ° · mylide 3-benzyl-1 -Piperidinyl 3,4-dichlorophenyl 4-pyridyl 3-benzyl-1-piperidinyl 3,4-difluorenylphenyl 4-exo 1: phenyl 3-benzyl-1- Piperidinyl 2-4phenyl 4-. Bisynyl 3-benzyl-1-piperidinyl 2-creanyl 4-17 Bistetrayl 3-benzyl-1-piperinyl 3-sigma: Yodophenyl 4-exo 1: Yodo 3-benzyl-1-piperidinyl 2-benzyl 4-phenyl 4- ° Dynyl 3-benzyl-1-piperinyl 2-benzofuranyl 4-pyridyl 3-benzyl -1-piperidinyl 3-fluorophenyl 2- (benzofuran-3-ylamino) -4-17 is more than 4-benzyl 4-fluorobenzyl 4-benzylamino-4 -Pyridyl 3-pyrrolidinylmethyl 1-fluorenyl 3-benzylamino-4-pyrimidinyl 1-benzyl-4-piperidinyl 2-¾: yl 4-pyridyl 1-methyl-4 -Piperidinyl 3-CF; -benzyl 6-benzylamino-4- ° Benzene 4-peak pyridinyl 3,4-dimethylbenzyl 2-benzyloxy-4-pyrimidinyl 1 -Peak alpha acyl

-47- 200303316 _ (43) Description of the invention continued on 3-tolyl 2- (benzenesulfonamido) -4-leafyl 1-peak sigma 3-CF3-benzyl 2- (1-benzene Ethyl) amino-4 -11 Biyl 2.Aminoethylamino 3,4-dichlorophenyl 2- (1- (4-fluorophenyl) ethyl) Amino 4-0 Biyl (4-Pestomethyl) amino 3,4-xylyl 2 ((anilinesulfonyl) -4-exozoyl 3-aminopropyl small aminoaminophenyl 4 Amino-3-phenylpropylamino 3-fluorophenyl 4-pyridyl 2-amino-3-phenylpropylamino 4-fluorophenyl 4-exo f: 2-amino-2-(-3-fluorophenyl) ) Alanyl 3-methylbenzyl 4-exo i: ydoyl 2-amino-3-phenylpropylamino 3-CF3-phenyl 4-pyridyl 2-amino-3- (3-CF3-phenyl) propylamine 3,4-Diaminophenyl 2-amino-4 · pyridyl 2-amino-3-phenylpropylamino 3,4-dimethylphenyl 4-pyridyl 2-amino-3-phenylpropylamino 3-fluoro Benzoyl 4-amino-2-amino-3-phenylalanyl 3-tolyl 4- ° * octyl 2-amino-3-phenylalanyl 2-4 phenyl 4-0 Amino-3-phenylalaninyl 2-succinyl 4- ° ¾-amino 2-amino-3-phenylalaninyl 2-benzylphene 4-pyridyl 2-amino-3-phenylalaninyl 2 -Benzylfuranyl 4-pyridyl 2-amino-3-phenylpropylaminophenyl 4-pyridyl 3-amino-3-phenylpropylamino 4-fluorophenyl 4-7 -Phenylamino 3,4-xylyl 4-¾Hexyl 3-amino-3-phenylpropylamino 3-fluorobenzyl 4-pyrimidinyl 3-amino-3-phenylpropylamine

-48- 200303316 Description of Invention Continued (44) 6-. Than keto 4-. More than pyridyl 3-amino-3-propanylamino 3-toluene: 1 14 4-pyridyl 3-amino-3-phenylpropylamino 3-CF3-phenyl 4-. Pyridoxine 3 -amino group · 3 -Extreme N fe: group 2 -σsedenyl 4-0 Pyridyl group 3 -amino-3 -epiamino 2 -pyranyl group 4pyridyl 3-amine 3--3-propylamino 2-benzo4phenyl 4-0 than 3-methyl-3-amino-3-phenylpropylamino 2-benzofuranyl 4- ° · mylide 3-amino Alanylphenyl 4-0 is more than 3-amino-3-hexyl · 2,2 · Dimethylpropylamino 3-fluorophenyl 4-0 is more than 3-amino-3-hexyl- 2,2 · Dimethylpropylamino 3-benzohumidyl 4-0 is more than 3-amino-3-phenyl-2,2-dimethylpropylamino 3-methylbenzyl 4. ·. Titanyl 3-amino-3-phenyl-2,2-dimethylpropylamino 3-CF; -phenyl 4-pyridyl 3-amino-3-phenyl-2,2-dimethyl Alanine 3,4-difluorobenzyl 4-. Titanyl 3-amino-3 · benzyl-2,2-dimethylpropylamino 3,4-xylyl 4-pyridyl 3-amino-3-phenyl-2,2 · dimethyl Alanyl 3-fluorophenyl 4- ° * Dynyl 3-Amino-3-phenyl-2,2-dimethylpropylamino 1-ethynyl 4- ° * Dynyl 3-amine 3-Methenyl-2,2-dimethylpropylamino 3-methylbenzyl 4-π-pyridyl 3.-amino-3-phenyl-2,2-dimethylpropylamino 200303316 Description of the invention Continued on page (45) 2 ^ Sedenyl 4-p ratios 3-amino-3-phenyl-2,2-dimethylpropylamino 2-17 cyano 2-amino-4 -° * denselyl 3-amino-3-phenyl-2,2-dimethylpropylamino 2-benzo4phenyl 4-. Titanyl 3-amino-3-phenyl-2,2-dimethylpropylamino 2-benzofuranyl 4-pyridyl 3-amino-3- + yl-2,2 · dimethylpropylamine Other preferred compounds are included in the above examples. The definitions of the following terms as used herein are as follows: '· alkyl π, when used alone or in combination, refers to a linear or branched alkyl group, which preferably contains 1 to 15 carbon atoms (C "C15), More preferably 1-8 carbon atoms (CVCs), even more preferably 1-6 carbon atoms (CVC6), and even more preferably 1-4 carbon atoms ((^-(: 4), and even more preferably 1-3 carbon atoms (CkC;), and most preferably 1-2 carbon atoms (CrCz). Examples of such groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, second butyl, third butyl, pentyl, isopentyl, hexyl, octyl, etc. &quot; Hydroxyalkyl &quot;, when used alone or in combination, means an alkyl group as defined above At least one hydrogen group is replaced by a hydroxyl group, preferably 1-3 hydrogen groups are replaced by a hydroxyl group, more preferably 1-2 hydrogen groups are replaced by a hydroxyl group, and most preferably one hydrogen group is replaced by a hydroxyl group ^ here Examples of equivalent groups include hydroxymethyl, 1-, 2-hydroxyethyl, 1-, 2-, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 1,3-difluorobutane , 1,2,3,4,5,6-hexahydroxy-2-hexyl, etc. "Alkenyl", alone When used in combination, it refers to a straight-chain or branched hydrocarbon group containing one or more double bonds, which preferably contains 1-2 double bonds, and more preferably 200303316_ (46) Description of the Invention And preferably contains 2-15 carbon atoms (C2-C15), more preferably 2-8 carbon atoms' (C2-C8), even more preferably 2-6 carbon atoms (C2-C6), also More preferably, it is 2-4 carbon atoms (C2-C4), and even more preferably, it is 2-3 carbon atoms (C2-C3). Examples of such alkenyl groups include: ethenyl, propenyl, 2-methacryl Group, 1,4-butanebiyl, etc. ^ '· alkoxy ", when used alone or in combination, refers to &quot; R-0- &quot; type groups, where R &quot; is an alkyl group as defined above, And "〇" is an oxygen atom. Examples of such alkoxy groups include: · methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and second butoxy , Third butoxy, etc. • 'alkoxycarbonyl ", when used alone or in combination, means" R-0-C (0)-&quot; type group, where "R-0-" is As defined above, "C (0) n is a carbonyl group." "Alkoxycarbonylamino", alone or in groups When used together, it refers to &quot; R-0-C (0) -NH ·· type groups, where "ROC (O) &quot; is an alkoxycarbonyl group as defined above, in which the amine group may be substituted as necessary, such as : Substituted by alkyl, aryl, aralkyl, cycloalkyl-, cycloalkyl, etc. π alkylthio ", when used alone or in combination, means" RS "type group, of which" R &quot; is an alkyl group as defined above, and "Sn is a sulfur atom. Examples of such alkylthio groups include: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutyl Thio, second butylthio, third butylthio, and the like. • 'Alkanesulfenyl ", when used alone or in combination, means" RS (0)-&quot; type group, where &quot; R &quot; is an alkyl group as defined above, and 1'5 (0) " Is a sulfur monoxide atom. Examples of such sulphuric acid groups include methylalcohol, ethylalcohol, n-propylalcohol, isopropylalcohol δ production base, n-butylalcohol si: base, isopropyl Butylsulfenyl, second butylenesulfinyl, third butylenesulfinyl, etc. 200303316 _ (47) Description of the Invention Continued "· Alkylsulfonyl" When used alone or in combination, means "RS ( 〇) 2- "type group, wherein" Rn is an alkyl group as defined above, and "S (0) 2" is a sulfur dioxide atom. Examples of these bases include methylphenidyl, ethylidene, ethylpropionyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, second butylsulfonyl, Tributylsulfonyl, etc. "Aryl", when used alone or in combination, refers to phenyl or biphenyl, which can be fused with benzo or heterocycle, if necessary, and can be substituted with one or more substituents selected from the following. : Alkyl, alkoxy, halide, hydroxyl, amine, azide, nitro, cyano, alkynyl, carboxyl, alkoxycarbonyl, cycloalkyl, alkylamino, amido, hydrazone Alkyl, alkoxycarbonylamino, N-alkylfluorenyl, alkylamino, dialkylamino, aminealkyl, alkylaminoalkyl, dialkylaminoalkyl, N-alkylamino, N, N- Dialkylfluorenylamino, aralkyloxycarbonylamino, alkylthio, sulfinylfluorenyl, alkylsulfinyl, oxo, and the like. Examples of aryl include phenyl, o-tolyl, 4-methoxyphenyl, 2- (third butoxy) phenyl, 3-methyl-4-methoxyphenyl, 2-CF3-phenyl, 2 -Fluorophenyl, 2-chlorophenyl, 3-nitrophenyl, 3-aminephenyl, 3-acetamidophenyl, 2-amino-3- (aminemethyl) phenyl, 6-methyl 3-Ethylamidophenyl, 6-methyl-2-aminophenyl, 6-methyl-2,3-diamine benzyl, 2-amino-3-tolyl, 4,6-dimethyl 2-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl, 4- (2-methoxyphenyl) phenyl, 2-amino beryl, 2-fluorenyl , 3-amino-2-fluorenyl, Nmethyl-3-amino-2-¾ ::, 2,3-diamino-bromo '4,8-dimethoxy-2-fluorenyl, and many more. "πaralkyl" and "arylalkyl", when used alone or in combination, means that at least one hydrogen atom, preferably 1-2 hydrogen atoms, of the alkyl group as defined above is defined as above Replacement of aryl groups, such as: benzyl, 1-, 2-benzylethyl 2-02-03303316 Description of the Invention Continued (48), benzhydryl, hydroxybenzyl, tolylmethyl, dibenzoyl , Dichlorobenzyl, cardiac methoxybenzyl, etc. For example: benzyl refers to a methylene divalent group substituted with a phenyl group, that is, Ph-CH2-, where tolyl refers to a phenyl divalent group, which is substituted with a methyl group, that is, CH3-Ph-. "Aralkoxy" and "arylalkoxy", when used alone or in combination, means that at least one hydrogen atom, preferably 1-2 hydrogen atoms in the alkoxy group as defined above, is as Aryl substitution as defined above, such as: benzyloxy, 1-, 2-phenethyloxy, benzylmethoxy, hydroxybenzylmethoxy, tolylmethoxy, dichlorophenylmethyl Oxy, 4-methoxyphenylmethoxy, etc. "· aralkoxycarbonyl" and "arylalkoxycarbonyl π, when used alone or in combination, means" R-O-C (0) -"Type group, in which" R-0- "is an aralkyloxy group as defined above, and MC (〇)-" is a carbonyl group. "Alkyl", when used alone or in combination, means "RC (O )-&quot; type group, in which &quot; Rn is an alkyl group as defined above, and nC (0)-"is a carbonyl group. Examples of such alkylalkynyl groups include ... Fluorenyl, propionyl, butylfluorenyl, pentamyl, 4-methylpentyl, and the like.

"Alkinoamino group π, when used alone or in combination, refers to an nR-C (0) -NH-" type group, where nR-C (0)? Is an alkylamino group as defined above, in which the amine group is visible Substitution is required, such as: alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, and the like. "πaminocarbonyl", when used alone or in combination, refers to a carbonyl group (carbamoyl) substituted with an amine group, wherein the amine group may be mono- or di-substituted as required, such as: alkyl, aryl, aralkyl, Cycloalkyl, cycloalkylalkyl, alkylfluorenyl, alkoxycarbonyl, aralkyloxycarbonyl, etc. • 53 · 200303316 _ (49) Description of the invention continued on "Aminosulfonyl", alone or When used in combination, it refers to a sulfofluorenyl group substituted with an amine group. "." Benzo ", when used alone or in combination, refers to the divalent group C6H4 = derived from benzene." Benzo is fused "to form a ring system in which benzene and cycloalkyl or aryl have two Carbon atoms, for example: tetrahydrofluorenyl, and so on. As used herein, "bicyclic" and "tricyclic" refer to fused ring systems (such as fluorenyl and β-carolinyl), and substituted ring systems (such as: biphenyl, phenylpyridyl) And dibenzylpiperidinyl) two kinds of ring systems. •• Cycloalkyl ”, when used alone or in combination, means saturated or partially saturated, preferably a single ring, bicyclic ring or tricyclic ring containing a double bond Carbocycloalkyl, preferably monocyclic, preferably containing 5-12 carbon atoms (C5-C12), more preferably containing 5-10 carbon atoms (C5-C1 ()), even more preferably containing 5-7 carbon atoms (C5-C7), which may be fused with benzo or heterocycle if necessary, and optionally as described above in the definition of aryl, as defined herein, substituted e Examples of such cycloalkyl include Cyclopentyl, cyclohexyl, dihydroxycyclohexyl, ethylenedioxycyclohexyl, cycloheptyl, octahydrofluorenyl, tetrahydrofluorenyl, octahydroquinolinyl, dimethoxytetrahydrofluorenyl, 2 , 3-dihydrofluorenyl, azabicyclo [3.2.1] octyl, etc. "Heteroatom" means nitrogen, oxygen, and sulfur heteroatoms. "Heterocycles are fused with π to form a ring system in which a heterocyclyl or heteroaryl group having 5-6 ring members has two carbon atoms with a cycloalkyl or aryl group, such as: Hydroquinoline, methylene dioxobenzene, etc. "Heterocyclyl" means saturated or partially saturated, preferably a monocyclic or bicyclic ring containing a double bond, preferably a monocyclic heterocyclic ring, which contains at least One nitrogen, oxygen or sulfur atom -54- 200303316 Description of the invention continued (50) Ring member, preferably U4, more preferably 1-3, even more preferably 1-2, and each contains 3-8 ring members are better, more preferably 5-8 members, even more preferably 5-6 ring members. &quot; Heterocyclic group π includes the sulfur ring member of the sulfonium group and the diarrhea derivative and the tertiary nitrogen ring member of the N-oxide, fused with the carbocyclic ring, preferably 3-6 ring carbon atoms, more preferably For 5-6 ring carbon atoms, and benzo fused ring system. '' Heterocyclyl π can be optionally on at least one carbon atom, preferably 1-4, more preferably 1-3, even more preferably 1-2 carbon atoms, substituted with the following substituents: Halogen, alkyl, oxy, oxo, oxo, oxo, aryl, aralkyl, heteroaryl, heteroaralkyl, fluorenyl, N-alkylfluorenyl, alkoxycarbonylamino , Alkanesulfonylamino, etc., and / or substituted on the secondary nitrogen atom with the following substituents: hydroxyl, alkyl, aralkyloxycarbonyl, alkanoyl, alkoxycarbonyl, heteroaralkyl, aryl Or aralkyl. More preferably, &quot; heterocyclyl π, when used alone or in combination, refers to a monocyclic or bicyclic saturated heterocyclic ring system containing 5 to 8 ring members in each ring, of which 1 to 3 ring members are oxygen, Sulfur or nitrogen heteroatom, which may be partially saturated or fused with benzo as required, and optionally substituted with [-2 oxo or thio groups. Examples of such heterocyclic groups include: pyrrolidinyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 4-benzyl-peak-farinyl, sulfonyl, tetrahydrofuranyl, Speaking of fluorenyl, pyrenyl, dacrotonyl, pyrrolidone, tetrahydro-4phenyl and its fluorene and fluorene derivatives, 2,3-dihydrofluorinyl, tetrahydroquinolinyl, 1, 2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro small oxo-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzopyranyl, Methyldioxyphenyl, ethylenedioxybenzyl, etc. &quot; Heteroaryl &quot; refers to a monocyclic or bicyclic, preferably monocyclic aromatic heterocyclic group, which contains at least one nitrogen, oxygen or sulfur atom ring member, preferably 1-4, more -55- 200303316 _ (51) Description of the invention The continuation page is preferably 1-3, even more preferably i-2, and each ring contains 5-6 ring members. It may be fused with a saturated carbocyclic ring as required. Preferably 3-4 carbon atoms

(C3-C4) to form a 5-6 member ring, which may be substituted as required in the definition of aryl, as defined above. Examples of such heteroaryl groups include: 4-phenyl, sulfanyl, 4-carbyl, succinyl, benzo4-benzyl, benzo-ranyl, benzo4-phenyl, imidyl, and alpha bihalyl ,? Titanyl, Sayodo, 3- (2-methyl) pyridyl, 3- (carditrifluoromethyl) pyridyl, pyrimidinyl, 5- (4-trifluoromethyl) sigmadenyl, p Bihuki, trisyl 'Ml tf dolyl, quelinyl, 5,6,7,8-tetraargonium 4-phosphonyl, 5, 6,7,8-tetrahydroisoquinolinyl, humin , Benzimidazolyl, benzoxazolyl, and the like. "ΙΠΝ" -heteroaryl "refers to a 5-10 member monocyclic or bicyclic aromatic group, preferably a monocyclic

Aromatic heterocyclic group, which contains at least one nitrogen atom, preferably 1-3, more preferably 1-2, even more preferably 1, the rest are carbon, and each ring contains 5-6 rings The group member is better, and it can be fused with a saturated carbocyclic ring if necessary, preferably 3-4 carbon atoms (C3-C4) to form a 5-6 member ring, which can be as described in the definition of aryl group, such as The above definition is replaced. Examples of such heteroaryl groups include: imidazolyl, pyrrolyl, pyrazolyl, pyridyl, 4- (2-amino) pyridyl, 3- (4-trifluoromethyl) pyridyl, pyrimidinyl, 5- (4-trifluoromethyl) pyrimidyl, glutamyl, trisynyl, oxalyl, succinyl, imidazopyridine, 5,6,7,8-tetrahydro, quinolinyl , 5,6,7,8-tetrahydroisoquinolinyl, benzimidyl, and the like. Those skilled in the art understand that these heterocyclic groups may be in several types of isomers, all of which are included in the scope of the present invention. For example: 1,3,5-Sangen Some groups are isoforms of 1,2,4-Sangen group. These positional isomers are all within the scope of the present invention. Similarly, a heterocyclic group or a heteroaryl group may be bonded to other groups in the compound of the present invention. The points of attachment to other groups do not limit the scope of the invention. Therefore, for example, a pyridyl moiety group can be bonded to other groups using the 2-, 3-, or 4-position of the pyridyl group, and a piperidinyl group can be bonded to other groups using the nitrogen or carbon atom of the piperidinyl group. All such configurations are within the scope of the invention. Examples of heterocyclyl or heteroaryl moiety groups within the scope of the present invention may include (but are not limited to) the following:

-57 · 200303316 Description of the Invention Continued (53) &quot; heteroaralkyl "and" heteroarylalkyl ", when used alone or in combination, refer to at least one hydrogen atom in an alkyl group as defined above, It is preferably 1-2 hydrogen atoms, which is replaced by a heteroaryl group as defined above, such as: 3-creanylpropyl, 2-pyrrolylpropyl, chlorofluorinylmethyl, 2 ^ sedenylethyl , Pyridylmethyl, 1-imidylethyl, etc. β "halogen" and "π", when used alone or in combination, refer to a fluorine, chlorine, bromine or fluorenyl group. "Haloalkyl", when used alone or in combination, means that at least one hydrogen atom, preferably 1-3 hydrogen atoms, of an alkyl group as defined above, is replaced by a halogen group, and more preferably by fluorine or chlorine Group substitution. Examples of such haloalkyl groups include trifluoroethyl, chloromethyl, 1-bromoethyl, fluoromethyl, difluorofluorenyl, trifluoromethyl, bis (trifluoromethyl) methyl, and many more.

"Pharmaceutically acceptable salt" means a salt prepared in a conventional manner and known to those skilled in the art. "Pharmaceutically acceptable salts" include salts of inorganic and organic acids, including (but not limited to): hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, and oxalic acid , Tartaric acid, citric acid, lactic acid, fumaric acid, acetic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid, and so on. When the compound of the present invention includes an acid functional group, such as: several groups, it is suitable for several groups of pharmaceutically acceptable cationics. Those who are familiar with this technique include alkali metals, alkaline earth metals, ammonium, Quaternary ammonium cations, etc. For other examples of &quot; pharmaceutically acceptable salts &quot;, see, for example, the aforementioned literature, and J. Pharm. Sci. 66: 1 (1977) by Berge et al. Compounds and Mono-, Di-, and Tri-58-200303316 _ (54) I Description of the Invention Continued on page Aza compound. "Leaving group" ("represented by" Ln "in the reaction diagram) usually refers to a group that is easily replaced by a nucleophile (such as: amine, thiol or alcohol nucleophile). Such leaving group is related to the related art. Examples of such leaving groups include, but are not limited to: N-hydroxysuccinimine, N-acylbenzotrisine, halide, trifluoromethaneate, tosylate, etc. Preferred leaving groups are Appropriate groups described herein. &Quot; Protective group &quot; generally refers to groups known in the art to protect selected reactive groups, such as carboxyl, amine, hydroxyl, hydrogenthio, etc., to prevent undesired occurrences. Reactions, such as: nucleophilic reactions, electrophilic reactions, oxidation reactions, reduction reactions, and so on. Preferred protecting groups are suitable groups as described herein. Examples of amino protecting groups include (but are not limited to): aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenylalkyl, propyl, substituted allyl, and fluorene Examples of β-aralkyl groups include, but are not limited to, phenylfluorenyl, o-methylphenylfluorenyl, tritylmethyl, and diphenylmethyl. It can be substituted by the following substituents as required: halogen, alkyl, alkoxy, hydroxyl, nitro, amido, fluorenyl, and the like, and salts, such as scales and ammonium salts. Examples of the aryl group include: phenyl, fluorenyl, indanyl, onionyl, 9- (9-phenylfluorenyl), phenanthryl, dendyl, and the like. The cycloalkenylalkyl or substituted cycloalkylenealkyl is preferably an example having 6 to 10 carbon atoms, including (but not limited to): cyclohexenylmethyl, and the like. Suitable fluorenyl, alkoxycarbonyl and aralkyloxycarbonyl groups include: benzyloxycarbonyl, tertiary butoxycarbonyl, isobutoxycarbonyl, benzamidine, substituted benzamidine, butylamyl, ethamyl, Trifluoroacetamido, trichloroacetamido, phthalofluorenyl, and the like. A mixture of protecting groups can be used to protect the same amine group,-• 59- 200303316 Description of the Invention Continued (55) For example: aralkyl and aralkyloxycarbonyl groups can be used to protect the primary amine group. The amine protecting group can also form a heterocyclic ring with the nitrogen to which it is attached, for example: 1,2-bis (methylene) benzene, si-imine, perylene imine, maleimide And so on, and these heterocyclic groups may further include a bonded aryl group and a cycloalkyl ring. In addition, the heterocyclic group may be mono-, di- or tri-substituted, such as: nitrophthalimide. It can also prevent unwanted reactions of amine groups (such as oxidation reactions) by forming addition salts such as hydrochloride, tosylate, trifluoroacetate, etc. Many amine-protecting groups are also suitable for protecting carboxyl, hydroxyl, and hydrogenthio groups. For example: aralkyl, alkyl is also suitable for protecting hydroxy and argonthio. For example, the third butyl 0 silyl protecting group is a silicon atom substituted with one or more alkyl, aryl, and aralkyl groups if necessary. Suitable silyl protecting groups include (but are not limited to) • Trimethylsilyl, triethylsilyl, triisopropylsilyl, tertiary butyldihydrazyl, xylsilyl, 1,2-bis (di Silyl) benzene, 1,2-bis (di · silyl) ethane and dibenzosilyl. The silylation of amino groups can form mono- or di-silylamine groups. The silylation of amino alcohols can form N, N, 0-trisilyl derivatives. The silyl functional group on the silyl ether functional group can be easily removed by treatment with, for example, a metal hydroxide or ammonium fluoride reagent, which can be a separate reaction step or performed in situ during the reaction with the alcohol group. Suitable silylating agents are, for example: trimethylsilyl chloride, third butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride, dibenzosilyl chloride or a combination product thereof with imidazole or DMF. The silane-based alkylation method of amines and the silane-based protective group are related to the related techniques. The method for preparing these amine derivatives from the corresponding amino acid, aminoamine or amino acid ester is also a well-known organic chemical technique-60-200303316 Description of the Invention Continued (56) Process (including amino acid / amino group Ester or amino alcohol chemistry) is known to beta-protecting groups that can be removed without affecting the rest of the molecule. These methods are related to the related art and include acid hydrolysis method, hydrogenolysis method, etc. ◎ The preferred method involves the removal of protective groups, such as: benzyloxycarbonyl removal method in a suitable solvent system such as: alcohol, Acetic acid, etc., or a mixture thereof, is removed by hydrogenolysis using palladium / carbon. Removal of the third butoxycarbonyl protecting group can be performed in a suitable solvent system, such as No. 2 or Dichloromethane, using inorganic or organic acids (such as HC1 or trifluoroacetic acid). The resulting amine salt is easily neutralized to produce a free amine. Carboxyl protecting groups such as methyl, ethyl, benzyl, tert-butyl, 4-methoxybenzyl, etc. can be removed under the conditions of hydrolysis and hydrogenolysis known in the relevant art. The definitions of some codes used in this article are as follows:, CRXR ya-= -NRXRY =-NR — =

-C (〇)--C (NR)--S (0) 2-

In addition, a carbon atom substituted with two hydroxyl groups represents a carbonyl group. For example, when each r2 is a hydroxyl group, -cr2r2- represents a carbonyl group. * It should be noted that the compounds of the present invention may contain tautomeric groups, such as: cyclic and acyclic fluorene and guanidine groups, heteroaryl substituted with heteroatoms (Yf = 0, S, NR), And so on, illustrated by the following examples: -61-200303316 Description of the invention continued (57)

And although one of the forms is named, illustrated, shown, and / or patented herein, all its tautomeric forms are included in such names, descriptions, displayed, and / or patented. Compounds of the invention are prodrugs Yihan is also included in the present invention. Prodrugs are active or inactive compounds. When administered to a patient, they can undergo physiological actions in vivo, such as hydrolysis, metabolism, and chemical modification to form the compounds of the present invention. Appropriate techniques involving the manufacture and use of prodrugs are known to those skilled in the art. For a general discussion of the prodrugs involved, see "Drug Metabolism Reviews 165" (1988) by Svensson and Tunek, and "Bundgaard" Design of Prod rugs' ·, Else vier (l985) e Masked acid-anion examples include a variety of esters, such as: alkyl (for example: methyl, ethyl), cycloalkyl (for example • cyclohexyl), Esters of aralkyl (for example: benzyl, p-methoxybenzyl), and alkoxyalkyl (for example: topenenyloxymethyl). The masked form of amines is arylcarbonyloxymethyl substituted derivatives, which can be cleaved by esterases in vivo to release free drugs and formazan (Bungaard J. Med. Chem. 2503 (1989)) β In addition, Acidic NH groups, such as ····································································································································································· 被. Coded ether form masking. EP 039,051 (Sloan Elsevier (1985)). Hydroxy hexanosine # • ,,,, / Manch-base iso # 1: Formic acid front and Little, 4 / 1 1/81) Reveals foreign medicines, medicines, preparation methods and uses. Compound VII according to the present invention is synthesized according to one or more of the following methods. It should be noted that the general processes shown therein are those relating to the preparation of compounds whose stereochemistry is not explicitly stated. However, 'these processes can usually be applied to their compounds with well-defined stereochemistry', for example, where the stereochemistry relative to a group is (S) or (R). In addition, compounds with one stereochemistry (e.g., (R)) are often-conventional methods can be used to make their compounds with opposite stereochemistry (i.e., (s)), such as inversion reactions. The present invention relates to substituted indole compounds. Substituted compounds called indole compounds according to specific embodiments of the present invention can be prepared according to the following reaction schemes and descriptions of synthetic examples. Class 41 compounds: Substituted indole alpha well compounds (v and W = N; and W4) of the specific known examples of the present invention may be substituted by 4 (3Η) · pyrimidone · or 2 (ιη) · Preparation of pyridone III (Reaction Diagram I) The III / III carbonyl group can be converted to a leaving group (L) using pOCi3, etc., such as: and heated to form a goo / batch w. After being reacted in an appropriate solvent (such as: 7 ethyl _), it is cyclized with R6-CL3 (such as: the normal acid ester R6-C (OCH3) 3) to form a substituted oxindole compound I (V = N and W = N). Or go, after the reaction of 哫 / 哫 哫 IV with 2-hydroxyethylamine (NH2CHR6CHR6〇H) in the name of the base (such as: K2C〇3, etc.) after reaction- · Using POC13, etc., convert this L group to form a leaving group (L), such as: L = cl, and then cyclize and oxidize, or form a keto group after oxidizing the oxonyl group w A s' Cyclized form, 63, 200303316 (59) I was invented as a substituted 4 丨 thorphine compound ι (w = N) β Or, Sidine M1: pyridine IV and amino acid (NH2CHR6C020H), in the presence of a base (Such as: K2C03, etc.) After the reaction, cyclization can also form a substituted Compound 4 of the type I (W = N), which can also be used as an intermediate at the 3-position (see for example: j. Med. Chem. 3 1: 454-61, 1988; Chem. Pharm. Bull. 33: 30-6, 1985; J. Heterocycl. Chem. 28: 503-7, 1991). Similarly, AcNHBi ^ k2C03 (Synth · Commun · 21: 1841-6, 1991), NH4OH (aqueous solution) were used. After reacting with CuS04 (Acta Chim. Hung. 127: 601-5, 1990), etc. to convert pyrimidine / pyridine IV to form aminopyrimidine / pyridine vi, then react and cyclize with R6_C (0) -CR6L, where L is a leaving group For example, CM, Br, or I 'can also form substituted indole alpha well compounds I (W = N) (see, for example, J. Med. Chem. 35: 877-85, 1992; J. Fluorine Chem. 73: 83-6, 1995; Chem Lett 13 17-20, 1993; J. Med. Chem 32: 1686-700, 1989) e Reaction Figure 1

-64- 200303316 __ (60) I invented the reaction diagram 2

VII

Substituted dodoxy compounds I (ν == N) in specific embodiments of the present invention can be prepared from substituted 4 (3H) -pyrimidone VI or 2 (1H) -pyridone VI (Reaction Figure 2). Amine VI can react with R6C (0) L or its equivalent, and the resulting amidine VII can be cyclized in the presence of POC13 to form an indole-like compound I (see J. Heterocycl. Chem. 23: 981-7, 1986). Alternatively, the amine VI can be reacted with carbochlorine or its equivalent, and the resulting 3-hydroxyl 4 indole compound I can also be used as an intermediate at the 3-position. The amine VI can be prepared by reacting cyanide ions, such as: sodium cyanide, etc., with pyrimidine-pyridine Mtidine IV in a suitable solvent (eg, dimethylformamide, dimethylformamide, etc.). Reduction of cyano groups to form amine methyl groups (see Synthesis 961-2, 1989). 4 (3m-pyrimidine: When synthesizing 4 (3H) -pyrimidinone II (or its tautomer, 4-hydroxy · pyrimidine), the method shown in Figure 3 can be followed (see WO98 / 24782; W0 98 / 24780; For an overview of the synthesis method, see DJ Brown's Heterocyclic Compounds: the Pyrimidines, Chapter 3, 1994, John Wiley &amp; Sons). This method involves a cyclization reaction between acrylate XII and 脒 V, and then oxidized The resulting dihydropyrimidone XIII, which produces π. -65- 200303316 (61).

Scheme 3 H2N R1 T NH 〇 Description of the invention continued on page

R 11

V fcNH • person r R12 / ^ N ，, R ，

OH

Rl1y ^ N r12 / ^ n ^^ r1 2-In the synthesis of 5- (4-fluorophenyl) -6- (4-pyridyl) -4-hydroxy-pyrimidine II (Reaction Figure 4), Disubstituted acrylate XII can be easily obtained by condensation of pyridine-4-carboxyaldehyde with 4-fluorophenylacetic acid and esterification reaction (R = methyl, ethyl, benzyl, etc.). XII can react with a variety of hydrazone compounds V under heating. Sodium nitrite / acetic acid is suitable as a dehydrogenating agent for the conversion of XIII to form II. Reaction Figure 4

• 66-

XIII 200303316 (62) Description of the Invention Continued Therefore, by properly selecting the starting material, compounds of formula II in which R12 is any other heteroaryl ring in the definition of R12 can be obtained. These starting materials include (but are not limited to): '2-methylpyridine-4-carboxyaldehyde, 2,6-dimethylpyridine-4-carboxyaldehyde (Chem. Ber. 88, 1276-, Mathes and Sauermilch) 1283 (1955)), -quinoline-4-carboxaldehyde, pyrimidine-4-carboxyaldehyde, 6-methylpyrimidine-4-carboxyaldehyde, 2.methyl sigma dense lake 4-jikiz, 2,6 -Dimethyl snoring-4-multiple chain (Chem. Ber. 97, 3407-3417 (1964) by Bredereck et al.). The use of a 2-nitro-para-4-amino chain can produce derivatives of formula II, where R12 represents 2-nitro-4-pyridyl. Nitro

After the catalytic reduction reaction to generate an amine group, a 2-amino-4-pyridinyl derivative of II can be formed. The method shown in Figure 2 can be applied to other arylacetic acids to form compounds of formula II with different aryl groups as R11. Pyrimidinone II can be substituted at the N-3 position after reacting with, for example, an alkyl halide (such as methyl iodide or ethyl bromide) in the presence of a suitable base (such as potassium carbonate, etc.). F.

Reaction Diagram 〇 〇Et

XVI

67- 200303316 (63) Description of the invention continued on another page, a method for forming 5,6-disubstituted-4-hydroxy-pyrimidine (Reaction Figure 5) involves the cyclization reaction of sulfonyl ester XIV with thiourea to produce thiourea Shout Lake derivative XV. XV can be S-monomethylated to form XVI. XVI reacts with the primary and secondary amines' to form a 4-amino-substituted π-amino group. The 2-thioether derivative of R1 = SR21 in other formula a can be prepared by, for example, χν firing an alkyl halide. XV or XVI is treated with Ruan Ni and Ha to produce a compound of structural formula π, where R1 is fluorene. Reaction Figure 6

Although Reaction Figure 5 illustrates that in the formula, R12 is a bipyridyl synthesis method, but this method can also be used to synthesize any other heteroaryl ring in the definition of R12. These starting materials include (but are not limited to) ... 2-ethyl isonicotinate (Bull · Soc · Chim. FR. 648-649 (1954) by Efimovsky and Rumpf), pyrimidine-4-kinoate Esters, methyl 2-methylpyrimidin-4-chitoate '6-methylpyrimidine-4-carboxylic acid methyl ester, and methyl 2,6-dimethylpyrimidine-4-carboxylic acid methyl ester (Heterocycles of Sakasi et al. 13, 235 (1978)). Similarly, after methyl 2-nitroisonicotinate (Stanonis, J. Org. Chem. 22, 475 (1957)) can be reacted with aryl acetate, the resulting β-ketoester can be similarly reacted as shown in FIG. 5, Cyclization reaction with thiourea. Subsequent catalytic reduction of the nitro group to the amine group 'yields ° .tight cross-linking II, where R12 represents 2-amino-4-pyridyl (Reaction Figure 6). The 2-amino group is then reacted with R31: -68- 200303316 _ (64) I Invention Description Continued and R32-L to form N-substituted pyrimidinone II. In addition, methyl 2-'acetamidinyl isonicotinate or methyl 2- (R32HN-) isonicotinate (Reaction Figure 7) can be similar to Figure 5 in the use of, for example, the third butyldimethysilyl Methyl (Acta Chem. Scand. B 42 384-389 (1988) by Benneche et al.), Tert-butyldimethylsilyl, benzyloxymethyl, benzyl, etc. (after proper protection of the nitrogen by PO Carry out the reaction. Alternatively, 2- (R3lR32N-) isonicotinate R31 and R32 which are not hydrogen groups, respectively, can be similarly reacted.

