TWI298722B - Novel substituted pyrido[2,3-d]pyrimidin-7-one compounds, pharmaceutical composition containing the same and their medical uses - Google Patents

Description

[298722 A7 B7 V. INSTRUCTION DESCRIPTION (1) Scope of the Invention The present invention relates to a novel 2,4,8-trisubstituted-8H-pyrido[2,3-d]pyrimidin-7-one compound, a process for the preparation thereof, Use in the treatment of diseases mediated by CSBP/p38 kinase, and pharmaceutical compositions for such treatment. 5 BACKGROUND OF THE INVENTION Intracellular message transduction is the way cells respond to extracellular stimuli. Irrespective of the nature of cell surface receptors (eg, protein tyrosine kinase or seven-transmembrane G-protein coupling), protein kinases and phosphatases are accompanied by phospholipases, which are necessary means for further intracellular delivery of information [ Marshall, 10 JC Cell, 80, 179-278 (1995)]. Protein kinases can be classified into five species, two of which are tyrosine kinases and serine/threonine kinases, depending on whether the enzyme is in a specific tyrosine or serine/threonine Residues are phosphorylated [Hunter, T., on enzymology (protein kinase classification), page 3, Hunter, T., Seflon, BM, vol. 200, University Press; 15 San Diego, 1991]. For most biological responses, multiple intracellular kinases are involved, and individual kinases may involve more than one signaling event. These kinases are often solute to the cytosol and can be translocated to the nucleus or ribosome where they can be individually mapped to transcriptional and translational events. The involvement of kinases in transcriptional control is currently well understood by 20's role in translation, as illustrated by studies of signal transduction induced by growth factors involving MAP/ERK kinases [Marshall, CJ Cell , 80, 179 (1995); Herskowitz, I. Cell, 80, 187 (1995); Hunter, T. Cell, 805 225 (1995); Seger, R. and Krebs, Ε·G. FASRR L 726-735 ( 1995)]. -3- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm). Please read the note on the back and fill out this page. Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives 90. 11. 2,000 1298722 A7 B7 V. Inventive Note (2) {Read the back of the note first and then fill out this page·0" Line - Although many of the signaling pathways are part of the stability of the cell, many cytokines (such as IL-1 and TNF) and certain other inflammatory mediators (such as COX-2 and iNOS) are produced only as a response to stress messages, such as bacterial lipopolysaccharide (LPS). It is pointed out that the message transduction pathway leads to LPS-induced cell biosynthesis and involves the first indicator of protein kinase, which is from the study of Weinstein [Weinstein et al., J. Immunol. 151. 3829 (1993)], but The specific protein kinase involved was not confirmed. Working on a similar perspective, Han [Han et al., Science. 265, 808 (1994)] confirmed that marine p38 acts as a kinase, which is a phosphonylated tyrosine in response to LPS. P38 kinase is involved in the 10 LPS-stimulated message transduction pathway leading to clear evidence for the biosynthesis of pre-inflammatory cytokines, which was independently provided by Lee to discover p38 kinase [Lee et al., NMum, 372, 739 (1994)], As a molecular marker of novel anti-inflammatory agents. The discovery of p38 (referred to by Lee as CSBP1 and 2) provides a mechanism of action for anti-inflammatory compounds, for which SK&F 86002 is a prototype example. Such an IS complex inhibits IL-1 and TNF synthesis in human/single cells at low/M range concentrations [Lee et al., Int. J. Immunopharmac. 10(7). 835 (1988)] And showed activity in an animal model in which the cyclooxygenase inhibitor is ruminant [Lee et al., Annals-N. 696, 149 (1993)]. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives, has firmly established CSBP/p38 as one of several kinases involved in the stress-responsive message transduction pathway20, which is parallel to and mostly associated with mitogen-activated protein kinases. (MAP) Kinase cascade reaction is irrelevant. Stress messages, including LPS, pre-inflammatory cytokines, oxidants, UV light, and osmotic pressure, activate kinases upstream of CSBP/P38, which in turn cause CSBP/p38 to be phosphoric acid at 182 and tyrosine 182醯基化, resulting in CSBP/p38 activation as the paper standard universal T-standard (CNS) A4 specification (2) 〇 90. 11. 2,000 X 297 mm 1299722 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed B7_ five , invention description (3) used. MAPKAP kinase-2 and MAPKAP kinase-3 have been identified as downstream receptors for CSBP/p38, which in turn are phosphorylated by thermal shock protein Hsp27 (Fig. 1). Other downstream receptors that are known to be phosphorylated by p38 include kinases (Mnkl/2, MSK1/2 and PRAK) and transcription factors (CHOP, MEF2, ATF2 and CREB). Although many of the signaling pathways that require cytokine biosynthesis are still unknown, it is clear that many of the warranties listed above for p38 are involved. [Cohen. P. Trends Cell Biol.. 353-361 (1997, and Lee, J. C. et al., Pharmacol· Ther. Vol. 82, Nos. 2-3, pp. 389-397, 1999]. However, it is clear that in addition to inhibiting IL-1 and TNF, CSBP/p38 10 kinase inhibitors (SK&F 86002 and SB 203580) also reduce the synthesis of a wide variety of pre-inflammatory proteins, including IL-6, IL- 8, GM-CSF and COX-2. Inhibitors of CSBP/p38 kinase have also been shown to inhibit TNF-induced expression of VCAM-1 on endothelial cells, TNF-induced phosphorylation of cytosolic PLA2 and Activation, and IL-1-stimulation synthesis of collagenase and matrix lysin. These and their data confirm that CSBP/p38 is involved not only in cytokine synthesis, but also in cytokines signaling [at Cohen, P. Trends Cell Biol.. 353_361 (I997) reviewed CSBP/P38 kinase]. Diurnal leukocyte-1 (IL-1) and tumor necrosis factor (TNF) are caused by a variety of cells (such as single cells or giant pythons). The biological material produced by the cell. IL-1 has been confirmed by 20 to mediate a variety of biological activities, which are in immune regulation and other physiological symptoms (譬Inflammation) is considered important [see, for example, Dinarello et al., Rev. Infect Disease, 6, 51 (1984)]. Various known biological activities of IL-1, including activation of T helper cells, fever Induction, stimulation of prostaglandin or collagenase production, neutrophil tropism, acute phase protein ______-5- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 public) 90. 11. 2,000 -------------i·^. (Please read the notes on the back and fill out this page b. - Line. 1298722