Figure 5 performs the reaction. Reaction Figure 7

Use appropriate reagents to remove the protective group Pi of the obtained pyrimidine II (for example: if it is a third butyldisilyloxymethyl group, then a third butyl ammonium fluoride is used), R12 will be represented 2-Acetylamino-4-pyridyl or 2- (R32HN-)-4-pyridylpyrimidinone II. Of course, in the process shown in FIG. 5, any aryl alkyl acetate or heteroaryl alkyl acetate can be used instead of p-fluorophenyl ethyl acetate to produce different R11 aryl and heteroaryl substituents. A compound of formula II. -69- 200303316 Invention Description Continued (65)

XVIII In another method, pyrimidone can be prepared by coupling a suitable derivative of χνιπ (L is a leaving group '%: a halogen group, etc.) with an appropriate aryl or heteroaryl equivalent. These fens, Coincidental reactions are known to those who are skilled in this art 'and-involving a reactive derivative of an organometallic component with a second compound (eg, a pixel derivative), which reacts in the presence of a catalyst The metal organics can be provided by shouting (if the Ru component provides a reactive pixel equivalent) or the cancer ketone can be in the form of a reactive% halogen derivative to react with a metal organic aryl or heteroaryl compound. Therefore, the XVHI% bromine and 5-broken derivatives (L = Br, I) can be passed through arylalkyltin or heteroarylalkyltin compounds (such as trimethylstannyl), inert Solvent (such as: tetrahydrofuran) in the presence of a palladium catalyst (such as: bis (triphenylphosphine) period (11) dichloride) (Peters et al. J. Heterocyclic Chem. 27, 2165-2173, (1990) β Alternatively, the halogen derivative of XVIII can be chlorinated with, for example, tributyltin alkyl After the reaction, it is lithiated with butyllithium, and then reacted with an aryl halide or heteroaryl halide in the presence of a catalyst to be converted into a trifluorenyltin derivative (L = BU3S11) (Sandosham and Undheim) Acta Chem · Scand · 43, 684-689 (1989)). Both methods can produce pyrimidine II, where R11 represents aryl and heteroaryl. • 70- 200303316 _ (66) I Description of the invention Continued reaction diagram 8

As illustrated in the literature (Kabbe, Ueb · Ann. Chem. 704, 144 (1967); German Patent Case No. 1271 1 16 (1968)) and the reaction shown in Figure 8, 5-Rn-2,6-dipyridyl-4 (3H) -pyrimidinone II can be synthesized in a single step, in which cyanopyridine is reacted with an aryl acetate, such as ethyl phenylacetate, in the presence of sodium methoxide. In Reaction Scheme 9, the compound of formula XXX of the present invention can be easily prepared by the reaction of methylsulfide intermediate XXXI with amine NHR5R21. For example, the mixture is preferably heated at a temperature higher than 100 ° C, and more preferably 150-210 ° C. . Alternatively, the compound of formula XXX can be easily prepared by the reaction of the methylsulfonyl intermediate XXXII with the amine NHR5R21. For example, the mixture is preferably heated at a temperature higher than 40 ° C, and more preferably 50-210 ° C. Reaction Figure 9 〇

〇

XXX 〇

The amines of the formula NHR5R21 are commercially available or can be easily prepared by those skilled in the art using starting materials. For example: amine, nitro or cyano can be reduced under -71-200303316 (67) Description of the invention continued under reducing conditions, such as reducing in the presence of a reducing agent such as lithium aluminum hydride, etc., to produce the corresponding amine. The related art of alkylation and tritiation of amino groups is known. Palmitic and non-palatable substituted amines can be made from palmitic amino acids and amidoamines (eg, via alkyl, aryl, heteroaryl, cycloalkyl, aralkyl, heteroaralkyl , Cycloalkylalkyl, etc. substituted glycine, beta alanine, etc.), prepared using methods known in the relevant art (such as: H. Brunner, P. Hankofer, U. Holzinger, B. Treittinger and Η Echo J. Med. Chem. 25, 35-44, 1990 by Schoenenberger; J. Am. Chem. Soc. 82, 696-698, 1960 by M. Freiberger and RB Hasbrouck; Chem. Ber. By Dornow and Fust. 87, 984, 1954; Bullock Chem. Soc. Jpn. 55, 1454-1459, 1982 by M. Kojima and J. Fujita; Journal of Labelled Compounds and Radiopharmaceuticals XXXI, 306, 1992 by W. Wheeler and D. CTBannon; And S. Davies, N. Garrido, J. Chem. Soc., Ichihara and I. Walters, Chem. Commun, 1153, 1993). Reaction Figure 10

VI 72- 200303316 _ (68) I Description of Invention Continued The amine methyl-4 (3H) -pyrimidine VI can be synthesized according to the method shown in FIG. 10. This method involves the Claisen Condensation of amines, esters XXV and Ru-substituted acetates XXVI, where -NP /! Represents an appropriately protected amine group to form a ketoester XXVII. During the decarboxylation reaction, the amino ketone XXVIII is formed. Amino ketone XXVIII and Claisen-Schmidt Condensation of the aldehyde Rl2-CHO form ethylene XXIX. Acetyl ketone XXIX and 脒 V are subjected to Michael reaction in the presence of a base, and then cyclized in the presence of POC13, etc., and then oxidized (eg, Mn02, etc.) and the amine protecting group is removed. To form 4 (3H) -pyrimidine VI (see Synlett 7-56-758, 1999). Alternatively, after the cyclization and condensation reaction of the vinyl ketone XXIX and the aldehyde R ^ CHO in the presence of ammonium acetate, oxidation (for example: Mη02, etc.) can form 4 (3H) -pyrimidine VI (see Pharmazie 53: 843- 847, 1998; Pharmazie 54: 35-41, 1999)

As shown in Reaction Figure 11, a suitable pathway for the formation of 2 (1 H) -pyridone III involves a, b-unsaturated ketone XXII and a fully reactive substituted acetamidine. Reaction (El-Rayyes and Hachi 1-1 ^ "&gt; 1:" 1. HeterocycL Chem. 21,1473 (1984)), followed by a dehydrogenation reaction. Reaction diagram 1 1

-73-

III 200303316 _ (69) [& Invention description continuation page] (Reaction Figure 12) Therefore, pyridine-4-carboxyaldehyde or other heteroaromatic carboxylic aldehydes (such as: pyrimidine-4-carboxaldehyde or quinoline-4- Carboxaldehyde) and f ^ CHaC ^ COR1, in the presence of piperidine / acetic acid, under heating (Bayer and Hartmann's Arch. Pharm. (Weinheim) 324, 815 (1991)), and with tetanone (CH3 -CO-C (CH3) 3) reacts in the presence of sodium hydroxide to produce unsaturated ketone XXII. After XXII reacts with phenylacetamide in the presence of sodium ethoxide, it undergoes 3,4-diargyridone to form 6-substituted 3-phenyl-4- (heteroaryl) -2 (3) of structural formula III. 1Η) -pyridine

Substituted halopyridines can easily be prepared from the corresponding pyridone using phosphatidyl chloride or a five gasifier. Reaction Figure 12

Figure 13 shows a pathway capable of forming 6-chloro-2 (1H) -pyridone XXIV, which is a versatile intermediate that can be further modified at the 6-position. This method (G 'Simchen, Chem. Ber. 103: 389-397, 1970) is based on • 74-200303316 (70) Description of the invention Continued page Unsaturated cyanocyanine XXHI, converted to XXIV in the presence of hydrochloric acid Response. The reaction of XXIV with gas (Katritzky and Rachwal's J. Heterocyclic Chem. 32, · 1007 (1995)), primary and secondary amines will produce 2-amino substituted pyridines, pyridone III. In addition, XXIV can react with alkyl, cycloalkyl, heteroaryl or aryl disuperborate or alkyl, cycloalkyl, heteroaryl or aryl zinc compounds in the palladium or nickel-catalyzed cross-coupling reactions. The reaction produces alpha ketone ill, where R3 is alkyl, cycloalkyl, heteroaryl or aryl. % Response Figure 13

Pyridone III can be substituted at the N-1 position by reacting it with, for example, an alkyl halide in the presence of a suitable base (e.g., potassium carbonate). In the synthesis of amine methylpyridine VI, the method shown in Fig. 14 was followed. This method involves the Claisen Condensation of amine esters XXV and R11 substituted acetates XXVI, where -NριΡι represents an appropriately protected amine-75- 200303316 description of the invention continued on the (71) group to form a ketone XXVII. Ketoester XXVII and ethynylketone Rl2CH = C (R2) -C (0) Rl ^: methoxide, etc.) can form diketoacetate XXXIII ( See J. Chem. Soc., Perkin Trans. 1, 3 14 1-3 1 50, 1997; J. Indian Chem. Soc. 67: 815-17, 1990). After the ester is hydrolyzed, the carboxyl group is removed to form the dione XXXIV. After the diketone XXXIV undergoes an ammonium acetate cyclization reaction, it can be oxidized (eg, 〇2, Mn〇2, etc.) to form orbital XXXV (see J. Med, Chem. 34: 2804-15, 1991; J Chem. Res. Synop. (4), 180-181, 870-875, 1 998; Tetrah'edron Lett. 34: 5063-6, 1993; Synth. Commun. 22: 351-7, 1992). Alternatively, after the diketyl ester XXXIII undergoes an ammonium acetate cyclization reaction, the ester is hydrolyzed, the carboxyl group is removed, and oxidation (for example, Mn02, etc.) can form pyridine XXXV. After the protective group of the amine of pyridine XXXV is removed, aminomethyl-pyridine VI is formed. -76- 200303316 (72) Description of Invention Continued Reaction Figure 14

R2 XXXVI

Alternatively, after the ketoester XXVII and R12CH = C (R2) CN are subjected to a Michael Reaction in the presence of a base (Tetrahedron Lett. 34: 4993-6, 1993; Tetrahedron 54: 9079-9088, 1998), Cyclization in the presence of POC13 (US • 77-200303316 (73) I Invention Description Continued 5,229,519; Khim. Geterotsikl. Soedin · 514-19, 1989) and oxidation (for example ... 2, M02, etc.), The formed intermediate XXXVI can be reacted as described in XXIV above to form aminomethyl-pyridine VI. The class member is called ikouduo g 4 compound: Alternatively, the substituted quinolonium compounds in the specific embodiment of the present invention can be prepared according to the reactions shown in Figures 15 and 16. Reaction Figure 15

To synthesize a substituted quinolone compound I, where X is N, the method shown in Fig. 15 can be reacted. This method involves the conversion of ketone XL into functional compounds-78- 200303316 (74) Description of the invention Continuation sheet XLI (chlorine, bromine or iodine), which makes ketone XL through a reducing agent (such as: sodium cyanoborohydride, etc.) Etc.) reduced to a hydroxyl group, and then used POC13, POB3, PBγ5, etc. to convert the hydroxyl group to form a halogen group, such as: bromine, and so on. The halogenated compound XLI is converted into an organometallic reagent anion XLII using, for example, zinc, copper, magnesium, and the like, and then reacted with R12-CO2R to remove the protective group of the nitrogen ring to form the ketone XLIII. Ketone XLIII is converted to ammonium XLIV using standard methods known to those skilled in the art, such as: reaction with ammonium acetate, and so on. Alternatively, the organometallic reagent anion XLII can be reacted with R12-CN to form an associative XLIV, and the protective group of the ring nitrogen can be directly removed. Enamine XLIV undergoes a cyclization reaction with I ^ (:( υ3 (such as: RiC ^ OEth, etc.) to form a substituted quinolonium compound I (see Synth. Commun. 29: 2617-2624, 1999; J. Heterocycl. Chem. 23: 1 829-3 1, 1986; Monatsh. Chem. 127: 955-962, 1996; J.

Heterocycl. Chem. 26: 613-18, 1989; Chem. Heterocycl. Compd. (N. Y.), 1997, 33: 854-856, 1998). Alternatively, the enamine XLIV can be reacted with C (S) L2, etc., and the thiol XLV formed can be converted into a substituted quinolomic compound I using the methods and reagents described above. Alternatively, the enamine XLIV can react with C (0) L2, etc. to form a hydroxyl group, replacing the thiol group in XL V, which can be converted into a substituted indole compound I or the like by the methods and reagents described above. The hydroxyl group forms a leaving group, such as: chlorine, bromine, etc., which can be converted into a substituted indole compound I using the methods and reagents described above. Alternatively, the ketone XLIII can react with HN = C = S to form a thiol XLV or react with HN = O0 to form the corresponding hydroxy compound. Ketone XL can be easily produced by the reaction of a 5-membered ring heteroaryl (with or without a protective group) with Rn-C (0) Cl, etc. (see Heterocycles · Ί9 · 200303316 (75) Description of the invention continued Page 27: 1 855-60, 1988; J. Org. Chem. 65: 7323-7344, 2000; J. Org. Chem. 65: 7323-7344, 2000; Synthesis 129M294, 2000; J. HeterocycL Chem. 26 : 1563-8, 1989; Tetrahedron Lett. 30: 241 1-12, 1989; J. Heterocycl. Chem. 27: 673-8, 1990; Synth. Commun. 20:32 1-3 1, 1990; Bioorg. Med Chem. Lett. 10: 1935-1938, 2000; J. Chem. Soc., Perkin Trans. 1, (6), 1 139-45, 1989) 0 Reaction Figure 1 6

Synthesis of substituted oxindole compounds I, where X is (:-{12, according to the method shown in Figure 16 of the reaction. This method involves the organometallic reagent anion XLII and R12CH = C (R2)- The Mike reaction of C (0) Ri forms the ketone XLVI. After removing the protective group of the ring nitrogen, cyclization and oxidation (for example: 02 'Mη02, etc.) can form substituted compounds called vocal 1 compound I For example, the amines of the formulas NHR5R21, NHR31R32 and NHR4lR42 can be substituted from the commodity or can be prepared by those skilled in the art using commercially available starting materials. For example: amidine, nitro or cyano can be reduced under reducing conditions, such as : Performing the formation of the corresponding amine in the presence of a reducing agent (such as lithium aluminum hydride, etc.) -80- 200303316 (76) I Description of the Invention Known. Bismuth and non-swath substituted bismuth can be bismuth amino acid and amino acid amine (for example: alkyl, aryl, heteroaryl, cycloalkyl, aralkyl, heteroaryl Alkyl, cycloalkylalkyl, etc.) are prepared using methods known in the relevant art (eg, H. Brunner, P · Hankofer, U. Holzinger, B. Treittinger and E. Schoenenberger, Eur. J. Med. Chem. 25, 35-44, 1990; M. Freiberger and R. B. Hasbrouck, J. Am. Chem. Soc. 82, 696-698, 1960: Chem. Ber. 87, 984, 1954 by Dornow and Fust; Bull. Chem. Soc. Jpn. 55, 1454-1459, 1982 by M. Kojima and J. Fujita; W. Wheeler and D. O'Bannon

Journal of Labelled Compounds and Radiopharmaceuticals XXXI, 306, 1992; and S. Davies, N. Garrido, 0. J. Ichihara and I. Walters

Chem. Soc., Chem. Commun. 1153, 1993) 0 Alkylsulfonic acid, arylsulfonic acid, heterocyclic sulfonic acid, heteroarylsulfonic acid, alkyl mercaptan, aryl mercaptan, heterocyclyl sulfur Alcohols, heteroaryl thiols, alkyl dentates, aryl functions, heterocyclic halides, heteroaryl compounds, etc. can be obtained from commercial products or can be obtained according to standard methods known in the relevant art. Preparation of starting materials. The thioether derivative can be oxidized in a suitable solvent using a suitable oxidizing agent and converted into the corresponding hydrazone or sulfonium. Suitable oxidants include, for example: hydrogen peroxide, sodium perborate, oxone peroxomonosulfate (oxone), methane peroxymonocarboxylic acid, periodic acid, etc., including mixtures thereof. Suitable solvents include acetic acid (eg Sodium perborate), and other peroxo shuttles, ethers (such as: THF and dihumane), and acetonitrile, DMF ', etc., including their compounds. The above chemical reactions are generally disclosed in the broadest sense of the method for preparing the compounds of the present invention -81-200303316 Description of the Invention Continued on page ^ Sometimes, the reaction may not be applicable to each compound within the disclosed scope ^ Those skilled in the art understand that this may occur Compounds in this case. In all cases, whether the reaction can be successfully performed in accordance with common modification methods known to those skilled in the art, such as: appropriate protection of interfering groups, use of other commonly used reagents, routine modification of reaction conditions, etc. , Or according to the disclosed or other commonly used reactions, can be used to prepare the corresponding compounds of the present invention. In all methods, all starting materials are known or can be easily prepared from known starting materials. Without further explanation, those skilled in the art understand that the present invention can be used to the fullest extent using the foregoing description. Therefore, the following specific and specific embodiments are for illustrative purposes only, and do not limit the rest of the disclosure in any way. The following examples are for illustrative purposes only and do not limit the invention in any way. Those skilled in the art will appreciate that the compounds disclosed herein may be modified and changed without departing from the spirit or scope of the invention. P0C13 is phosphonium chloride. TFA is trifluoroacetic acid, DMF is dimethylformamide, DCM is dichloromethane, BINAP is racemic -2,2 · -bis (diphenylphosphino) -1,1, two crops, and Boc is The third butoxycarbonyl group (t-C4H9OCO-), Me is methyl, Et is ethyl, and iPr is isopropyl. The heating method used herein refers to increasing the temperature, for example: 40 to 250 ° C. Those skilled in the art understand that in some cases it is necessary to use different solvents or reagents to achieve some of the transformations described above. Synthetic method of 3 -methyl-2 -methyl · pentyl-5 -naphthalene-2 -yl-6 -external dagger-4-3 Η-° * 密 * -4 -S3

4-cyanopyridine

MeNCS

Mel

OMF -82-200303316 _ (78) I Description of the Invention Continued In a 5-liter round bottom flask with a stir bar, add 4-cyanopyridine (83.9 g, 805.5 mmol) to ethyl acetate (172.6 g, 800.5 mmol) in DMF (800 mL). Using an addition funnel, a 1 M potassium tert-butoxide solution (805.5 mL) was added dropwise. The resulting red / brown solution was stirred at room temperature for 2 hours. DMF (400 mL) solution containing thioisocyanate (58.9 g, 805.5 mmol) was added dropwise

To the reaction. The reaction was heated to 45 ° C for 2 hours. The container was cooled in an ice bath to about 0 ° C. When this temperature was reached, the ice bath was left and a dilute solution of DMF (300 mL) containing methyl iodide (114 · 3 g, 805.5 mmol) was added dropwise to the reaction. Stir vigorously for 14 hours. Operation method: add water to increase the volume by 3-4 times and stir vigorously for 2-4 hours until solid appears. The solid was filtered through a coarse porous glass funnel and washed with plenty of water. The filtered solid was collected, stirred in ethyl acetate for 1 hour, and filtered through a moderately porous glass funnel. At this time, solid 'was washed with ether and collected. TLC (4% MeOH / CHCl3) showed only one compound ... 3-methyl ) -2-Mesophyl · 6- (4-# (: bite) shout bite synthesis

poci3

150 ° C In a 1-liter round-bottomed flask with a reflux condenser and stir bar attached, add phosphonium chloride (107.7 g, 65.3 mL, 700 mmol) to methylthiopyrimidone (25.01 g, 70.0 mmol). The resulting solution was heated at 150 ° C under vigorous stirring for 14 hours. At this point, TLC (4% MeOH / CHCl3) showed that the starting material had been completely consumed. The mixture was cooled to room temperature again and excess POCl3 was removed in vacuo. Residue weight -83 · 200303316 _ (79) Description of the invention continued page Redissolved in methylbenzyl and concentrated (4 X 50 mL methylbenzyl) to azeotropically remove a small amount of POC3. The residue was dissolved in CH2C12 and adsorbed on 30 g of silicone. The resulting slurry was vacuum dried and adsorbed on a short silica gel column. Dissolved in 2.5% MeOH / CHCl3. The initial fraction contains the desired product (TLC). The product-containing fractions were collected and concentrated to give 4-chloro-0- (fluorenyl) -2-methylthio-6- (4-pyridyl) pyrimidine as a yellow / brown oil. Synthesis method of (2-methylsulfanyl-5-naphthalen-2-yl-6-supridin-4-yl-pyrimidin-4-yl) -hydrazine

In a 1 liter round bottom flask with a reflux condenser and stir bar attached, add isocyanate

Propanol (300 mL) and hydrazone monohydrate (52.4 g, 54.1 mL, 104.6 mmol) to chlorosulphur sigma (18.9 g, 52.3 mmol). The resulting solution was heated at 60 ° C for 14 hours under vigorous stirring. A yellow precipitate formed during this period. At this point, TLC (4% MeOH / CHCl3) showed that the starting material had been completely consumed. Excess IPA was removed in vacuo. The obtained residue was dissolved in CH2C12, washed with saturated NaHC03 aqueous solution, dehydrated with MgSO4, and concentrated to give (2-methylsulfanyl-5-fluoren-2-yl-6-pyridin-4-yl- In bite-4-yl) and. Synthesis of 5-methylsulfanyl.-8-fluoren-2-yl-7-0 than pyridin-4-yl- [1,2,4] triazolo [4,3-c] pyrimidine

• 84 · 200303316 _ (80) I Description of the Invention Continued In a 1 liter round bottom flask with a stir bar, add dichloromethyl tiger (300 mL) and trimethyl n-formate (16.7 g, 16.2 mL 156,9 mmOl) to hydrazine (18.9 g, 52.3 mmol). After 1 hour, trifluoroacetic acid (5 96 g, 4.02 mL, 52.3 mmol) was added to the stirred solution. A yellow precipitate was allowed to settle overnight. At this time, TLC (4% MeOH / CHCl3) showed that the starting material had been completely consumed. The resulting solution was poured into running and NaHC03 aqueous solution to stop the reaction of TFA. The organic layer was collected, washed with saturated NaHco; aqueous solution, dehydrated with MgSCU, and concentrated. The residue was dissolved in a minimum amount of methane (50-75 mL), and a large amount of ether (500 mL) was slowly added until a yellow / orange solid precipitated from the solution. The β slurry was filtered and the solid was collected. The filtrate was concentrated and the steps described above were repeated to produce methylsulfanyl-8-tea. 2, yl-7.pyridin-4.yl- [ι, 2,4] triazolo [4,3-c] pyrimidine. Example 1 The following amines were prepared as intermediates and used to prepare compounds within the scope of the present application. Example 1 A: Preparation of 3-phenylbutylamine

Take a mixture of methanol (50 ml) containing 3, phenylbutyraldehyde (3 mL, 20.18 mmol), ammonium acetate (i5 g, 195 mmol) and sodium cyanoborohydride (900 mg, 14.32 mmol) in argon. Stir overnight. Add concentrated HC1 to adjust to pH 2. Evaporate the solvent, add · Dimethylformate and water, add alkali hydroxide solid to the aqueous phase to make it alkaline ... (PH12). Extraction (digas methane) and concentration to give the title compound as an oil. ES-MS (m / z): 150.2 (M + H) VH NMR (CDC13) ... d 7.40-7 · 17 (m, -85- 200303316 _ (81) I Description of the invention continued on 5H, Ph) , 2.81 (q, 1H, CH), 2.62 (m, 2H, CH2), 1.76 (dq, 2H, CH2), 1.29 (d, 3H \ CH3). Example IB: Preparation of 3- (2-tolyl) propylamine

nh2

Add diethyl cyanomethylphosphonate (5.0 mL, 30.9 mmol) to argon, and stir with tetrahydrofuran (50 ml) containing sodium hydride (60% oil suspension, 1.24 g, 31 mmol). In suspension. After 30 minutes, 2-methylbenzaldehyde (3.6 mL, 31.1 mmol) was added, and stirring was continued for 1 hour. The reaction was stopped by adding water. After extraction with methane, the organic solution was dehydrated and evaporated. 3 Column chromatography (hexane: hexane: ethyl acetate = 3: 1) yielded 2- (2-tolyl) acrylonitrile Oily. Methanol (125 ml) containing this material (3.8 g), 10% palladium / carbon (3.8 g) and 12 N hydrochloric acid (1 1.8 mL, 142 mmol) was hydrogenated under normal pressure for 2 days using hydrogen. Filter off the catalyst and evaporate the solvent. The resulting material was distributed between dichloromethane and water. 10 N sodium hydroxide was added to the aqueous phase to make it alkaline. After extraction (dichloromethane), the mixture was dehydrated and evaporated. The resulting material was purified on a silica gel column (chloroform: methanol: triethylamine = 85: 10: 5) to give the title compound as an oil. Example 1C: Preparation of 2 · methyl-3-phenylamine

nh2 A mixture containing 2-methyl-3-phenylpropanamide (4.32 g, 26.5 mmol) and tetrahydrofuran (1.3 g, 34.3 mmol) obtained from a commercial product in tetrahydrofuran (i84 ml) was obtained from a commercial product. Stir for 5 hours at room temperature. The reaction mixture was poured into a saturated aqueous sodium sulfate solution, and then extracted with methane gas. The combined organic extracts are dehydrated (sodium sulfate) and evaporated • 86 · 200303316 _ (82) Description of the Invention Continued on page, producing an amine oil. Another method can be found in: Dornow and Fust Chem. Ber., 87, 984 (1954). Example ID: Preparation of 3-fluoro-3-benzylpropylamine

F

Step A._ 3-Liquid-3-benzylpropionitrile: Add sodium borohydride (1.4 g, 37.00 mmol) in batches. At the temperature of the ice bath, benzyl acetonitrile (10 g, 68.90 mmol) is added. The solution was stirred with methanol (200 ml). After 30 minutes, the reaction was stopped by adding a few drops of acetic acid and evaporated. The mixture is distributed between dichloromethane and water, and the combined organic extracts are dehydrated (magnesium sulfate) and evaporated to produce a slurry of the compound of Step A (see Florin, C ·; Chantegrel, J ·; Charlon, C ·; Marsura , A ·; Luu-Duc, C. Nouvelle voie de synthese des a-fluorophenylacetonitriles. Ann · pharmaceuttiquesfr · 1985, 43, 595-599) o Step B. 3-Ga-3- 苽 propionitrile: at -78 ° Under C, add a solution of 3-hydroxy · 3 · phenylpropionitrile (3.5 g, 23.8 mmol) in dichloromethane (20 ml) to diethylaminosulfur trifluoride (5 g, 3 1 mmol) Twice methane (23 ml) was stirred in the solution. After 1.5 hours, the mixture was allowed to warm to room temperature. After the reaction was stopped by adding water, extraction was performed with dichloromethane, and the organic phase was dehydrated and evaporated. Flash chromatography on a silica gel column (hexane-ethyl acetate = 5M) yielded 3-fluoro-3-phenylpropionitrile. 1H NMR (CDC13): d 7.50 ^ 7.29 (m, 5H, Ph), 5.73 (dt, 1H, Jh.f 46.2 Hz, CHF), 3.00 and 2.96 (dd, t, each 1H, CH2). Step 骡 C. 3-Ga-3-benzylpropylamine: dropwise add tetrahydrofuran solution (8.8 mL, 17.6 mmol) containing 2N methylboron-dimethylsulfide complex to 3-fluoro-3-benzene at room temperature. -87- 200303316 _ (83) Description of the invention Continued Propionitrile (2 g, 13.41 mmol) in a tetrahydrofuran (12 ml) stirred solution. The mixture was warmed to 50 ° C, dimethylsulfide was distilled off, and the mixture was refluxed for 2.5 hours.

After cooling to 0 ° C, 1N hydrochloric acid in methanol (20 ml) was added, and the mixture was concentrated. Dichloromethane and water were added to the obtained concentrate. Add potassium hydroxide solids to about pH 12. Extraction (dichloromethane) and concentration gave the crude product as a mixture of benzylpropylamine and 3-fluoro-3-phenylpropylamine. Column chromatography on [atrobeadsR column (chloroform-methanol-triethylamine = 90: 7: 3) gave the first eluate of the title compound 3-fluoro-3-phenylpropylamine. ES-MS (m / z): 154.0 (Μ deuterium; lH NMR (CDC13): d 7.45-7.28 (m, 5H, Ph), 5.60 (ddd, 1H, JH F 48.2 Hz, CHF), 2.91 (t , 2H, CH2N), 2.15 and 1.96 (2m, each 1H, CH2). Example IE: Preparation of 2-fluoro-3-benzylpropylamine

Step A. 1. · Amino-2-hydroxy-3-benzylpropane: Take (2,3-epoxypropyl) benzene (9.69 g, 72.22 mmol), sodium azide (16.5 g, 253.8 mmol) ) And ammonium chloride (6.3 g, 109.5 mmol) in a mixture of methanol (190 ml) and water (32 ml) and heated at reflux for 1.5 hours. The solvent was evaporated and the remainder was distributed between dichloromethane and water. The organic solution was dehydrated and evaporated to produce the compound of Step A, iMS (m / z): 178.1 (M + H); lH NMR (CDC13): d 7.43-7.15 (m, 5H, Ph), 4.08 (m, 1H, CH), 3.4 [and 3.32 (2dd, each 1H, CH2), 2.85 and 2.83 (2d, each 1H, CH2), 1.98 (bs, OH ”Step B. 1-azido-2-Gas-3 -Benzylpropane: At -78 ° C, add digas methane containing 1-azido-2-hydroxy-3-phenylpropane (3.5 g, [9.75 mmol] -88- 200303316) Description of the invention continued ( 84) (23 ml) solution into a stirred solution of dichloromethane (23 ml) containing diethylaminosulfur trifluoride (3.4 mL, 25.74 mmol). Within 2.5 hours, slowly return the mixture to the chamber Warm. After adding water to stop the reaction, extract with dichloromethane. Concentrate and flash chromatography on a silica gel column (hexane-ethyl acetate = 8: 1 to 6: 1: 1) to produce K azido-2-fluoro Oil of 3-phenylpropane. 4 NMR (CDC13): d 7.46-7.20 (m, 5H, Ph), 4.86 (m, 1H, JH.F 48.2 Hz, CHF), 3.41 (m, 2H , CH2), 3.04 (m, 2H, CH2). Step C. 2-Ga-3-benzylpropylamine: Take U azido-2-fluoro-3-phenylpropane (900 mg, 5.0 mmol) and 20% palladium / carbon (wet weight, 50%, 500 mg) of a methanol (40 ml) mixture was hydrogenated under an argon balloon for 2 hours. The catalyst was evaporated to remove the solvent. The obtained product was purified on a short column of IatrobeadsR (gas-methanol-triethylamine = 90: 7: 1) ES-MS (m / z): 153.9 (M + Η) +; ιΗ NMR (CDCI3): d 7.40-7.22 (m, 5H, Ph), 4.68 (m, 1H, JH F 48.7 Hz, CHF), 3.11 · 2 · 83 (m, 4H, 2CH2). Example IF ·· 2-amino-3- (2-fluorophenyl) -propylamine production method

Step A. 2-Amine 3- (2-aminobenzyl) propanoic acid methyl ester: Take 3 g (27 · 3 mmol) of (D, L)-(2-fluorophenyl) alanine and suspend in 50 ml The methanol solution of HC1 was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo 'dried' to give a yellow oil. MS (m / z): 198 (M + ΗΓ; C 丨 〇H | 2FN〇2 theoretical value 197.2. Step B. 2-Amine is a stilbyl group) Propanamide: Take 2-Amino-3- (2-Fluorophenyl) Methyl propionate was suspended in 50 ml of a 30% ammonium hydroxide solution and stirred at room temperature -89- 200303316 __ (85) Description of the invention continued on page 18 hours. The mixture was filtered and washed with cold water to collect 2-amino-3- (2-fluorophenyl) propanamine 'as a white solid. iMS (m / z): 183.1 (M + ΗΓ; C9HhFN20 requires 182.2.

C. 2-Amino-3- (2-minimum propylamine: Carefully add 2 · amino-3- (2-fluorobenzyl) propanamine to argon, and cool it at 5t). In a mixture of LAH (1.0 g '26.3 mmol) and 20 ml of THF. The reaction was heated at reflux for 10 hours. The reaction was cooled to 5 ° C and treated with Na2S04 · 10 H20 carefully. After the resulting mixture was stirred for 18 hours, the solid was filtered off to remove the filtrate. The filtrate was concentrated in vacuo , Produces a white oily substance. MS (m / z): 169 (M + H) +; C9H 丨 3FN2 theoretical value 168.19. Example 1G: 2-amino-2-methyl-3-phenylpropylamine Manufacturing method

nh2

Step A ·· D, La-methylbenzylpropyl acetic acid: Take 28% hydroxide of D, La-methylbenzyl alanine methyl acetate (5.0 g, 25.7 mmol) obtained from the product. The aqueous solution (50 ml) was kept at room temperature for 3 days. The resulting white precipitate D, L-a-methylphenylalanine was filtered and dried. Long Su B · 2-Amino-2-methyl · 3-watch curtain rain neck: Take D, La-methylbenzyl alanine (2.0 g, 11.22 mmol) via lithium aluminum hydride (ι · 3 g (34.26 mmol) was reduced in boiling tetrahydrofuran for 24 hours. The reaction was stopped by adding sodium sulfate decahydrate at an ice bath temperature. After the salt was filtered off, it was evaporated to leave an oily title compound. MS (m / z): 165.1 (M + H) +; Cl0H16N2 requires 164.2. Another method is described in M. Freiberger and R. b. Hasbroucki J. Am. Chem. Soc 82, 696-698 (1960). -90- 200303316 (86) Description of the Invention Continued Example: (S) -1,2-Benzylmethyldiamine Production Method

NH2 (S)-[, 2-benzylethylenediamine is prepared according to the literature (H. Brunner, P. Hankofer, U. Holzinger, B. Treittinge_η · Schoenenberger ^

Eur. J. Med. Chem. 25, 35-44, (1990)) ′ is reduced from L-benzylalanine amidine by hydrogenation. The (R) -enantiomer was prepared from D-phenylalanine amidine in the same manner.例 II · (S) -2-N, N · dimethylamino · 3-phenylpropylamine production method

Η2Ν Add diethylgg: oxyhydrogenated steel (13.0 g '61 · 3 mmol) to i containing phenylalanine ammonium amine (3.6 g, 21.9 mmol) and 37% formaldehyde solution (4.4 mL, 58.7 mmol) , 2-Dichloroethane (77 ml) was stirred in the mixture. After stirring for 2 hours, a saturated sodium bicarbonate aqueous solution was added to stop the reaction. After adding hydroxide pellets, extract the organic solution with chloroform to dehydrate and evaporate the (S) _2-N, N-dimethylamino-3-phenylpropylamine based on the instructions in the literature. Hydrogenation via chain reduction (H. Brunner, P. Hankofer, U. Holzinger, B. Treittinger and H. Schoenenberger, Eur. J. Med. Chem. 25, 35-44, (1990)) yielded the title compound. Example [J: (S) -2-N-Ethylamino-3-phenylpropylamine production method

H2N -91-200303316 _ (87) Description of the invention continued (SV2-N-Ethylamino-3-benzylpropylamine: Add acetic anhydride (1.2 mL, 12,7 mmol) to L-phenylalanine amidoamine (1.0 g, 6,10 mmol) in a stirred solution of methanol (25 ml). After 1.5 hours at room temperature, it was evaporated and dried under oil pressure pump vacuum: ^ LN-ethylphenylalanine obtained (6.1 mmol) at 55C using aluminum hydride (570 mg, 15.0 mmol) in tetrahydrofuran (65 mml) for 4 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen bicarbonate, followed by dichloromethane. Methane extraction, dehydration and evaporation. Chromatography on a silica gel column (chloroform: methanol: triethylamine = 90: 7: 3) 'yielded a yellow oily amine. MS (m / z): 179.1 (M + H ) +; The theoretical value of CuHl8N2 is 178.3. Example IK: (S) -2-Phenylmethyl pipegon production method Under Ot :, lithium aluminum hydride (1.6 g, 42.16 mmol) is added in portions to (S) -2- After stirring the benzyl peak-3,6-dione (3.0 g, 14.70 mmol) and tetrahydrocondensate (80 ml) in a mixture of β at an ice bath temperature for 30 minutes, the mixture was stirred at reflux for 4 hours. Batch addition of sparse acid fishing decahydrate and some methanol suspension The reaction was continued until the hydrogen evolution ceased. Filtration and washing of the solid several times with digas methane. The combined filtrate was evaporated to leave a white solid. MS (m / z): 177.1 (M + Huang Guang; CuH16N2 theoretical value 176.3. Example 1L: Method for preparing (〇1,2,3,4-tetrahydroiso4-line-3-ylmethyl) amine

The title compound of NH2 was prepared by reducing (S) -decahydro-4-line-3-carboxamidin according to the method shown in Example lc. Alternatively, according to the method described in Example If, the title compound can be prepared from (S) -decahydro • 92-200303316_ (88) Description of the Invention Continued Example: Preparation of 1-phenyl-1,3-propanediamine

nh2 is converted from 3-phenyl-3-aminopropionic acid (SG Cohen and S. Υ · Weinstein J. Am. Chem. Soc. 86, 725-728, 1964) into 1-phenyl according to the method in the literature -1,3-propanediamine (Bull Chem. Soc. Jpn. 55, 1454-1459 (1982) by M. Kojima and J. Fujita).

nRn = F, or Me, or Cl Similarly, using the above method and appropriately substituted 3-phenyl-3-aminopropionic acid, 1- (2-fluorophenyl) -1,3-propanediamine is prepared. , 1- (2-Tolyl) -1,3-propanediamine and Bu (2-chlorobenzyl) -1,3-propanediamine. Example IN · (S) Production method of small phenyl-1,3-propanediamine NK η

ΝΗ 2 According to literature methods, S-3-N-tertiary-butoxycarbonylamino-3-benzylpropionitrile was prepared from D- (+ a-phenylglycerol (W. J. Wheeler and DD CTBannon J. Label. Compds. Radiopharm. XXXI (4), 305-3 1 5, 1992). When reduction is performed (D. Mitchell and TK Koenig, Synth. Comm. 25 (8), • 93- 200303316 DESCRIPTION OF THE INVENTION CONTINUED (89)

123 1-1238, 1995), and added the borane-dimethylsulfide complex (2N, 3 mL, 6 mmol) to tetrahydrofuran (6 ml) containing the nitrile (lg, 4.06 mmol). In solution. Dimethyl sulfide was removed by distillation, and the resulting solution solution was refluxed for 2.5 hours. Under ice-cooling, a solution of hydrochloric acid in methanol (IN, 3 ml) was added, and then evaporated. The remaining material was dissolved in methanol (10 ml) and 4N hydrochloric acid / dioxane (10 mi) was added. After 1 hour at room temperature, it was evaporated and the aqueous solution containing the resulting product was washed with dichloromethane. A potassium hydroxide solid was added to the aqueous solution to make it alkaline, followed by repeated extraction with dichloromethane. After dehydration and evaporation of the dichloromethane solution, the crude diamine was left as an oil. MS (m / z): 150 · 8 (M + ΗΓ; theoretical value of C9Hi4N2 150.2. Enantiomers, (R) -1-phenyl-1,3-propanediamine are similarly prepared from L- ( +)-cc-phenylglycerol. MS (m / z): 150.9 (M + H) +; C9H14N2 theoretical value 150.2. Example 10: (lR, 2R) -2-methyl-1-phenyl Preparation method of -1,3-propanediamine

Preparation method of 3--3-benzyl propionate such as 2R, 3S, aR, enantiomer (S) G. Davies and I.A.S. Walters, J. Chem. Soc. Perkin Trans. I, 1 129-1139 (1994). -Step B: (2S, 3R) -3-Amino-2-methyl-3 · benzyl propionate: Take -94- 200303316 Description of the invention Continued on page (90) (2S, 3R, aS) -3- (N-benzylmethyl-N-α-fluorenylbenzylamino) methyl-2-methyl-3-phenylpropanoate (13.0 g, 33.55 mmol) and 10% palladium / carbon (13.0 g) Glacial acetic acid (260 mi) was hydrogenated under a hydrogen balloon for 24 hours. The catalyst was 'evaporated' and co-distilled with toluene after filtering off the catalyst to give the title compound as a white solid. MS (m / z): 194.2 (M + H) +; ChH | 5N02 requires 193.3. Step 骝 C: (2S, 3RV3-amine · 2-methyl · 3-benzylpropanamide: Take (2S, 3H) -3-amino-2-methyl-3-phenylpropanoate Ester (6.3 g, 33 mmol) in 2N ammonia in methanol (20 ml) and ammonium hydroxide (28-30%, 40 ml) were stirred at room temperature. After 4 days, concentrated, and then placed in a silica gel short column Chromatography (Dichloromethane · Yodo-methanol-concentrated ammonium hydroxide = 93: 7: 0.7; 90: 10: 0.8) yielded a white solid of amidine. MS (m / z): 179.2 (M + H) ; Theoretical value 178.2.

Step D: HR.2R) -2-methyl · 1-benzyl-1 · 3 · propanediamine: Lithium aluminum argon (2.3 g, 60.60 mmol) was added in batches to an ice bath temperature containing , 3R) -3-Amino-2-methyl-3-phenylpropanamine (2.6 g, 14.59 mmol) in tetrahydrofuran (54 ml) was stirred in the solution for β 4 for 5 minutes. The mixture was heated at reflux for 16 hours. It was cooled in an ice bath, and the reaction was stopped by adding sodium sulfate decahydrate and some methanol in portions until hydrogen evolution ceased. The solids were removed by filtration, and the combined filtrate was washed with two methane methane and the filtrate was evaporated to give the title compound. MS (m / z): 165.2 (Μ + Η) +;

Cl () H16N2 requires 164.3. Example IP: Preparation of (l_S, 2S) -2-methyl-1-phenyl-1,3-propanediamine

NH According to the preparation of the enantiomers, the combination of (lR, 2R) -2-methyl small phenyl-1,3-propanediamine-95- 200303316 2R, 3S, aR) -3- (N-benzylmethylmethylbenzylamino, methyl-2-methyl-3 "phenylpropionate to prepare the title compound

Chem. Soc. Chem. Commun. 1 153-1 155, 1993). The resulting titled human was a crystalline oil. MS (m / z): 165.3 (M + H) +; Ci0H16N2 requires 164.3. Example IQ: Preparation of 3-phenyl · 2,2 · dimethyl-1,3-propanediamine

The title compound is prepared in a similar way: by W. Ten Hoeve and H. Wynberg

Synth. Commun. 24 (15), 2215-2221, 1994. MS (m / z): 179 · ί (M + H) +; ChH18N2 Theoretical value 168.1. Example 1R · 3 -Phenyl-2, -Methyl-1-aminopropyl cyanide *

nh2

Step A · 2,2-Methyl · 3-Hexyl-1 · Dentanylpropene Sodium diisopropyl azodiisocyanate (19.7 mL, 100 mmol) was added dropwise to the content containing 2,2-difluorene 3-Phenyl-1-propanol (8.2 gm, 50 mmol), triphenylphosphine (26.2 gm, 100 mmol) and Zn (N3) 2 · 2 pyridine (Π · 5 gm, 37.5 mmol) Toluene (250 mL) in a stirred mixture (see: Synthesis, (1.990) ρ · 131). After 2.5 hours, Yin's salt (25 gm) was added, and the mixture was filtered and concentrated to an oil. Purification (SiO2, 40% EtOAc / hexane) gave the product of Step A as an oil. Step ·% B · 2,2-—methyl · 3-yl-1-aminopropane: take 2,2-dimethyl · 3-dongyl small azidopropane (3 gm), A mixture of 10% Pd-C, methanol (60 mL), and tetrahydro-squeak-96-200303316 (92) I. Description of the Invention (15 mL) The mixture was stirred at 1 atmosphere of hydrogen and room temperature for 18 hours. The mixture was filtered 'and concentrated to give the title compound as an oil, MS (m / z): 164.1 (M + H) +; ChH ^ N requires 163.1. Example IS: Production method of 1- (aminomethyl dimethylcyclopentane

ΝΗ2

Step A: 1-benzylmethyl-1-cyclopropionitrile--: dropwise add 20 mL of THF solution of cyclopropyl cyanide (3.0 mL, 40 mmol) to -78 ° C, containing freshly prepared diisopropylamine Lithium (40 mmol) in THF (100 mL) was stirred off the mixture. After 30 minutes, a solution of benzyl bromide (7.8 mL, 60 mmol) in THF (20 mL) was added dropwise. The resulting mixture was slowly warmed over several hours and stirred at room temperature for 48 hours. The reaction was stopped (250 mL of saturated NH4C1), extracted with ether (3 X 100 mL), and the combined organic extracts were dehydrated (MgS04). After being concentrated, a yellow oil was produced. Step 骢 B: 1- (Aminomethyl V2-benzidine): Take 1-benzyl-1-cyclopropanenitrile (9.16 gm, 58 mmol) '10% Pd-C (1.5 gm) MeOH (200 mL)

, THF (50 mL) and concentrated HC1 (6 mL) solution under a hydrogen blanket (50 psi) and shake for 15 hours. The mixture was concentrated, water (300 mL) was added, and it was made alkaline with 2N NaOH (pH 10- 〖1). The mixture was extracted with EtOAc (2 X 100 mL), and the combined organic layers were dehydrated (MgSO4), filtered and concentrated to give the title compound. Example 2

-97- 200303316 _ (93) Description of the invention Continued on page 8- (4-Anaphthyl) -5-methylthio-7- (4-pyridyl 1,2,4-triazolo 1 Method for preparing pyrimidine · Step A: 5- (4-Jail. Stupid) -3-methyl-2-methylthiopyridinyl V3H-pyrimidin-4-one

In a 12 liter three-necked round bottom flask with a magnet stir bar, a thermometer, and a 1 liter addition funnel, take ethyl 2- (4-fluorophenyl) acetate (273 g '1.5 mol) and 4-cyano A mixture of pyridine (156.1 g, 1.5 mol) was dissolved in 1.5 liters of DMF. At room temperature, slowly add 1.5 liters of 1.0M tBuOK / tBuOH (1.5 mol) to the solution via an addition funnel. The resulting brown solution was stirred at room temperature for 1 hour. At room temperature, slowly add 750 ml of DMF solution containing 109.7 g of MeNCS (1.5 mol) to the reaction solution. The solution temperature rose from 26 ° C to 33 ° C. The resulting brown solution was stirred for 1 hour. The reaction solution was cooled to about 0 ° C using an ice-water bath, and 93 ml of Mel (1.5 mol) was added to the reaction solution via a 125 ml dropping funnel. The reaction solution was stirred at room temperature. After 30 minutes, a precipitate precipitated. Suspension in chamber

Stir overnight at warm temperatures. The solid was filtered off, washed with water (2 X 200 ml) and dried under vacuum at 50 ° C overnight. 5- (4-fluorophenyl) -3-methyl-2 · methylthio-6- (4-pyridyl) -3H-pyrimidin-4-one was obtained; MS: m / z (M + H) + 328; Ci7Hi4FN3OS theoretical value 327. Step B: 4-Gasbenzyl) -2-methylthio-6- (4 ^ pyridinyl) pyrimidine In a 15 ml round bottom flask with a stir bar, make 5- (4-fluorobenzyl ) -3-methyl-2-methylthio-6- (4-pyridyl) -3H-pyrimidin-4-one (0.327 g, 1 mmol) and 5 ml of POCI3 were stirred at 120 ° C for 16 hours. The remaining POCl3 was evaporated in vacuo. Dark brown residue mixed with ice-water. The resulting acidic dark brown solution was neutralized to pH 7-8 with saturated NaHC03, extracted with EtOAc (2 x 10 ml), and combined with -98-200303316 (94). ) Washed and dehydrated over Na2S04. 4-Chloro-5- (4-fluorophenyl) -2-methylstearyl-6- (4-pyridyl) pyrimidine was isolated by flash chromatography with 50% EtOAc in hexane; MS: m / z (M + H) + 332; CmHhCIFNJ theoretical value 331.8. Step C: 844-Phenylmethylthio-7- (4-pyridyl) -1,2,4-tri ^^ 4,3-clp in a 50-ml round bottom flask with a stir bar In this case, 0.28 g of 4-gas, 5 &lt; fluorofluorophenyl) -2-methylthio-6 · (4-leaf 1: symptomatic) ° * dense bite (0.85 mmol) and 3 ml of ΝΗ2ΝΗ2-Η20 20 m! The EtOH solution was stirred below. The solvent was evaporated, and the residue was mixed with toluene. The residue was dehydrated with toluene and dried under vacuum at 50 ° C overnight. The obtained pale yellow solid was mixed with 40 ml of DCM and 4 ml of CH (OCH3). 3 and 2 ml of TFA were mixed in a 100-ml round bottom flask with a stir bar. The reaction solution was stirred overnight at room temperature. The acidic reaction solution was neutralized to pH 8 using saturated NaHC03. The DCM layer was brine (10 ml) after washing and dehydration with Na2S04. After removing DCM under vacuum, 8- (4-fluorophenyl) -5 · methylthio-7- (4-pyridyl) -1,2,4-triazolo [ 4,3-c] pyrimidine as a yellow solid; MS m / z (M + H) + 338.1; C17H, 2FN5S theoretical value 337.3. FExample 3

Bu (8- (4-qibenjibu attack) -1 meaning 4-trisyl JAJ.-cl pyrimonia. 5-, and amino amines H and its production method -99- (95) ( 95) 200303316 Description of the invention Continued on page 8- (4-fluorophenyl) -5-methylthio-7- (4-pyridyl) -1,2,4-triammonio [4,3- (: ] ° 50 ml of dense bites (1.0 g, 3.0 mmole), potassium carbonate (1.5 g), and (2S) -3-benzylpropan-1,2-diamine (540 mg, 3.6 mmole) The DMF mixture was stirred at room temperature for 48 hours. The reaction solution was poured into water (200 mL), and the resulting precipitate was filtered and washed with water. The crude product was purified by flash chromatography (3% -15% MeOH / NH3 in DCM), Yields 1- (8- (4-fluorophenyl) -7- (4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidin-5-yl) amino-2 ( S) -Amino-3-phenylpropane as a white solid; MS: m / z (M + H) + 440.1; C25H22FN7 theoretical value 439.5. Example 4

2-Ga-3-methyl-6- (4-pyridylmethylamidino V4 (3HV pyrimidinone, 2-Ga-3-methyl-6- (4-exo I: syndrome group) · 5 · ( Preparation method of 3-trioxobenzyl and 2-air-3-methyl-6- (4-pyridyl) 〇 彳 4-1 茇 1 pyrimidinone

Step A: 3-methyl 〇- (3 · methylbenzyl) -6 彳 4-pyrimidinyl M1H, 3H) -pyrimidine · 2.4-dione and 2,6-bis (2-pyridyl) -3 -Methylmetylbenzyl) -3Η-pyrimidinone with 10 N sodium hydroxide (25 ml) and water (50 ml) to 3-methyl-5- (3-methylbenzyl) -2-methylthio -6- (4-pyridyl) -4 (3H) -pyrimidinedione (16.17 g, 0.05 mm) in a solution of dihenane (65 ml). The mixture was stirred at 80 ° C for 16 hours under argon. The mixture was allowed to return to room temperature, adjusted to pH 9 with 1 N hydrochloric acid, and the precipitate was filtered and washed with water to give the title compound; MS (m / z): 292 (M-H) +; Cl7Hi5N302 theoretical value 293.3. -ιοο- 200303316 Description of the invention continued (96) The filtrate was extracted with ethyl acetate (100 mL) and dehydrated with Na2S04. The solution was concentrated in vacuo and the residue was subjected to flash chromatography (10-30% EtOAc in hexanes) to give 2,6-bis (2-chloropyridin-4-yl) -3-methyl-5- (3-toluene Group) -3'-pyrimidin-4-one; MS (m / z) 424.2 (M + H) +; C22Hi6C12N40 theoretical value 423.3. Step B: 2-Gas-3-methylmethylbenzyl) -6- (4-pyridyl) -4 (3Η) -pyrimidinone containing 3-methyl-5- (3-tolyl) -6- A mixture of (4-pyridyl)-(1,3,3) -pyrimidin-2,4-dione (12.5 g, 0.043 mol) and phosphatidyl chloride (65 ml) was refluxed for 16 hours. After excess phosphonium chloride was evaporated, it was co-distilled with toluene. Take the residue and carefully distribute it between a gas-fired solution and an acidic argon solution. The organic solution was washed with water; strip, dehydrated and evaporated, leaving the title compound; MS (m / z): 312 (M + Η) +; C17H14CIN3O theoretical value 311.8. ^ Chloro-3-methyl-6- (4-pyridine and V543-trifluoromethylbenzyl) · 4 (3Η) -pyrimidinone 2-#-1-methyl-6- (4- Pyridinylphenyl) -4Pi))-pyrimidinone. Example 5

2- (8- (4 · Phenylphenyl) -7 彳 4-g specific cold 1,2,4-tris and f4.3-cl-snell-5-yl) Amino-2 -benzyl propyl Sweep ▲ of step _ Method A: 5- (4-fluorobenzyl succinate, succinylmethyl, succinyl, amine, amine) -6- (4- mouth ratio &lt; ^ 4 sides _ take 2-chloro- 3-methylpyridinyl) -5- (4-fluorophenyl) -4 (3H)-° * denseness_ .101-200303316 Description of the Invention Continued (97) (5.43 g, 17.2 mmol) and The cumylamine (4.65 g, 34.4 mmol) was combined in anhydrous isopropanol (about 40 mL), and the mixture was heated at reflux for 48 hours. The reaction was cooled to room temperature, and the solvent 'residue was distributed between a saturated aqueous solution of NaHC03 and CHCh in vacuo. The organic layer was dried over Na2S04 and concentrated. The residue was purified by flash chromatography (1% MeOH / NH3: CHC13) to give a yellow-brown solid product; MS: m / z (M + H) + 415; C25H23FN40 theoretical value 414.5. Step 戤 Β: 2 "Π-methyl · 1-benzyl amine) amine) -4-chloro-5- (4-qiben a certain ice morbidity __ take 5- (4-fluorophenyl)- 3 · methyl-2-((1-methyl-1-phenethyl) amino) -6- (4-pyridine) group (1.24 g '2.99 mmol), benzyl triethyl gasification Ammonium (2.04 g, 8.97 mmol) was combined with diisopropylethylamine (1.16 g, 1.6 mL 8.97 mmol) in phosphorochlorine (approximately 20 mL), and the resulting solution was heated at 100 ° C for 16 hours. The reaction was cooled to Phosphorus chloride was evaporated under vacuum at room temperature, and the residue was distributed between saturated NaHC03 aqueous solution and CHC13. The organic layer was dehydrated with Na2S04 and concentrated. The residue was purified by flash chromatography (20% EtOAc: CHCl3) to give a white solid product ; MS m / z (M + ΗΓ 419; C24H20C1FN4 theoretical value 418 · 8. Step C: 2-((l · methylexthylethyl) amino) -4-Yuejingji · 5 · (4 -random Radical) -6 · (4 · pyridyl) pyrimidin 2-((1-methyl-budongethyl) amino) -4-lact-5--5- (4-gas + yl) -6- (4 -σ ratio Bite) ° • Dense bite (218 mg '0.52 mmol) is combined with a solution containing Moonwell Hydrate (130 mg 2.60 mmol) and isopropanol (about 10 mL). The mixture is heated at 70 ° C for 4 hours. It should be cooled to room temperature, the solvent was evaporated in vacuo, and the residue was purified by flash chromatography (2% MeOH: CHCl3) to give an off-white solid product; MS m / z (M + H) + 415; C24H23FN6 theoretical value 414.5. -I 〇2- 200303316 _ (98) Description of the invention Continued on step D: 2- (8- (4-Phenylbipyridyl) -1,2, cardiac triazolo "4,3-cl pyrimidin-5-yl ) Amine'yl-2-benzylpropane to 2-((1-methyl-1-benzylethyl) amino) -4-fluorenyl-5- (4-fluorophenyl) -6- (4- Exogenous syndrome) σ dense bite (95.1 mg, 0.23 mmol) and trimethyl n-formate (58.4 mg, 0.54 mmol) in CH2C12 (approximately 5 mL). Trifluoroacetic acid (62 · 6 mg, 0.54 mmol) was added, The solution was kept for 1 hour. The reaction mixture was washed with saturated NaHC03. The organic phase was dehydrated with Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography to give an off-white solid product; MS m / z (M + ΗΓ425; C25H2iFN6 theory Value 424.5. Example 6 CF,

5-Ga-7- (2-fluoro-4 "pyridinyl) -8- (3- (trifluoromethyl) fluorenyl-1,2,4-triazolo" 4,3-cl pyrimidine Step A: Preparation of 6- (2-argon-4-α than pyridyl V3-methyl-2-methylthio-5- (3- (trifluoromethyl) benzyl W3H) -pyrimidin-4-one 5-. (4-fluorophenyl) -3-methyl-2-methylthio-6- (4 ^ pyridinyl) -3H-pyrimidin-4-one was prepared in the same manner as 6- (2-chloro- 4-.pyridyl) -3-methyl-2-methylthio-O- (3- (trifluoromethyl) benzyl)-(3Η) -pyrimidin-4-one. Step B: 4-chloro- 6- (2-Chloro-4-pyridinyl V2-methylthio (trifluoromethyl) benzyl) ° ¾-103- 200303316 Description of the invention continued (99) Take 6- (2-Ga-44pyridine) Yl) -3-methyl-2-methylthio-5- (3- (trifluoromethylbubenzyl)-(3Η) -σ-meta-4-one (2.05 g, 5 mmol), P. Ci3 (3.05 g '20 mmol) and diisopropylethylamine (2.58 g, 20 mmol) were stirred in a round bottom flask with a stir bar at 120 ° C for 16 hours. The reaction was cooled to room temperature and added 20 ml of EtOAc and 5 g of 5-2-02 gel into a cooled solution, and then the solvent was evaporated in vacuo at 40 ° C. A brown solid was placed on a piece of SiO 2 gel (approximately 20 g) in 20 ml of 30% EtOAc. Wash with alkane solution The brown filtrate was evaporated in vacuo to give an oily product; MS m / z (M + H) +416.2. The crude intermediate was used directly in the next step without further purification. Step C: 5-methylthio-7- (2 -Steam.-4 "than pyridyl r #methyl tomb) benzyl) -1.2.4-triazolo 1 &gt; 4.3 &lt; 1 pyrimidine containing 4-Ga-6- (2-Ga-4-Mizuki Group) -2-methylthio-5- (3- (trifluoromethyl) · dongyl) ° * dense lake (0.873 g, 2.1 mmol) and 90 ml EtOH of 16.5 ml NH2NH2-H20 In a 150 ml round bottom flask with a stir bar, stir at 7 ° C. The reaction is cooled to room temperature. The solvent is evaporated in vacuo. Toluene is added and the toluene is removed in vacuo to remove the moisture in the residue. C. Dry under vacuum. The obtained pale yellow solid was mixed with 40 ml of DCM, 20 ml of CH (OCH3) 3 and 10 ml of TFA in a 150 ml round bottom flask with a stir bar. The reaction solution was stirred overnight at room temperature. Add Saturated NaHC03 solution into the acidic reaction solution, neutralized to pH 8. The DCM layer was washed with brine (3. X 20 ml) and dehydrated with Na2S04. After DCM was removed in vacuo, a dark brown oil (MS m / z 421.8 (M + H) +), used directly without purification Step β Step D: 5 · # ϋ 二 7J2-Fluoro-4-pyridyltrifluoromethane) (苽)) -1.2,4- 200303316 _ (100) Description of the invention Continuation page takes crude ig containing 5-methylthio -7- (2-chloro-4-pyridyl) -8- (3- (trifluoromethyl) phenyl) -1,2,4-triazolo [4,3-c] pyrimidine with 15 ml 2M 15 ml of 1,4-dihumane in NaOH was stirred in a 150-ml round bottom flask with a stir bar at 80 ° C. The alkaline solution was cooled to room temperature and neutralized to pH 7.5 with 10% HC1. A precipitate formed, filtered, and washed with water (2 X 10 ml). The solid was dried under vacuum at 7 ° C overnight to give a solid product; MS m / z (M + H) + 392.1. Step E: 5-chloro-7- (2-argon-4-pyridyl) -8- (3 -(Trifluoromethyl) benzyl) -1,2,4-

Three-seater and "4,3-c bumiting to get 5-hydroxy-7- (2-chloro-4-pyridyl) -8- (3- (trifluoromethyl) phenyl) -1,2,4 -Trituro [4,3-c] ° dense disease (0.3 g, 0.76 mmol), POC13 (0.459 g, 3 mmol) and diisopropylethylamine (0.387 g, 3 mmol) In a 50-ml round bottom flask with a stir bar, stir overnight at 120 ° C. The reaction solution is cooled to room temperature.

Add 20 ml of EtOAc and 5 g of 3 gel to the cooled solution. The solvent was evaporated under vacuum at 40 ° C. The resulting brown solid was placed on a piece of SiO2 gel (approximately 20 g) and the strip was washed with 250 ml of EtoAc. Brown; the liquid was evaporated in vacuo to produce 5-chloro-7- (2-chloro-4 «^ pyridyl) -8- (3- (trifluoromethyl) phenyl) -1,2, cardiac triazolo [4,3-c] pyrimidine; MS m / z (M) + 410; Cl7H8Cl2F3N5 requires 410.2. Example 7 CF3

-105- 200303316 _ (101) Description of the invention continued 5- (7- (2-argon-4-pyridyl) -8- (3- (trifluorofluorenyl) benzene , 3-cl pyrimidin-5-yl 丨 -2 彳 third butane carbonyl M1RV2.5- heavy 氤 -bicyclic

Take 5-chloro-7- (2-chloro-4-pyridyl) -8- (3- (trifluorofluorenyl) -phenyl) -1,2,4-triammonio [4,3 -c] ° * dense lake (820 mg, 2.0 mmole), potassium carbonate (about 1.0 g) and (-)-2- (third butoxycarbonyl)-(lR, 4R) -2,5-diazo · A 10 ml DMF mixture of bicyclo [2.2.1] heptane (436 mg, 2.2 mmole) was stirred at room temperature for 16 hours. The reaction solution was poured into water (50 mL), and the precipitate was filtered off, washed with water, and dried under vacuum to give an off-white solid product; MS m / z (M) + 572.3: C27H25C1F3N704 theoretical value 572. Example 8

5- (piperidin-4-ylbenzylethyl) amino-4 ^ pyridinyl) -8- (3- (trifluoromethyl) benzyl) -1,2,4-triazolo "4, Step A of the method for preparing 3-cl pyrimidine: the third butane carbonyl group) -4- (trifluoromethanesulfonylamino group 2,3,6-tetrafluorene_ mouth ratio 0 ^ Take lithium diisopropylamine (7.3 mll, 5M, 1 1 mmol) in 25 ml of tetrahydrofuran solution was cooled to -78 ° C, and N (third butoxycarbonyl) -4-oxopiperidine (2.0 -106- 200303316) was added. (102) g, 10.0 mmol) in 25 ml of tetrahydrofuran solution, stir the mixture for 20 minutes. Add N-phenyltrifluoromethanesulfonylimide ((CF3S〇2) 2N-C6H5; 3.9 g, 11 mmol) and leave the cooling tank The mixture was allowed to stir for 3 hours. At this time, the solvent was evaporated, and the residue was purified by an alumina neutral column (5% ethyl acetate in hexane) to give the product; MS m / z (M 10 H) + 332.2; ChHi6N05S theoretical value 331.1. Step B: the third butane carbonyl group M, 2,3,6-tetrapyridin-4-yl) -7- (2-chloro-4 ^ pyridinyl) -8- (3 -(Trifluoromethyl) benzyl M, 2.4-triazolo "4,3-cl pyrimidine

Take 5-chloro-7- (2-chloro-4-pyridyl) -8- (3- (trifluoromethyl) phenyl) -1,2,4-triazolo [4,3-c] pyrimidine (2.0 g, 5.0 mmol), 1- (third butoxycarbonyl) -4- (trifluoromethylphenoxy) -1,2,3,6-tetrahydro leaf 1: Yodo (2.0 g, 6.0 mmol), chlorinated chain (6.64 g, 15.0 mmol), hexamethylditin (2.0 g, 6.0 mmol), and tri-triphenyl scale

Palladium (0.3 g, 0.25 mmol) was combined in dihumane (25 ml), and the resulting solution was heated to 90 ° C for 18 hours. The mixture was added to an aqueous KF solution, and after stirring for 2 hours, it was distributed in methane gas. The organic layer was dried over sodium sulfate, filtered and concentrated to a slurry. Purified by silica gel column chromatography (30% ethyl acetate in hexane) to give a syrupy product; MS m / z (M + H) + 557.2; C27H24F3C1N602 theoretical value 556.2. Step C: 5-Π- (Third butanecarbonyl) -1.2.3.6-tetramethylpyridin-4-yl) -7-benzylethyl) amino-4 · pyridyltrifluoromethyl) benzyl) -1,2,4-three mouth full f 4,3-c 1 mouth bite 5- (1- (third butoxycarbonyl) -1,2,3,6-tetrahydropyridine-4- ) -7- (2-chloro-4-pyridyl) -8- (3- (trifluoromethyl) benzyl) -1,2,4-triazolo [4,3-c] pyrimidine (0.93 g, 1.7 mmol), (S) -a-methylbenzylamine (0.48 g, 4 mmol), oxalic acid acetate (0.06 g, 0.26 mmol), and racemic BINAP (0.16 g, 0.26 mmol) in toluene (15 ml) -107-200303316 _ (103) Description of the invention Consolidated in the following pages, the resulting solution was degassed with nitrogen. Sodium tert-butoxide (0.48 g, 5 mmol) was added and the resulting mixture was heated to 90 ° C for 1 hour. The mixture was distributed between saturated chloroform and ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to a slurry. The residue was purified by silica gel column chromatography (30% ethyl acetate in hexane) to give a syrupy product; MS m / z (M + H) + 642.4; C35H34F3N702 theoretical value 641.3.

Step D: 5-Π- (Third-butanecarbonyl) pyridin-4-ylbenzylethyl) amino-4-pyridyltrifluoromethyl) benzyl) -1.2.4-triazolo "4, 3-(: 1 pyrimidine is 5- (U (third butoxycarbonyl) -1,2,3,6-tetrahydropyridin-4 · yl) -7- (2- (l (S) -phenethyl ) Amino group than pyridyl) -8- (3- (trifluoromethyl) phenyl) -1,2,4-triazolo [4,3-(:] ° dense bite (0.12 g, 0.2 mmol) was combined with platinum oxide (0.03 g, 0.13 mmol) in ethanol (5 ml) and kept at room temperature under a hydrogen blanket for 18 hours. The catalyst was removed by filtration, and the filtrate was concentrated to a slurry. Purified by silica gel column chromatography (30% ethyl acetate in hexane) to give a syrupy product; MS m / z (M + H) + 644.5; C35H36F3N704 theoretical value 643.3.

Step 骡 E: 5- (piperidin-4-ylbenzylethyl) amino-4-pyridyl) -8- (3- (trifluoromethyl) benzyl VI, 2.4-triazolo f4.3- cl pyrimidine is 5- (1- (third butoxycarbonyl) piperidin-4-yl) -7- (2- (l (S) -phenethyl) amino-4-pyridyl) -8- ( 3- (trifluoromethyl) phenyl) -1,2,4-triazolo [4,3-c] pyrimidine (0.03 g, 0.05. Mmol) and trifluoroacetic acid (1 ml) in dichloromethane ( 5 mi), and kept at room temperature for 24 hours. The solution was concentrated, and the residue was distributed between dichloromethane and 10% sodium carbonate. The organic layer was separated, dehydrated with sodium sulfate, filtered, and the solvent was evaporated to give a syrupy product. ; MS m / z (M + H) + 544.1; C3〇H28F3N7 theoretical value 543.2. -108 · 200303316 _ (104) Description of the invention continued example 9

(Ethylbenzyl) amino-4-exo: pyridyl (trifluoromethyl) benzyl) -1.2,4-triazolo "4,3-(: 1pyrimidin-5-yl" -2- ( Tributane carbonyl)-(110-2,5-heavy gas-bicyclic "2.2.ΠHeptane production method according to the preparation of 5- (1- (third butoxycarbonyl) -1,2,3,6-tetrahydro Pyridin-4-yl) -7- (2- (l (S) -phenethyl) amino-4-pyridyl) -8- (3- (trifluoromethyl) phenyl) -1,2, 4-triazolo [4,3-c] pyrimidine was synthesized in the same manner as the title compound; MS m / z (M + H) + 657.4; C35H35F3N802 theoretical value 656.7. Example 10

5- (2,5-Heavy gas-bicyclic "2.2.11 hept-2-yl) -8- (3- (trifluoromethyl) benzyl) -7- (2- (1 0-benzylethyl) Amino-4 ^ pyridinyl) -1,2,4-triazolo "4.3-(: 1 pyrimidine method for preparing 5- {7- (2- (丨 (S) -phenethyl) amino group -4-pyridyl) -8- (3- (trifluoromethyl) • 109- 200303316 __ (105) I Description of the invention ϋ phenyl) -1,2,4-dithalo [4,3-c] 0 dense 5 -yl} -2- (third butoxy carbon)-(lR) -2,5-diazo · bicyclo [2 · 2 · 1] heptane (240 mg, 0.4 mmole) in acetic acid Ethyl acetate (5 mL) solution, treated with HCU ether solution (1M, 4 mL) at room temperature. The suspension was stirred at room temperature for 5 minutes. The resulting precipitate was filtered, washed with ether, and dried under vacuum to give a pale yellow solid product ; MS m / z (M) + 557.3; C30H27F3N8-theoretical value 557.4.

5- (2-Bentylethyltrifluoromethyl) benzyl I than pyridyl 1-1,2,4-triarseno and f4,3-cl pyrimidine method Step A: -6- (4-pyridyltriazine 1-based) Benmou -3H-pyrimidine-2-carbonitrile

At room temperature, add 1,4-diazobicyclo [2,2, to a solution containing NaCN (55 mg) and water (0.1 ml) in methyl methyl-2-α-pyrrolidone (50 mL)] 2] Octane (220 mg, 2 mmole) and 365 mg of 6- (4-leaf |: syndyl) -3-methyl-2-methylthiotrifluoromethyl) phenylhydrazone) · (3Η)- A solution of pyrimidin-4-one in 1-methyl-24-role steel (2 mL). The resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was distributed between water and ethyl acetate. The organic layer was dried over Na2S04 and concentrated. The residue was purified by flash chromatography (20% EtOAc: hexane) to give a colorless oily product; MS (m / z) 357 (M + ΗΓ: CuHhFAW theoretical value 356.3. Step B: 3-methyl-2- (2-benzylethyl) -644 "than pyridyltrifluoromethane) • 110- 200303316 (106) Description of the invention Continued on phenyl —): 3H, densely packed, 4 zero _ at 0 % Methyl-4 · oxo · M4-pyridyl) -5- (3- (trifluoromethyl) -benzyl) -3H, pyrimidine-2-carbonitrile (280 mg, 0.79 mmole) in THF (20 mL ) To the solution was added benzylethylethylmagnesium chloride (1.0M in THF, 1.2 mL). The reaction solution was stirred at 0 ° C for 5 minutes. The β mixture was distributed between saturated ammonium chloride and ethyl acetate. The layer was dehydrated with sodium sulfate, filtered, and concentrated to a slurry. The residue was purified by silica gel column chromatography (30% ethyl acetate in hexane) to give a polymer-like product; MS (m / z) 436 ( M + H) +; C25H2OF3N30 theoretical value 435.4.-Step .m · :. 4-Gas-2- (2-jasperone) -6- (4-pyridyl three most. A, benzyl) Synthesized according to the same method for preparing 2-((Umethyl-1-phenethyl) amino) -4-chloro〇- (4-fluorophenyl) -6- (4- ^ specific bityl) σ Mark The title compound; MS m / z (M plant 440; C24H17C1F3N3 theoretical value 439.9. Step 骡 D: 5- (2-fluorenylethyltrifluoromethyl) fluorenyl V7J4-pyridyl) -1,2,4-tri Preparation of 2- (8- (4-fluorophenyl) -7- (4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine · The same method for pyridyl-5-yl) amino-2-benzylpropane, from 4-chloro-2- (2-phenethyl) -6- (4 ^ pyridyl) -5- (3- (Trifluoromethyl) phenyl) pyrimidine Synthesis of the title compound: MS m / z (M + H) + 446; C25H18F3N5 requires 445.4. Example 12

Cl Cl • 111-200303316 _ (107) Description of the invention continued on 8-Π-methylbenzyl) -5,7-bis (2-chloro-4-pyridyl) -1,2,4-triazolo M, Preparation method of 3-cl pyrimidine Step A · 2 · 6 -Bis (2- (Ga (4 -outer dangling group))-4 -Lan-5- (3-methylexyl) (1-methyl-N-phenethyl) amino) -4-chloro-5- (4-fluorophenyl) -6- (4-pyridyl) pyrimidine, from 2,6-bis (2 -Chloropyridin-4-yl) -3-methyl-5- (3-tolyl) -3fluorene-pyrimidin-4-one to synthesize the title compound.