Μ V. Invention Description (4) 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 20 Inducement and inhibition of blood iron content. There are multiple disease states, and excessive or unregulated U production lines are associated with f and/or cause the disease. #Include rheumatoid arthritis, osteoarthritis, endotoxemia and / or toxic shock syndrome, other acute or chronic inflammatory disease states, such as inflammatory reactions caused by endotoxin, or inflammatory bowel disease; Tuberculosis, atherosclerosis, muscle deterioration, cachexia, psoriatic arthritis, Reed's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, and acute synovitis. Evidence also links the activity of several-丨 to diabetes and pancreatic cells [has been attributed to the review of the biological activity of Jiang-丨, Dinarello, L Clinical Immunology; 5(5), 287-297 (1985)] ° Excess or not Regulated TNF production, associated with media or aggravation of a variety of diseases 'including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritis symptoms; septicemia, septic shock, internal Toxin shock, Gram-negative septicemia, toxic shock syndrome, adult dyspnea syndrome, cerebral malaria, chronic pneumonia disease, stagnation, pulmonary sarcoma, bone degeneration, reperfusion injury, transplantation to host Response, allograft rejection, fever and myalgia due to infection, such as influenza-infected or malignant cachexia, acquired cachexia (AIDS), cachexia, AIDS, arC (aids related complex) Signs, tumor formation, scar tissue formation, Crohn's disease, ulcerative colitis or fever. Interleukin-8 (IL-8) is a chemokine produced by several cell types including monocytes, fibroblasts, endothelial cells, and keratinocytes. It is produced from endothelial cells and is caused by IL_i, tnF or lipopoly (LPS). IL-8 will spur a lot of functions in vitro. It has been confirmed (please read the note on the back and fill in this page first) · ·. • Line · -6 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Cooperative, Printed 1298922 A7 __ —_ B7____ V. Description of invention (5) Neutrophil white blood cells, T-lymphocytes and basophils, which have chemical attractant properties. Release of histamine-derived basophils from ectopic individuals, as well as lysosomal enzyme release, and respiration from neutrophils. IL-8 has also been shown to increase Mac-1 (CDllb/CDl8) Surface manifestation on neutrophil 5 blood cells without re-protein synthesis, which contributes to the increased adhesion of neutrophils to vascular endothelial cells. Many diseases are characterized by massive neutrophil immersion and increased IL -8 production (which is responsible for the neutrophil to the inflammatory site) is associated with symptoms that will benefit from inhibition of IL-8-producing compounds. 10 IL-1 and TNF affect many cells and Tissue and cytokines And other white blood cell-derived, cytokines, are important and critical inflammatory mediators of many disease states and symptoms. The inhibition of these cytokines is beneficial to control, reduce and alleviate many of these diseases. The CSBP/p38 signaling is related to the production of IL-1, TNF, IL-8, IL-6 15 , GM-CSF, COX-2, collagenase and matrix lysin, and is transduced by CSBP/p38. [Ono, K. and Han, J. Cellular Signalling. I2 I-I3 (2〇00)] required for the same pre-inflammatory protein plus many other proteins (VEGF, PDGF, NGF). CSBP/ P38 is a multi-stress-induced message transduction pathway that provides an additional theoretical basis for the potential use of CSBP/p38 in the treatment of diseases caused by excessive and destructive activation of the immune system 20. This expectation is based on CSBP. The /p38 kinase inhibitor is effective and supported by a variety of different activities [Badger et al, L Pharm. Rxp. Thera. 279 (3): 1453-1461, (1996); Griswold et al., Pharmacol. Γοττπη 7, 229 (1996); Jackson et al., J. Pharmacol·Exp· Ther. 284, 687-692 (1998); This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 public) 90. 11. 2,000 (please read the notes on the back and fill out this page ^· : Line · 1298722 A7 B7 V. Description of invention (6 )

Underwood et al, J. Pharmacol. Exp. Ther., 293, 281-288 (2000); Badger et al, Arthritis Rheum. 43, 〒 5· 183 (2000)]. There is still a need in the art for a therapeutic compound which is a cytokine inhibitory anti-inflammatory drug, i.e., a compound capable of inhibiting CSBP/p38/RK kinase. 5 BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a p38 kinase cascade reaction. SUMMARY OF THE INVENTION The present invention relates to novel compounds of formula (I) and (la) and formula (II) and (Ila), and pharmaceutical compositions comprising formula (I) and (la) and formula (II) and (Ila a compound, and a pharmaceutically acceptable diluent or carrier. The present invention relates to a method of treating a disease vectored by CSBP/RK/p38 kinase in a mammal in need thereof, which comprises administering to the mammal an effective amount of formula (I) and (la) and formula (tt) and Ila) compound. The invention also relates to a method of inhibiting cytokine and treating a disease mediated by a cytokine in a mammal in need thereof, which comprises administering to the mammal an effective amount of formula (I) and (la) and formula ( II) and (iia) compounds. More specifically, the present invention relates to a method of inhibiting IL-1 production in a mammal in need thereof, which comprises administering to the mammal an effective amount of formulas (1) and (la) and formulas (II) and (Ila). Compound. More specifically, the present invention relates to a method of inhibiting the production of IL-6 in a mammal in need thereof, which comprises administering to the mammal an effective amount of formulas (1) and (la) and formulas (11) and (1). More specifically, the present invention relates to a method for inhibiting the production of IL-8 in a mammal in need thereof, which comprises administering an effective amount to the mammal (1) -8 - the paper scale is applicable to the Chinese national standard (CNS) A4 specification (21〇X 297 mm) (Please read the notes on the back and fill out this page y into so. --Line. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 90. 11. 2,000 1298722 A7 5. Description of the invention (with (la) and compounds of formula (II) and (Ila). More specifically, the present invention relates to a method for inhibiting the production of TNF in a mammal in need thereof, which includes the mammal An effective amount of the compounds of formula (1) and (10) and formula (II) and (Ila) is administered. Accordingly, the present invention provides compounds of formula 1 and (Ia):

, x (I) or

(Please read the notes on the back and fill out this page) (la) 15 Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative 20 where Ri is an optionally substituted aryl or optionally substituted heteroaryl ring; &amp;; is hydrogen, c1M0 alkyl, 4 <cycloalkyl, c3 7 cycloalkylalkyl, aryl, aryl C1M decyl, heteroaryl, heteroaryl*cll decyl, heterocyclic or heterocyclic a group of Ci-i decyl groups, all of which are optionally substituted, or R2 is a moiety Xi(CRi〇R2〇)qC(Ai)(A2)(A3) or C (A1) (A2) (A3); Αι is optionally substituted C1M calcining group; A2 is optionally substituted Cl-10 alkyl; 八3 is hydrogen or optionally substituted Cl_lG alkyl; R3 is C1M0 alkyl, (: 3-7 cycloalkyl, c3-7 cycloalkyl Ci-4 alkyl, aryl, aryl c1M () alkyl, heteroaryl, heteroaryl Cl_1G alkyl, heterocyclic Or a heterocyclic group &lt;^-10 alkyl moiety, the moiety being substituted as appropriate;

90. 11. 2,000 1298722 A7 V. INSTRUCTIONS (8 10 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed 20 &amp; Rl 4 are each independently selected from hydrogen, optionally substituted Ci * alkyl, as the case may be Substituted C: 3·7 ring-burning i, C3_7 cycloalkyl C!—4 alkyl, optionally substituted aryl or optionally substituted aryl-C14 alkyl, or heart with Ri 4 and The nitrogen to be joined together forms a optionally substituted 4 to 7 membered heterocyclic ring which optionally contains another hetero atom selected from the group consisting of oxygen, sulfur or nr9; the heart is hydrogen, C1M0 alkyl, cycloalkyl, a heterocyclic group, a heterocyclic alkyl group, an aryl group, an arylalkyl group, a heteroaryl group or a heteroarylalkyl group, wherein each of these groups may be optionally substituted; % is hydrogen, qz)% or Substituted Ci i () alkyl, optionally substituted aryl or optionally substituted aryl-Ci4 alkyl; Ri 〇 and ho are independently selected from hydrogen or Cl 4 alkyl; X is 112, 0112 , 8 (0) 111 to 2, (〇 12) 11 10 10) 8 (0) 111112, ((: 112) 11 carved 10) - c (o) R2, (CH2) n nr4 ~ 4 or (CH2) Nn(r2 )2 ; X^N(R10), ο, S(0)n^CRl()R2() ; · n is 0 or There are an integer of value 1 to 10; or pulled having square value of the integer 1 or 2; Q is a square or an integer having a value of 1 to ίο; Z is oxygen or sulfur; or a pharmaceutically acceptable salt of. Another aspect of the present invention provides compounds of the formula (Π) and (IIa): (Please read the notes on the back and then fill out this page.

90. 11. 2,000 [298722

V. Description of the invention (9

15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 where Ri is a partial group YRa; R2 is hydrogen, Ci-io alkyl, A-7 cycloalkyl, C3_7 cycloalkylalkyl, aryl diaryl f Cl-10 alkyl, heteroaryl, heteroaryl q-w alkyl, heterocyclic or heterofluorenyl C1M decyl moiety, all of which are optionally substituted, or R2 is a partial group CR (CRioR^qCWXAAAs) or c(ai )(A2)(A3); Αι is an optionally substituted Cl_iQ alkyl group; 八2 is optionally substituted c1M〇 alkyl; 八3 is hydrogen Or a Ciig alkyl group which is optionally substituted; R3 is Α-10 alkyl group, C&gt;7 cycloalkyl group, A7 cycloalkyl group, 4 alkyl group, aryl group, arylalkyl group, heteroaryl group, a heteroarylalkyl, heterocyclic or heterocyclylalkyl moiety which is optionally substituted; α and heart 4 are each independently selected from hydrogen, optionally substituted qΜalkyl , optionally substituted A-7 cycloalkyl, Ο3" cycloalkyl Ciq alkyl, optionally substituted aryl or optionally substituted aryl A. 4 alkyl, or heart and heart 4 and The nitrogen to be joined together forms a 4- to 7-membered heterocyclic ring which is optionally substituted. The ring contains another hetero atom, depending on the situation, selected from oxygen, thioindole-11. This paper scale applies to the Chinese National Standard (CNS) A4 specification (21G x 297 public) 90. 11. 2,000 ----I- ----— II · 11 (Please read the notes on the back and then fill in this page i -πίΐϊΓ · Line · i1298722 A7 B7 V. Inventions (10) nr9 ; R6 is hydrogen, Ci-io alkyl, £3_7 a cycloalkyl, a heterocyclic group, a heterocyclylalkyl group, a aryl group, a aryl group, a C1-alkyl group, a heteroaryl group or a heteroaryl group, a C1-alkyl group, wherein each of these groups may be optionally substituted 5 R9 is hydrogen, c(z)R6 or optionally substituted Cl M decyl, optionally substituted aryl or optionally substituted aryl-C1_4 alkyl; R10 and R2G are independently selected from Hydrogen or C1M alkyl; Y is C(Rb)(Rd), C(O), N(Rd), I^R^CXRcXRd), oxygen, OCXReXR^i), S(0)n^S(0) mC(Rc)(Rd); ίο Ra is an aryl or heteroaryl ring which is optionally substituted;

Rb is hydrogen, 〇ι-2 alkyl, NRe, hydroxy, thio, Cu alkoxy, §(0)mCb 2 alkyl;