Step B: 8-Π-methylbenzyl) -5,7-bis (2-chloro-4-pyridyl) VI.2.4-triazolo f4,3-cl -Fluorophenyl) -7- (4-0 than pyridyl) -1,2,4-triazolo [4,3-c] pyrimidin-5-yl) amino-2-phenylpropane The title compound was synthesized from 2,6-bis (2-chloro (4-pyridyl))-4-chloro-5- (3-tolyl) -pyrimidine; MS (m / z) 434.9 (M + H) + C22H14C12N6 Theoretical value 433.29. Example 13

8- (2-¾: yl) -5-methylthio-7- (4-pyridyl1,2.4-triazolo, "4.3-cl pyrimidine production method according to the preparation of 8- (4-fluorophenyl) -5 -Methylthio-7 · (4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine, the title compound was synthesized by the same method; MS (m / z) 370.1 (M + ΗΓ C2iH15N5S theoretical value 369.4. -112- 200303316 _ (108) Description of the invention continued example 14

5- (2 (R)-(hydroxymethyl) pyrrolidinyl) -7- (2-chloro-4-gpyridinyl) -8- (3- (trifluoromethyl) benzyl) -1.2 , 4-Triazolo "4,3-(: 1 pyrimidine production method according to the preparation of 5- {7- (2-chloro-4-pyridyl) -8- (3- (trifluoromethyl) phenyl)- 1,2,4-triazolo [4,3-c] pyrimidin-5-ylb2- (third butoxycarbonyl) · (1ΙΙ) -2,5-diazo-bicyclo [2.2.1] heptane The title compound was synthesized in the same manner as for alkanes; "5 (111/2) 475 (ΜΓ; C22Hi8C1F3N60 theoretical value 474.87. Example 15

Amino-3-benzylpropanyl-U) amino-8- (2-¾: yl) -7- (4-pyridyl) -1,2,4-triazolo [4,3 ^ 1pyrimidine Preparation method: 8- (2-fluorenyl) -5-methylthio-7- (4-exo (: pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine (350 mg (1 mmol), K2C03 (100 mg) and (2S) -3-benzylpropane-1,2-diamine (150 mg, 1 mmol) in anhydrous DMF (about 5 mL), and the mixture was stirred at room temperature 48 hours. At room temperature, water (approximately 10 mL) was added to the reaction solution -113- 200303316 _ (t〇9) Description of the invention continued, a precipitate formed. The suspension was stirred at room temperature for 1 hour. The solid was filtered off, Wash with water (3 X 10 ml) and dry under vacuum at 50 ° C overnight; MS (m / z) 472.3 (iM + H) +; C29H25N7 theoretical value 471.56. Example 16

8- (3,4-Diaminobenzyl V5-methylthio-7- (4-pyridyl VI, 2,4-triazolo "4,3-cl -(Fluorophenyl) -5-methylthio-7- (4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine, the title compound was synthesized; MS (m / z) 388.3 (M) +; C17HhC12N5S theoretical value 388.27. Example 17

5- (3 (SV stupid methyl-pipeten-1-yl) -8- (2-fluorenyl) -7- (4-pyridyl) -1,2,4-triazolo f4,3-cl Preparation of pyrimidine: 8- (2-fluorenyl) -5-methylthio-7- (4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine (200 mg, 0 · 54 mmol), K0C03 (100 mg) and (S) -2-benzylmethylpiperine (170 -114- 200303316 (110) I Description of the invention Continued mg, 0.97 mmol) in anhydrous DMF (about 4 mL ), The mixture was heated at 100 ° C for 48 hours. The reaction was cooled to room temperature and distributed between water and ethyl acetate. The organic layer was dehydrated with Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography (2 -8% Me0H / NH3: CH2Cl2) to give a yellow-brown solid product; MS (m / z) 498.3 (M + H) +; C3lH27N7 theoretical 497.59.

Fluorenyl) pyhalidin-1-ylbenzylethyl) amino-4-pyridyl) -8-((3- (trifluorofluorenyl) benzyl M.2,4-triazolo The method for preparing pyrimidine is 5- (1- (third butoxycarbonyl) -1,2,3,6-tetrahydropyridin-4-yl) -7- (2- (l (S) -phenethyl) Amino-4-pyridyl) -8- (3- (trifluoromethyl) phenyl) -1,2,4-triazolo [4,3-c] pyrimidine, from 5- (2 (R)-(hydroxymethyl) -pyrrolidin-1-yl) 7- (2-chloro-4-pyridyl) -8- (3- (trifluoromethyl) phenyl) -1,2, Cardiotriazolo [4,3-c] pyrimidine to synthesize the title compound; MS (m / z) 560 · 4 (Μ + Η) +; C30H28F3N70. Theoretical value 559.59. Example 19 Using the above general description and the above example, The compounds in Table 1 below were prepared. • 115-200303316 _ (111) Description of the invention continued on Table 1 ^ Name Experimental formula MS (M + H) + 5- (3-phenylpropanyl) amino-8- (4- Fluorophenyl) -7- (4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine C25H2lFN6 425.0 5- (3-Benzylpropanyl) amino-8- ( 3-tolyl) -7- (4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine c26h24n6 420.51 8- (3- (trifluoromethyl) phenyl) -7 -(4-pyridyl) 1,2,4-triazolo [4,3- c] Pyrimidine Ci7H10F3N5 342.0 5- (Upiperidinyl) -8- (3-tolyl) -7- (2-chloro-4-hydroyl) -1,2,4-Sanjun [4,3 -c] ° * dense lake C2iH2〇C1N7 406.0 5- (3-benzylpropanyl) amino-8- (3- (trifluoromethyl) phenyl) -7- (4-pyridyl) -1 , 2,4-triazolo [4,3-c] σ dense lake C26H21F3N6 475.3 5- (2 (S) -amino-3-phenylpropanyl) amino-8- (3,4-di Chlorobenzyl) -7- (4-pyridyl) -1,2,4-trisigma [4,3-(:] ° * dense c25h21ci2n7 491.0 5- (2 (S) -amino-3 -Phenylpropanyl) amino-8- (3- (trifluoromethyl) phenyl) -7- (4 · pyridyl) -1,2,4-triazolo [4,3-c] Pyrimidine c26h22f3n7 490.0 5- (4- (Third butoxycarbonyl) piperin-1-yl) -8- (3- (trifluoromethyl) phenyl) -7- (2- (2-phenylpropane- 2-yl) amino-4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine C35H37F3N802 659.5 5- (piperin-1-yl) -8- (3- (tri Fluoromethyl) benzyl) -7- (2- (2-phenylprop-2-yl) amino-4-pyridyl) 1,2,4-trisigma [4,3-c] Shout bite C30H29F3N8 559.0 5- (4- (Third-butoxycarbonyl) piperinyl) -8- (3-tolyl) -7 · (2-chloro-4-tonidinyl) -1,2,4 -Triazolo [4,3-c] ° Bite c26h28cin7〇2 507.0

-116- 200303316 _ (112) Description of the Invention Continued 5- (piperinyl) -8- (3- (trifluoromethyl) phenyl) -7- (2- (l (S) -phenethyl) ) Amino-4-Saldinyl) 1,2,4-triazolo [4,3-c] pyrimidine C29H27F3N8 545.2 5- (2 (S) -amino-2-methyl-3-phenyl Prop-1-yl) amino-8- (3- (trifluoromethyl) benzyl) -7- (2-chloro-4-lipidyl) -1,2,4-trisigma [ 4,3-(:) σ dense bit C27H23C1F3N7 538.2 5- (2 (S) -amino-2-methyl-3 · phenylprop-1-yl) amino-8- (3- (trifluoromethyl Phenyl) -7- (4-pyridyl) 1,2,4-triazolo [4,3-c] pyrimidine C27H24F3N7 504.4 5- (3,5-dimethylpiperin-1-yl) -8- (3- (trifluoromethyl) yl) -7- (2- (l (S) -phenethyl) amino-4-pyridyl) 1,2,4-triazolo [4, 3-c] pyrimidine c3 丨 h3 丨 f3n8 573.5 5- (3,5-dimethylpiperin-1yl) -8- (3- (trifluoromethyl) benzyl) -7- (2-chloro- 4-Speaking pyridyl) -1,2,4-triazolo [4,3- (:) c23h21cif3n7 488.1 5- (2 (S) -amino-3-phenylpropanyl) amino- 8- (3- (trifluoromethyl) phenyl) -7- (2-chloro-44 (: pyridyl) 1,2,4-triazolo [4,3-c] pyrimidine C26H2lCiF3N7 524.3 5- (2 (S) -amino-3-phenylpropanyl) Yl-8- (3-chloro-4-fluorophenyl) -7- (4-exo i: pyridyl) -1,2,4-triazolo [4,3-cp dense lake c25h21cifn7 474.3 5- ( 2 (S) -pyrrolidinylmethyl) amino-8- (3,4-dichlorophenyl) -7- (4 ^ pyridinyl) -1,2, triazolo [4,3- c] σ dense bit C2iH19C12N7 441.3 5- (2 (S) -pyrrolidinylmethyl) amino-8- (2-fluorenyl) -7- (4-pyridyl) -1,2,4-triazole Benzo [4,3-c] pyrimidine c25H23n7 422.2

-U7- 200303316 _ (113) Description of the invention continued 5- (2 (S)-(hydroxymethyl) pyrrolidinyl) -8- (3- (trifluorofluorenyl) phenyl) -7- (2 -(l (S) -phenethyl) amino-4-.pyridinyl) -1,2,4-triazolo [4,3-c] pyrimidine C30H28F3N7O 560.5 5- (1- (2-propyl Yl) pyrrolidine-2 (S) -ylmethyl) amino-8- (3,4-dichlorobenzyl) -7- (4-pyridyl) -1,2,4-trisigma [ 4,3-c] ° C24H25CI2N7 483.3 5- {7- (2- (Cyclopropyl) amino-4-pyridyl) -8- (3- (trifluoromethyl) phenyl) -1 , 2,4-triazolo [4,3-c] pyrimidin C30H31 F3N8〇2 593.5 pyridin-5-ylb 2- (third butoxycarbonyl)-(lR) -2,5-diazo-bicyclo [ 2.2.1] Heptane-2- {7- (2- (cyclopropyl) amino-4-pyridyl) -8- (3- (trifluoromethyl) phenyl) -1,2, triphenylene Zolo [4,3-c] pyrimidine · 5 · kib ([R) -2,5-diazo-bicyclo [2.2.1] heptane C25H23F3N8 493.5 5- (4- (third butoxycarbonyl) piper Phen-1-yl) -8- (3- (trifluoromethyl) phenyl) -7- (2- (cyclopropyl) amino-4-carboxyl) -1,2,4-tri σ and [4,3-(:] ° dense lake C29H31F3N8O2 581.3 5- (piperidin-1-yl) -8- (3- (trifluoromethyl) phenyl) -7- (2- (cyclopropyl ) Amino-4-pyridine ) -1,2,4-triazolo [4,3-(:] hypertensive C24H23F3N8 481.4 5- (1- (2-propyl) piperidin-3-yl) amino-8- (3,4 -Dichlorobenzyl) -7- (4- said pyridyl) -1,2,4-triazolo [4,3-(:] pyrimidine c24h25ci2n7 483.4 5- (1- (2-propyl) pyrrolidine -2 (S) -ylmethyl) amino-8- (2-fluorenyl) -7- (4-pyridinyl M, 2,4-triazolo [4,3-c] ° * dense lake C28H29N7 464.3 5- (1- (Third-butoxycarbonyl) pyrrolidine-2 (S) · methylmethyl) amino-8- (3- (trifluoromethyl) phenyl) -7- (2-chloro -4-leaf blade base) 1,2,4-triturate [4,3-(:] 11 dense lake c27h27cif3n702 574.5

-118- 200303316 _ (114) I Description of the invention continued on 5- (1- (Third-butoxycarbonyl) piperidin-3-yl) amino-8- (3- (tri ~ fluoromethyl) phenyl) -7- (2-chloro-4 ^ pyridinyl) -1,2,4-triazolo [4,3-c] pyrimidine c27h27cif3n7o2 574.4 5- (piperidin-3-yl) amino-8- ( 3- (trifluoromethyl) phenyl) -7- (2- (cyclopropyl) amino-4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine c25h25f3ns 464.3 5- (1- (Third butoxycarbonyl) piperidin-3-yl) amino-8- (3- (trifluoromethyl) phenyl) -7- (2- (cyclopropyl) amino- 4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidinyl C30H33F3N8O2 483.4 5- (1- (third-butoxycarbonyl) piperidin-3-yl) amino-8- (3,4-- Yiqidongji) -7-(4-3 than Dianji) -1,2,4-trisigma [4,3-(:] ° ¾ ° ¾ C26H27C12N702 541.3 5- (2 (S) -Amino-3 · (4 · fluorophenyl) prop-1-yl) amino-8- (3-chloro-4-fluorophenyl) -7- (4-pyridyl) -1, 2,4-Sanjun and [4,3-c] ° * close c25h2〇cif2n7 492.4 5- (1- (2-propyl) piperidin-3-yl) amino-8- (3-trifluoro Methylphenyl) -7- (2- (cyclopropyl) amino-4-.pyridinyl) -1,2,4-triazolo [4,3-c] pyrimidine C28H3 1 F3N8 537,4 5 · ( Piperidin-3-yl) amino-8- (3-trifluoromethylphenyl) -7- (2- (cyclopropylmethyl) amino-4-pyridyl) -1,2,4- Triazolo [4,3-c] pyrimidine C26H27F3N8 509.5 5- (N (third butoxycarbonyl) piperidin-3-yl) amino-8- (3-trifluoromethylphenyl) -7- ( 2- (Cyclopropylmethyl) amino-cardiopyryl) -1,2, carditriazolo [4,3-c] pyrimidine c31h35f3n8o2 609.3 5-((1- (2-butylpyridine- 2 (S) -yl) methyl) amino-8- (2-fluorenyl) -7- (4-pyridyl) -1,2,4-triazolo [4,3-(:] ° dense C29H31n7 478.4

-119- 200303316 Description of the invention continued on 5-((l- (Upropyl) pyrrolidin-2 (S) -yl) methyl) amino-8 · (2-theyl) -7- (4-7 Biyodo group)-[, 2,4 · tripyrido [4,3-c] pyrimidine C28H29N7 464.4 5-((pyrrolidin-2 (S) -yl) methyl) amino-8- (3-chloro -4-fluorobenzyl) -7- (4-pyridyl) -1,2,4-triazolo [4,3-c] ° * close bit C2lHl9ClFN7 424.2 5-fluorenylthio-8- (3- Murine · 4-((ratio 1 ~ 2 (S) -yl) methyl) aminophenyl) -7- (4-pyridyl) · 1,2,4 · triazolo [4,3 -c) pyrimidine C22H22CiN7S 452.2 Example 20

Add 5-cyanopyridine to a 5-liter round bottom flask with a magnet stir bar

(83.9 g, 805.5 mmol) into a solution of theophylethyl acetate (172.6 g, 805.5 mmol) in DMF (800 mL). During the period, potassium tributoxide (805.5 mL, 1M third butanol solution) was added dropwise via a dropping funnel. A solution of methyl thioisocyanate (58.9 g, 805.5 mmol) in DMF (400 mL) was added dropwise over 30 minutes. The resulting red-brown mixture was stirred at room temperature for 2 hours. After the mixture was cooled to 0eC, a solution of methyl iodide (1 14.3 g, 805,5 mmol) in DMF (300 mL) was added dropwise over 30 minutes. The β mixture was stirred vigorously at room temperature for 14 hours. At this point, the mixture was diluted with water to increase the solvent volume by a factor of four. The mixture was stirred vigorously for 4 hours' to form a suspension. The solid was collected by filtration and washed with plenty of water. The solid was stirred in ethyl acetate to form a suspension, then collected by filtration, and washed with diethyl ether. • 120 · 200303316 _ (116) I Description of the invention Continuation sheet After drying, a pale yellow solid was produced. The product was purified by TLC (4% MeOH: CHC13). MS m / z 360 (MH) +. Example 2 1 ci

Cl

Prepared according to Example 20. Example 22

In a 1 liter round bottom flask with a reflux condenser and a magnetic stir bar, add

Add cans of brewed chlorine (107.7 g, 65.3 mL, 700 mmol) to methylthio ° * bite ketone (25.01 g, 70.0 mmol) * β. Heat the solution to 150 ° C and stir vigorously for 14 hours. At this time, TLC (4% MeOH: CHCl3) showed that the starting material was consumed. After the mixture was allowed to cool to room temperature, POC13 was removed in vacuo. The residue was repeatedly combined with toluene and concentrated (4 X 50 mL methylbenzyl) to azeotropically exclude a small amount of POC13. The residue was dissolved in CH2C12 and adsorbed on silica gel powder (30 g). The resulting slurry was dried under vacuum, then applied to a short silica column, and dissolved in 2.5% MeOH: CHCl3. The relatively non-polar fractions contain the desired product. These fractions were concentrated to give a yellow / brown oil. The product was purified by TLC (4% MeOH: CHCl3), and the purity was judged by 1H NMR> 95%. MS m / z 364 (MH) +. -121-200303316 (117) Example 23

Description of the invention

Prepared according to Example 22. Example 24

In a 1-liter round-bottomed flask with a magnetic stir bar, add isopropyl alcohol (300 mL) and Tsutsui Monohydrate (52.4 g, 54.1 mL, 104.6 mmol) to chlorine ° density (18.9 g '52.3 mmol )in. The resulting solution was heated at 60 ° C for 14 with vigorous stirring

hour. At this point, a yellow precipitate formed and TLC (4% MeOH: CHCl3) showed that the starting material had been completely consumed. The mixture was concentrated and the residue was distributed between saturated aqueous NaHC03 and CH2C12. The organic layer was dehydrated with MgS04, and concentrated to give a yellow-brown solid product. The purity was judged by 1H NMR &gt; 90%. MS m / z 360 (MH) +. Example 25

-122-200303316 (118) Description of the invention continued

TMJA

In a 1-liter round-bottomed flask with a magnet stir bar, add trimethyl vinegar (16.7 g, 16.2 mL '156.9 mmol) and CH2Cl2 (300 ml) to Yuejingji * dense lake (18.9 g, 52.3 mmol) The medium β mixture was taught at room temperature, and then trifluoroacetic acid (5.96 g, 4.02 mL, 156.9 mmol) was added. The resulting solution was stirred at room temperature for 16 hours. At this point, a yellow precipitate formed and TLC (4% MeOH: CHCl3) showed that the starting material had been completely consumed. The reaction mixture was washed with a saturated NaHC03 aqueous solution, and the organic layer was dehydrated with MgS04 and concentrated. After the residue is dissolved in the minimum amount of CH2CI2 (about 60 ml), add Yimei (500 ml) slowly until it forms.

The solids were collected until the orange precipitate was collected, and the filtrate was concentrated. A second portion of the precipitated product was collected according to the previous step to produce a yellow / orange solid. The purity was judged by 1H NMR &gt; 95%. MS m / z 370 (ΜΗ) +. Example 27

Cl CI

Prepared according to Example 26. -123- (119) (119) 200303316 Description of Invention Continued

Ditome methylpyrimidine dimethyl sulfide (from Example 27) (103 g, 28.7 mmol) was suspended; in dioxane (200 mL), 2N aqueous NaOH (100 mL) was added. The quinone was stirred at 70 ° C for 2 hours, at which time TLC (10% MeOH: CHCl3) showed that the starting material had been completely consumed. The reaction mixture was made acidic by the addition of an IN HC1 aqueous solution, and then neutralized by adding a saturated NaHC03 aqueous solution. The resulting mixture was vigorously stirred and flushed with nitrogen in a fume hood for 2 hours to exclude toxic methyl mercaptan gas. After the mixture was concentrated, it was distributed between saturated NaHC03 aqueous solution and CHC13. The organic layer was dried over Na2S04 and concentrated to give a yellow semi-solid, which was used directly in the next step without further purification. MS m / z 340 (MH) +.

Take triazolomethylpyrimidine dimethyl sulfide (from Example 27) (1.62 g, 29 · 92 mmol) and suspend it in No. 2 (100 mL), and add 2N NaOH aqueous solution (100 mL) . The mixture was stirred at 60 ° C for 2 hours, at which time TLC (10% MeOH: CHCl3) showed that the starting material had been completely consumed. After adding IN HC1 aqueous solution -124- 200303316 (120) to the reaction mixture, the reaction mixture was made acidic and neutralized by adding saturated NaHC03 aqueous solution. The resulting mixture was stirred vigorously and flushed with nitrogen in a fume hood for 2 hours to exclude toxic methyl mercaptan gas. The mixture was concentrated to an aqueous suspension. The solid was collected, rinsed with water and ether sequentially, and dried under vacuum to produce an off-white solid, which was used directly in the next step without further purification. MS m / z 359 (MH) +. Example 30

Hydroxytriazolopyrimidine (9.07 g, 27.50 mmol) was combined with POCi3 (100 mL), and the resulting suspension was heated at 115 ° C for 16 hours. The resulting dark solution was concentrated, and the residue was repeatedly combined with toluene and concentrated (3 X 50 mL toluene) to azeotropically exclude a small amount of POCl. The residue was purified by flash chromatography (3% MeOH: CHCl3), and the relatively non-polar product was taken and concentrated to give a red-brown oil. MS m / z 359 (MH) +. Example 3 l

A hydroxytriazolopyrimidine (from Example 29) (10.49 g, 29.3 mmol) was suspended in POCl13 (about 120 mL). The suspension was heated at 115 ° C for 16 hours. The resulting dark solution was concentrated, and the residue was repeatedly combined with toluene and concentrated (3 X 50 mL -125- Description of the Invention Continued 200303316 (121) methylbenzyl) in order to azeotropically remove the residual POC13. The residue was purified by flash chromatography c (3% MeOH: CHCl3), and a relatively non-polar product was taken off and concentrated to give a red-brown oil. MS m / z 377 (MH) +. Example 32a h2n

nh2 BOC-ON ___

100 ml of dioxane containing 1,2-diamino-2-methylpropane (17.6 g, 0.2 mo1) and 100 ml of aqueous solution were cooled to Ot: 0 and triethylamine (30 g, 0.3 mo1) was added. ) And BOC-ON (54 g, 0.22 moi), stirred for 16 hours, allowed it to rise to room temperature. The β mixture was concentrated, extracted twice with 100 ml of ethyl acetate, and the combined organic phases were washed with saturated sodium chloride and sodium sulfate. Dehydrate, filter, and concentrate to a slurry. Purification by silica gel chromatography (2% methane solution containing 2M ammonia in methanol) gave a solid. MS m / z (M + Η) 189.2; C9H20N2O2 requires 188.2.

Example 32b

5 ml of chloroform containing triazolopyrimidine (from Example 30) (1.1 g '3 mmol) and diamine (from Example 32a)-(1.7 g, 9 mmol) were heated to 60 ° C for 2 hours. The mixture was distributed between dichloromethane and 10% sodium carbonate. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated to a slurry. Purification by silica gel chromatography (sequentially 20% and 50% ethyl acetate in hexane) yielded a slurry. MS m / z (M + H) 510.4; C29H31N702 requires 509.3. -126- 200303316 (122) Description of the Invention Continued Example 32c

Take three σ sitting and σ dense lakes (from Example 32b) (0.72 g, 1.4 mmol) and 3 ml of trifluoroacetic acid in 20 ml of dichloromethane and stir at room temperature for 3 hours. The mixture was distributed between 10% sodium carbonate and dichloromethane. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dehydrated over sodium sulfate, dried over sodium sulfate, and evaporated to give a solid. The solid was washed with hot ethyl acetate, filtered and dried. MS m / z (M + Η) 410.3; C24H23N7 requires 409.2. Example 32d

Take amine-containing trispit and σ-tight bite (from Example 32c) (0.12 g, 0.3 mmol), acetone (0.06 g, 1 mmol), and sodium triethyloxyborohydride (0.21 g, 1 mmol) 5 ml of gas was stirred at room temperature for 3 hours. The mixture was distributed between chloroform and 10% sodium carbonate. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layers were dehydrated over sodium sulfate, filtered and the solvent was concentrated to give a slurry. Purification by silica gel chromatography (2% ethyl acetate containing 2M ammonia in methanol) gave 0.12 g of a slurry. This slurry was dissolved in ethyl acetate, and 1 ml of a 2M HC1 ether solution was added. The solvent was concentrated to give a solid. MS m / z (M + H) 452.3; C27H29N7 -127- 200303316 (123) Description of the invention Continued $ Theoretical value 451.3.

Example 32e.

Na (OAc) 3BH was obtained from aminotriazolopyrimidine (from Example 32c) (0.12 g, 0.3 mmol), ring steel (0.08 g, 1 mmol), and sodium triacetoxyoxyborohydride (〇 • 21 g, 1 mmol) of 3 is called chloroform and stirred at room temperature for 3 hours. The mixture was distributed between chloroform and 100 / o &amp; Junner. The organic layer was separated and the aqueous layer was extracted with chloroform. Combined Organic 0 ^

51 sound sodium sulfate is dehydrated, the solvent is filtered and concentrated to produce a slurry. Purified by the silica gel method (2% ethyl acetate containing 2M ammonia in methanol), resulting in 0.14 g of a slurry. This slurry was dissolved in ethyl acetate, and 1 ml of a 1M HCli bond solution was added to shrink the solvent to give a solid. MS m / z (M + H) 478.2; C29H31N7 requires 477.3. fExample 33

g, 0. 6 mmol) and diisopropylethylamine (0.13 g, 1 mmol) in 5 ml of digas. The solution was stirred at room temperature for 3 hours. The β solution was distributed between dichloromethane and 10% carbonic acid. The organic layer was separated and the aqueous layer was extracted with methane. Combined organic .128-200303316 (124) Description of the invention continued page The layer was dehydrated with sodium sulfate, filtered and the solvent was concentrated to form a slurry. Purified by silica gel chromatography (2% ethyl acetate in methanol containing 2M ammonia) to give a slurry of 0.1 g. This slurry was dissolved in ethyl acetate, and 1 ml of a liM HC1 ether solution was added. The solvent was concentrated to give a solid. MS m / z (M + H) 464.3; C28H29N7 requires 463.3. Example 34

Combine triazolopyrimidine chloride (from Example 30) (7.84 g, 22.0 mmol) with Boc-protected aminopiperidine (14.9 g, 70.0 mmol) and a minimum amount of CHC13 (about 40 mL). CHCl ^ oily residue was evaporated at 105 ° C and heated at 105 ° C for 15 minutes. The residue was distributed between saturated Na2CO3 aqueous solution and CHCU. The organic layer was dried over Na2S04 and concentrated. The residue was purified by flash chromatography (2 ° / MeOH / CHCl3) to give a Boc-protected intermediate as a yellow foam (4.67 g). MS m / z 536 (MH) +. This material was dissolved in CHC13 (20 mL) and trifluoroacetic acid (5 mL) was added. The solution was stirred at room temperature for 2 hours -129- 200303316 (125) Description of the Invention Continued, and then slowly diluted by adding a saturated Na2C03 aqueous solution. The aqueous mixture was extracted with CHC13, and the organic layer was dehydrated with Na2SO4. The aqueous mixture was extracted with CHC13, and the organic layer was dehydrated with Na2S04. The residue was purified by flash chromatography (20% NH3 / MeOH: CHC13) to give a yellow foam which was removed from the protected piperidine. 1H NMR δ MS m / z 436 (MH) +. Example 36a h3ch2co2c

Take 100 ml of ethyl acetate containing ethyl piperidinate (15.7 g, 0.1 mol) and 100 ml of a 10% sodium carbonate solution and cool to 0 °. Add di-tert-butyl dicarbonate (24 g, 0 · H mol) 'Stir for 4 hours and allow to rise to room temperature. The ethyl acetate layer was separated and the aqueous phase was distributed in ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over sodium sulfate, filtered and concentrated to a slurry. Silica gel chromatography

Purification (10% ethyl acetate in hexane) gave a syrup. MS m / z (M + H) 258.1; C13H23N04 requires 257.2. Example 36b

A 100 ml THF solution containing Example 36a (2L2 g, 0.082 mol) was cooled to -70 ° C. Add lithium bis-trimethylsilylamine (100 ml of 1M osmium, O.i m〇i), and search for 15 minutes. Add Methyl Kee (15.1 g, 0.11 mol), search and stir for 1 hour, and let it rise to room temperature. The mixture was poured onto saturated ammonium chloride, and the chain extraction was 2-130-200303316 (126) Description of the invention continued on page. The combined ether layers were distributed in saturated sodium chloride, dehydrated over sodium sulfate, filtered, and the solvent was concentrated to produce a slurry. MS m / z (M + H) 272.1; C14H25N04 requires 271.2. Example 36c

Take a solution containing Example 36b (16.8 g, 0.062 mol), 100 ml IN sodium hydroxide and _100 φ ml ethanol solution and heat to 80 ° C for 18 hours. The mixture was concentrated, acidified with 1 M phosphoric acid, and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated to a solid. MS m / z (M + H) 244.4; C12H21N04 theoretical 243.2 ° Example 36d

A 100 ml toluene solution containing Example 36c (7.9 g '0.033 mol), diphenylphosphonium azide, (10.7 g, 0.039 mol), and triethylamine (3.9 g, 0.039 mol) was heated to 100 ° C for 1 hour. The solution was washed with saturated sodium bicarbonate, dehydrated with sodium sulfate, and the solvent was reduced to form a slurry. Purified by silica gel chromatography (5% ethyl acetate in hexane) to give a slurry. MS m / z (M + H) 241.2; C12H21N203 requires 240.2. Example 36e

νγ ο 1 -131-200303316 (127) Description of the invention Continued Take a 50ml THF solution containing Example 36d (4 g, 0.017 mol) and potassium trimethylsilanolate (4.5 g, 0.035 mol) and stir at room temperature for 18 hours . The solvent was concentrated to a slurry. The slurry was distributed between saturated sodium bicarbonate and dichloromethane. The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dehydrated over sodium sulfate, filtered and concentrated to a slurry. 3.5 g MS m / z (M + H) 215.3; theoretical value 214.2. Example 36f

Example 37

Example 38

-132- 200303316 (128) Description of the Invention Continued Example 39

Combine triazolopyrimidine chloride (from Example 31) (3.27 g, 8.7 mmol) with Boc-protected aminopiperidine (3.73 g, 17.4 mmol) and a minimum amount of CH.C13 (about 20 mL) The resulting solution was heated to evaporate CHC13 at 105 ° C. The oily residue was heated at 105 ° C for 15 minutes. The residue was distributed between saturated Na2C03 aqueous solution and CHC13. The organic layer was dried over Na2S04 and concentrated. The residue was purified by flash chromatography (1% MeOH: CHCl3) to give a BocM intermediate as a yellow foam. MS m / z 554 (MH) +. This material was dissolved in CHC13 (20 mL) and trifluoroacetic acid (10 mL) was added. The solution was stirred at room temperature for 2 hours and then slowly diluted with saturated Na2C03. The aqueous mixture was extracted with CHC1; the organic layer was dehydrated and concentrated with Na2S04, and the residue was purified by flash chromatography (20% NH3 / MeOH: CHC13) to produce a yellow foam with deprotected pyridine. MS m / z 454 (MH) +. -133- 200303316 Description of Invention Continued (129) Example 4 1

In a 250 ml round-bottomed flask with a reflux condenser and a magnetic stir bar, the chloropyrimidine (from Example 22) (8.95 g, 24.66 mmol) was dissolved in aminoacetaldehyde dimethyl acetal (5.44 g, 5.64 mL, 51.78 mmol). The resulting solution was heated to 140 ° C and stirred for 1.5 hours. At this point, TLC (10% MeOH: CHCl3) and MS showed that the starting material was consumed. After the mixture was cooled to room temperature, water was added to stop the reaction, and the mixture was extracted with CHC13, dried over NaS04 and concentrated. The residue was purified by flash chromatography using a 5-95% EtOAc / hexane gradient and the product fractions were concentrated to give a yellow solid. MS m / z, M + 1 433.3, M-1 431.3 'C24H24N402S Theoretical value 432.16.