Rc is a mouse or C1 _ 2姨* base,

Rd is a rat or C1 _ 2 base,

15 XC(0)R2, (CH2)n NR4 R! 4 or (CH2 )n N(R2 )2 ; Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative (please read the notes on the back and fill in this page again ^: · - line · 乂1 is 1^ speak 1()), O, S(O)n^CR10R20; n is 0 or an integer having a value between 1 and 10; m is 0 or an integer having a value of 1 or 2; 20 q is hydrazine or has an integer of from 1 to 10; Z is oxygen or sulfur; or a pharmaceutically acceptable salt thereof. The present invention is directed to novel compounds of formula (1) and (la) and formula (II) and (Ila), or a pharmaceutically acceptable salt thereof. As will be immediately apparent, in the combination of formula (I) and (la) _______ -12-_ This paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 public love ^ 9〇. 11. 2,000 1298722 A7 - ----------g^_ _____ V. Description of the invention (11) The difference between the substance and the formula (9) and (IIa) is due to the unsaturation of the pyridodone ring. Individual &amp;&amp;, Χ and % terms, for the two groups within the chemical formula itself, such as 1 and to, for the purposes of this article, for each of the matters of formula (I), also applies to formula (Ia) ), unless otherwise indicated, and 5 applies to every item of formula (9), and applies to formula (Ila), unless otherwise indicated. Where appropriate, for compounds of formula (I) and (la), &amp; Is an aryl or heteroaryl ring which is optionally substituted. The Ri aryl or heteroaryl ring may be independently substituted one or more times by substituents, preferably from 4 to 4, and the substituents are selected from halogen. , Ch-based, halogen-substituted heart ^alkyl, cyano, nitro, (CRio^o^N^R^ &gt; (CR10R2〇)vC(Z)OR8 ' (CR10R20 )vC〇Ra, v (CR10R20)vC(〇)H ^ SR5 &gt; S(0)R5 &gt; S(0)2R5 (CR10R20)v〇R8, ZC(Z)RU, dish 1〇&lt;:(2)1111 or he 1〇8(〇)2117. Preferably, the heart is a square base group, preferably Substituted one or more times by halogen, C 4 alkyl or halo substituted -4-alkyl. 15 Suitably, V is 0 or an integer having a value of 1 or 2. Where appropriate, Z is oxygen or Sulfur. Ministry of Economic Affairs, Intellectual Property Bureau, Bayer Consumer Cooperative, Printed ------------ku (Please read the notes on the back and fill out this page again) - i line · Appropriately尺&, is (11, 4 alkyl, substituted by halogen (^Bu 4, C2·4 alkenyl, C2_4 alkynyl, C3_7 cycloalkyl, c5-7 cycloalkenyl, aryl, aryl (^_4 alkyl, heteroaryl, heteroaryl*C14 alkyl, heterocyclic, heterocyclic 20 CH alkyl, (CR10R20) vOR7, (CR10R20)vS(O)mR7, (CR10R2())vNH -S(0)2R7 or (CR10R20)vNR4Rm; and wherein an aryl group, an aralkyl group, a heteroaryl group, a heteroaryl group is optionally substituted. Suitably, for a compound of formula (II) and (Ila) In the appropriate case, Y is C(Rb)(Rd), C(0), N(Rd), NCRdC^XRd) _____ -13- This paper scale applies to China Quasi (CNS) A4 size (210 χ 297 Kimiyoshi) 1,298,722 2,000 90. 11. V. invention is described (η) 15 20, oxygen, OCdXR ^, _ paw or 8⑼mC (R ^) (Rd). Suitably, Rb is i, a 2 alkyl group, a Q-2 alkoxy group, or a s(o)mc1-2 alkyl group. Suitably, K is hydrogen or a C12 alkyl group. Rd is hydrogen or cle2 hospital base. The melon is ... or an integer having a value of 1 or 2. Ra is an optionally substituted aryl ring or, as the case may be, an optional substituent of the same, which is the same as the above formula (I) and (la) % aryl and heteroaryl ring. As will be apparent, the difference between the compounds of formula (1) and (9) is due to the substitution of r. The remaining substituents are all the same and, for the purposes of this document, all four chemical formulas can be used unless otherwise indicated. Where appropriate, 'Chemical and !^4 are each independently selected from hydrogen, optionally substituted Ch, a base, optionally substituted C37 cycloalkyl, optionally substituted C3-7 cycloalkyl. And optionally substituted aryl aryl groups, or &quot; together with the nitrogen to which they are attached may form an optionally substituted 4 to 7 membered heterocyclic ring which optionally contains another hetero atom selected from Oxygen, sulfur or NR9. Ch group, 〇3-7 ring, c3-7 cycloalkyl Ci 4, aryl and aryl-q.4 alkyl groups, which may be independently substituted one or more times, as compared Preferably, the substituent is a dentate, such as fluorine, chlorine, molybdenum or iodine; a base, a Cl_10 substituent substituted by a radical; a ClM oxime alkoxy, such as a methoxy or ethyl lactyl; Halo-substituted alkoxy group; s(0)m alkyl group, such as methyl sulfite methyl sulfite or methyl fluorescene; acid (_c (9)) or hydrazine, 譬 appropriate The situation is appropriate to replace the heteroaryl ring. __- 14- This paper size applies to the Central Standard (CNS) A4 specification coffee X 297 public). Base, sulfur-based reading line 90. 11. 2,000 A7 1298722 ------—B7_________ V. Invention Description (13) ------------丨έ·ί”1 (Please read the notes on the back and fill out this page) If -(: (0) &amp;, such as C (〇) Cy1 () alkyl or c (0) aryl; guanamines, such as C (0) NR4, R14 • ' or nR ^ CCCOCho alkyl or NR4fC (〇) Fang NR4, RM, 'where 仏' and !^4, each independently hydrogen or alkyl, or wherein R4, Rm' can be The attached nitrogen is cyclized together to form a 5 to 7 membered ring, 5 optionally containing another heteroatom selected from 0/N/S; cyano, nitro, alkyl, C3-7 cycloalkyl or : 3 · 7 cycloalkyl c1-1Q alkyl, such as methyl, ethyl, propyl, isopropyl, tert-butyl, etc., or cyclopropylmethyl; halo substituted ^-(9) alkyl , for example, CFsCFsH, CH2CF3 or CF3; optionally substituted aryl, such as phenyl, or optionally substituted aralkyl, 譬10 such as benzyl or phenethyl, wherein these aryl-containing partial groups The group may also be substituted one to two times, the substituent is dentate; hydroxyl group; alkyl group substituted by hydroxy group; &lt;: 1-1 () alkoxy group; 8 (0) 111 alkyl group; amine group, single and double Substituting (::1_4 alkylamino group g as in NR4, Ri4, medium, Ci_4 alkyl or CF3. - Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed when R4 and Ri4 and nitrogen are cyclized together to form a ring In this case, such a ring system suitably includes, but is not limited to, tetrahydropyrrole, hexahydropyridine, hexahydropyridin, phoxim, thiofolf (including sulfur oxidation). This ring may be independently replaced by circumstances. One or eve - The human ' is preferably 1 to 4 times, the substituent is a halogen, such as a halogen, a gas, a desert or a hydrazine; a transradical; an alkyl group substituted by a hydroxyl group; a C a 1 alkoxy group such as a methoxy group or an ethoxy group; Substituted by: (^^ alkoxy; s(0)m alkyl, 20 4 such as sulfonylthio, fluorenyl sulfhydryl or fluorenyl fluorenyl; _(-〇 on the cyclized ring : 〇)) or a ketone or aldehyde (-C(0)R6), such as c(0)Ci_iG alkyl or c(o)aryl; nr4, r14, wherein r4, and r14. are independent Is hydrogen or Cl 4 alkyl ' C!