Example 43

200303316 (130) Description of the invention Continuation sheet In a 250 ml round bottom flask with a reflux condenser and a magnetic stir bar, take 3,4-monochloro-milk ° dense lake (from Example 23) (7.0 g '1 8 · 4 mmol) was dissolved in aminoethyl dimethyl condensation (4,06 g, 4.2 ml, 38.6 mmol) *. The resulting solution was heated to 140 ° C and stirred for 1.5 hours. At this time, TLC (10% MeOH: CHCl3) and

MS showed starting material was consumed. After the mixture was cooled to room temperature, water was added to stop the reaction, and the mixture was extracted with CHC13, dried over Na2S04 and concentrated. The residue was purified by flash chromatography using a 5-60% EtOAc / hexane gradient and the product was concentrated to give a yellow solid. MS m / z, M + 1 451.1, M-1 449.1, C20H2 () Ci2N402S theoretical value 450.07 Example 44

In a 150 ml round-bottomed flask equipped with a reflux condenser and a magnetic stir bar, fluorenyldimethylacetal (from Example 42) (3.16 g, 7.32 mmol) was dissolved in 2N HCI aqueous solution (60 ml). The resulting solution was heated to 130 ° C and stirred for 2 hours. At this point, TLC (1 ·· 1 EtOAc: hexanes) and MS showed that the starting material was consumed. After the mixture was allowed to cool to room temperature, the HC1 solution was slowly poured into a 1-liter Erlenmeyer flask containing 300 ml of an aqueous solution of sodium bicarbonate. The pH of the solution was measured to be about 8 and then extracted with CHC13, dehydrated with Na2S04 and concentrated. The residue was repeatedly combined with methylbenzyl and concentrated (3 X 30 ml toluene) to azeotropically remove trace amounts of water and dried overnight in an oven at 60 ° C. MS m / z, M + 1 357.2, 355.2. C2 丨 HI6N4 02S theoretical value 356.13. -135- 200303316 (131) Description of Invention Continued Example 45

In a 250 ml round-bottomed flask with a reflux condenser and a magnet stir bar, take 3,4-digas dimethyl condensate (from Example 43) (5.9 g, 13.1 mmol) and dissolve it in 2N HC1 aqueous solution ( (0 ml). The resulting solution was heated to 130 ° C and searched for 2 hours. At this point, TLC (1 ·· 1 EtOAc: hexanes) and MS indicated that the starting material was consumed. After the mixture was allowed to cool to room temperature, the HCI solution was slowly poured into a 2-liter Erlenmeyer flask containing 600 ml of an aqueous solution of sodium bicarbonate. The pH of the solution was measured to be about 8, and then extracted with CHC13, dehydrated with Na2S04, and concentrated. The residue was repeatedly combined with toluene and concentrated (3 X 50 ml methylbenzyl) to azeotropically exclude a small amount of water, and dried in a 60 T oven overnight. MS m / z, M + 1 375.4, 373.2. C17H12C12N402S Theoretical value 374.02. fExample 46

In a 100 ml round-bottomed flask with a reflux condenser and a magnetic stir bar, add phosphonium chloride (23.3 g, 15 mL, 152 mmol) to fluorenyl pyrimidine (from Example 44) (2.17 g, 6.08 mmol) * . The resulting solution was heated to 150 ° C 'and stirred vigorously for 18 hours. At this point, TLC (10% MeOH..CHCl3) showed that the starting material had been consumed. • 136-200303316 (132) Description of the Invention Continued. After the mixture was allowed to cool to room temperature, POC13 was removed in vacuo. The residue was repeatedly combined with methylbenzyl and concentrated (4 X 50 ml toluene) to azeotropically remove a small amount of POC13. The residue was dissolved in 10% MeOH: CHCl3 and adsorbed on a silica gel powder (40 mg). The obtained Rong: the material was dried under vacuum, and then added to the short crushed stone column at 5-10 ° /. MeOH: CHCl3 gradient dissolution. The product fractions were concentrated to give a brown solid. MS m / z, M + 1 357, C21Hi3C1N4 theoretical value 356.08. Example 47

In a 25 ml round bottom flask with a reflux condenser and a magnet stir bar, add

Add canister gas (766.65 mg, 5ml, 5mmol) to 3,4-dichlorohydrin. Dense lake (from Example 45) (750 mg, 0.2 mmol). The resulting solution was heated to 150 ° C and stirred vigorously for 18 hours. At this time, TLC (10 ° / .MeOH: CHCl3) showed that the starting material had been consumed. After the mixture was allowed to cool to room temperature, POC13 was removed in vacuo. The residue was repeatedly combined with toluene and concentrated (4 X 10 ml toluene) in order to azeotropically exclude a small amount of POC13. The residue was dissolved in 10% MeOH: CHCl3 and adsorbed in Silicone powder (10 mg). The resulting slurry was dried under vacuum, then applied to a short crushed stone column, and dissolved in a gradient of 5-10% MeOH: CHCl3. The product fractions were concentrated to give a brown solid. MS m / z M + 1 375.1. C17H9ChN4 requires 373.99. Example 48

• 137- 200303316 (133) Description of the Invention Continued In a 50ml round-bottom flask with a magnet stir bar, take a moss-based double-ringed vomit

Chloride (from Example 46) (600 mg, 1.69 mmol) was dissolved in DMF (10 ml) and R-N- (2-pyrrolidinylmethyl) -isopropylamine (502.6 mg, 3.54 mmol) was added. The resulting solution was stirred at room temperature for 1 hour. At this point, TLC (10% MeOH / CHCl3) and MS showed that the starting material was consumed. Add water to stop the reaction, extract with CHC13, dehydrate with NaS04 and concentrate. The residue was purified by flash chromatography using a 3-10% MeOH / CHCl3 gradient, and the product fractions were concentrated to give a yellow solid (260 mg). 4 NMR, MS m / z M + 1 463.4, C29H30N6 requires 462.25. Example 49

In a 50 ml round bottom flask with a magnetic stir bar, take 3,4-dichlorobicycloimidazole, and the gaseous pyrimidine (from Example 47) (1.1 g, 2.94 mmol) was dissolved in DMF (15 ml). Add RN- (2-a1: Hardidinemethyl) -isopropylamine (800 mg, 6.18 mmol). The resulting solution was stirred at room temperature for 1 hour. At this point, TLC (10% MeOH / CHCh) and MS showed that the starting material was consumed. The reaction was quenched by adding water, extracted with EtOAc, dried over NaSCU and concentrated. The residue was purified by flash chromatography using a 70-100% EtOAc / hexane gradient and the product fractions were concentrated to give a yellow solid. MS m / z M + 1 481.2, M-i 479.2, C25H26C12N6 theoretical value 480.16 β -138- 200303316 (134) Description of the invention continued on Example 50

Example 5 1

Example 53

-139- 200303316 (135) Description of the Invention Continued Example 54

Example 55

Example 56

Example 57

-140-200303316 (136) Description of the title page Example

Example 59

Example 60

Δ

In a μ W sealed tube with a magnetic stir bar, take three tons of lysine ° · dense lake chloride (from Example 30) (610 mg, 1.65 mmol) and dissolve in R-(-)-2-external I: Luo Methanol (500 mg,-4.95 mmol). The resulting solution was heated to 12 CTC and stirred under microwave conditions for 5 minutes. At this point, MS showed that the starting material had been completely consumed. The mixture was quenched by addition of water, and the resulting product precipitated, collected through a porous glass funnel, and dried in an oven at 60 ° C. A yellow solid product was produced. MS m / z 422.19, C25H22N60, M + 1 423.3, M-1 421.1. -141. 200303316 (137) Description of the Invention Continued Example 6 0 a

Take alcohol (298 mg, 0.70 mmol) (from Example 60) and dissolve it in dichloromethane (40 mL), and add triethylamine (77.9 mg, 0.77 mmol) and methanesulfonyl chloride (88.2 mg, 0.77 mmol) in this order. . The solution was stirred for 4 hours. At this time, isopropylamine (207 mg φ, 3.5 mmol) was added and the resulting solution was heated under reflux for 16 hours. At this time, the mixture was distributed between dichloromethane and a saturated aqueous solution of sodium hard acid. The organic phase was dried over Na2S04 and concentrated. The residue was purified by flash chromatography (20% NH3 / MeOH: CHCl3) to give the product 3 MS m / z 464 (MH) + as a yellow foam. Example 60b

In a sealed rW tube with a magnetic stir bar, take 3,4-dichlorotriazole pyrimidine chloride (500 mg, 1.29 mmol) (from Example 3 1) and dissolve it in R-fluorene-2-pyrrolidine methanol (391 mg, 3.88 mmol). The resulting solution was heated to i20 ° C and stirred under microwave conditions for 5 minutes. At this point, MS showed that the starting material was consumed. Water was added to stop the reaction, and the resulting product was collected in a fritted glass funnel and dried in an oven at 60 ° C. A yellow solid product was obtained ^ MS m / z 440.09 C2 丨 丨 8Cl2N6O, M + 1441.2 'M-1 439.0. -142- 200303316 (138) Description of the Invention Continued Example 60c

ci I) MsCI, NEt3 OH 2) iMe2CHNH ,, Δ

Take alcohol (322 mg, 0.73 mmol) (from Example 60b) and dissolve it in dichloromethane (40 mL), and then add triethylamine (80 · 9 mg, 0 · 80 mmol) and methanesulfonyl chloride (91 · 6) in this order. mg, 0.80 mmol) β solution was searched out for 4 hours β At this time, isopropylamine (207_mg ^, 3.5 mmol) was added, and the resulting solution was heated under reflux for 16 hours ^ At this time, the mixture was distributed between dichloromethane and a saturated sodium carbonate aqueous solution. The organic phase was dried over Na2S04 and concentrated. The residue was purified by flash chromatography (20% NH3 / MeOH: CHC13) to give a yellow foamy product. MS m / z 483 (MH) +. Example 61

In a 5-liter round bottom flask with a magnetic stir bar, add 4-cyanopyridine (38.08 g, 366.0 mmol) to DMF containing 3,4-dichlorobenzyl ethyl acetate (85.26 g, 366.0 mmol) ( 360 ml). Via a dropping funnel, potassium tert-butoxide solution (366.0 mL, 1M tert-butanol solution) was added dropwise to the reaction within 1 hour. A solution of methyl thioisocyanate (26.77 g, 366.0 mmol) in DMF (180 mL) was added dropwise over 30 minutes. The resulting red-brown mixture was stirred at room temperature for 2 hours. After the mixture was cooled to 0 ° C, a solution of methyl iodide (22.7 g, 366.0 mmol) in DMF (100 mL) was added dropwise over 30 minutes. The mixture was stirred vigorously for 14 hours at room temperature -143 · 200303316 Description of the invention continued (139). At this point, the mixture was diluted with water to increase the solvent volume by a factor of four. The mixture was stirred vigorously for 4 hours to form a suspension. The solid was collected by filtration and washed with plenty of water. The solid was stirred in ethyl acetate to form a suspension, then collected by filtration, washed with ether, and dried to give an off-white solid. The product was purified by TLC (4% MeOH: CHC13). MS m / z 379.3 (MH) +. Example 62

In a 1 liter round bottom flask with a reflux condenser and a magnetic stir bar, add

Add $ 粦 brewed chlorine (107.7 g, 65.3 mL, 700 mmol) to methylthio sigmadol (26 · 5 g, 70.0 mmol) *. The resulting solution was heated at 150 ° C for 14 hours. At this time, TLC (4% MeOH: CHCl3) showed that the starting material was consumed. After the mixture was allowed to cool to room temperature, POC13 was removed in vacuo. The residue was repeatedly combined with toluene and concentrated (4 X 50 ml toluene) in order to azeotropically exclude a small amount of POC13. After the residue was dissolved in CH2C12, it was adsorbed on a silica gel powder (30 g). The resulting slurry was dried under vacuum, then applied to a short silica column, and dissolved in 2.5% MeOH: CHCl3. The relatively non-polar fractions contain the desired product. These fractions were concentrated to give a yellow / brown oil. The product was purified by TLC (4% MeOH: CHCl3), and the purity was judged by 1H NMR &gt; 95%. MS m / z 383.7 (MH) +. Example 63

-144- 200303316 _ (140) Description of the invention Continued In a 1 liter round bottom flask with a reflux condenser and a magnetic stir bar, add isopropyl alcohol (300 ml) and osmium monohydrate (52.4 g, 54.1 mL, 104,6 mmol) to chlorosigmaemia (20.1 g, 52.3 mmol). The resulting solution was heated vigorously at 60 ° C for 14 hours. At this point, a yellow precipitate formed and TLC (4% MeOH: CHCl3) showed that the starting material had been completely consumed. The mixture was concentrated and the residue was distributed between a saturated aqueous solution of NaHC03 and CH2C12. The organic layer was dehydrated by MgSCU and concentrated to give a yellow-brown product solid. The purity was judged by 1H NMR &gt; 90%. MS m / z 379 · 3 (ΜΗ) + 0 f Example 64

Esters (16.7g, 16.2mL, 156.901011101) and ^ (: 12 (30000)) to Yuejingji (1 9.8 g, 52.3 mmol). The mixture was allowed to incubate at room temperature. After the reaction, add trifluoroacetic acid (5.96 g, 4.02 mL, 156.9 mmol). The resulting liquid was stirred at room temperature for 16 hours. At this time, a yellow precipitate formed, and TLC (4% MeC> H: (: H (: 13) showed that the starting material had been completely consumed. The reaction mixture was washed with saturated NaHC037iC $ solution, and the organic layer was dehydrated with MgS04 and concentrated. The residue was taken up in a small amount of CH2C12 (about 60 ml). Ether (500 ml) was added slowly until a yellow / orange precipitate formed. The solid was collected, and the filtrate was concentrated. The second precipitated product was collected according to the previous steps to produce a light yellow / white solid. Purity judged by 1H 1 ^ 乂 11> 95%. MS m / z 389 (MH) +. • 145- 200303316 _ (141) Description of the invention Continued Example 65

Take triazolomethylpyrimidine dimethylsulfide (from Example 64) (1 1.62 g, 29.92 mmol) and suspend it in No. 57 (100 mL), and add 2N NaOH solution (〖00 mL). The mixture was stirred at 60 ° C for 2 hours, at which time TLC (10% MeOH: CHCl3) showed that the starting material had been completely consumed. After adding IN HC1 aqueous solution to the reaction mixture to make it acidic, saturated NaHC03 aqueous solution was added to neutralize. The resulting mixture was vigorously stirred off and flushed with nitrogen in a fume hood for 2 hours to exclude toxic methyl mercaptan gas. The mixture was then concentrated to an aqueous suspension. The solid was collected, rinsed with water, rinsed with ether, and then dried under vacuum to produce an off-white solid, which was used directly in the next step without further purification. MS m / z 359 (MH) +. Example xx

Using the above general description and the above examples, the compounds of Table 2-6 can be prepared. -146- 200303316 _ (142) Description of the invention continued on Table 2

U V W X Rl 丨 R12 C-H N N C-H 3-CF3-phenyl 4-0 than C-H N N C-H 4-F-phenyl 4-. Chalolinyl CH NN CH 3-Me-4-F-benzyl 4- ° * dense octyl CH NN CH 3-CU4-F-phenyl 2-Me-4 "than octyl CH NN CH 3,4- Di-Cl-phenyl 2-NH2-4-pyrimidinyl CH NN CH 3-cyclopropyl-4-F-phenyl 4 ^ pyridinyl CH CH NN 3-CF3-phenyl 4-cholyl CH NN 4-F-phenyl 4 -σ dense lake CH CH NN 3-Me-4-F-phenyl 2-NΗ2-4-pyridyl CH CH NN 3-C1-4-F-phenyl 2- Me-4- ° * Dyssyl CH CH NN 3,4-di-Cl-benzyl 4-diphenyl CH CH NN 3-cyclopropylbenzyl 4 -speaking methyl CH CH N CH 3-CF3- Phenyl 4-. Benzyl CH CH N CH 4-F-phenyl 4-pyridyl CH CH N CH 3-Me-4-F-benzyl 4-4 sigmathio CH CH N CH 3-CU4- F-benzyl 4-CH-CH NCH 3,4-di-CU Benthyl 2-Me-4-p than CH-CH N CH 3-cyclopropylphenyl 2-NH2-4-pyrimidine N c-ch3 N CH 3-CF3-phenyl 4-succinyl N CH N CH 4-F-phenyl 4-quinolinyl

-147-200303316 _ (143) Description of the invention continued

N C-〇HN CH 3-Me-4-F-benzyl 4- ° * dense group N c-cf3 N CH 3-CN4-F-phenyl lake N CH N CH 3,4-di-CU Phenyl 2-NH2-4-pyrimidinyl N CH N CH 3-cyclopropylphenyl 4-? Pyridyl N CH CH N 3-CF3-phenyl 4-4 linyl N CH CH N 4-F- Phenyl 4-π dense group N CH CH N 3-Me-4-F-phenyl 2-NH-2-4-pyridyl N CH CH N 3-CN4-F-phenyl 2-Me-4-pyrimidinyl N CH CH N 3,4-di-CU Phenyl 4-p-synyl-N CH CH N 3-Cyclopropylphenyl 4-t7 than Yodo N CH NN 3-CF: r Benzyl 4-0 Benzyl N CH NN 4-F-phenyl 4 ^ specific octyl N C-OH NN. 3-Me-4-F-phenyl 4 ^ quinolinyl N CH NN 3-C1-4-F-benzene Benzyl group N CH NN 3,4-di-C1-phenyl 2-Me-4 ^ pyridyl N c-ch3 NN 3-cyclopropyl-4-F-phenyl 2-NH2-4 -Pyrimidinyl CH NN CH 6-F-2-fluorenyl 4 -p-pyridyl CH NN CH quilinyl 4-0 pyridyl CH NN CH 3-isoquin 4-yl 4-pyrimidinyl CH NN CH 7- Isoquinolinyl 2-NH2-4-pyridinyl CH NN CH 7 ^ quinolinyl 2-Me-4- ° ^ yl yl CH CH NN 2- theyl 4-yl yl yl CH CH NN 6-quinolyl 2-ΝΗ2 · 4-pyridyl CH CH NN 3-iso 喳Phenyl 2-Me-4- ° * dense octyl CH CH NN 7-isoquinolinyl 4-exo (: syndyl CH CH NN 7-fluorenyl 4 ^ than octyl-148- 200303316 _ η 44 ^ 1 Description of the invention Continued CH CH N CH 5-Indolyl 4-leaf 1: Syndio CH CH N CH 6-quinolinyl 4-continyl CH CH N CH 6-benzimidazolyl 2-NH2-4 -# fc 淀 基 CH CH N CH 7-Isophosphorinyl 2-Me-4- ^ octyl CH CH N CH 7-σ chalin 4-phyllyl N c-ch3 N CH 6-CF3- Sulfan-2-yl 4 -17 haloyl N CH N CH 6-benzofuranyl 4-4 linyl N C-〇HN CH 6-benzothienyl 4-pyrimidinyl N c-cf3 N CH 2- Benzothienyl 2-Me-4 "Bidyl N CH N CH 5-Benzo 4-phenyl 2-NH2-4-0 • Dynyl N CH N CH 6-Benzhumidyl 4 N CH CH N 2-σsedenyl 4-4 phenyl group N CH CH N 1 -Me-6-4 sigmayl 4-sigmadenyl N CH CH N 1-Me-6-pyridyl 2 -NΗ2-4-ρ specific group N CH CH N 3 -creanyl 2-Me-4-amino group N CH CH N 5-benzofuranyl 4-7 specific group N CH CH N 5-benzene Benzothienyl 4-0 is NCH NN 2-benzofuranyl 4-exobenzyl N CH NN 6. Sedazolyl 4-tonyl N C-OH NN 5-benzohumidyl 4-® Charinyl N CH NN 2-fluorenyl 4-pyrimidinyl N CH N 'N 2-quinolinyl 2-Me -4 ^ specific group N c-ch3 .NN 6-F-2-fluorenyl 2-NH2.4-group

table 3

-149- 200303316 _ (145) Description of the invention Continued UVWX R11 R12 CH NN CH 3-CF3-phenyl 4-0 than Yodo CH NN CH 3-isopropyl-4-F-phenyl 4-p CH NN CH 3-Me-4-F-phenyl 4 ^ Dyssyl CH NN CH 3-C1-4-F-phenyl 2-Me-4-p than Y CH NN CH 3,4-di -Cl-phenyl 2-NH2-4-pyrimidinyl CH NN CH 3-cyclopropylphenyl 4-p-pyridyl CH CH NN 3-CF3-phenyl 4-4 linyl_OH CH NN 3-iso Propylphenyl 4-chrysyl CH CH NN 3-Me-4-F-phenyl 2-ΝΗ2-4-α than pyridyl CH CH NN 3-C1-4-F-phenylpyridyl CH CH NN 3,4-di-CU phenyl 4-0 than CH CH NN 3-cyclopropyl-4-F-phenyl 4-pyridinyl C, H CH N CH 3-CF3-phenyl 4- . C-H C-H N C-H 3-isopropylphenyl 4-. Titanyl CH CH N CH 3-Me-4-F-phenylchalcyl CH CH N CH 3-C1-4-F-phenylene 4- into bityl CH CH N CH 3,4-di-C1 -Benzyl 2-Me-4-p than phenyl CH CH N CH 3-cyclopropylphenyl 2-NH2-4-pyrimidinyl N c-ch3 N CH 3-CF3-benzylyl N CH N CH 3-Isopropyl-4-F-phenyl 4-benzyl N C-OH N CH 3-Me-4-F-phenyl 4-π dense bite: N C-CF N CH 3-C1- 4-F-phenyl 2-Me-4-, BiYenyl N CH N CH 3,4-di-CU Benzoyl 2-NH2-4- ^

-150- 200303316 Description of the Invention Continued (146) N C-H N C-H 3-cyclopropylphenyl 4-0 compared to N-C-H C-H N 3-CF3-phenyl 4-. Charinyl N CH CH N 3-Isopropylphenyl 4-sigmadenyl N CH CH N 3-Me-4-F-benzyl 2-NΗ2-4-pyridyl N CH CH N 3-C1- 4-F-phenyl 2-Me-4- ° compactyl N CH CH N 3,4-di-Cl-phenyl 4 N-methyl ethyl N CH CH N 3-cyclopropyl-4-F-benzene The radical 4-sigma is NCH NN 3-CF3-phenyl4-. Pyridyl N CH NN 4-F-phenyl 4-0 Pyridyl N C-OH NN 3-Me-4-F-benzyl 4-portalinyl N CH NN 3-CU4-F-phenyl 4-. Densyl N CH NN 3,4-di-CN phenyl 2-Me-4-p than octyl N c-ch3 NN 3-cyclopropyl-4-F-phenyl 2-NH2-4-pyrimidinyl CH NN CH 6-F-2-S: Base 4-leaf symptomatic group CH NN CH 6-4 Porphyrinyl 4-orbital group CH NN CH 3- Isophosphorinyl 4-Oral compact group-CH NN CH 7-isoquinolinyl 2-NH2'4-pyridyl CH NN CH 7-quinolinyl 2-Me-4-methyl-CHCH NN 2-fluorenyl 4- ° * denselyl CH CH 'NN 6 ^ quinolinyl 2-NH2-4-pyridinyl CH CH NN 6 -isoσchrysyl 2-Me-4- in octyl CH CH NN 7-isoquinolinyl 4-. Pyridinyl C-H C-H N N 7-orallyn

-151-200303316 __ (147) I Description of invention continued on Table 4

GUVWQG R1 CH NN CH H (1,1- -mono-Mc-2- NH2 &quot; 3- (4-Cl-phenyl) propyl) amino group CH NN CH H (2-Me-2-NH2-3- (4-F-phenyl) propyl) amino CH NN CH H (2-Me-2-NH2-3-cyclohexylpropyl) amino CH NN CH H (3-p than 0-4 -yl- (Propyl) amino CH NN CH H (1,1-di-Me-2-imidazol-4-yl-ethyl) amino CH NN CH H 3-benzyl-piperin-1-yl CH NN CH H (1 -Isopropyl · Taste-3 -yl) amino CH NN CH 1 (R) -Phenyl-1-ylamino 1-Chenyl CH NN CH Phenethynyl1-Phenyl CH NN CH 1 (R) -phenethyl-1-ylamino 4-piperidinyl

-152- 200303316 Description of the Invention Continued (148) CH CH N CH 5-Pyridinyl 4-r than Phenyl CH CH N CH Charinyl Methyl CH CH N CH 6-Benzimidazolyl 2-NΗ2- 4 · Pyridyl CH CH N CH 7-isofluorinyl 2-Me-4-e denselyl CH CH N CH 7-quinolinyl 4-supridinyl N c-ch3 N CH 6-CF3-furan- 2-yl 4 -P ratio N CH N CH 6-benzofuranyl 4-4 linyl N C-OH N CH 6-benzo 4 phenyl 4-dimethyl N c-cf3 N CH 2- Benzo 4-phenyl 2-Me-4 "pyridinyl N CH N CH 5-benzo 4-azolyl 2-NΗ2-4 · pyrimidinyl N CH N CH 6-benzohumazolyl 4-0 N CH CNH N 2 -σsedenyl 4-tiquinolyl N CH CH N 1 -Me-6-M 丨 Junyl 4- ° * denselyl N CH CH N l-Me-6-indolyl 2 · ΝΗ2-4 "than pyridinyl N CH CH N 3 -σ glutanyl 2-Me-4- ° § N-CH CH N 5-benzofuranyl 4-titanium N CH CH N 5 · Episigma sedenyl 4-pyridyl N CH NN 2-benzofuranyl 4-0 than pyridyl N CH NN 6-benzo 4 azolyl 4-α specific octyl N C-OH. NN 5-benzene Benzozolyl 4-fluorinyl N CH NN 2-fluorenyl 4 pentyl N CH NN 2-quinolinyl 2 -Me-4 "Byodo group N c-ch3 NN 6-F-2-fluorenyl 2-ΝΗ2 · 4-σ compaction group CH NN CH ethoxy (3-phenyl-2-ΝΗ2-propyl) Amino-153-200303316 Description of the Invention Continued (149) CH NN CH (Cyclopropylamidino) Amine 3,5-Di-Me-piperinyl CH NN CH (4-piperidinylmethyl) amine ΗCH NN CH (cyclohexylmethyl) amino 4-piperidinyl CH NNN Η (1,1-di-Me-2-NH2-3- (4-CUphenyl) propyl) amine CH NNN Η (2-Me-2-NH2-3- (4-F-phenyl) propyl) amino CH NNN Η (2-Me-2-NH2-3-cyclohexylpropyl) amino CH NNN Η ( 3-leaf &lt; -4-yl-propyl) amino CH NNN Η (1,1-di-Me-2-imidazol-4-yl-ethyl) amino CH NNN Η 3-benzyl- Piperin-1-yl CH NNN Η (1 -isopropyl-17nonyl-3 · group>) Amino CH NNN 1 (R) -Phenyl-1-ylamino 1-piperinyl CH NNN Phenylethynyl 1-Chenyl CH N-NN 1 (R) -Phenethyl-1-ylamino 4-piperidinyl CH NNN Ethoxy (3-phenyl-2 · ΝΗ2-propyl) amino CH NNN (cyclopropylmethyl) amino 3,5-di-Me-piperinyl CH NNN (4-piperidinylmethyl) amine Η

-154- 200303316 _ (150) Description of the invention Continued CH NNN (Cyclohexylmethyl) Amino 4-Phenyl CH CH N CH Η (1,1-Di-Me-2-NH2 -3- (4- Cl · phenyl) propyl) amino CH CH N CH Η (2-Me-2-NH2-3- (4-F-phenyl) propyl) amino CH CH N CH Η (2-Me-2 -NH2-3-cyclohexylpropyl) amino CH CH N CH Η (3-^ ratio-4 -yl-propyl) amine CH CNH N CNH Η (1,1-di-Me-2-imidazole- 4-yl-ethyl) CH CNH N CH Η 3-benzyl-pipen-1-yl CH CH N CH Η (1-isopropyl- &amp; Chenzhen-3 -yl) amino CH CH N CH 1 (R) -Phenethyl-1-ylamino-1-piperidinyl CH CH N CH Phenylacetylene: yl1-piperinyl CH CH N CH 1 (R) -phenethyl-1-ylamino 4-Methenyl CH CH N CH ethoxy (3-phenyl-2-ΝΗ2-propyl) amino CH CH N CH (cyclopropylmethyl) amino 3,5-di-Me-piperin -U group CH CH N CH (4-piperidinylmethyl) amino group CH CH N CH (cyclohexylmethyl) amino group 4-17

-155-200303316 _ Π5Π Description of the invention Continued Table 5

UVWQG R1 CH NN CH Η (1,1-di-Me-2-NH2-3- (4-Cl-phenyl) propyl) Amino CH NN CH Η (2-Me-2-NH2-3- ( 4-F-phenyl) propyl) amino CH NN CH Η (2-Me-2-NH2-3-cyclohexylpropyl) amino. CH NN CH Η (3-α 比 --4 -yl- (Propyl) amino CH NN CH Η (1,1-di-Me-2-imidazol-4-yl-ethyl) amino CH NN CH Η 3-benzyl-piperin-1-yl CH NN CH Η (1-Isopropyl-σ Nong Dian-3 -yl) amino CH NN CH 1 (R) -phenethyl-N-aminoamine 1-piperidinyl CH NN CH phenylethenyl 1-piperidinyl CH NN CH 1 (R) -phenethyl-1-ylamino 4

-156- 200303316 Description of the invention continued (152) CH NN CH ethoxy (3-phenyl-2-NH2-propyl) amino CH NN CH (cyclopropylmethyl) amino 3,5-diyl CH NN CH (4-piperidinylmethyl) amino Η CH NN CH (cyclohexylmethyl) amino 4-propidinyl CH NNN Η (1,1-di-Me-2-NH2-3- ( 4-Cl-phenyl) propyl) amino CH NNN Η (2-Me-2-NH2-3- (4-F-phenyl) propyl) amino CH NNN Η (2-Me-2-NH2 -3-cyclohexylpropyl) amino CH NNN Η (j-0 ratio · 4-yl-propyl) amino CH NNN Η (1,1-di-Me-2-imidazol-4-yl-ethyl ) Amino CH NNN Η 3-phenyl f7-piperidin-1-yl CH NNN Η (1-isopropyl-17 agro-3 -yl) amino CH NNN 1 (R) -benzyl-[-yl Amino 1-piperidinyl C »HNNN Benzoethynyl 1-peak glutenyl CH NNN 1 (R) -Phenyl-1-ylamino 4-bromidyl CH NNN Ethoxy (3-phenyl-2 · ΝΗ2-propyl) amino

-157- 200303316 _ (153) Description of the invention continued

Ri

CH NNN (cyclopropylmethyl) amino 3,5-di-Me-piperinyl CH NNN (4-piperidinylamido) aminoΗCH NNN (cyclohexylmethyl) amino 4- Table 6 UVWQG R1 CH NN CH H (2-NH2-3-phenyl-propyl) Amino CH NN CH H (2-Me ^ 2-NH2-3- (4-F-phenyl) propyl ) Amino group CH NN CH H (2-Me-2-NH2-3-cyclohexylpropyl) amino group Γ UX 4L NN CH H (j -.Chen-1 -yl-1 -Hexyl-3-oxo (Propyl) amino CH NN CH H (1, N di-Me-2-imidazol-4-yl-ethyl) amino CH NN CH H 3-benzylmethyl-piperidin-1-yl CH NN CH 1 (R) -Phenethylamino 1-σ-Chenyl CH NN CH Phenethynyl 1-CH 17 phenyl CH NN CH 1 (R) -Phenyl-phenylamino 4-Hydroyl

-I58- 200303316 Description of the Invention Continued (154) CH NN CH ethoxy (3-phenyl-2-ΝΗ2-propyl) amino CH NN CH (cyclopropylmethyl) amino 3,5-di- Me-piperinyl CH NN CH (4-piperidinylmethyl) amino Η CH NNN Η (2-NΗ2-3-phenyl-propyl) amine CH NNN Η (2-Me-2-NH2 -3- (4-F-phenyl) propyl) amino CH NNN Η (2-Me-2-NH2-3-cyclohexylpropyl) amino CH NNN Η (3-^ chen-1 -yl- 1-Allyl-3-oxopropyl) amino CH NNN Η (1,1-di-Me-2-imidyl-4-yl-ethyl) amino CH NNN Η 3-benzyl-piper Fluoren-1-yl CH NNN 1 (R) -benzyl-1-ylamino 1-sulfanyl CH NNN. Phenethyl 1-yl. Chlorinated CH NNN 1 (R) -benzyl-1-ylamino 4-Methionyl CH NNN Ethoxy (3-phenyl-2 · ΝΗ2-propyl) Amino CH NNN (Cyclopropylmethyl) ) Amino 3,5-di-Me-piperin-1-yl CH NNN (4-piperidinylmethyl) amino Η CH CH N CH Η (2-ΝΗ2-3-phenyl-propyl) amine • 159-200303316 (155) Description of the invention CH CH N CH H (2-Me-2-NH2-3- (4-F-phenyl) propyl) amino CH CH N CH H (2-Me -2-NH2-3-cyclohexylpropyl) amino group CH CH N CH H (3 -17 octyl-1 -yl-1 -yl-3-oxopropyl) amino group CH CH N CH H (1, 1-Di-Me-2-imidazol-4-yl-ethyl) amino CH CH N CH H 3-benzyl-pipero-1-yl CH CH N CH 1 (R) -benzyl-1- Amino 1-peak phenyl CH CH N CH phenylethynyl 1-piperidinyl CH CH N CH 1 (R) -phenethyl-1-ylamino 4-peak pyridyl CH CH N CH ethoxy ( 3-phenyl-2-NH2-propyl) amino CH CH N CH (cyclopropylmethyl) amino 3,5-di-Me-pipero-1-yl CH CH N CH (4-piperidine Methyl) amine group CH CH NN Η (2-NΗ2-3-benzyl-propyl) amine group CH CH NN Η (2-Me-2-NH2-3- (4-F- ) Propyl) amino CH CH NN Η (2-Me-2-NH2-3-cyclohexylpropyl) amino CH CH NN Η (3 --1 -yl · 1 -yl-3-oxopropyl (Amino) -amino-160-200303316 Description of the invention Continued (156) CH CH NN Η (1,1-Di · Me-2-imidyl) 4 -yl-Ethyl) CH CH NN Η 3-Benzyl -Phenyl-1-yl CH CH NN 1 (R) -Phenyl-N-ylamino 1-sigma stiltyl CH CH NN Phenethynyl U-Phenyl CH CH NN 1 (R) -phenethyl Amino 4-Chloridinyl CH CH NN Ethoxy (3-phenyl-2-ΝΗ2-propyl) Amino CH CH NN (Cyclopropylmethyl) Amino 3,5-Di-Me-pipehyl Small group CH CH NN (4-piperidinylmethyl) amino hydrazone

Biological analysis The following analysis was used to determine the ability of the compounds of the present invention to inhibit the production of TNF-α and IL-1-β. The second analysis method can be used to determine the inhibitory effect of TNF-a and / or IL-1-β after oral administration of test compounds to mice. The third analysis method can be used to determine the ability of the compounds of the present invention to inhibit glucagon binding by using an in vitro analysis of glucagon binding inhibition. The fourth φ analysis method, the in vitro assay of cyclooxygenase enzymes (COX-1 and COX-2) inhibitory activity, can be used to determine the ability of the compounds of the present invention to inhibit COX-1 and / or COX-2. The fifth assay, the Raf-kinase inhibition assay, can be used to discriminate the ability of the compounds of the present invention to inhibit the phosphorylation of MEK by activated Raf-kinases. Analytical method of lipopolysaccharide activating mononuclear white blood cells to produce TNF. Mononuclear white blood cell isolation method Analyze test compounds in vitro for their ability to inhibit the production of TNF by mononuclear white blood cells activated by bacterial lipopolysaccharide (LPS). Residual blood obtained from the local blood bank -161-200303316 __ (157) I Description of the invention Continuing ball (a by-product of platelet separation), f: icObPaqUe plus (Pharmacia Pharmaceutical Factory), density gradient centrifugation Peripheral blood monocytes

(PBMCs). Suspend PBMCs in DMEM (complete medium) supplemented with 2% FCS, 10 mM, 0.3 mg / ml lysinate, 100 Lf / ml penicillin G, and 100 mg / ml streptavidin stearate, 2 X 1 〇6 个 / mi. Cells were plated in Falcon 96-well flat-bottomed culture plates (200 μl / well) and cultured overnight at 37 ° C and 6% C02. Wash with 200 μl / well of fresh medium to exclude unattached cells. Concave pores containing attached cells (approximately 70% mononuclear leukocytes) were supplemented with 100 µl of freshly cultured test compound preparation method. The test compound was dissolved in DMZ. Compound storage solutions were prepared at an initial concentration of 10-50 μM. Dilute the stock solution to 20-200 μM before complete medium. Each compound was then prepared at a concentration of two serial dilutions of two each. Treatment of cells with test compounds and activation of TNF with lipopolysaccharide

100 microliters of each test compound dilution was added to the wells of a microtiter plate containing adherent mononuclear leukocytes and 100 microliters of complete medium. Mononuclear leukocytes were incubated with the test compound for 60 minutes, at which time 25 microliters of complete medium containing 30 ng / ml lipopolysaccharide from E. coli K532 was added to each well. The cells were further cultured for 4 hours. The culture supernatant was excluded, and the T.NF content in the supernatant was quantified by ELISA.

TNF ELISA Use 3 pg / ml murine anti-human TNF-α MAb (R &amp; D Systems, Inc. # MAB2iO) to coat a 96-well Corning high-binding ELISA flat-bottom plate overnight (4 ° C), 150 μl / hole. Then at room temperature, supplement with 20 mg / ml -162 · 200303316 Description of Invention Continued (158)

BSA's CaCl2-free ELISA buffer (standard ELISA buffer: 20 mM, 150 mM NaCl, 2 mM CaCl2 '. 15 mM ethylmercury thiosalicylate'ρ 7 · 4) Block the wells for 1 hour, 200 μl / well . Wash and supplement the culture plate with 100 μl of test supernatant (dilution 1: 3) or standard solution. The standard solution includes 11 kinds of serially diluted 1.5-fold concentrations of 1 ng / ml recombinant human TNF (R &amp; D Systems) preservation solution. The culture plate was cultured on a ring shaker (300 rpm) at room temperature. At 100 μl / well goat anti-human TNF-α (R &amp; D Systems Inc. # AB-210-NA) Peptide ratio 4: 1) (0.5 pg / ml) Wash and supplement the culture plate. The plate was incubated for 40 minutes, and the plate was washed and supplemented with 100 μl / well of alkaline phosphate-conjugated streptavidin (Jackson ImmunoResearch # 016-050-084) (0.02 pg / ml). The plate was incubated for 30 minutes, and the plate was washed and supplemented with 200 μl / well of p-nitrophenyl phosphate (1 mg / ml). After 30 minutes, read the plate data at 405 nm on a Vmax plate reader. Data analysis The standard curve data was substituted into a quadratic polynomial, and the concentration equation was solved from its 0D to determine the unknown TNF-α concentration. Then, using a quadratic polynomial, the TNF concentration was plotted against the test compound concentration. This equation can be used to calculate the concentration at which the test compound caused a 50% decrease in TNF production. The compounds of the present invention can also inhibit the release of IL-ip, IL-6 and / or 4-8 from monocytes induced by LPS, which are determined by methods known to those skilled in the art to determine IL-1β, IL-6 and / or -8 concentration. In a method similar to the above-mentioned analytical method involving LPS-induced monocyte leukocyte release of TNF, the compounds of the present invention can also inhibit * LPS-induced monocyte leukocyte release of IL-Ιβ, IL-6, and / or IL-8, which is dependent Methods known to those skilled in the art determine IL-1β, IL-6 and / or IL-8 concentrations. In -163-Invention Description Continued

200303316 (159) Thus, the compounds of the present invention can reduce the concentrations of TNF-α, IL-1, IL-6 and IL-8. Reducing these inflammatory cytokines to basal or lower levels is beneficial in controlling many conditions and slowing and reducing their development. For all conditions treated by these compounds, TNF-a, IL-Ιβ, IL-6 and IL-8 all play a role in the complete definition of the TNF-a-mediated disease described herein. Lipopolysaccharide-activated THP1 cell TNF production analysis method THP1 cells were resuspended in fresh THP1 medium (RPMI 1640, 10% heat-reactive FBS, 1 XPGS, 1 XNEAA, plus 30 μM βΜΕ) at a concentration of I e6 / mL. 100 microliters of cells per well were plated on a polystyrene 96-well tissue culture plate. One microgram of bacterial LPS per milliliter was prepared in THP1 medium and added to each well. The test compound was dissolved in 100% DMSO and serially diluted 3 times in a polypropylene 96-well microtiter culture plate (drug culture plate). The pits of the HI control group and the B control group contained only DMSO. After removing 1 microliter of the test compound from the drug culture plate and adding it to the cell culture plate, 10 microliters of LPS was added. Treat cells for 3 hours at 37 ° C to induce TNF-a synthesis and secretion. Take 40 microliters of conditioned medium and add 110 microliters of ECL buffer (50 mM Tris-HCl pH 8.0, 100 mM NaCl, 0.05%). Tween 20, 0.05% NaN3 and 1% FBS) and supplemented 0.44 nM MAB610 single Ab (R &amp; D Systems), 0.34 nM ruthenium-based AF210NA multiple Ab (R &amp; D Systems) and 44 pg / mL sheep anti-mice M280 Dynabeads (Dynal drug waste) in a 96-well polypropylene lysate culture plate. After shaking culture at room temperature for 2 hours, read the reaction data on an ECL M8 instrument (IGEN Inc.) ^ Apply a low voltage to the ruthenium-based TNF-α immune complex.