-1 fluorenyl, C 3-7 cycloalkyl or C 3-7 cycloalkyl Cl-10 alkyl, such as methyl, ethyl, propyl, isopropyl, Tri-butyl, etc., or cyclopropyl-based paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1298722 A? _;___ B7 V. Invention description (14) 15 Ministry of Economic Affairs Intellectual Property Bureau The employee consumption cooperative prints a 20-base, halo-substituted CH〇alkyl group, such as cf2cf2h, ch2cf3 or cf3; optionally substituted aryl i, such as phenyl, or optionally substituted aralkyl, such as benzyl Or phenethyl, wherein some of the groups containing an aryl group may also be substituted Second, the substituent is _ s; hydroxy; alkyl substituted by hydroxy; CbM alkoxy; s (0) m alkyl; amine, mono and disubstituted Ch alkyl amine, such as ah and 4, Medium; CH alkyl or cf3. Suitably, R5 is hydrogen, Ch alkyl, C2-4 alkenyl, C24 alkynyl or NR4R14, excluding SR5 as SNR4R14, s(0)2R^s〇2h, and a portion of the group that is converted to SOH. Suitably, the heart is hydrogen, (:!) decyl, C3-7 cycloalkyl, heterocyclyl: heterocyclylalkyl, aryl, aryl C110 alkyl, heteroaryl or heteroaryl Cido An alkyl group, wherein such a moiety may be optionally substituted. Where appropriate, the core is ^6 alkyl, aryl, aryl C16 alkyl, heterocyclic, heterocyclic C!_6 alkyl, hetero Aryl or heteroaryl C12_6 alkyl; and wherein each of these groups may be optionally substituted. · Where appropriate, Rs is hydrogen, Cl.4 alkyl, halo substituted Ci-4 alkyl, C2 4-alkenyl, c: 2·4 alkynyl, c: 3-7 cycloalkyl, c5-7 cycloalkenyl, aryl, aryl (^-4 alkyl, heteroaryl, heteroaryl*Ci4 alkyl, heterocyclic , heterocyclyl Ch alkyl, (CR10R20)t〇R7, (CRi〇R2〇)tS(〇)mR7, (CRi〇R2' NHS(0)2R7 or (CR10R2〇)tNR4Rl4; and wherein cycloalkyl The 'cycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic and heterocycloalkyl moiety may be optionally substituted. Suitably, t is a value from 1 to 3. Integer, where appropriate, R9 is hydrogen, (: (8), as appropriate, Cii〇^ -1 6- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 9〇· 11. 2, 〇〇〇 (Please read the note on the back and then fill out this page) 1-line · 1298722 A7 _____— Β7 _____ V. INSTRUCTIONS (15) Base, optionally substituted aryl- or optionally substituted aryl-C1_4 alkyl. Suitably, R1〇 and 1〇 are independently selected from hydrogen or alkane. In the case of S, Rn is C 4 alkyl, halogen-substituted alkyl, c: 2 · 4 alkenyl, C 2 - 4 alkynyl, C 3 · 7 cycloalkyl, C 5 7 cycloalkenyl, aryl , aryl 5-yl A-4 alkyl, heteroaryl, heteroaryl C-4 alkyl, heterocyclyl, heterocyclylalkyl, (CR10R2())t〇R7, (CRiQR2(〇tS(〇) mR7, (CRwR2a_NHS(0)2R7 or (CR10R2〇)vNR4R14; and wherein an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group and a heterocyclic group may be optionally used. Substituted. 10 Where appropriate, m is 0 or an integer having the value 1 or 2. Where appropriate, % is optionally substituted Q-alkyl, c3-7 cycloalkyl, C3-7 cycloalkylalkyl , aryl, aryl 〇 1-1 () alkyl, heteroaryl. ^ burn Or a heterocyclic qi oxime group, the moiety is optionally substituted one or more times, preferably 1 to 4 times, and the substituent is Cl_1()alkyl 15, _ group Substituted q 丨〇 丨〇, C 2 -丨 σ alkenyl, C 2 -fluorenyl, C 3 -7 cycloalkyl, C 3-7 cycloalkyl Ci — w alkyl, C 5 —7 cycloalkenyl, C 5 —7 cycloalkenyl Cho Alkyl, halogen, cyano, nitro, (CRwR^nOI^, (CR1()R2())nSH, (CR10R20)nS(O)mR7, (CR10R20)nNHS(O)2R7 ^ (CR10R2〇)n - Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative printing (please read the note on the back and fill in this page first) wide--line. NR4R14 &gt;(CR10R20)nCN '(CR10R20)nS(O)2NR4R14 '(CRi〇 R2〇)n·20 CXZ&amp;^CRwI^ohOCXZ&amp;ICRioF^ohCXZpi^^CRwI^o^-C(Z)NR4Ry 4 &gt; (CR! 〇R2〇)nNR! 〇C(Z)R6 ^ (CR{ 〇Κ2〇)η^ιο C(=NRi 〇)-NR4R14 &gt; (CR10R2〇)nOC(Z)NR4R14 ^ (C^ 〇R2 〇)n 〇C(Z)NR4 ^ 4 4(CR10R20)nNR10C(Z OR7〇 is preferably selected from the group consisting of il, alkyl, hydroxy, alkoxy. _ 17-_ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297) PCT) 90. 11. 20 129872215 Intellectual Property Office employee Economic Co-op invention described printed 20 (16), a cyano group, a nitro group, this amino group substituted by alkyl of _. More preferably, it is a halogen or a burnt base. The four preferred & is Ci_ig alkyl, C37 cycloalkyl, 2 alkylalkyl or aryl which are optionally substituted. More preferably &amp; alkyl or aryl which is optionally substituted. When % is an optionally substituted aryl group, the aryl group is preferably substituted at the 2_ position or disubstituted at the 2-, 6-position. Suitably, 'η is 0, or an integer having a value of 1 to 1〇. Suitably, X is r2, 〇r2, s(0)mR2, (CH2XiN(RiQ)s(())mR2, (CH2)nN(R10)C(O)R2, (CH2)nNR4R14 or (CH2) nN(R2)2. Preferably, X is 〇R2, (CH2)nNR4RM4(CH2)nN(R2)2. Suitably, & is independently selected from hydrogen, optionally substituted alkyl, and Substituted C; 3 _7 cycloalkyl, optionally substituted q 7 cycloalkylalkyl, optionally substituted aryl, optionally substituted aryl q·10 alkyl, optionally substituted a heteroaryl group, optionally substituted heteroaryl Ci-iQ alkyl group, optionally substituted heterocyclic group, optionally substituted heterocyclic group Q i fluorenyl moiety, or R 2 is Part of the group (CRi〇&amp; 〇)q _ C(Ai )(A2 )(A3 ) or CA )(A2 )(A3 ), part of R2, except hydrogen, which may be replaced by one or more independently Further, preferably 1 to 4 times, the substituent is an alkyl group, a qi-substituted qi alkyl group, a c2_1G alkenyl group, a c2-1G alkynyl group, a c3-7 cycloalkyl group, a c3-7 cycloalkyl Ci-10-alkyl group, 05_7 cycloalkenyl, C5-7 cycloalkenyl Choalkyl, halogen, -C(0), cyano, nitrate S'CCRioI^oLOR^CCRMR^nSH'CCRwI^oi S(〇)m R7 (CR1 0 R2 0 )n 佩 1 0 S(〇)2 R7, (CRi 〇R2 〇)n NR4 Ri 4, (CR10R20)nCN, (CR10R20)nS(O)2NR4R", (CRwRWn-COl^, - ------------#.u &lt;Please read the notes on the back and fill out this page ^*· Order: i-line - -18- This paper scale applies to China National Standard (CNS) A4 Specifications (210 x 297 mm) 90. 