In the presence of TPA (active ingredient in Origlo), a cyclic reductive oxidation reaction occurs, emitting a light of 620 nM. Using the formula: Control group% (POC) = (cpd -LO -164-200303316 Description of the invention continued (160) average value) / (HI average value-LO average value) * 100, compare NF-α when containing compounds Secretion and secretion with DMS0 only (HI control group). Levenburg-Marquardt nonlinear regression algorithm was used to substitute the data (including POC and inhibitor concentration, expressed in μM) into a four-parameter formula (y = A + ((BA) / (i + ((x / CTD))) , Where A is the minimum y (POC) value, B is the maximum y (POC), C is the X (cpd concentration) at the inflection point, and D is the slope). The following compounds were analyzed by THP1 (LPS-induced TNF release) Out) with an IC50 value of 20 μM or less:

5- (3-phenylprop-1-yl) amino-8- (4-fluorophenyl) -7- (4-pyridyl) -1,2,4-triazolo [4,3-c ] Pyrimidine; 5- (3-phenylpropan-i-yl) amino-8- (3-tolyl) -7- (4-pyridyl) -1,2,4-triazolo [4,3 -c] pyrimidine; 5- (Upiperidinyl) -8- (3-tolyl) · 7- (2-chloro-4-pyridyl) -1,2,4-triazolo [4,3- c] pyrimidine; 5- (3-phenylprop-1-yl) amino-8- (3- (trifluoromethyl) phenyl) -7- (4-pyridyl) -1,2,4- Triazolo [4,3-c] pyrimidine;

5- (2 (S) -amino-3-phenylpropanyl) amino-8- (3,4-dichlorophenyl) -7- (4-.pyridinyl) -1,2, 4-triazolo [4,3-c] pyrimidine; 5- (piperin-butyl) -8- (3- (trifluoromethyl) phenyl) -7- (2- (2-phenylpropyl) -2-yl) amino-4-pyridine roll) 1,2,4-triazolo [4,3-c] pyrimidine; 5- (3,5-dimethylpiperazine-Uyl) -8 -(3- (trifluoromethyl) phenyl) -7- (2- (l (S) -phenethyl) amino-4-pyridyl) -1,2,4-triazolo [4, 3-c] pyrimidine; 5- (piperidinyl) -8- (3- (trifluoromethyl) phenyl) -7- (2- (I (S) -benzylethyl) amino group • 4 ^ ratio (Yodoki) 1,2,4-trito [4,3-c] ° * Dense disease: -165- 200303316 _ (161) Description of the invention continued on 1- (8- (4-fluorophenyl)- 7- (4 ^ pyridinyl) -1,2,4-triazolo [4,3-c] pyrimidin-5-yl) amino-2 (S) -amino-3-phenylpropane; 2 -(8- (4-fluorobenzyl) -7- (4-saypyridinyl) -1,2,4-triazolo [4,3-c] pyrimidin-5-yl) amino-2-benzene Propane; 5- (2 (S) -amino-2-methyl-3-benzylprop-1-yl) amino-8- (3- (trifluorofluorenyl) benzene-yl) -7- (4-pyridinyl) -1,2,4-triazolo [4,3-c] pyrimidine; 5- (2,5-diazobicyclo [2.2 · 1] hept-2-yl) -8- (3- (trifluoromethyl) phenyl)- 7- (2- (l (S) -phenethyl) amino-4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine; i 5- (2 (S) -Amino-3-phenylpropanyl) amino-8- (2-fluorenyl) -7- (4-pyridyl) 1,2,4-triazolo [4,3-c] pyrimidine ; 5- (3 (S) -benzyl-piperonyl) -8- (2, fluorenyl) -7- (4-methylpyridyl) -1,2,4 ^ Sanjun and [4 , 3-(:] ° close-bite; 5- (2 (S) -amino-3-phenylpropanyl) amino-8- (3-chloro-4-fluorophenyl) -7- (heart Piperidinyl) -1,2,4-triazolo [4,3-c] pyrimidine; 5- (2 (S) -pyrrolidinylmethyl) amino-8- (2-naphthyl) -7 -(4-0 than pyridyl) -1,2,4-triazolo [4,3, c] pyrimidine; 5- (1- (2-propyl) pyrrolidin-2 (S) -ylmethyl ) Amino-8- (3,4-dichlorophenyl) -7-^ (4-saidyl) -1,2,4-triazolo [4,3-c] pyrimidine; 5- (piperidine Phen-1-yl) -8- (3 · (trifluoromethyl) phenyl) -7- (2- (cyclopropyl) amino-4-pyridinyl) -1,2,4: triazole Ac [4,3-c] pyrimidine; 5- (1- (2-propyl) piperidin-3-yl) amino-8- (3,4-dichlorophenyl) -7- (4-said (Pyridyl) 1,2,4-triazolo [4,3-c] pyrimidine; and "5- (1- (2-propyl) pyrrolidin-2 (S) -ylmethyl) amino -8- (2-fluorenyl) -7- (4- said pyridyl-yl) 1,2,4-tri And [4,3-c] pyrimidine. -166 · 200303316 Description of the invention continued (162) The following compounds are active in THP1 cell analysis (LPS-induced TNF release) with IC50 values of 5 μM or less: 5- (3-phenylpropan-1- Aminyl) amino-8- (4-fluorophenyl) -7- (4-pyridyl) -1,2,4-trijuno [4,3-c] ° * dense bite; 5- (3- Phenylprop-1-yl) amino-8- (3-tolyl) -7- (4-pyridyl) -1,2, carditriazolo [4,3-c] pyrimidine;

5- (1-piperidinyl) -8- (3-methylphenyl) -7- (2-chloro-4-pyridyl) -i, 2,4-triazolo [4,3-c] ° Dense lake; 5- (3-phenylprop-1-yl) amino-8- (3- (trifluoromethyl) phenyl) -7- (4 ^ pyridinyl) 1,2,4 -Triazolo [4,3-c] pyrimidine; 5- (2 (S) -amino-3 -unpropylprop-1-yl) amino-8- (3,4--qi-unradical ) -7- (4 -7 Biyodoyl) -1,2,4-triazolo [4,3-c] pyrimidine: 5- (piperin-1-yl) -8- (3- (trifluoro (Methyl) phenyl) -7- (2- (2-phenylprop-2-yl) amino · 4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine; 5- (3,5-dimethylpiperin-1-yl) -8- (3- (trifluoromethyl) phenyl) -7- (2- (l (S) -phenethyl) amino -4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine;

5- (piperin-1-yl) -8- (3- (trifluoromethyl) phenyl) -7- (2- (l (S) -phenethyl) amino-4-oxopyridyl ) 1,2,4-trito [4,3-cp close bite; 1- (8- (4-fluorophenyl) -7- (4-pyridyl) -1,2,4-triazole Benzo [4,3-c] pyrimidin-5-yl) amino-2 (S) -naphthyl-3 · benzylpropane; 2- (8- (4-fluorobenzyl) -7- (4-pyridine) ) -1,2,4 · triazolo [4,3-c] pyrimidin-5-yl) amino-2-benzylpropane; 5- (2 (S) -amino-2-methyl- 3-phenylpropyl) amino-8- (3- (trifluoromethyl) benzyl) -7- (4-saypyridyl) -1,2,4-triazolo [4,3-c ] Pyrimidine; • 167- 200303316 _ (163) Description of the invention continued on 5- (2,5-diazobicyclo [2.2.1] hept-2-yl) -8- (3- (trifluoromethyl) phenyl ) -7- (2- (l (S) -phenethyl) amino-4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine; 5- (2 (S ) -Amino-3-phenylprop-1-yl) amino-8- (2-¾: yl) -7- (4- said pyridyl) 1,2,4-triazolo [4, 3-c] pyrimidine; 5- (3 (S) -benzylmethyl-pipenyl) -8- (2-fluorenyl) -7- (4-pyridinyl) -1,2,4-tri σ sat and [4,3- (:]. dense lake;

5- (2 (S) -amino-3-phenylpropanyl) amino-8- (3-chloro-4-fluorophenyl) -7- (4-piperidinyl) -1,2, 4-triazolo [4,3-c] pyrimidine; 5- (2 (S) -pyrrolidinylmethyl) amino-8- (2 · fluorenyl) -7- (4-pyridyl) -1 , 2,4-three tons and [4,3-(:] ° dense lake; 5- (1- (2-propylpyrrolidine-2 (S) -ylmethyl) amino-8- (3 , 4-dichlorophenyl) -7- (4-saidinyl) -1,2,4-triazolo [4,3-(:) pyrimidine; 5- (piperin-1-yl) -8 -(3- (trifluoromethyl) phenyl) -7- (2- (cyclopropyl) amino-4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine ; 5- (1- (2-propyl) piperidin-3-yl) amino-8- (3,4-dichlorophenyl) -7- (4-pyridyl) 1,2,4- Triazolo [4,3-c] pyrimidine; and

5- (1- (2-propyl) pyrrolidin-2 (S) · methylmethyl) amino-8- (2-fluorenyl) -7- (4-pyridyl) -1,2,4- Triazolo [4,3-c] pyrimidine. Inhibit LPS-induced TNF-α production in mice. Male DBA / 1 LACJ mice were administered a vehicle or a vehicle containing a test compound (the vehicle contains 0.5% tragacanth 0.03 N HC1 solution), 30 minutes later. , Injection of lipopolysaccharide (2 mg / kg, IV). Ninety minutes after LPS injection, blood was collected and analyzed for serum TNF-α content by ELISA. The compounds of the present invention show anti-inflammatory shellfish such as deer in modes of inflammation of animals, including carrageenan sugar foot edema-168-200303316 (164) I. Description of the invention continued pages, collagen-induced arthritis and adjuvant arthritis Using Cai Kuqing's edema pattern (c · a. Et al. Proc · s〇c.

Exp. Biol · Med · (1962) vol 111, ρ · 544; K. F · Swingle described in "Antiinflammatary Agents, Chemistry and Pharmacology 'Vol. 13- edited by R · A. Scherrer and M · W · Whitehouse. n, Academic, New York, 1974, p. 33) and collagen-induced hair arthritis (dET re 11111 &amp; 〇1, etc. plant. Med. (1977) vol. 146, p 857; JS Courtenay , Nature (New Biol.) (1980), Vol 283, p. 666) e. Using the CHOI / hGLUR cell l25I-glucagon binding screening method This assay is described in WO 9 7/1644 2 and its contents have been It is fully incorporated herein by reference. Reagents Reagents were prepared as follows: (a) Preparation of fresh iM phenanthroline (Aldrich drug waste) (198.2 mg / ml ethanol); (b) Preparation of fresh 0.5M DTT (Sigma Pharmaceutical); (c) Protease inhibitor mixture (ι000χ): 5 mg of anti-plasmin peptide, 10 mg of stupid formazan, 40 mg of bacitracin and 5 ^ soybean trypsin inhibitor per ml of dmSO, And divided into several aliquots and stored under · 20χ; (d) human human glycogenin (peninsula pharmaceutical factory) at 250 mM: take a 0.5 mg vial and dissolve it in 575 microliters of 0.1 in. In acid (in non-specific binding assays, i μl produces a final concentration of 1 μ%) and stored at -20t; (e) analysis buffer: 20 mM Tris (pH 7.8), 1 mM DTT and 3 mM o-phenanthroline; (f) analysis buffer containing 0]% BSA (for dilution markers only; final concentration in the assay is 0.001. / ()): 10 microliters 10% BSA (heated (Deactivation) and 990 microliters of analysis buffer; (g) I. Glucagon (NEN, receptor grade, 2200 Ci / mmol): in BSA-containing analysis buffer (in points • 169, 200303316 _ ( 165) Description of the invention The final concentration in the continuation analysis method is about 50 pM) diluted to 50,000 cpm / 25 μΐ. CH0 / hGLUR cell collection method for analysis 1. Remove the medium from the fusion flask, and take PBS (Ca, Mg-free ) Wash each with enzyme-free dissociation solution (Specialty Media, Inc.); strip once. 2. Add 10 ml of enzyme-free dissociation solution and keep at 37 ° C for 4 hours. 3. Gently knock down the cells, grind and take a part of the count, and centrifuge the rest at 1000 rpm for 5 minutes.

4. Resuspend the centrifuge block in analysis buffer at 75,000 cells per 100 μl. Membrane preparations of CHO / hGLUR cells of the same analysis volume can be used instead of intact cells. The final protein concentration of the membrane preparation is determined once per batch. Analytical method The assay for the inhibitory effect on glucagon binding is to measure the degree of decrease in 125I-glucagon binding in the presence of the compound of formula I. Reagent group

The combination is as follows: Compound vehicle / 250 μM glycidin 1225-glucagon CHO / hGLUR Total cell binding W5 μΐ-25 μΐ 100 μΐ + compound 5 μΐ / — — 25 μΐ 100 μΐ Non-specific knot-/ 5 μΐ i μΐ 25 μΐ 100 μΐ The synthetic mixture was shaken at 22 ° C for 60 minutes at 275 rpm. The mixture has been pre-soaked (0.5% polyethylene imine (PEI)) in GF / C; it should be conditioned and used Innotech collector • 170-200303316 invention description sheet (166) or Tomtec collector; it should be icy 20 Wash in mM Tris buffer (pH 7.8); strip 4 times. Measured with a Gamma flicker counter; consider radioactivity. Therefore, the compounds of the present invention also have inhibitory activity on the binding properties of glucagon and glucagon receptor. Cycloenzyme activity analysis of human monocyte leukemia leukemia cell line differentiated by exposure to euphorbia diterpene ester, ΤΗΡ-1 only shows COX-1; human bone cancer cell line 143B mainly shows COX-2 β Τ-2Ρ- 1 cell was cultured in RPMI complete medium supplemented with 10% FBS as usual, and human osteocarcinoma cells (HOSC) were cultured in minimal medium supplemented with 10% fetal bovine serum (MEM-10% FBS); all cell cultures were in Culture at 37 ° C with 5% (: 02 and moisture). COX-1 Assay In COX-1 assay, THP-1 cells are grown to confluence, divided into 1: 3 and added to 2% FBS and In 10 mM euphorbia diterpene alcohol 12-cinnamate 13-acetate (TPA) in RPMI, incubate on a shaker for 48 hours to prevent attachment. Cells were agglomerated and resuspended in Hanks Buffered physiological saline (HBS) at a concentration of 2.5 X 106 cells / ml, coated in a 96-well culture plate with a density of 5 X 105 cells / ml. The test compound was diluted in HBS and added to the required At the final concentration, the cells were cultured for another 4 hours. Arachidonic acid was added to a final concentration of 30 mM, and the cells were cultured at 37 ° C for 20 minutes. The enzyme activity was determined as described below. COX-2 Assay COX-2 Assay, trypsinized subfused HOSCs were resuspended in MEM-FBS containing 1 ng of human IL-lb / ml, 3 X 106 cells 200303316 (167) Invention description read_

/ Ml, coated on a 96-well tissue culture plate, with a density of 3 x 104 cells per well, and cultured on a shaker for 1 hour to evenly distribute the cells, and then allowed to stand for 2 hours to allow the cells to attach. Change the medium to MEM containing 2% FBS (MEM-2% FBS) and 1 nanogram of human IL-lb / ml, culture the cells for 18-22 hours, then change the medium to 190 ml of MEM and add to HBS

10 mL of test compound was diluted in medium to reach the required concentration, and the cells were cultured for 4 days. The supernatant was drained, replaced with MEM containing 30 mM arachidonic acid, and the cells were incubated at 37 ° C for 20 minutes. The enzyme activity was measured according to the method described below. CoX activity assay After culturing with arachidonic acid, the reaction was stopped by the addition of IN HC1, then neutralized with 1N NaOH, and centrifuged to produce cell debris and agglomerates. The commercially available ELISA (Neogen # 4041 10) was used to determine the concentration of PGE2 to determine the activity of cyclooxygenase in the supernatants of HOSC and THP-1 cells. Calibration was performed using a standard PGE2 curve, which included COX-1 and COX-2 inhibitors available from the commodity as a standard control group.

Raf kinase assay

According to the method described in GB 1,238,959 (the content of which is fully incorporated herein by reference), the in vitro Raf kinase is determined by the degree of phosphorylation of the substrate MEK (Map kinase / ERK kinase) and activated Raf kinase. active. Phosphorylated MEIC was collected on a filter, and the content of labeled radioactive canate was quantified by flash butterfly counting. Materials: Activated Raf is a triple transfection of Raf, val12-H-Ras, and Lck baculovirus by Sf9 cells showing "Glu-Glu &quot;-epitope-tagged end tags. 172- 200303316 (168) Description of the invention is produced on the continuation sheet. '* Glu-Glu &quot; -Epitope' Glu-Try-Met-Pro-Met-Glu, fused to the carboxy terminus of a full-length c-Raf ° MEK (K97A mutation without tritiated activity) Sf9 cells are produced by triple transfection of a baculovirus of K97A MEK-1 with a c, terminal &quot; Glu-Glu &quot; -epitope end tag. Purified from cells grown as described in Proceedings of the Grussenmeyer et al., The National Academy of Science, USA pp 7952-7954, 1985 '.

Column buffer: 20mM Tris pH = 8, 100 mM NaCl, 1 mM EDTA, 2.5mM EGTA, 10mMMgCl2, 2mMDTT, 0.4mMAEBSF, 0.1 / 0 n-octyl p-glucopyranose, 1 nM eufolate ( okadeic acid) and benzamidine, anti-plasmin peptide, pepsin and anti-protease peptide each at 10 gg / mL. Reaction embroidery solution: 125 mM HEPES pH = 8, 25 mM MgCl2, 5 mM EDTA, 5 mM Na3V04, 100 pg / mL BSA.

Enzyme dilution buffer: 25 mM HEPES pH = 8, 1 mM EDTA, 1 mM

Na3V04, 400 pg / mL BSA 0 Stop reaction solution: 100 mM EDTA, 80 mM sodium pyrophosphate. Passing plate: Milipore multiscreen # SE3M078E3, Immobilon-P (PVDF). Methods:. Protein purification method: Sf9 cells were infected with baculovirus and grown according to the method described in Proceedings of the National Academy of Science, U.S.A. pp 2922-2926, 1992 by Williams et al. All subsequent steps are performed on ice or at 4 ° C. Cells were centrifuged to form lumps, and were lysed in column buffer with ultra-173-200303316 _ (169) I Invention Description Continued. The lysate was centrifuged at 17,000 x g for 20 minutes and filtered through a 0.22 micron. The epitope-tagged protein is purified by GammaBind Plus affinity column chromatography, which has been coupled with Glu-Glu &quot; antibody. After adding the protein to the column, use twice the column volume of tube buffer. Wash and dissolve in a column buffer containing 50 pg / mL G u-Tyr-Met-Pro-Met-Glu.

Analytical method: The test compound is analyzed by using a 3-fold serial dilution (10-100 μM) to analyze β. Add 10 microliters of test inhibitor or control substance dissolved in 10% DMSO to the analysis plate, and then add 30 microliters. Contains 10 μl of 5x reaction buffer, 1 mM 33P-γ-ATP (20 pCi / mL), 0.5 μl MEK (2.5 mg / mL) '1 μl of a mixture of 50 mM P-hydrothioethanol. Add 10 microliters of enzyme dilution buffer containing 1 mM DTT and quantitatively activated Raf, which produces one of the linear kinetics with reaction time. The reaction was mixed. After incubating at room temperature for 90 minutes, 50 μl of the stop reaction solution was added to stop the reaction. ^ Take 90 μl of the stop reaction solution and add it to the GFP-30 cellulose microtiter filter plate (Polyfiltronics). The filter plate was washed with 5% phosphoric acid with double the volume of the wells and dried, and then 25 microliters of the scintillation counting mixture was replenished. The board uses a TopCount flashing counter reader to calculate the 33P gamma emission. Therefore, the compound of the present invention or a pharmaceutically acceptable composition thereof is suitable for treating rheumatoid arthritis; Patzell's disease; osteoporosis; multiple myeloma; uveitis; acute and chronic myeloid leukemia; Cell destruction; osteoarthritis: rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS): psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; Allergic reactions; -174 · Description of the invention continued on 200303316 (170) contact dermatitis; asthma; muscle degeneration; cachexia; Reiter's syndrome; type I and II diabetes; bone resorption disease; and plates Antihost response; reperfusion injury after ischemia: atherosclerosis; brain trauma; Alzheimer's disease; stroke; myocardial infarction; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock symptom cluster Fever; and myalgia due to infection. The compounds and methods of the present invention are HIV sensitive to their TNF-a and / or IL-1 inhibitory effect or glucagon antagonist], HIV-2

, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, sore virus (including HSV-1, HSV-2) and shingles also have positive effects.

The compounds of the invention also have tumor-lytic properties and are suitable for treating cancer. The compounds of the present invention can also block signal transduction caused by extracellular mitogenic stimuli and oncogenic proteins by inhibiting Raf kinase. Therefore, the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of one of them is also suitable for treating cancers mediated by Raf and Raf-induced proteins, such as cancers involving Raf kinase overexpression and Raf Or Raf activates oncogenic genes upstream of activators of cancer. Examples of cancers involving Raf kinase overexpression include brain cancer, laryngeal cancer, lung cancer, lymphatic cancer, urinary tract cancer and gastric cancer, including uterine bladder lymphoma, lung adenocarcinoma, small cell lung cancer, and the like. Examples of cancers involving the overexpression of Raf or Raf-activated oncogene upstream activators include pancreatic and breast cancer tumors' and the like. The compound of the present invention also has analgesic properties and is suitable for treating painful lesions, such as hyperalgesia caused by excessive IL-I. The compounds of the present invention can also prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid / prostaglandin pathway, including cyclooxygenase (WO 96/03387, the contents of which have been cited by reference. 175-200303316 Description of the Invention continued ( The method of 171) is fully incorporated herein) ° Since the compounds of the present invention have the ability to reduce TNF-a and 乩 -1 concentrations or inhibit glucagon and its receptor binding, it is also suitable for exploring and blocking these effects. Related physiological research tools ° The compounds of the present invention include administering an effective dose of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of one of them, which requires the reduction of TNF-a, IL-1, IL-6 and / or Π-8 content and / or lower blood glucose levels and / or individuals who may suffer from the following diseases (ie animals, preferably mammals, _ the best Lujia is human) · rheumatoid arthritis; Patzell's disease, osteoporosis: multiple myeloma: uveitis; acute and chronic osteoblastic leukemia: patella beta cell destruction: osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel Disease Respiratory distress syndrome (ARDS), psoriasis; Crohrt, s disease; allergic rhinitis, ulcerative colitis; allergic reactions: contact dermatitis: asthma; muscle degeneration; cachexia; Reiter's syndrome syndrome); type I and type II diabetes; bone resorption disease; graft versus host response; reperfusion injury after ischemia; atherosclerosis; brain trauma; multiple sclerosis, brain cancer: sepsis: septic shock; Symptoms of Lutoxic Shock: Fever: and myalgia due to infection, or infection with HIV-1, HIV-2, HIV-3, cytomegalovirus (CmV), influenza, adenovirus, herpes virus (including HSV-1, HSV-2), or individuals with shingles. Another aspect of the invention includes the use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of TNF- (X, IL-1β, il-6, and / or * IL-8 vehicle acute or 1¾ Use in sexually transmitted diseases (including the aforementioned diseases) ^ The compounds of the present invention are also suitable for the manufacture of anticancer drugs ^ The compounds of the present invention are also suitable for use • 176-200303316 Description of the Invention Continued (172) In the manufacture of medicine for reduction by inhibiting Raf kinase Or prevent signal transduction caused by extracellular mitogenic stimulants and oncogenic proteins. In addition, the compounds of the present invention are also suitable for the manufacture of painkillers and medicines for treating painful lesions (such as hyperalgesia). The compounds of the present invention are also applicable In the manufacture of medicine, it prevents the production of prostaglandins by inhibiting enzymes in the human arachidonic acid / prostaglandin pathway, including cyclooxygenase.

Another method of the present invention includes administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of one of them to a patient in need of treatment of Raf, Raf-induced proteins, and / or Raf or Raf-activated oncogenes. Activator-mediated cancers and / or individuals who may have the following cancers (ie, animals, preferably mammals, and most preferably humans): brain cancer, laryngeal cancer, lung cancer, lymphatic cancer, urethral cancer, and gastric cancer, Including uterine bladder lymphoma, lung adenocarcinoma, small cell lung cancer, pancreatic cancer and breast cancer, and so on. In addition, the compounds of the present invention can be used in the manufacture of medicine for treating cancers, such as: brain cancer, laryngeal cancer, lung cancer, lymphatic cancer, urethral cancer and gastric cancer, including uterine bladder lymphoma, lung adenocarcinoma, small cell lung cancer, and pancreatic cancer Tumors, breast cancer tumors, etc. Another aspect of the present invention provides a pharmaceutical composition comprising an effective amount for reducing the content of TNF-α, IL-1β, IL-6 and / or IL-8 and / or an effective amount for reducing blood glucose and / or an effective amount for suppressing tumors The compound of the invention and a pharmaceutically acceptable carrier or diluent, and other active ingredients used if necessary. The compounds of the present invention can be administered by any suitable route, preferably in the form of a pharmaceutical composition that is compatible with these routes and in a dose effective for the desired treatment. In order to prevent or prevent the development of tissue injury related to the disease, the compound of the present invention (177) 200303316 _ (173) Description of the Invention Continued The necessary medically effective dose can be easily determined by those skilled in the art using standard methods. In the treatment of TNF-α, IL-1β, IL-6 and IL-8-mediated diseases, cancer and / or hyperglycemia, the compounds of the present invention may contain commonly used pharmaceutically acceptable carriers, adjuvants and vehicles Unit-dose formulations for oral, parenteral, inhalation spray, rectal or topical administration. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrasternal, infusion techniques or transdermal

Intraperitoneally. The treatment of diseases and lesions herein also includes the preventive administration of individuals (ie animals, preferably mammals, and most preferably humans) who are deemed to require preventive treatment, such as: pain, inflammation, etc. A compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

The dose course of the compounds and / or compositions of the present invention for the treatment of TNF-a, IL-1, IL-6 and IL-8-mediated diseases, cancer and / or hyperglycemia is determined based on a number of factors, including the disease type Status, patient's age, weight, gender, medical condition, severity of the condition, route of administration, and specific compounds used. Therefore, the dose course may vary greatly, but can be determined by standard methods as usual. Suitable dosages for all methods disclosed herein are between about 0.01 mg to 30 mg per kg of body weight per day, preferably between about 0.1 mg to 1.0 mg / kg, and more preferably between about 0.25 mg to 1 mg / kg. ^ The pharmaceutically active compounds of the present invention can be manufactured according to general pharmaceutical methods, and are prepared for administration to patients, including humans and other mammals. Pharmaceutical compositions for oral administration may be in the form of, for example: capsules, tablets, suspensions -178- 200303316 _ (174) Description of the Invention Continued or Liquid. Pharmaceutical compositions are preferably made in unit doses containing a specified amount of the active ingredient. For example, the content of the active ingredient may be about 1 to 2000 mg, preferably about 1 to 500 mg, and more preferably about 5 to 150 mg. The daily dose suitable for humans or other mammals may vary greatly depending on the patient's conditions and other factors, but it can still be determined routinely.

The active ingredient may also be combined with a suitable carrier (including physiological saline, dextrose or water) and administered by injection. The daily dosage of parenteral treatment is about 0.1 to 30 mg / kg, preferably about 0.1 to 10 mg / kg, and more preferably about 0.25 mg to 1 mg / kg.

Injectables (eg sterile aqueous or oily suspensions for injection) can be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be an injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, to form a 1,3-butanediol solution. Among the acceptable vehicles and solvents that can be used are water, Ringef's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are often used as solvents or suspension media. Therefore, any brand of fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can also be used in the preparation of injectables. Suppositories for transrectal administration of drugs can be mixed with suitable non-irritating excipients, such as cocoa butter and polyethylene glycol, which are solid at normal temperature but liquid at the rectal temperature, so It melts in the rectum and releases the drug. A suitable topical active ingredient dose for a compound of the present invention is 0.1 mg to 150 mg, preferably 1 or 2 times per day. When administered topically • 179-200303316 _ (! 75) Description of the invention Continuation page, the active ingredient may account for 0.001% to 10% w / w of the formulation weight, for example: 1% to 2%, but may also be as high as 10% w / w , But preferably not more than 5% w / w, more preferably 0.1% to 1% of the formulation. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin (eg, dressings, lotions, ointments, creams or pastes) and drops suitable for administration to the eyes, ears or nose.

When administered, the compounds of this invention are usually combined with one or more adjuvants suitable for the intended route of administration. The compound can be mixed with lactose, sucrose, starch, cellulose esters of alkanoic acid, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, acacia gum, gelatin, sodium alginate , Polyethylene-pyrrolidine and / or polyvinyl alcohol, and tableting or embedding, for general pharmaceutical use. Alternatively, the compounds of the present invention are soluble in physiological saline, water, polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth, and / or various buffers. Other adjuvants and modes of administration are those skilled in pharmaceutical technology. The carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, which may be used alone or in combination with a wax, or other materials known in the relevant art. Pharmaceutical compositions can be made in solid form (including granules, powders, or suppositories) or in liquid form (eg, solutions, suspensions, or emulsions). The medical composition can be subjected to general pharmaceutical operations, such as: sterilization and / or can include general adjuvants, such as: preservatives, stabilizers, wetting agents, emulsifiers, buffers, and the like. Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose or starch. These dosage forms may also contain -180- 200303316 _ ^ 176) Description of the Invention Continued Substances other than inert diluents, such as lubricants such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents. Lozenges and pills can be prepared separately with an enteric coating. Oral medicinal liquid dosage forms may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and jumping agents containing inert diluents commonly used in the related art. These compositions may also include adjuvants, such as: wetting agents, sweeteners, flavoring agents and flavors.

The compounds of the present invention may have one or more asymmetric carbon atoms, and thus optical isomers and racemic or non-racemic mixtures thereof may occur. The method for preparing optical isomers is based on general methods, such as: formation of diastereomeric salts, treatment with optically active acids or bases, and analysis of racemic mixtures. Examples of suitable acids are tartaric acid, diethylfluorenyl tartaric acid, dibenzylidene tartaric acid, xylylene tartaric acid and camphorsulfonic acid, and then crystallize and separate the mixture of diastereoisomers, which is then released from such salts Optically active base. Another method of separating optical and chemical isomers involves the use of palmar chromatography columns, which are most appropriately selected to separate the enantiomers as much as possible. Another possible method involves synthesizing a covalent diastereomeric molecule by reacting a compound of the present invention with a purely optically active acid or purely optically isocyanate. The synthesized diastereomers can be separated by general methods, such as chromatography, distillation, crystallisation, or sublimation, and then hydrolyzed to produce pure enantiomeric compounds. The optical compounds of the present invention can also be prepared using active starting materials, and these isomers can be in the form of a free acid, a free base, an ester or a salt. Likewise, the compounds of the present invention may appear to be isomers, i.e., compounds having the same molecular formula, but in which the relative arrangement of the atoms is different. In particular, this -181-200303316 (177) Description of the Invention The continuation of the alkylene substituents of the compounds of the invention is a normal and better arrangement, as indicated in the definitions of these groups, embedded in the molecule, from the left Read the name to the right. However, those skilled in the art understand that sometimes the substituents in the compounds of the present invention may be prepared in opposite directions relative to other atoms in the molecule. That is, the substituents embedded may be the same as those specified, but the orientation of the embedded molecules is opposite. Those skilled in the art understand that such isomeric forms of the compounds of the present invention are also included in the scope of the present invention.

The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include (but are not limited to): acetate, adipate, alginate, citrate, aspartate, benzoate, benzoate, bisulfate, butyrate, Camphor salt, camphor sulfonate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethane sulfonate, glucoheptate, glycerol phosphate, hemisulfate, heptane Acid salt, hexanoate salt, fumarate salt, hydrochloride salt, hydrobromide salt, hydroetanoate salt, 2-acyl-ethanoate salt, lactate salt, maleate salt, formate salt, Acid salt, 2-carrageenate, oxalate, palmitate, pectate, persulfate, 2-phenylpropionate, picrate, pivalate, propionate, amber Acid salt, tartrate salt, thiocyanate salt, toluate salt, formic acid salt, and undecanoic acid salt. In addition, test nitrogen-containing groups can be quaternized using reagents such as low-carbon alkyl dentates, such as: methyl, ethyl, propyl and butyl chlorides, bromides and iodides; Alkyl esters, such as: dimethyl sulfate, diethyl ester, dibutyl ester, and dipentyl ester: long chain halides, such as: decyl, lauryl, cinnamyl and stearyl chloride, bromide and iodine Compounds; alkylaryl compounds, such as: benzyl and phenethyl bromide, and so on. So water or oil is soluble or dispersible -182- 200303316 (178) Description of the invention Continued page Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid , And organic acids, such as: oxalic acid, maleic acid, succinic acid, and citric acid. Other examples include salts with alkaline metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium salts or salts with non-trivial effects. Also included within the scope of the present invention are pharmaceutically acceptable esters containing carboxylic acid or hydroxyl groups, including the metabolically active esters or prodrug forms of the compounds of the present invention. Metabolically active esters are, for example, ... substances which increase the blood content and prolong the potency of the corresponding non-ester type of the compound. Prodrug types are not active when administered, but have undergone some in vivo activities or biotransformation methods, such as metabolic effects, such as enzymatic or hydrolytic cleavage to become medically active molecules. For a general discussion of ester foot prodrugs, see Svensson and Tunek's "Drug Metabolism Reviews 165 (1988)," and Bundgaard's "Design of Prodrugs, Elsevier (1985). Examples of carboxylate anions that are covered include A variety of esters, such as: alkyl (for example: methyl, ethyl), cycloalkyl (for example: cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and cyanocarbon Esters of oxyalkyl groups (eg, Tentamidine oxymethyl). Amines that are in the form of aromatic derivatives substituted with arylcarboxymethyl can be cleaved by esterases in vivo, releasing free drugs and formaldehyde ( Bimgaard J. Med · Chem · 2503 (1989)). In addition, drugs containing acidic NH groups (such as ··················, etc.) have been masked with N-Lethoxymethyl (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxyl groups have been masked by esters and ethers. EP 039,051 &quot; (Sloan and Little, 4/1 1/8 1) reveals Mannich diastereohydroxamic acid prodrugs, their Production method and use. The esters of the compounds of the present invention may include, for example, methyl esters, ethyl esters, and propyl esters. ., And butyl, and the other suitable esters formed between an acidic moiety of -183 and-200 303 316 _ (179) described on page Continued hydroxyl group-containing part of the invention yl metabolic active esters include, for example: methoxymethyl

Group, ethoxymethyl, isopropoxymethyl, α-methoxyethyl, such as: a-((CrC4) alkoxy) ethyl groups; for example: methoxyethyl, ethoxyethyl, Propoxyethyl, isopropoxyethyl, etc .: 2-oxo-1,3 · dioxopenten-4-ylmethyl groups, such as: 5-methyl-oxo · 1,3- Dioxopent-4-ylmethyl, etc .; CnC3 alkylthiomethyl groups, such as: methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, etc .; Radicals, such as: pivaloyloxymethyl, a-acetamidomethyl, etc .; ethoxycarbonyl-1-methyl; or a-methyloxy-a-substituted methyl groups, such as : A -Ethyloxyethyl. In addition, the compound of the present invention may be a crystalline solid, which may be crystallized from a common solvent such as ethanol, N, N-dimethyl-formamide, water, and the like. Therefore, the crystalline form of the present compound may be a solvate and / or a hydrate of the parent compound or a pharmaceutically acceptable salt thereof. All such forms are also within the scope of the invention.

Although the compounds of the invention can be administered as a single active agent, they can also be used in combination with one or more compounds of the invention or other formulations. When administered as a combination, the medical agents may be formulated separately into a composition and administered at the same time or at different times, or the medical agents may be administered as a single composition. The above description is only illustrative of the present invention and is not intended to limit the present invention to the compounds disclosed therein. Those skilled in the art understand that changes can be made within the scope and nature of the invention as defined by the appended patent claims. Those skilled in the art can easily confirm the basic characteristics of the present invention from the above description, and can make various changes and modifications to the present invention in accordance with various uses and conditions without departing from the spirit and scope thereof. • 184-

Claims (1)

200303316 Patent application scope 1. A compound of the following formula: Or a pharmaceutically acceptable salt thereof, in which X is C-R2 or N;-11 | and R2 are independently -ZY or -Y; but the restriction is that aryl, heteroaryl, and naphthene in 1 and R2 The total number of radicals and heterocyclic groups is 0-3; U, V and W are independently C-R6 or N, but the limitation is that when U is N, then V is C-R6; each R6 is independently hydrogen , Halo, alkyl, alkoxy, alkylthio, haloalkyl, li alkoxy, hydroxy, or cyano: each Z is independently (1) an alkyl, alkenyl, or alkynyl group, which may The following substituents replace (a) 1-3 of the following substituents: amine, amido, dialkylamino, alkylamino, oxocarbonylamino, oxoamino, meridian, and oxy , Sulfanyl or halo, and (b) 1-2 of the following substituents: heterocyclyl, aryl, or heteroaryl: or (2) heterocyclyl, aryl, or heteroaryl; wherein heterocycle The base may be substituted with 1 to 3 of the following substituents as required: amine, alkylamino, dialkylamino, alkylamino, alkoxycarbonylamino, sulfamoylamino, mesyl, alkoxy, alkyl Sulfur group, alkyl group, aryl group, heteroaryl · pit group 200303316 Continuation page or halo: And aryl and heteroaryl can be substituted with 1-3 of the following &amp; groups as needed: amino, alkylamino, di-peptamine, p-peptamine, and peroxo ^ Amine group, amine group, triphenyl group, pitoxy group, thiol group, cyano group, dentyl group, alkyl group, or haloalkyl group; each Y is independently (1) hydrogen group; (2) halo group or Nitro; (3) -C (〇) -R2〇, -C (0) -OR2i, -C (0) -NR5R2i or -C (NR5) -NR5R2 group; (4) -〇r21, -〇 -c (o) -r21, -〇-c (〇) -nr5r21 or -〇-c (〇) -nr22-s (o) 2-r20 group; (5) -SR21 '-S (0) -R2 〇 '* δ (Ο) 2 * Ι ^ 20' -S (0) 2 &quot; NRsR21 '* S (0) 2eNR22 &quot; C (0) -R21, -S (0) 2-NR22-C (0)- 0R2. Or -S (0) 2-NR22-C (0) -NR5R21 group; or (6) -NR5R2 丨, -nr22-c (o) -r2 丨, -nr22-c (o) -or20, -nr22- c (o) -NR5R2i, -nr22-c (nr5) -nr5r2 丨, -nr22-s (o) 2-r20 or -nr22-s (o) 2- N R5 R] 1 groups, each R5 is independently (1) Hydrogen group; (2) Alkyl, alkenyl or alkynyl, which may be substituted with 1-3 of the following substituents as needed: amine, amine, diamine, meridian, alkoxy, Thio, -S03H or halo; or (3) aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocycloalkyl, cycloalkyl or cycloalkylalkyl, where Aryl, heteroaryl, heterocyclyl, and cycloalkyl can be optionally substituted with 1-3 of the following substituents: amine, 200303316 _ application for patents continued on alkylamines, dialkylamino, hydroxyl, alkoxy , Alkylthio, alkyl or haloalkyl; each r20 is independently (1) alkyl, alkenyl or alkynyl, which may be substituted with 1-3 of the following substituents as required: (a) 1-3 The following substituents: amine, alkylamino, dialkylamino, burned amino, burned oxocarbonyl, N- (burned oxycarbonyl) -N- (burned) amine, aminocarbonyl, fired Performance Amine group, triphenyl group, fluorenyloxy group, thiothio group, thioalkylene group, thiophenyl group or iiyl group and (b) aryleneoxy group, arylthio group, aralkylsulfonyl group, cycloalkyl group , Heterocyclyl, aryl, or heteroaryl, in which aryl, heteroaryl, heterocyclyl, and cycloalkyl are optionally substituted with 1-3 of the following substituents: amino, alkylamino, dialkylamino , Alkylamino, alkoxycarbamino, burn-in amino, sS-based, mesyl, pitoxy, sulfanyl, alkylsulfinyl, alkylsulfonyl, halide, alkyl, or Haloalkyl; (2) Heterocyclyl, which may be substituted with 1-3 of the following substituents as needed: amine, amine, diamine, amine, oxoamino, and Amine, triphenyl, alkoxy, sulfanyl, thio or alkynyl; or (3) aryl or heteroaryl, optionally substituted with 1-3 of the following substituents: amine, alkylamine Group, dialkylamino group, alkylamino group, alkoxycarbonylamino group, burned amino group, burned carbon group, warp group, burned oxygen group, burned sulfur group, cyano group, halo group, and azide group , Alkyl or haloalkyl; each R21 is respectively a mouse or R20, and each R 2 is 2 minutes The only three are (1) a hydrogen group; (2) an alkyl group, which may be optionally substituted with the following substituents: heterocyclic group, aryl 200303316, a patent application, continuation group, or equivalent aryl group, in which the heterocyclic group, aryl group, or Heteroaryl may be optionally substituted with U3 of the following substituents: amine, alkylamino, dialkylamino, alkylamido, alkoxycarbonylamino, sulfoamido, hydroxyl, alkoxy, alkylthio Group, alkenesulfinyl, polofluorenyl, cyano, halo, alkyl, or fluorenyl: or (3) heterocyclyl, aryl, or heteroaryl, which may be subjected to 1-3 if necessary Substituent substitution: amine, amine, dialkylamino, alkylamino, alkoxyamino, amine, amino, alkoxy, sulfanyl, sulfonium: Shiling Alkyl, alkanesulfonyl, cyano, halo, alkyl, or alkynyl; Ru is aryl or heteroaryl, and R12 is heteroaryl, of which aryl, heteroaryl, and heteroaryl can be modified as needed 1-3 of the following substituents: (1) R; o: (2) functional or cyano; (3) -C (O) -R30, -C (0) -0R; 29, -C (0 ) -NR3lR32 or -C (NR31) -NR3iR32; (4) -OR29, -0-C (0) -R29, -0-C (0) -NR3 丨 R32 -〇-C (0) -NR33-S (0) 2-R3〇, (5) -SR29, -S (0) -R3〇, -S (0) 2-R3〇, -S (0) 2NR3iR32 , -S (0) 2_NR33-C (0) -R; 5〇 ...- s (o) 2 «nr33-c (〇v〇r30 or -s (o) 2-nr33-c (o) -nr31r32; Or (6) -NR3iR32 '-NR33-C (0) -R29' -NR33-C (0) -OR3〇 '-NR33-C (0) -NR31R32' -NR33-C (NR3l) -NR3iR32 '-NR33 -S (0) 2.R3〇il-NR33-S (0) 2-NR3tR32 but the restriction is that the total number of aryl, heteroaryl, cycloalkyl and heterocyclic substituents on each Ru and R12 is 0 -1; each R00 is independently (1) alkyl, alkenyl or alkynyl, which may be optionally substituted with the following substituents: (a) 1-3 of the following substituents: -NR31R32, hydroxyl, alkoxy Alkanethio 200303316 patent application scope continuation base, arylene group, siyl group, cyano or dentyl group, and (b) aralkyloxy, aralkylthio, aralkylsulfonyl, heterocyclic Group, aryl group or heteroaryl group, wherein heterocyclic group, aryl group and heteroaryl group may be optionally substituted with 1 to 3 of the following substituents: amino group, alkylamino group, dialkylamino group, alkylamino group, alkyl group Oxycarbonylamino, alkylsulfonamido, hydroxyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl , Cyano, self-radical, alkyl, or alkanyl; (2) Heterocyclyl, which may be optionally substituted with 1-3 of the following substituents: amino, alkylamino, dialkylamino, alkylamido , Alkoxycarbonylamino, alkanesulfoφamino, hydroxyl, alkoxy, alkylthio, cyano, alkyl, or oxyalkyl; or (3) aryl or heteroaryl, which can be adjusted as required 3 of the following substituents: amine, amine, diamine, amine, amine, amine, amine, thio, thio, thio, cyano, Halo, alkyl or alkyl: each R29 is independently hydrogen or R3G; each R31 is independently (1) Hydrogen group; (2) Alkyl group, optionally substituted with the following substituents: cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein cycloalkyl, aryl, heterocyclyl and heteroaryl The group may be substituted with 1 to 3 of the following substituents as required: amine, alkylamino, dialkylamino, alkylamino, alkoxycarbonylamino, sulfamoylamino, hydroxyl, alkoxy, alkylthio Group, cyano, alkyl, or self-alkyl: or (3) aryl, heteroaryl, heterocyclyl, or cycloalkyl, optionally substituted with 1-3 of the following substituents: amine, amine Amines, diamines, amines, alkoxycarbonylaminos, sulfamolamidos, hydroxyls, alkoxys, alkylthios 200303316 _ Application for a continuation of the scope of patents, cyanocarbons, alkyls or deltas; And each r32 is independently (1) a hydrogen group; (2) an alkyl group, which may be optionally substituted with the following substituents: a cycloalkyl group, an aryl group, a heterocyclic group, or a heteroaryl group, wherein the cycloalkyl group, the aryl group, Heterocyclic groups and heteroaryl groups may be substituted with 1-3 of the following substituents as needed: amine, alkylamine, dipitamine, amine produced by burning, oxocarbonyl, burning amino, Alkoxy , Alkylthio, cyano, alkyl or _alkyl; or (3) aryl, heteroaryl, heterocyclyl or cycloalkyl, optionally substituted with 1-3 of the following substituents: amine , Alkylamino, dialkylamino, alkylamido, alkoxycarbonylamino, alkanesulfonamido, hydroxyl, alkoxy, alkylthio, cyano, alkyl, or alkanyl; and each R33 They are each independently (1) hydrogen: or (2) alkyl, which may be optionally substituted with the following substituents: heterocyclyl, aryl, or heteroaryl, in which aryl, heterocyclyl, and heteroaryl may be optionally substituted. 1-3 of the following substituents: amine, alkylamino, dialkylamino, alkylamino, oxocarbonylamino, oxamino, amino, thiol, thiol, cyano Radical, alkyl or haloalkyl. 2. A compound or a pharmaceutically acceptable salt thereof according to item 1 of the scope of patent application, wherein X is C-R2 or N; 1 ^ and r2 are independently -ZY or -Y: but the limitation is Xin and R2 The total number of aryl, heteroaryl, cycloalkyl and heterocyclic groups is 0-3; -6- 200303316 _ Scope of patent application Continued u, V and W are independently C-R64 N, but the restrictions are When U is N, then V is C-R6; each R6 is independently hydrogen, halo, C "C4 alkyl, (VC4 alkoxy, c" c4 alkylthio, and 1 to 3 halogen groups (: "(: 4-haloalkyl, Ci-Cq haloalkoxy, hydroxy or cyano containing 1 to 3 halo groups; each Z is independently (1) CVCs alkyl, C2-C8 alkenyl or &lt;: 2-0: 8 alkynyl, which may optionally be substituted with the following substituents (a) 1-3 of the following substituents: amine, CrCU alkylamino, di- (CVC4 alkyl) amino, C!- C5 alkylamino, (CKC4 alkoxy) carbonylamino, Ci-C4 alkylsulfonamido, hydroxyl, CrC4 alkoxy, C4 alkylthio or functional group, and (b) 1-2 The following substituents: heterocyclyl, aryl, or heteroaryl; or (2) heterocyclyl, aryl, or heteroaryl; wherein hetero The group may be substituted with 1 to 3 of the following substituents as required: amine, C, C4 alkylamino, di- (CVCU alkyl) amino, CrCs alkylamido, (Ci-C # alkoxy) carbonylamino C, C4 alkylsulfonamido, hydroxyl, CkCU alkoxy, CrC4 ^ thio, CrC4 alkyl, aryl-C, C4 alkyl, heteroaryl-CpCU alkyl, or 1-3 halo groups Haloalkyl: and aryl and heteroaryl can be optionally substituted with 1-3 of the following substituents: amine, CrC4 alkylamino, bis- (C "C4 · alkyl) amino, C" C5 alkyl Amine group, (CVC4 alkoxy) carbonylamino group, (^-(: 4 alkanesulfonylamino group, hydroxyl group, (^ 0: 4 alkoxy group, alkylthio group, cyano group, halo group, ("匸4-alkyl or 1-3 halo-containing groups: "(: 4-haloalkyl; each Y is independently 200303316 Patent Application Continued ⑴Hydrogen 碁; (2) Halo or nitro; (3) -C (〇) -R2〇, -C (〇) -〇R2i, -C (0) -NR5R2i or · 〇 (ΝΙ15) -ΝΙΙΙΙ 121 group; (4) -OR21, -〇-C (0) -R2i , -〇-C (0) -NR5R2i or 〇-C (0) -NR22-S (〇) 2 · r2〇 group; (5) -SR2l '-S (O) -R20' -S (O) 2-R20 '-S (0) 2-NR5R2i' -S (0) 2-NR22-C (〇) -R2 1, -S (〇) 2-NR22-C (O) -〇R20 or -S (0) 2-NR22-C (0) -NR5R2; or-(6) -NR5R2 !, -nr22-c (o)- r21, -nr22-c (o) -or2. , -Nr22 and c (o) "NR5R21, -NR22-C (NR5) -NR5R2 丨, -NR22-S (O) 2-R20, or -NR22-S (0) 2-NR5R21®: Each R 5 is independent It is a hydrogen group: (2) (: "〇8 alkyl, c2-c8 alkenyl, or c2-c8 alkynyl, which may be substituted with 1.3 substituents as follows: amine, alkylamino, di- (Ci-C4 alkyl) amino, hydroxyl, CkC4 alkoxy, Cnc4 alkylthio, -so3h or halo; or (3) aryl, heteroaryl, aryl-Cl-C4-alkyl, hetero Aryl-C "c4-alkyl, heterocyclyl, heterocyclyl-CVC4-alkyl, (: 3- &lt;: 8cycloalkyl or C3-C8-cycloalkyl-Ci-CU-alkyl, Wherein aryl, heteroaryl, heterocyclyl and cycloalkyl can be optionally substituted with 1-3 of the following substituents: amine, CkC4 alkylamino, di- (Cl-C4 alkyl) amino, C1-C4 gas group, C1-C4 alkyl group, C "C4 alkyl group or CVC4 haloalkyl group with 1-3 halo groups; each R2G is 200303316 independently _ Scope of patent application continued (1) cl: c8 alkyl, c2-c8 alkenyl or c2-c8 alkynyl, which may be optionally substituted with the following substituents: (a) 1-3 of the following substituents: amino, alkylamino, di- (Ci-CU alkyl Group) amine group, C "C5 alkane Amino group, (CVC4 alkoxy) carbonylamino group, N-((C "C4 alkoxy) carbonylalkyl) amino group, aminocarbonylamino group, CVC4 alkanesulfonylamino group, hydroxyl group, CVC4 alkoxy group, CrC4 alkylthio, C4C4 alkylsulfinyl, CkG alkylsulfonyl or halo, and (b) aryl-CVCV alkoxy, aryl-CVC4-alkylthio, aryl-CrC4-alkane Sulfonyl, C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl, in which aryl, heteroaryl, heterocyclyl and cycloalkyl can be substituted with 1-3 of the following substituents as needed: amine Group, CVC4 alkylamino group, di- (CrC4 alkyl) amino group, CrC5 alkylamino group, ((^-(: 4 alkoxy) carbonylamino group, CrC4 alkylsulfonylamino group, ("(: 5 Alkyl group, hydroxyl group, CrC4 alkoxy group, CVC4 alkylthio group, 0 ((4 alkylsulfinyl sulfonyl group, CVC4 alkylsulfonyl group, halo group, CnC4 alkyl group or CVC4 containing 1-3 halo Haloalkyl; (2) heterocyclyl, which may be optionally substituted with 1-3 of the following substituents: amine, C, C4 alkylamino, di- (Ci-C * alkyl) amino, Ci- C5 alkylamino, ((^ -0: 4 alkoxy) carbonylamino /, CKC4 alkylsulfonamido, hydroxyl, CVC4 alkoxy, CVCU alkylthio, C KC4 alkyl or CrC4 haloalkyl containing 1-3 halo: or (3) aryl or heteroaryl, which may be substituted with 1-3 of the following substituents as needed: amine, CVC4 alkylamino, di -((VC * alkyl) amino, CVC5 alkylamino, (C "C4 alkoxy) carbonylamino., C" C4 alkylsulfonamido, (CnC4 alkoxy) carbonyl, hydroxyl, cvc4 Alkoxy, CVC4 alkylthio, cyano, halo, azide, C "C4 alkyl or C" C4 haloalkanes containing 1-3 halo groups 200303316 _ Application for patent continuation; _ each r2I Each independently is hydrogen or r20 and each R22 is independently (1) hydrogen; (2) CnC4 alkyl, optionally substituted with the following substituents: heterocyclyl, aryl, or heteroaryl, wherein aryl, heteroaryl, and heterocyclyl may be substituted with 1-3 of the following substituents as needed: Amine, CVC4 alkylamino, di- (CrC ^ alkyl) amino, C "C5 alkylamino, (CkC4 alkoxy) carbonylamino, CrC4 alkylsulfonamido, hydroxyl, CVC4 alkoxy , Ci-CU alkylthio, CVC4 alkylsulfinyl, C4 alkylsulfonyl, cyano, halo, CKC4 alkyl or CnG haloalkyl containing 1-3 halo groups; or (3) Heterocyclyl, aryl or heteroaryl, optionally substituted with 1-3 of the following substituents: amine, C | -C4 alkylamino, di- (C "C4 alkyl) amino, CrC5 alkyl Amine, alkoxy) carbonylamino, CrC4 alkylsulfonamido , Hydroxyl, CrG alkoxy, (VC4 alkylthio, C "C4 alkylsulfinyl, CVC4 alkylsulfonyl, cyano, halo, CrC4 alkyl, or C" C4 Haloalkyl: Ru is aryl or heteroaryl, and R12 is heteroaryl, in which aryl, heteroaryl and ΠΠΠ heteroaryl is optionally substituted with U2 of the following substituents: (1) R30: '( 2) Self- or cyano; (3) -C (〇) -R30, -C (〇H) R29, -C (〇) -NR31R32 or -C (NR31) -NR31R32; (4) -OR29,- 〇-C (〇) -R29, -〇-C (〇) -NR31R32 or -OC ^ OhNRw-SWrl ^ o; • i0-200303316 _ Application for patents continued page (5) -Sg29, -S (〇), R30, -S (O) 2-R30, -S (〇) 2NR31R32, -S (〇) 2-NR33-C (〇) -R3〇, -S (O) 2-NR33-C (O) -OR30 Or -S (〇) 2-N R3: rC (〇) -NR31R32: or (6) -NR3 | R32 '-NR 3 3-C (0)-R2 9'-N R3 3-C (0)- 0 R3 0 '-NR33 * C (0) -N R3 1 R3 2, -N R3 3-C (N R3 1) -N R3 1 R3 2, -N R3 3-S (〇) 2 * R3 0 or -N R3 3- s (o) 2-nr3 丨 R32; but its limitation is that the total number of aryl, heteroaryl, cycloalkyl and heterocyclic substituents on each 1111 and R12 is 0-1; each R 3Q is independently (1) C "C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, which may be optionally substituted with the following substituents: (a) 1-3 of the following substituents: -NR31R32, hydroxyl, C "C4 alkoxy, Ci-CU alkylthio, CkC4 alkylsulfinyl, CrC4 alkylsulfonyl, cyano or halo, and (b) arylalkoxy, aryl-CVC4-alkane Thio, aryl-C, C4, alkanesulfonyl, heterocyclyl, aryl or heteroaryl, wherein heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine Group, CVC4 alkylamino group, di- (CVC4 alkyl) amine group, C "C5 · Chen SS amine group, (C", C4 gas group) fluorenyl group, CVC4 sulfonium amine group, hydroxyl group, (VC4 Alkoxy, CrC4 alkylthio, CVC4 alkylsulfenyl, CkCa alkylsulfonyl, cyano, halo, C "C4 alkyl or C ^ -Ci haloalkyl containing 1-3 halo groups; (2) Heterocyclic group, which may be substituted with 1-3 of the following substituents as needed: amine group, (VCU alkylamino group, di- (CVC4 alkyl) amino group, C "C5 alkylamino group, (CVC4 alkyl group) (Oxy) carbonylamino, CnC4 alkylsulfonamido, hydroxyl, C "C4 alkoxy, Ci-Cj alkylthio, cyano, C" C4 Or "C4 200303316 _ application scope of patents continued on halides, or: (3) aryl or heteroaryl, which may be substituted with 1-3 of the following substituents as needed: amine Group, Ci-C * alkylamino group, dialkyl) amino group, CVC5 alkylamino group, (CrC4 alkoxy) carbonylamino group, C "C4 alkylsulfonamido group, hydroxyl group, CrC4 alkoxy group 'CrC4 Alkylthio, cyano, halo, CrC4 alkyl or C "C4 haloalkyl containing 1-3 halo groups; each R29 is independently hydrogen or R30; Each R31 is independently _ (1) hydrogen group; (2) Ci-C # alkyl group, which may be optionally substituted with the following substituents: C3-C8 cycloalkyl, aryl, heterocyclic or heteroaryl, wherein the ring Alkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine, C "C4 alkylamino, di- (CrC4 alkyl) amino, C" C5 alkyl Amine, ((: "(: 4 alkoxy) carbonylamino, CrC4 alkylsulfonamido, hydroxyl, C" C4 alkoxy, CVC4 alkylthio, cyano, C "C4 alkyl or containing 1 -3 halogen CVC4 halogen Alkyl; or (3) aryl, heteroaryl, heterocyclyl or C3-Cs cycloalkyl, optionally substituted with N3 of the following substituents: amine, Ci-C4 alkylamino, di- (CkG Alkyl) amino, CrCs alkylamino, (CVC4 alkoxy) carbonyl, C, C4 alkylsulfonamido, hydroxyl, CVC4 alkoxy, CVC4 alkylthio, cyano, CVC4 alkyl or CVC4 haloalkyl group containing 1-3 halo groups; each R32 is independently (1) hydrogen group; (2) alkyl group, which may be substituted with the following substituents as required: C3-C8 ring • 12- 200303316 _ Apply for a patent Range Continued Alkyl 1 aryl, heterocyclyl or heteroaryl, in which cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine, C, C4 Alkylamino, di- (CVC4 alkyl) amino, CVC5 alkylamino, (Ci-CU alkoxy) carbonylamino, CrC4 alkylsulfonamido, hydroxyl, C / C4 alkoxy, (: "C4 alkylthio, cyano, CVC4 alkyl or CrC4 haloalkyl containing 1-3 halo groups; or (3) aryl, heteroaryl, heterocyclyl or C3-C8 cycloalkyl, which can be seen Need to be substituted with 1-3 of the following substituents: amine, (^-(: 4 alkylamino, di- ( CVC4 alkyl) amino, CVCs alkylamino, (CrG alkoxy) carbonylamino, C "C4 alkylsulfonamido, hydroxyl, C" C4 alkoxy, CVC4 alkylthio, cyano, CVC4 Alkyl or CVC4 haloalkyl containing 1-3 halo groups; each R33 is independently (1) argon; or (2) C "C4 alkyl, which may be substituted with the following substituents as required: heterocyclyl, Aryl or heteroaryl, in which aryl, heterocyclyl and heteroaryl are optionally substituted with 1-3 of the following substituents: amino, (VC4 alkylamino, di- (CkCU alkyl) amino, CVC5 Alkylamino, (Ct-Ce pitoxy) carbonylamino, CrC # Alkylsulfonamido, hydroxyl, CrC4alkoxy, C4C4 alkylthio, cyano, CrC4 alkyl or containing 1-3 CVCU haloalkyl groups of 1 halo group; and wherein the heterocyclic group is a monocyclic or bicyclic saturated heterocyclic ring system containing 5-8 ring members in each ring, of which 1-3 ring members are oxygen, sulfur or aza Atoms, which are partially saturated or benzo-fused as required, and optionally substituted with 1-2 oxo or thio groups; aryl is benzyl or fluorenyl; and heteroaryl is contained in each ring A monocyclic or bicyclic aromatic heterocyclic ring of 5-6 ring members , • π · 200303316 _ Continued patent application range where the L-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which can be fused with benzo or saturated C3-C4 carbocyclic rings as required. 3. According to the patent application The compound of the second item or a pharmaceutically acceptable salt thereof, wherein each Z is independently (1) c "c8 alkyl or c2-c8 alkenyl, which may be substituted with the following substituents as necessary: (a) 1- 3 of the following substituents: amine, CpCU alkylamino, di- (C | -C4 alkyl) amino, CkCs alkylamido, (C "C4 alkoxy) carbonylamino, quinyl, (: rC4 alkoxy, CVC4 alkylthio or halo, and (b) 1-2 of the following substituents: heterocyclyl, aryl, or heteroaryl; or (2) heterocyclyl, aryl, or heteroaryl Wherein, the heterocyclic group may be substituted with N3 substituents as necessary: amine group, CVC4 alkylamino group, di- (CrC4 alkyl) amino group, CVC5 alkylamino group, (CrC4 alkoxy) carbonylamino group, hydroxyl group , CrC4 alkoxy, C "C4 alkylthio, CVC4 alkyl, aryl-C" C4 alkyl, heteroaryl-CrG alkyl, or C! -C2 haloalkyl containing U3 halo groups; and aromatic And heteroaryl groups Substituent substitution: amine, CT-C4 alkylamino, di- (CVC4 alkyl) amino, CrC5 alkylamino, (CrC4 alkoxy) carbonylamino, hydroxyl, CVC4 alkoxy, CVCU alkanethio Group, cyano group, halo group, C "C4 alkyl group or C" C2 haloalkyl group containing 1-3 halo groups; each Y is independently fluorenyl hydrogen or self-radical; (2) -C (〇) -R20 , -C (〇) -〇R2 丨, -C (0) -NR5R21 or-(:( Νί15) -ΝΙ15Ι121 200303316 _ Application for a patent (continued) (3) -Og21, -〇-C (〇) -Rn or -〇-C (〇) -NR5R21 group; (4) -SR21, -S (O) -R20, -S (0) 2-R2〇 or -S (0) 2-NR5R21 group; or (5)- NR5R21, -NR22-C (〇) -R21, -NR22-C (〇) -〇R20 or -NR22-C (〇) -nr5r2 group; each R5 is independently (1) hydrogen group; (2) Ci-Ci alkyl or C2-C5 alkenyl, which may be substituted with 1 to 3 of the following substituents as necessary: amine, di- (CrCV alkyl) amino, hydroxyl, (: "(: 4 alkyl Oxy, c, c4 alkylthio, -S03H or halo; or (3) phenyl-CrC2-alkyl, heteroaryl-CrCralkyl, heterocyclyl-CrC2-alkyl or C3-C6-ring Alkyl-C ^ Cz-alkyl, in which cycloalkyl, phenyl, heterocyclyl and heteroaryl are optionally substituted with 1-3 of the following substituents: amino, di- (CrCV alkyl) amino, Hydroxyl, CrC4 alkoxy, Ci-C * alkylthio, (: "(: 4 alkyl or CrC2 haloalkyl containing 1-3 halo groups; each R20 is independently (1) C "C8 alkyl or C2-C5 alkenyl, which may be substituted with 1 to 3 of the following substituents as needed: ^ ^ ^ the following substituents: amine ^ ^-alkylamino ~ di- (C "C4 alkyl) amino, C" C5 alkylamino, (C "C4 alkoxy) carbonylamino, N-UCi-G alkoxy) carbonyl) -N- (C" C4 alkyl) amine Group, amine carbonylamino group, hydroxyl group> CVC4 alkoxy group, CVC4 alkylthio group, cvc4 alkanesulfinyl group, C "C4 alkanesulfonyl group or halo group, and (b) aryl-CrCV alkoxy group, Aryl-Ci-CV alkylthio, aryl- (VC4-pitsulfonyl, c3-c6 cycloalkyl, heterocyclyl, aryl or heteroaryl, of which cycloalkyl, aryl, heterocyclyl With heteroaryl, optionally substituted with N3 of the following substituents: amine group, Ci-Cj alk-15-200303316 _ patent application scope continuation amine group: di- (CVC4 alkyl) amine group, crc5 alkyl amine group, (C "c4 alkoxy) carbonylamino, (VC4 alkanesulfonylamino, CrC5 alkylsulfonyl, hydroxyl, CnC4 alkoxy, C" C4 alkylthio, halo, CVC4 alkyl or 1-3 Ci-C: haloalkyl with 2 halo groups; (2) Heterocyclic group, which may be substituted with 1-2 following substituents as needed: amine, di- (CrG alkyl Amine group, (CrC4 alkoxy) carbonylamino group, hydroxy group, (C: (4 alkoxy group, CKC4 alkylthio group, or C "C4 alkyl group; or (3) aryl or heteroaryl group, as required Substitute φ with 1-2 of the following substituents: amine, C "C4 alkylamino, di- (C" C4 alkyl) amino, acetamido, (C "C4 alkoxy) carbonylamino, CVCU alkanesulfonylamino, alkoxy) carbonyl, hydroxyl, CVC4 alkoxy, CVC4 alkylthio, cyano, halo, azide, CVC4 alkyl, or trifluoromethyl: each R is independently Wang Weizhi or R20, each R22 is independently (1) a hydrogen group; or (2) Alkyl, optionally substituted with the following substituents: phenyl or heteroaryl, of which benzyl and heteroaryl are optionally substituted with 1-3 of the following substituents. · Amine, di- (CrCz Alkyl) amino, CVC5 alkylamino, (CVC4 alkoxy) carbonylamino, hydroxyl, CVC4 alkoxy, (VCU alkylthio, cyano, halo, CrG alkyl or 1-3 CnC2 haloalkyl of halo; Ru is aryl or heteroaryl, and R12 is "N &quot; -heteroaryl, in which aryl, heteroaryl and Π" -heteroaryl may be subjected to 1-2 following if necessary Substituent substitution: (1) R30: (2) painting group or cyano group; -16-200303316 _ Application for patent scope continued (3 Bu Cod R30, -C (0) -0R29, -C (0) -NR31R32 or -C (NR31) -NR3lR32: or (4)-(DR29, -SR] 9, -S (〇) -R30, -S (O) 2-R30, -S (〇) 2-NR3iR; 52, -NR33-S (〇) 2-R30 '-NR31R32 or -NR33-C (0) -R29, each R 3 0 is unique (1) Ci-Ce alkyl or c2-c5 alkenyl, which may be optionally substituted with the following substituents: (a) 1-3 of the following substituents: -NR31R32, hydroxyl, CVC4 alkoxy or halo, and ( b) Heterocyclyl, aryl or heteroaryl, wherein heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 of the following substituents: amine, Ci-C4 alkylamino, di- (CVC4 Alkyl) amino, CVC5 alkylamino, (Cr-C4 alkoxy) carbonylamino, C! -C4 alkylsulfonamido, hydroxyl, (VC4 alkoxy, CrC4 alkylthio, CkC4 alkylsulfonyl Fluorenyl, cyano, halo, CVC4 alkyl or CrC4 haloalkyl containing 1-3 halo groups; (2) Heterocyclyl, which may be optionally substituted by 1-3 of the following substituents: amine, (: "C4 alkylamino, di- (CnC4 alkyl) amino, (: 5 alkylamine (CVC4 alkoxy) carbonylamino, CVC4 alkanesulfonylamino, hydroxyl, CnC4 alkoxy, CrQ alkylthio, cyano, CrC4 alkyl, or C 1-C 4 halogenated halogenated Group; or (3) aryl or heteroaryl, which may be substituted with 1-3 of the following substituents as needed • Amine, -CnG alkylamino, di- (CVC4 alkyl) amino, CVC5 alkylamine (CnC4 alkoxy) carbonylamino, C4C4 alkanesulfonylamino, hydroxyl, CVC4 alkoxy, CVC4 alkylthio, cyano, halo, CkC4 alkyl, or 1-3 halo (^-(: 4 haloalkyl groups; each R; 29 respectively is the king or gas 30, -17- 200303316 _ Patent Application Continued page each R31 contains independently as (1) hydrogen group; or (2) ) CrC # alkyl, optionally substituted with the following substituents: aryl or heteroaryl, where aryl and heteroaryl are optionally substituted with 3 of the following substituents: amino, CrG alkylamino, di- ((VC4 alkyl) amino, C, C5 alkylamino, (CrC4 alkyloxy Carboxamide, hydroxyl, CrCi alkoxy, C 丨 -C4 alkylthio, cyano, Ci-C4 alkyl, or trifluoromethyl; each R32 is independently (1) hydrogen; (2) Ci-G Alkyl, optionally substituted with the following substituents: aryl or heteroaryl, where aryl and heteroaryl are optionally substituted with 1-3 of the following substituents: amino, C, C4 alkylamino, di- (CrCU alkyl) amino, C ^ Cs alkylamino, (C "C4 alkoxy) carbonylamino, hydroxyl, CrC4 alkoxy, C4C4 alkyl or trifluoromethyl; or (3) An aryl or heteroaryl group, which may be optionally substituted with 1-3 of the following substituents: amine, CrC * alkylamino, di- (CrC ^ alkyl) amino, CkCs alkylamino, ( C "C4 alkoxy) carbonylamino, meridian, CVC4 pitoxy, C" C4 alkyl or trifluoromethyl: and each R33 is independently hydrogen or CnC4 alkyl. 4. According to the scope of patent application No. 3 Item of the compound or a pharmaceutically acceptable salt thereof, wherein RA -ZY or -Y; but the limitation is that the total number of aryl, hetero.aryl, cycloalkyl and heterocyclic group in R! Is 0-2; R2 is hydrogen, CVC4 alkyl, halo, cyano, hydroxy, CVC4 alkoxy, -18-200303316 _ Patent Application Continued C ^ C containing 1 to _3 halo: Haloalkoxy, CnC4 Alkylthio, amine, Ci-Cq alkylamino, di- (C "C4 alkyl) amino or CkQ haloalkyl containing 1 to 3 halo groups; each Z is independently (1) alkyl or C2-C5 alkenyl, optionally substituted with the following substituents: (a) 1-3 of the following substituents: amine, di- (CrC2 alkyl) amino, (VC5 alkylamino, (C ! -C4 alkoxy) carbonylamino, hydroxyl, CVC2 alkoxy, CVC2 alkylthio or halo, and (B) 1-2 heterocyclyl, aryl, or heteroφaryl: or (2) heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl is optionally substituted with 1-3 of the following substituents: Amine, di- (CnC) alkyl) amino, CVC5 alkylamino, (CVC4 alkoxy) carbonylamino, hydroxyl, CVC4 alkoxy, CnCU alkylthio, CrC4 alkyl, aryl-CkCU Alkyl, heteroaryl-alkyl or trifluoromethyl; and aryl and heteroaryl may be optionally substituted with 1 to 3 of the following substituents: amino, di -(CrC2 alkyl) amino group, CrCs alkylamino group, (CVC4 alkoxy) carbonylamino group, hydroxy 'Ci-C4 alkoxy group, C "C4 alkylthio group, cyano group, functional group, X1- Γ4 alkyl or trifluoromethyl; each Y is independently a hydrogen atom;-(2) -C (0) -R2O or ·: (0) -Νί15Ι121 group; (3) -〇R21, -SR21 , -S (〇) -R20, -S (〇) 2-R20 or -S (〇) 2-NR5R2l group: or (4) -NR5R21 or -NR22-C (0) -R2i group, each R5 is independent For -19-200303316 _ Application for patent continuation (1) Hydrofluorene; (2) C "C4 alkyl, which may be substituted with 1-3 of the following substituents as needed: amine, di- (CVCr alkyl) amine Group, hydroxyl, C, C2 alkoxy, (^-(: 2 alkylthio or halo); or (3) phenyl-CrCV alkyl, heteroaryl-CVCr alkyl, heterocyclyl-CrCy alkyl, or C3-C6 cycloalkyl-CrCy alkyl, of which phenyl, heteroaryl, heterocyclyl, and cyclic The alkyl group may be optionally substituted with 1 to 3 of the following substituents: amine, di- (CrC) alkyl) amino, hydroxyl, CnC2 alkoxy, CVC2sulfanyl, alkyl, or trifluoromethyl; each R2Q Are independent of (1) CVC8 alkyl, which may be substituted with the following substituents as necessary: (a) 1-3 of the following substituents: amine, CrC4 alkylamino, di- (CrC4 alkyl) amino, CVC5 alkylamino , (CrC4 alkoxy) carbonylamino, N-GCi-C * alkoxy) carbonyl) -N- (CrC4alkyl) amino, aminocarbonylamino, hydroxyl, C, C4 alkoxy, C "C4 alkylthio, CkC4 alkylsulfenyl, CVC4 alkylsulfonyl or halo, and (b) C3-C6 cycloalkyl, heterocyclyl, aryl or heteroaryl The cyclic group, aryl group and heteroaryl group may be optionally substituted with 1-2 of the following substituents: amine group, di- (CVC4 alkyl) amino group, CVC5 alkylamino group, (C | -C4 alkoxy) carbonyl group Amine group, C "C4 alkylsulfonamido group, hydroxyl group, C" C4 alkoxy group, C "C4 alkylthio group, halo group, CVC4 alkyl group or trifluoromethyl group; (2) Heterocyclyl group, if necessary Substituted by 1-2 of the following substituents: hydroxyl, CnC4 alkoxy, C "C4 alkylthio or C" C4 alkyl; or (3) aryl or heteroaryl, which may be replaced by 1-2 if necessary Substituent substitution-20- 200303316 _ Application for patents Continued: Amine, CVC4 alkylamino, di-((VC4 Group) amino group, (cvc4 alkoxy) carbonyl group, hydroxyl group, CrC4 alkoxy group, CrCU alkylthio group, cyano group, halo group, azido group, Ci-C4 alkyl group or trifluoromethyl group; each R21 is independent Is hydrogen or R20; each R22 is independently hydrogen or Ci-C4 alkyl; Ru is aryl or heteroaryl, where aryl and heteroaryl are optionally substituted with 1-2 of the following substituents: (1) R40:. (2) halo or cyano; or (3) -C (〇) -NR4lR42, OR39, -SR39, · (3) (0) -1140, -S (0) 2-R4〇, -S (0) 2-NR4 丨 R42, -NR41R42 or -NR33-C (0) -R39, each R4Q is independently: (1) c "c4 alkyl, which may be substituted with the following substituents as required: phenyl or heteroaryl, wherein phenyl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine, diamine Group, acetamido, hydroxy, halide, methoxy, methyl or trifluoromethyl: (2, trifluoromethyl; or (3) aryl or heteroaryl, which can be Each of the following substituents: amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl, or trifluoromethyl; each R39 is independently a hydrogen group or R40; each R41 is The sole king is (1) hydrogen group; or (2) alkyl group, which may be substituted by the following substituents as required: benzyl or hetero-21-200303316 _ application for patents continued on aryl i where phenyl and heteroaryl are as required Substituted by 1-3 of the following substituents: amine, CVC2 alkylamino, di- (CVC2 alkyl) amino, acetamido, hydroxyl, CrCz alkoxy, C | -C2 alkylthio, cyano , C "c2 alkyl or trifluoromethyl; each R42 is independently (1) hydrogen; (2) substituted with aryl or heteroaryl (^-(: 4 alkyl or Ci-G alkyl, Where aryl and heteroaryl are visible Substituted by 1-3 of the following substituents: amine group φ, dimethylamino, acetamido, hydroxyl, methoxy, methyl or trifluoromethyl; or (3) aryl or heteroaryl It can be substituted with 1-3 of the following substituents as needed: amine, dimethylamino, acetamido, hydroxyl, methoxy, methyl or trifluoromethyl. Each R33 is independently argon or methyl And its heterocyclic group is a monocyclic saturated heterocyclic ring system containing 5-6 ring members in the ring, of which 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which may be fused by benzo, as required, And optionally substituted with 1-2 oxo or thio groups; aryl is phenyl or fluorenyl; and heteroaryl is a monocyclic aromatic heterocyclic ring system containing 5-6 ring members in the ring, of which 1 -3 ring members are oxygen, sulfur or nitrogen heteroatoms, which can be dull and fused or fused with saturated C3-C4 carbocyclic rings as required. 