11. 2,000 1298722 A7 JB7_____ V. Description of invention (17) (Please read the notes on the back and fill out this page again. 0 (CR1〇R2〇)n〇C(Z) R6 '(CRjo^o^CCZPI^ ' (CRj 〇R2 〇)n C(Z)NR4 ^ 4 -(CR1〇R2〇)nNR1〇C(Z)R6 &gt; (CR10R20)nNR10C(=NR1〇)NR4R14 '(CR1〇R2〇)nC(=NOR6)NR4R14 ' (C^ 〇R2 〇)n 〇C(Z)NR4 R2 4 '(CR10R20)n. 〇C(Z)NR4 4 or d 0 R2 0 ) n 〇 〇 c (Z) OR7. 5 Suitably, Xi is N(R10), 〇, S(O)m4CR10R20. Suitably, q is 〇 or an integer having a value between 1 and 10. Suitably, Ai is an i-based base that has been replaced as appropriate. Suitably, A2 is a c-substrate that has been replaced as appropriate. Suitably, A3 is hydrogen or is optionally substituted c1M() alkyl. 10 Ai, A2 and A3 Q i anthracenyl group, optionally substituted one or more times, preferably 1 to 4 times, the substituent is halogen, such as chlorine, fluorine, bromine or iodine; a substituted base of Cho, such as CF3 or CHF2CF3; c2_1(), a C2 -1 ο fast radical, a C3 -7 jade, a C3-7, a C1 - 1 , a C5 - 7 cycloolefin Base, c5_7 cycloalkenyl Choalkyl, (CRwhiOnOI^, Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative Printed 15 (CR10R20)nSH ^ (CR10R20)nS(O)mR7 &gt; (CRf〇R2 〇)n NHS(0 ) 2 R7 ^ (CR10R2〇)nNR4R14 ^ (CR10R20)nCN &gt; (C^ 〇R2〇)nS(0)2NR4^ 4 &gt; (CRi〇R2〇)nC(Z)R6 &gt; (CR^^o ^OCCZ)^ &gt; (C^ 〇R2〇)n&gt; (CRi〇R2〇)nC(Z)NR4R14 ^ (CR^^o^NR^CCZ)!^ &gt; (CR10R20)n. NR1〇C( =NR1〇)NR4R14 &gt; (CR10R20)n〇C(Z)NR4R14 ^ (CRi〇R2〇)n&gt; 20 NRi 〇C(Z)NR4 Heart 4 or (C& 〇R2 〇)n Nh 〇C(Z OR7. One to more of the heart to VIII, preferably hexyl (CRioR^LOF^. More preferably R6 is hydrogen. Preferably, the C(At)(A2)(A3) group is CH(CH2OH) ) 2 or c(ch3 )(ch2 oh)2, x! (CRi 〇R2 〇)q CH(CH2 OH ) 2 or Xi (CR! 0 R2 〇)q C(CH3 )(CH2 OH)2. X! -19- 90. 11. 2,000 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1298722 A7 B7 V. INSTRUCTIONS (18) 15 The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative prints preferably oxygen or nitrogen. a group such as halogen, such as fluorine, gas, bromine or iodine; a hydroxyl group, a c-alkyl group substituted by a base; a chitoalkoxy group such as a methoxy group or an ethoxy group; C1_120 alkoxy; s(0)m alkyl, such as methylthio, methylsulfinyl or methylsulfonyl; _C(0); W •, wherein R4· and RM are each independently hydrogen or Cr·4 院, such as an amine group or a mono- or a bis-substituted C1M alkyl group, or wherein the core 4 can be cyclized with the nitrogen to which they are attached to form a 5 to 7 membered ring, which is The case contains another hetero atom selected from O/N/S; Ch〇 alkyl, 〇3 Cycloalkyl or C37 cycloalkyl A, alkyl, such as methyl, ethyl, propyl, isopropyl, Third _ butyl, etc., or cyclopropyl a benzyl group substituted with a q_10 alkyl group, such as Cf2CF2H4CF3; optionally substituted aryl, such as phenyl, or optionally substituted aralkyl, such as benzyl or phenethyl, wherein such aryl Some of the groups may be substituted one to two times, the substituent is a halogen; a group; a carboxylic group substituted by a hydroxy group; a Cbw alkoxy group; a s(0)m alkyl group; an amine group, a mono- and a di-substituted group An alkylamine group, such as in the NR^Rm group; a Cl_4 alkyl group or a Cf3 group. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfinic acid. Acid, acetic acid, malic acid, tartaric acid, lactic acid, acid, sulfuric acid, antibutanic acid, cis-succinic acid, benzoic acid, salicylic acid, phenylacetic acid and phenylglycolic acid. Further, the pharmaceutically acceptable salt of the compound of the formula (I) may also be formed by a pharmaceutically acceptable cation, for example, if the substituent includes a carboxyl moiety -20 - the paper scale applies to the Chinese National Standard (CNS) A4 Specifications (21〇X 297 mm) (Please read the note on the back of the M and then fill out this page. V' Order: i line · 90. 11. 2,000 1298722 A7 B7 V. Invention description (19) 15 20 hours. Appropriate The pharmaceutically acceptable cations are well known to those skilled in the art and include alkali metal, alkaline earth metal, ammonium and quaternary ammonium cations. The term "based" or "pure" is used herein. Means halogen, chloromei, phenotypic, molybdenum and ruthenium. , soil, '= decyl group' or "burning base" or "alkyl hydrazine", terminology, used herein It means that the linear and branched chain groups of 1 to 10 carbon atoms are limited, including but not limited to methyl, ethyl, n-propyl, n-butyl, di-butyl, isobutyl, Third butyl, n-pentyl, etc. &quot;cycloalkyl is used herein to mean a cyclic group to 8 carbons, including but not limited to The propyl, cyclopentyl, cyclohexyl and the like are used to mean a cyclic group: to = have a Μ-bond [including but not limited to cyclopentyl] Dilute, the word is used in this context to mean a straight or branched chain group of (four) carbon atoms, unless the chain length is limited, not limited to vinyl, !·propenyl, 2_propyl, 2-methyl; monobutenyl, 2-butenyl, etc. The term "endenyl" "aryl" is used herein to mean phenyl and naphthyl. In any combination, such as "heteroaryloxy", or in the middle or evening soil containing - or a plurality of heteroatoms, selected from the group consisting of n, 〇 or § '譬 such as, but not limited to, 吼, 吼嗤, 吱 &&quot;塞, 〇 嘴, 里心林&quot; 奎 咐 咐 吼 吼 吼 吼 奎 奎 奎 奎 奎 奎 奎 奎 奎 尿 尿 号 号 号 号 号 号 号 号 号 号 号 号 号 号 号 号 号 号 号 号 号 号 号 号 号 号 号 号 号Saliva, ten sitting, one or benzene (four) Please | Item book paper size standard (CNS) A4 specification curry) 90. 11. 2,000 [298722

V. Description of invention (2〇) 15 The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed the word 20 squat/heterocyclic (alone or in any combination, such as “heterocyclylalkyl,”) By means of a saturated or partially unsaturated ring system, wherein one or more of the oximes contain one or more heteroatoms selected from the group consisting of N, 〇, S or S(〇)m, and m is 〇 or has 1 or An integer of 2; for example, but not limited to, a saturated or partially saturated variant of a heteroaryl moiety as defined above, such as tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, tetrahydrothiophene (including a sulfur moiety) Oxidative modification of the group), tetrahydropyrrole, hexahydropyridinium, hexahydropyrrole, muffle, thiofolf (including oxidative modification of a sulfur moiety) or imidazolium. π aralkyl" or "hetero An arylalkyl" or "heterocycloalkyl" term is used herein to mean a C 4 alkyl group, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, such as Also defined in this document, unless otherwise indicated, the term "a stone page" is used herein to mean The oxide sulfide s (o) ' "thio" shall mean a sulfide, and the &quot; continued acyl ,, the term refers to whole completely oxidized s (o) 2 moiety. The term "π-aryl" is used herein to mean c(0)Ar, wherein Ar is a phenyl, naphthyl or aralkyl derivative, as defined above, such a group includes The term "π-alkyl" is used herein to mean C(0)C1 · decyl, wherein the alkyl group is as defined above. It should be understood that the compounds of the present invention may exist as stereoisomers, regioisomers or diastereomers. These compounds may contain one or more non-standard paper scales applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 ______ — 丨1·” ill! (Please read the notes on the back first) Fill in this 1 &gt; one &quot;-δ line - 1298722 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 20, invention description (21) ^ called carbon atoms, and can be de-rotated and optically active forms exist. All this The specific compounds are all included in the scope of the present invention. Exemplary compounds of the compounds include the compounds of the examples herein, or pharmaceutically acceptable salts thereof, and the following tow. 2 methylthio-4,8-one Phenyl Na is more than 唆[2,3_d] shouting bit 7_ ketone to burn ~ 醯 base * 4,8_ phenyl than bite and [lid] pyridinium _7_ ketone 厶 (2 · 2 Amino-ethylamino H,8-diphenyl-muscle-pyridinium md]pyrimidine-7-one 8-(2,6-difluoro-phenyl M_(4)fluoro-2-methyl-phenyl&gt;; 2_methoxy_8h_pyrido[2,3_d]pyrimidin-7-one 8-(2,6-difluoro-phenyl)2-ethoxylated hailylfluoro- 2•methyl _Phenyl)_8h_pyrido[2,3-d], -7-keto-2-butoxy-8_(2,6-difluoro-phenyl&gt;4_(4-fluoro-2) -Methyl-phenyl)-8H-pyridine and P,3-d], bite_7-keto 8-(2,6-difluoro-phenyl M_(4-fluorol-methyl-phenyl)_2 ·Methylthio-5 mustard dihydro-cation_pyrido[2,3-d]pyrimidin-7-one. · Formula (I), (Ia), (II) and (iia) compounds can be applied The synthetic procedure described is obtained. The synthesis provided can be applied to produce formula (1), (Ia), (9) and compounds having a plurality of different Ri, &amp;, gamma, oxime and % groups, such groups being employed The substituents are suitably protected and the reaction is carried out to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in which case compounds having generally disclosed properties are obtained, although shown herein. a specific chemical formula with a specific substituent, but its synthesis can be applied to all chemical formulae and all substituents herein. Once the nucleus has been established, other compounds of formula 1, (Ia), (9) and (IIa) can be scaled on wood paper. Timely National Standard (CNS) A4 Specification (210 χ2&amp;7 90· π· 2, 〇〇〇 (Please read the notes on the back and fill in this t· i^T_ line·A7 1298722 __B7_ V. Description of the Invention (22) (Please read the notes on the back and fill out this page first)\, using the standard techniques known in the art for the mutual conversion of functional groups. For example: C(0)NR4R14 is via With or without the use of catalytic metal cyanide (eg NaCN), with HNI^Ri 4 in (:1130 «[heated from C02 CH3; 0C(0)R3 uses, for example, C1C(0)R3 in pyridine Available from 0H; 5 Grab 11()-(:(8) 1^Fence 14 is the use of alkyl isothiocyanate or thiocyanate, obtained from 1^^1() -- Line · Ministry of Economic Affairs Intellectual Property Bureau employees Printed by the consumer cooperative; NR1()C(0)OR7 is obtained using naphthenic acid alkyl ester from NHR1(); NR10C(O)NR4R14 is via isocyanate, for example HN=C=0 or Ri 〇N= 00 treatment, obtained from NHRi 〇; NE^ 〇C(0)R7 is obtained by treating C1-C(0)R7 in pyridine from NHR10; C(=NR10)NR4R14 is using 10 H3NR3 + OAc-, via Heating in alcohol, obtained from C(NR4R14)SR3; C(NR4R14)SR3 using R6·[, in an inert solvent such as acetone, from C(S)NR4R14; C(S)NR4R14 (where R4 or 1114 is not HNR4R14 is used for hydrogen), from C(S)NH2; C(=NCN)-NR4R14 is used for nh2cn. From C(=NR4R14)_SR3 by heating in an anhydrous alcohol, or from C(=NH)-NR4R14 by treatment with 15 BrCN and NaOEt in EtOH; NR10-C(=NCN)SR8 is via (R8 S) 2ONCN treatment, obtained from NHR10; nr10so2r3 is obtained by treatment with C1S02R3, heated by pyridine in NHRi 〇; 丨〇C(S)R6 is via Lawesson's reagent [2,4-double (4·methoxy-based)-1,3,2,4·-sulfur>«««石粦四0 _2,4·-monosulfide] treatment 'paid from 20 NRioQO)!^ ; NR10SO2CF3 is used Trifluoromethane sulfonate and base, obtained from NHh, wherein the ruler 3, chemistry, ruler 7, heart 0, and ruler 14 are as defined in formula (1) herein. The precursors of the radicals and the precursors of 112 may be other core and scale 2 groups which can be converted into each other via standard techniques using interconversion of functional groups. For example, some of the groups are alkyl groups substituted with il groups, which can be reversed by the appropriate azide salt. 94 - 90. 11. 2,000 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297). [298722 A7 _ B7 V. Description of invention (23) 15 The Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives, printed 20, and was converted into its current Ci-M alkyl n3 derivative, and then if needed Reducing it to its corresponding C1 _ 1 hydrazine compound, which can then be reacted with R7 S(0) 2 X 'where X is a south group (eg, a gas group), resulting in its corresponding 〇ν10 alkane Base nhs(o)2r7 compound. Alternatively, a part of the group is a halogen-substituted Ci i (r alkyl group which can react with the amine R4RWNH to produce its corresponding ClM (r alkyl NR4R14 compound, or can react with the alkali metal salt of R7SH) The corresponding Cii decyl SRWb conjugate is produced. Suitable protecting groups for the benzyl and nitrogen groups are known in the art and are described in a number of references, for example, in organic synthesis. Protecting group, Greene TW, Wiley-Interscience, New York, 1:1. Suitable examples of hydroxy protecting groups include decyl ethers such as tert-butyldimethyl