5. The compound according to item 4 of the scope of patent application or its pharmaceutically acceptable Salt, in which R2 is hydrogen, Ci-G alkyl, halo, cyano, hydroxy, CnC4 alkoxy, 'trifluoromethoxy or trifluoromethyl; -22- 200303316 Patent Application Continued R6 Others are hydrogen, C | -C4 alkyl, CrG alkoxy, -cf3, -〇cf3 or hydroxyl: each Z is independently (1) c "c4 alkyl or c2-c5 alkenyl, which may be subjected to Substituent substitution: (a) 1-3 of the following substituents: amine, di- (Ci-C: alkyl) amino, (C "C4alkoxy) carbonylamino, hydroxyl, CrC: alkoxy , (: "(: 2 alkylthio or halo, and (b) 1-2 of the following substituents: heterocyclyl, aryl or heteroaryl: or (2) heterocyclyl, aryl or heteroaryl Wherein the heterocyclic group is optionally substituted with 1-2 of the following substituents: C ^ C4 alkyl, arylalkyl, or heteroaryl-CnCz alkyl; and wherein aryl and heteroaryl are optionally substituted with 1- 3 of the following substituents: amino, di- (CVC2 alkyl) amino, acetamido, (CVC4 alkoxy) carbonylamino, hydroxyl, C, C2 alkoxy, CpC: alkylthio, Cyano, halo, CVC4 alkyl or trifluoromethyl; Each Y is independently argon, -0R21, -SR2i, -s (o) -r2〇, -s (o) 2-r20, or 屮 115112! Groups: each R5 is independently (1) argon; (2) C | -C4 alkyl, which may be substituted with 1-3 halo groups as required; or (3) benzyl-CrC ^ alkyl or heteroaryl-Ci-Cy alkyl, where benzyl and heteroaryl may be required Substituted by 1-3 of the following substituents: amino, dimethylamino, hydroxy, methoxy, methylthio, methyl or trifluoromethyl; each R2Q is independently -23- 200303316 _ Scope of patent application continued Page (1) CL-C6 alkyl, which may be optionally substituted with the following substituents: (a) 1-3 of the following substituents: amino, methylamino, dimethylamino, third butoxycarbonylamino, N-((third butoxy) carbonyl) -N- (methyl) amino, aminocarbonyl, hydroxyl, butoxy, methoxy, butylthio, methylthio, methylsulfinyl , Methanesulfonyl or halo, and (b) C5-C6 cycloalkyl, heterocyclyl, phenyl, or heteroaryl, which may be substituted with 1-2 of the following substituents as necessary: amine, dimethylamine (2) a heterocyclic group, which may be substituted with 1-2 of the following substituents as necessary: hydroxy group, acetamido group, hydroxy group, methoxy group, methylthio group, halo group, methyl group or trifluoromethyl group; Or C "C4 alkyl: or (3) aryl or heteroaryl, which may be substituted with 1-2 of the following substituents as necessary: amino, dimethylamino, hydroxyl, methoxy, methylthio, halogen Group, methyl group or trifluoromethyl group; each R21 is independently hydrogen or R2G; Ru is aryl or heteroaryl, which can be taken through 1-2 substituents as required Generation ... (1) «40 · (2) functional or cyano; or (3) -C (0) -NR41R42 'OR39' * SR39 '-S (0) -R4〇' * S (0) 2 * R4〇 '-S (0) 2_NR4iR42, -NR4 丨 R42 or · Νί ^ 33 · (Γ (0) -ί ^ 39, R12 is "N" -heteroaryl group, which can be adjusted by 1-2 as required Substituent substitution: (1) R30: (2) halo or cyano; or (3) -C (0) -NR41R42, -OR39, -SR39, -NR4, R42 or -NR; 53-C (0) -R39, each R4Q is independently -24-200303316 _ Scope of patent application continued (1) CuC4 alkyl, which may be substituted with the following substituents as required: phenyl or heteroaryl, of which phenyl and heteroaryl may be required Substituted by 1-2 of the following substituents: amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl, or trifluoromethyl; (2) trifluoromethyl; or ( 3) aryl or heteroaryl, which may be substituted with 1-3 of the following substituents as needed: amine, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl, or trifluoromethyl Groups; _ each R39 is independently I or R40, each R4l is independently hydrogen or CrC4 alkyl; each R42 is independently hydrogen or (^-(: 4 alkyl); and Mesoheterocyclyl is a monocyclic saturated heterocyclic ring system containing 5-6 ring members in the ring, of which 1-2 ring members are oxygen, sulfur or nitrogen heteroatoms, which can be fused with benzo, and 1-2 oxo or thio group substitutions; aryl is phenyl or fluorenyl: and heteroaryl is a monocyclic aromatic heterocyclic ring system containing 5-6 ring members in the ring, of which 1-2 rings The group members are oxygen, sulfur or nitrogen heteroatoms. They can be stupid and condensed as required. 6. The compound according to item 5 of the scope of patent application or a pharmaceutically acceptable salt thereof, wherein R: is argon, -CVC2 alkyl, halogen Cyano, hydroxy, (: "(: 2 alkoxy, trifluoromethoxy, or trifluoromethyl; each Z is independently (1) C! -C4 alkyl, which may be optionally substituted with the following substituents Substitutions: (a) 1-2 of the following substituents: amine, di- (C "C2 alkyl) amino, hydroxyl, CVC2 -25-200303316 _ application for patents continued alkoxy period or (^ -0: 2 alkylthio, and (b) heterocyclyl or aryl: or (2) heterocyclyl, optionally substituted with 1-2 of the following substituents: CrC # alkyl, aryl-CVC2 alkyl or hetero Aryl-CnC2 alkyl; wherein And heteroaryl are optionally substituted with N2 of the following substituents: amine, di- (CVC2 alkyl) amino, hydroxyl, CVC2 alkoxy, CnC2 alkylthio, cyano, halo, Ci-C2 alkane Or trifluoromethyl; each Y is independently hydrogen, -〇R21, 41121 or -NR5R21: Each R5 is independently hydrogen or (: "(: 4 alkyl; _ each R20 is independently (1) alkyl, which may be substituted with the following substituents as required: (a) 1-3 of the following substituents: amine Methyl, methylamino, dimethylamino, tertiary butoxycarbonylamino, N-((tertiary butoxy) carbonyl) -N- (methyl) amino, aminocarbonylamino, hydroxyl, butoxy Methyl, methoxy, butylthio, methylthio, methylsulfinyl , Methanesulfonyl or halo, and (b) C5-C6 cycloalkyl, heterocyclyl, phenyl, or heteroaryl, which may be substituted with 1-2 of the following substituents as necessary: amine, dimethylamine Group, acetamido, hydroxy, methoxy, methylthio, halo, tallow or trifluoromethyl: (2) heterocyclyl; or (3) aryl or heteroaryl, which may be modified as required 1-2 of the following substituents: amino, dimethylamino, hydroxy, methoxy, methylthio, functional, methyl, or trifluoromethyl: each R2I is independently hydrogen or R2G; RM is Benzoyl, fluorenyl, furyl, 4-phenyl, benzofuranyl, or benzo4-phenyl, which may be substituted with 丨 -2 of the following substituents as needed: methyl-26200303316 Amine, diamido, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methanesulfenyl, methanesulfonyl, aminocarbonyl, methyl or trifluoromethyl And R12 is 4-pyridyl, 4-pyrimidinyl, 4-quinolinyl, 7-imidazo [4,5-b] pyridyl, 8-quinazolinyl, 6- (1Η) -purine or 4 -Imidazolyl, optionally substituted with the following substituents: amine, A group, acetyl group, a hydroxyl group, a functional group, cyano, methoxy, methyl or trifluoromethyl. 7. The compound or pharmaceutically acceptable salt thereof according to item 6 of the scope of patent application, wherein R2 is hydrogen; each R6 is hydrogen, methyl, methoxy, -CF3, OCF3, or hydroxyl; each Z is independent Is (1) a CkG alkyl group, which may be optionally substituted with the following substituents: (a) 1-2 of the following substituents: amino, dimethylamino, hydroxy or methoxy, and (b) heterocyclic Or phenyl; or (2) heterocyclyl; where heterocyclyl may optionally be substituted with 1-2 of the following substituents: C "C4 alkyl or phenylmethyl: wherein phenyl may optionally be substituted with 1-2 of the following Group substitution: amine, di-((: κ (: 2 alkyl) amino, hydroxyl, (: "(: 2 alkoxy, CkC! Alkylthio, cyano, halo, Ci-C2 alkyl Or trifluoromethyl; each R5 is independently hydrogen or methyl; each R2Q is independently (i) an alkyl group, which may be substituted with the following substituents as required: (a) 1-3 of the following substituents: amine, Methylamino, dimethylamino or hydroxyl, and (b) • 27-200303316 patent application continuation page phenyl heteroaryl, which may be substituted with 1-2 of the following substituents as needed: amino, dimethyl Group, hydroxy group, methoxy group, methylthio group, halo group, methyl group or trifluoromethyl group; (2) heterocyclic group; or (3) aryl group or heteroaryl group. Substituent substitution: amine, dimethylamino, hydroxy, methoxy, methylthio, fluorenyl, methyl, or trifluorofluorenyl; each R21 is independently hydrogen or R2Q; and R12 is 4-pyridyl Or 4-pyrimidinyl, which can be optionally substituted with the following substituents: amine, dimethylamino, ethylamino, methyl, fluorenyl, aryl, methoxy, methyl, or trifluoromethyl. 8. A compound or a pharmaceutically acceptable salt thereof according to item 4 of the scope of patent application, wherein Or trifluoromethyl: each Z is independently (〖) Ci-C4 alkyl or c2-c5 alkyl, which may be substituted with the following substituents as required: (a) 1-2 of the following substituents: amine, di -(CVC2 alkyl) amino, hydroxyl or C2C2 alkoxy, and (b) heterocyclyl, aryl or heteroaryl; or (2) heterocyclyl, aryl or heteroaryl; wherein hetero Cyclic groups can be substituted with 1-2 Substitution: amine, di- (C | -C2 alkyl) amino, hydroxyl, (^-(: 2 alkoxy, CVC4 alkyl, or trifluoromethyl); where aryl and heteroaryl groups can be modified by 1 if necessary -3 substitutions of the following substituents: amine, di- (CnCz alkyl) amino, acetamido, hydroxy-28 · 200303316 _ Application for patents continued page, (: 丨-2 alkoxy, halo, c "c2 alkyl or trifluorofluorenyl; each γ is independently (1) hydrogen; (2) -C (〇) -R2〇 or -c (o) -nr5r21 group; (3) -〇R21, -SR21, -S (〇) -R20, -S (O) 2-R20 or -s (o) 2-nr5r21 group; or (4) -N R5 R] 1 or -NR22-C (〇) -R21 Each R5 is independently hydrogen or methyl; each R20 is independently. (1) CrC4 alkyl, which may be substituted with 1-2 of the following substituents as necessary: amine, C, C2 alkylamino, di -(CVC2 alkyl) amino, hydroxyl or CVC2 alkoxy; or (2) trifluoromethyl; each R2l is independently hydrogen or R20; R12 is pyridyl or pyrimidinyl, which can be treated by 1-2 if necessary The following substituents replace (1) R3O: (3) -C (〇) -R30, · 0: (0) -Οί129, -C (0) -NR31R32 or -C (NR3l) -NR31R32: or (4) -0R] 9, -SR] 9, -S (〇) -R3〇, -S (0) 2-R3〇, -S (0) 2-NR3 1 R32, -NR33-S (O) 2-R30, -NR3iR32 Or -NR3: rC (0) -R29: each R 3 〇 is independently (1) CVC4 alkyl, which may be substituted with the following substituents as required: (a) 1-2 of the following substituents: -NR31R32, hydroxyl Or CVC] alkoxy, and (b) aryl-29- 200303316 _ application for patents, continuation or heteroaryl, in which aryl and heteroaryl can be substituted with 1-2 of the following substituents as needed: amine, Alkylamino, di- (CrC2 alkyl) amino, CpCs alkylamino, (CrC4alkoxy) carbonylamino, CrG alkylsulfonamido, hydroxyl, CVC4 alkoxy, C | -C4 alkylthio Group, alkanesulfonyl, cyano, halo, Ci-C4 alkyl or trifluoromethyl: or (2) aryl or heteroaryl, optionally substituted with 1-2 of the following substituents Group, Ci-C2 alkylamino group, di- (CVC2 alkyl) amino group, CVC5 alkylamino group, (CVC4 alkoxy) carbonylamino group, c "c4 alkylsulfonamido group, hydroxyl group, K4 alkoxy group , CrCq alkylthio, CVC4 alkylsulfonyl, cyano, halo, CVC4 alkyl, or trifluoromethyl; each R29 is independently derived or R30, each 1131 Don't independently be hydrogen or methyl; each R32 is independently fluorenyl; (2) alkyl, which can be optionally substituted with the following substituents: aryl or heteroaryl, where aryl and heteroaryl are optionally substituted with 1 -2 substitution of the following substituents: amine group, C! -C2 alkylamino group, di- (CnC2 alkyl) amino group, Cr-Cs amine amino group, (C1-C4 alkyloxy group) amine group, Via a radical, C1-C2 oxo, C | -C2 alkyl or trifluoromethyl; or (3) an aryl or heteroaryl, which may be optionally substituted with 1-2 of the following substituents: amine, CVC2 Alkylamino, di- (CrC: alkyl) amino, CkC5 alkylamino, (C "C4 alkoxy) carbonylamino, hydroxyl, (^ -〇2alkoxy, C" C2 alkyl or Trifluoromethyl; and each R33 is independently hydrogen or methyl. • 30 · 200303316 _ Scope of patent application continued 9. The compound according to item 8 of the scope of patent application or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, methyl, halo, cyano, hydroxyl, methoxy, Trifluoromethoxy or trifluoromethyl; Rl2 is pyridyl or pyrimidinyl, which may be substituted with 1-2 of the following substituents R30; (2) Funky;. (3) -C (0) -NR3iR32 or -C (NR31) -NR31R32: or (4) -〇 民 29, -S (0)?-NR3 1 R32 '-NR33 * S (O) 2-R30 '-NR31R32 or -NR33-C (0) -R29. 10. The compound according to item 1 of the scope of patent application, which is: 5- (3-benzylprop-1-yl) amino-8- (4-fluorophenyl) -7- (4-pyridyl)- 1,2,4-Trisigma Sitting and [4,3-c] ° · Dense Syndrome: 5- (3-benzylprop-1-yl) amino-8- (3-methylbenzyl) -7- (4-pyridyl) -1,2,4-tri ° all-merged [4,3- (:) 〇 * dense &lt; 5- (1-piperidinyl) -8- (3-methylbenzyl &gt; 7- (2-chloro-4-curidinyl) -1,2,4-tri Azolo [4,3-c] pyrimidine; 5- (3-benzylprop-1-yl) amino-8- (3- (trifluoromethyl) benzyl) -7- (4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine; 5- (2 (S) -amino-3-phenylpropyl-1 · yl) amino-8- (3,4- Dichlorophenyl) -7- (4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine; 5- (piperin-1-yl) -8- (3- (Trifluoromethyl) phenyl) -7- (2- (2-phenylprop-2-yl) amino-4-pyridyl) -1,2,4-triazolo [4,3- ( :] Pyrimidine; -31-200303316 _ Application for Patent Continued 5- (3,5: Dimethylpiperin-1-yl) -8- (3- (trifluoromethyl) phenyl) -7- ( 2- (l (S) -phenethyl) amino) -4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine; 5- (piperin-1 · yl) -8- (3- (trifluoromethyl) phenyl) -7- (2- (l (S) -phenethyl) amino) -4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine; 1- (8- (4-fluorophenyl) -7- (4-pyridyl) · 1,2,4-triazolo [4,3-c] pyrimidine-5 -Yl) amino) -2 (S)- 3-Phenylpropane; 2- (8- (4-fluorophenyl) -7- (4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine-5 · base) Amino-2-phenylpropane; 5- (2 (S) -amino-2-methyl-3-phenylpropanyl) amino-8- (3- (trifluoromethyl) phenyl ) -7- (4 ^ pyridinyl) -1,2,4-triazolo [4,3-c] pyrimidine: 5 · (2,5-diazobicyclo [2.2.1] hept-2-yl ) -8- (3- (trifluoromethyl) phenyl) -7- (2- (l (S) -benzylethyl) amino-4-supridinyl) -1,2,4-triazole Ac [4,3-c] pyrimidine; 5- (2 (S) -amino-3-phenylprop-1-yl) amino · 8- (2 · fluorenyl) -7- (4-pyridyl ) 1,2,4-triazolo [4,3-c] pyrimidine; 5- (3 (S) -benzylmethyl-pipen-1-yl) -8- (2-¾: yl)- 7- (4-pyridyl) -1,2,4- Trituro [4,3-(:] ° * Dense disease; 5- (2 (S 'cadaveryl-3-phenylprop-1-yl) amino-8- (3-chloro-4-fluoro Phenyl 7- (4-pyridyl) -1,2,4-triazolo [4,3-(:] pyrimidine; 5- (2 (S) -pyrrolidinylmethyl) amino-8- (2-¾: yl) -7- (4-pyridyl) -1,2,4-trituro [4,3-c] ° · close bite; 5- (1 · (2-propyl) pyrrole Pyridin-2 (S) -ylmethyl) amino-8- (3,4-dichlorobenzyl) -7- (4-pyridyl) -1,2,4-triazolo [4,3- c] Pyrimidine: 5- (piperidinyl) -8- (3- (trifluoromethyl) benzyl) -7- (2- (cyclopropyl) amino-4-pyridyl) -1,2 , 4-triazolo [4,3-c] pyrimidine; -32- 200303316 _ Applications for patents continued on 5- (1- (2 ^ propyl) piperidin-3-yl) amino-8- (3 , 4-dichlorophenyl) -7- (4-pyridyl) -1,2,4-triazolo [4,3-c] pyrimidine; 5- (1- (2-propyl) pyrrolidine- 2 (S) -ylmethyl) amino-8- (2-¾: yl) -7- (4-pyridyl) -1,2,4-trito [4,3-(:] σ · Syndrome; 2-methyl-N2- (8-tea-2-yl-7-lipidin-4-yl- [1,2,4] triazolo [4,3-c] pyrimidine-5 -Yl) -propane-1,2-diamine; N1-isopropyl-2-methyl-N2- (8-fluoren-2-yl-7-pyridin-4-yl- [1,2,4] triazolo [4,3 -c] Yodo-5 -Yl) -propane-1,2-diamine, N1-cyclopentyl-2-methyl-N2- (8-^-2-yl-7-lipidin-4-yl- [1,2 , 4] triazolo [4,3-c] pyrimidin-5-yl) -propane-1,2-diamine; isopropyl-0 (8-fluoren-2-yl-7-pyridin-4-yl -[1,2,4] triazolo [4,3-c] pyrimidin-5-yl) -pyrrolidin-2-ylmethyl] -amine: [1 · (1-isopropyl-piperidine- 2-yl) -1-methyl-ethyl]-(8-fluoren-2-yl-7-pyridin-4-yl- [1,2,4] triazolo [4,3-(:] pyrimidine -5-yl) -amine: (4 · methyl-piperidin-4-yl)-(8-tea-2-yl-7-pyridin-4-yl- [1,2,4] triazolo [4,3 -c] ° * Secret-5 -yl) -amine, (N isopropyl-3-methyl-piperidinyl)-(8-fluoren-2-yl-7-pyridin-4-yl- [1,2,4 ] Triazolo [4,3-c] pyrimidin-5-yl) -amine: N, [8- (3,4-dichloro-phenyl) -7-pyridin-4-yl- [1,2, 4] triazolo [4,3-c] pyrimidin-5-yl] -N1-isopropyl-2-methyl-propane-1,2-diamine; [8- (3,4-digas- Benzyl) -7-pyridin-4-yl- [1,2,4] triazolo [4,3-c] pyrimidin-5-yl]-[1- (1-isopropyl ^ pyrrolidine · 2-yl) -1-methyl-ethyl] -amine; [8- (3,4-digas-benzyl) -7-pyridin-4-yl- [1,2,4] triazolo [ 4,3 -c] pyrimidin-5-yl]-[1- (1-isopropyl-piperidin-2-yl) small methyl-ethyl] -amine; -33- 200303316 _ Application for patent continued page [8- (3,4-dichloro-phenyl) -7-pyridin-4-yl- [1,2,4] triazolo [4,3-c] pyrimidin-5-yl]-(4 · Methyl-piperidine-cardiyl) -amine; [8- (3,4-dichloro-phenyl) -7-pyridin-4-yl- [1,2,4] triazolo [4,3- c] pyrimidin-5-yl]-(1-isopropyl-3-methyl-piperidin-3-yl) -amine; isopropyl- [1- (8-fluoren-2-yl-7-pyridine -4-yl-imidazo [l, 2-c] pyrimidin-5-yl) ^ Pyrrolidin-2-ylmethyl] -amine; {1- [8- (3,4-dichloro-phenyl) -7-pyridin-4-yl-imidazo [l, 2-c] pyrimidine -5-yl] -pyrrolidin. 2-ylmethylisopropyl-amine; _N1-isopropyl-2-methyl-N2- (8-fluoren-2-yl-7-pyridine-4- -Imidazo [l, 2-c] pyrimidin-5-yl) -propane · 1,2-diamine; [1- (1-isopropyl-exo 1: pyridin-2-yl) -1- Methyl-ethyl]-(8-fluoren-2-yl-7-pyridin-4-yl-imidazo [l, 2-c] pyrimidin-5-yl) -amine; [1- (1-isopropyl -Piperidin-2-yl) -1-methyl-ethyl]-(8-tea-2-yl-7-pyridine-4 · yl-tidomi [1,2-c] -Yl) -amine, (4-methyl-piperidine · 4-yl)-(8-fluoren-2-yl-7-pyridin-4-yl-imidazo [l, 2-c]. Dense lake · 5 -yl) -amine, (1-isopropyl-3-methyl-piperidin-3-yl)-(8-fluoren-2-yl-7-pyridin-4-yl-imidazine [l, 2-c] pyrimidin-5-yl) -amine; N2- [8- (3,4-digas-benzyl) -7-pyridin-4-yl-imidazo [l, 2-c] pyrimidin-5 · Kib N1-isopropyl-2-methyl-propane-1,2-diamine; [8- (3,4-dichloro-benzyl) -7-pyridin-4-yl-imidazo [ 1,2-c] pyrimidin-5-yl]-[1- (buisopropyl-pyrrolidin-2-yl) -1-methyl-ethyl] -amine; [8- (3,4 -Dichloro-benzyl) -7-. Pyridin-4 · yl-imidazo [1,2-c] pyrimidin-5-yl]-[U (Uisopropyl-piperidin-2-yl) -1 -methyl-ethyl] -amine; -34- 200303316 Scope of patent application continuation [8- (3-Small-chloro-phenyl) -7-outer (: Yodo-4-kilmidine i [l, 2-c] yodo · 5 · base]- (4-methyl-piperidine-4_ylhexylamine; or [8- (3,4-chloro-phenyl) -7-0 than Yodo-4-yl-β rice taste benefits [1,2- c] ° Midian · 5-based] • (1-isopropyl · 3 · methyl-propidin-3 · yl) -amine: or a pharmaceutically acceptable salt thereof. η · A pharmaceutical composition, It contains the compounds according to claims 1 to 10 and a pharmaceutically acceptable carrier. 12. A pharmaceutical composition for treating inflammation, which includes an effective amount of the compounds according to claims 1 to 10 And a carrier accepted by Paeonia Kamimachi. 13. A pharmaceutical composition according to the scope of application for patent No. 丨 1, which is used to treat inflammation. 14. A pharmaceutical composition for treating the following diseases in mammals: rheumatoid arthritis; Paget's disease; osteoporosis; multiple myeloma; uveal membrane Inflammation: acute or chronic myelogenous leukemia; pancreatic beta cell destruction &gt; osteoarthritis: rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS): psoriasis: Crohn's disease ( Cronohn disease); allergic rhinitis; ulcerative colitis: allergic reaction 'named Λ anemia dermatitis: asthma; muscle degeneration: cachexia, coming ♦ * Reiter's syndrome: I and Π Type 2 diabetes' bone resorption ^ • Mountain r7 • Myocardial infarction; lack of anti-host response; Alzheimer's disease, stroke, • «Episode · Multiple sclerosis after blood reperfusion injury; Atherosclerosis; Brain trauma 'i 1 gram symptom group:: cerebral malaria; septicemia: septic shock' middle mother, 〖main uiV-3, giant cell disease mother CMV) fever; infection with HIV-1, H1V-2, ^ ^ — + of Myalgia, its ^ ^, a —Mainly caused by seven maggots, flu, adenovirus, herpesvirus, or anemia -35- 200303316 _ Patent Application Scope Continuation Sheet Includes Effective Amount Based on Items 1 to 10 of Patent Application Scope Compounds and pharmaceutically acceptable Accepted vehicle. 15. The pharmaceutical composition according to item 11 of the scope of patent application, which is used to treat the following diseases in mammals: rheumatoid arthritis; Patzell's disease; osteoporosis; multiple myeloma; uveitis: acute or Chronic myelogenous leukemia; pancreatic beta cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); dry addiction: Crohn's disease; Allergic rhinitis; ulcerative colitis: allergic reaction: contact dermatitis; asthma: muscle remodeling; cachexia; Reiter's syndrome: Type I and II diabetes: bone resorption disease; graft versus host response Alzheimer's disease: stroke; myocardial infarction; reperfusion injury after ischemia: atherosclerosis: brain trauma: multiple sclerosis; cerebral malaria; sepsis: septic shock; toxic shock symptom cluster; fever: Myalgia due to infection with HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, herpes virus or shingles A pharmaceutical composition having a concentration of one or both of TNF-α and IL-1, which comprises an effective amount of a compound according to claims 1 to 10 of the patent application scope and a pharmaceutically acceptable carrier. 17. The pharmaceutical composition according to claim 11 of the patent application scope, which is used to reduce the concentration of one or both of TNF-a and IL-1 in plasma. 18. A pharmaceutical composition for reducing the concentration of one or both of IL-6 and IL-8 in plasma, comprising an effective amount of a compound according to claims 1 to 10 and a pharmaceutically acceptable carrier. • 36- 200303316 _ Patent application continuation page 19. The pharmaceutical composition according to item 11 of the patent application scope is used to reduce the concentration of one or both of IL-6 and IL-8 in plasma. 20. A pharmaceutical composition for treating diabetes in a mammal, comprising an effective amount of a compound according to claims 1 to 10 and a pharmaceutically acceptable carrier to produce a glucagon antagonist effect. 21. The pharmaceutical composition according to item 11 of the application, which is used for treating diabetes in mammals. 22.-A pharmaceutical composition for treating painful lesions in mammals, comprising an effective amount of a compound according to claims 1 to 10 and a pharmaceutically acceptable carrier β 23. According to claim 11 A pharmaceutical composition for treating painful lesions in mammals. 24. A pharmaceutical composition for reducing the production of prostaglandin in mammals, comprising an effective amount of a compound according to claims 1 to 10 and a pharmaceutically acceptable carrier β 25. The pharmaceutical composition according to item 11 of the scope of patent application, which is used to reduce the production of prostacyclin by mammals. 26. A pharmaceutical composition for reducing the activity of a mammalian cyclooxygenase, comprising an effective amount of a compound according to claims 1 to 10 of the patent application scope and a pharmaceutically acceptable carrier. 27. The pharmaceutical composition according to item 26 of the patent application, wherein the cyclooxygenase is COX-2. 28. The pharmaceutical composition according to item 11 of the scope of patent application, which is used to reduce mammalian cyclooxygenase activity β • 37- 200303316 _ Application scope of patents continued page 29. The pharmaceutical composition according to item 28 of scope of patent applications Of which the cyclooxygenase enzyme is COX-2. 30. A pharmaceutical composition for treating cancer in a mammal, comprising an effective amount of a compound according to claims 1 to 10 of the patent application scope and a pharmaceutically acceptable carrier. 31. The pharmaceutical composition according to claim 30, wherein the cancer is mediated by Raf and Raf-induced proteins. 32. The pharmaceutical composition according to item 30 of the scope of the patent application, wherein the cancer is cancer, breast cancer, brain cancer, laryngeal cancer, lung cancer, lymphatic cancer, urethral cancer or gastric cancer. 33. The pharmaceutical composition according to item 11 of the scope of patent application, which is used for treating cancer in mammals. 34. The pharmaceutical composition according to claim 33, wherein the cancer is mediated by Raf and Raf-induced proteins. 35. The pharmaceutical composition according to item 33 of the scope of the patent application, wherein the cancer is cancer, breast cancer, brain cancer, laryngeal cancer, lung cancer, lymphatic cancer, urinary tract cancer or gastric cancer '36. A compound of the following formula: CI Where Ru is aryl or heteroaryl, and R12 is heteroaryl, of which aryl, heteroaryl, and heteroaryl can be substituted with 1-3 of the following substituents as needed • 38-200303316 Application scope of patents continued: ⑴ R30; (2) halo or cyano; (3) -C (O) -R30, -C (〇) -OR29, -C (〇) -NR3 | R32 or -C (NR3 ± NR31R32: ( 4) -OR29, -〇-C (0) -R29, · 〇-[(0) -ΝΚ3ΐΙΐ32 4-〇-C (〇) -NR33- S (〇) 2-R3〇; (5) -SR29, -S (O) -R30, -S (O) 2-R30, -S (O) 2NR3iR32, -S (O) 2-NR33. C (〇) -r30, -s (o) 2-nr33-c (o) -or30 or -S (0) 2-NR33-C (0) -NR3lR32 φ •, or (6) -NR3iR32, -NR33-C (〇) -R29, -NR33-C (O) -OR30 , -NR3: rC (〇) -N R3 [R32 '-NR33-C (NR3 |) -NR3iR32' -NR33-S (〇) 2-R3〇 or -NR33-S (0) 2-NR31R32 »but its The limiting condition is that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl substituents on each Ru and Rl2 is (M: each R 3 0 is independently fluorenyl, alkenyl or alkynyl, which can be seen Need to be substituted with the following substituents: (a) 1-3 -NR3iR32, hydroxy, · oxy, sulfanyl, alkylsulfinyl, alkylsulfonyl, cyano or halo, and (b ) Aralkoxy, aralkylthio, aralkylsulfonyl, heterocyclyl, aryl, or heteroaryl, where heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 of the following substituents : Amine, Alkylamino, Dialkylamino, Alkylamino. ,, Oxycarbonylamino, Alkylamino, Hydroxyl, Alkoxy, Alkylthio, Alkylsulfinyl, Alkyl Sulfofluorenyl, cyano, alkynyl, alkynyl, or pentyl; (2) heterocyclic groups, which may be substituted with N3 of the following substituents as needed: amino-39-200303316 Alkyl, dialkylamino, alkylamino, alkoxycarbonylamino, sulfamoylamino, hydroxyl, alkoxy, alkylthio, cyano, alkyl, or monoalkyl; or (3) aromatic Or heteroaryl, which can be optionally substituted with 1-3 of the following substituents: amine, alkylamino, dialkylamino, alkylamido, alkoxycarbonylamino, # alkanesulfonylamino, hydroxyl , Alkoxy, alkylthio, cyano, dentyl, alkyl, or haloalkyl; each R29 is independently a hydrogen group or R30; Each R31 is independently: (1) a hydrogen group; (2) an alkyl group, which may be optionally substituted with the following substituents: a cycloalkyl group, an aryl group, a heterocyclic group, or a heteroaryl group, wherein the cycloalkyl group, the aryl group , Heterocyclyl and heteroaryl can be substituted with 1 to 3 of the following substituents as needed: amine, alkylamine, diamine, amine, amine, amine, amine, etc. Group, alkoxy group, alkynyl group, cyano group, oxo group, or halo group: or (3) aryl, heteroaryl, heterocyclyl, or cycloalkyl, which may be substituted by 1-3 if necessary Substituted groups: amine, alkylamino, dialkylamino, alkylamino, alkoxyamine: group, alkyl diamino, #i group, alkoxy, thiothio, cyano, tiger Each group is independently: (1) a hydrogen group; (2) an alkyl group, which may be optionally substituted with the following substituents: a cycloalkyl group, an aryl group, a heterocyclic group, or a heteroaryl group, wherein Cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with 1 to 3 of the following substituents: amine, alkylamino, dialkylamino, alkylamino, alkyloxycarbamino, pyrene Amine, approved by -40-200303316 Please cover the scope of patents: base, alkoxy, alkylthio, cyano, alkyl, or alkanyl; or (3) aryl, heteroaryl, heterocyclyl, or cycloalkyl, which can be treated as necessary by 1 -3 substitutions of the following substituents: amino, alkylamino, dialkyl. Amino, alkylamino, alkoxycarbonylamino, alkylsulfonamido, hydroxyl, alkoxy, alkylthio, cyano, An alkyl group or an alkyl group; and each R 3 3 is independently (1) a hydrogen group; or (2) an alkyl group, which may be optionally substituted with the following substituents: a heterocyclic group, an aryl group, or a heteroaryl group, wherein Aryl, heterocyclyl and heteroaryl are optionally substituted with 1-3 of the following substituents: amine, alkylamino, dialkylamino, alkylamido, alkoxycarbonylamino, alkanesulfonamido , Hydroxy, alkoxy, alkylthio, cyano, alkyl, or alkyl. 37. The compound according to item 36 of the application, wherein Rn is 4-fluorophenyl or 2-fluorenyl. 38. The compound according to item 36 of the application, wherein R12 is 4-pyridyl. 39. The compound according to item 36 of the scope of patent application, wherein: Rh is cardiofluorophenyl or 2-fluorenyl; and ... R12 is a 4-0 pyrido group. -41-200303316 Lu, (a), the designated representative of this case is: Figure _ (b), the representative symbols of this representative diagram are briefly explained: 柒, if there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention W vv