or tert-butyldiphenyl, and alkanes An ether group, such as a thiol group attached by an alkyl chain of a variable chain (CRl〇R20)n. A pharmaceutically acceptable acid addition of a compound of the formula (I), (Ia), (II) and (Ila) Salts can be obtained in a known manner, for example, by treatment with an appropriate amount of the acid in the presence of a suitable solvent. Starting material 1 - Scheme I can be obtained from commercially available 4,6-dihydroxy 2 -indenyl fluorenyl Pyrimidine, by known literature procedures, as described in San Man et al., JHetei Jyd Chem. (1971), 445_53, in which p〇c is used. l4DMF. Intermediate 2_Form I is made by two different routes. In the first way, dichloroaldehyde 1-graph I and arylamines, in the presence of NaH, in DMs Coupling (Santilli et al., J. Heterocyc L Chem. (INI), 445_53), obtaining the desired compound 2-indole I, along with the imine 13-pattern ϊ. by treatment with Ηα aqueous solution in THF Conversion of Amine to Aldehyde 2_Form I. l Converting Formula I to 2 -25 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 9〇· 11. 2,〇〇〇( Please read the precautions on the back and then fill in this I) one order ·· - line 1298872 A7 --------B7 V. Invention description (24 ) (Please read the note on the back and fill in this page) Formula I can also be obtained by using triethylamine and the desired amine in a gas bath at room temperature for 1 minute. This reaction is highly effective for a range of alkylamines (78-95% yield). For the arylamines, high temperature (reflux) and longer reaction time (24 hours) are necessary to complete the reaction. When 3 or more equivalents of amine are used, the use of the base can be omitted. Other suitable bases, including but not limited to pyridine, diisopropylethylamine or tetrahydropyrrole, may also be used in suitable organic solvents including, but not limited to, THF, diethyl ether or dioxane. Among the routes, the nitrile 9_囷 I was prepared in three steps from the aldehyde r pattern (^jaim et al., J. Hetemcyd Chem. (mi), MW3). The dichlorocarbonitrile seven-form Γ is coupled with a 10 arylamine in the presence of NaH in DMSO to obtain the desired compound 10-oxime I. Other suitable bases, such as pyridine, diisopropylethylamine or sodium, may also be employed in suitable organic solvents such as THF, dmf* dioxane. The manufacture and use of nitrile 9-round-I can also be found in PCT/US01/06688, the entire disclosure of which is incorporated herein by reference. , --. Nitrile is easy to use DffiAL, in di-methane, reduced at room temperature (Boschellmt et al, J. Med. Chem. (I&quot; 8), 43654377), and get the desired r The Property Bureau employee consumption cooperative printed version I, accompanied by the unsubstituted imine 13-pattern 1 (11=11). The latter was hydrolyzed to 2_Form I in the presence of HC1. Other reducing agents, such as lithium aluminum hydride, monidron 20 or SnCl2, can be used in a suitable organic solvent, such as THF, diethyl ether or dioxonium, to effect the conversion of Figure 1 to Form I. Under the conditions of Suzuki coupling, a palladium catalyst, such as ruthenium (triphenylphosphine) palladium (9), is used to couple the aldehyde 2 to the diarylborane to obtain a good yield to the 3 - pattern. I. Alternatively, the bis-aryl coupling reaction of 2_囷I can be carried out using 芳1298722 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing ___B7_5, invention description (25) base or heteroaryl organic rhetoric, organic copper, Organotin or other known organometallic reagents are carried out to obtain a bisaryl cross-coupling product, such as 3-Figure 1 [see, for example, Solberg, J.; Undheim, K. Acta Chemica Scandinavia 1989, 62-68]. For the replacement of the chlorine in 2-Fig. I, a nitrogen nucleophile can also be used [related amination 5 action, see U.S. Patents 3,631, 〇45 and 3,910,913], sulfur nucleophiles [see Tumkevicius, S. Liebigs Ann·I&quot; 5, 17〇3·Π05], an oxygen nucleophile or a ketone nucleophile is achieved. Then, 3-form I is converted to pyridopyrimidinone 5-scheme I by one of three procedures. The first procedure uses the Wittig reaction, as modified by Homer-10 Emmons, to convert 3-pattern I to 4-graph I. In this reaction, the aldehyde 3-formula I is treated with a suitable phosphorus alkylene compound, such as triethyl phosphonate acetate or diethyl phosphonate decyl acetate, to obtain an olefin intermediate 4-pattern. I. This reaction is carried out under reflux in a suitable base such as sodium hydride, sodium or sodium hydroxide, and in a suitable organic solvent such as diethyl ether, dioxane 15 or ethanol. The conversion of 3-form I to 4-pattern oxime can also be carried out using Peterson olefination or aldol reaction, using acetic anhydride, malonic acid and its monoalkyl esters or ethyl acetate. . 4-Form I, in a stupid, heated in a sealed tube at 22 (TC (Matyus et al., Heterocycle (1985), 2057-64), followed by removal of the solvent to obtain the desired product 2〇5_ Scheme I. This reaction can be carried out in the presence of a suitable hydrazine such as DBU or diisopropylethylamine, pyridine, lithium bis(trimethyldecyl)amine or LDA, and in a suitable organic solvent such as an organic hydrocarbon, cresol, Operation in dioxane, DMF, pyridine or xylene. The first procedure uses the Still-corrected Homer-Emmons reaction (Still et al. -27- This paper scale applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) 90. 11. 2,000 (Please read the note on the back and fill in this I..), order: Line · 1298722 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 — --- ---2Z__ V. Description of invention (26) Person, Tetrahedron Lett (1983), 4405-8; Jacobsen et al., Tetraheto 4323-34) 'To produce the desired product 5_图〗 and trans isomers a mixture of the formula i. The trans isomer 4_round I is separated and heated to 220 ° C in a sealed tube via toluene as described above. Conversion to the desired product 5_图ϊ. 5 The second procedure involves the acetylation of 3_circular I, followed by intramolecular aldol condensation 'by an acetamylating agent (such as acetic anhydride, gasification B) Anthracene, alkene and an appropriate test (such as pyridine, diisopropylethylamine or tetrahydropyrrole) promote the production of 5_circular oxime in very good yield. When &amp; is optionally substituted aryl or heteroaryl The third procedure is most suitable. When &amp; is an aralkyl or heteroarylalkyl 10 substituent, it is not clear that this reaction will form a key intermediate of formula (1¥) as follows It is shown that it may be isolated as appropriate. The compound of formula (IV) is preferably not isolated, but further reacted with a base or, using heat, is cyclized to the formula -I. For all other R3 moiety, it should be utilized The first and second procedures. 15 Sulfide 5_Oxidation of sulfone to sulfone 6_Form I, using m-chloroperoxybenzoic acid (mCPBA), obtained in high yield and purity. The appropriate oxidation method used, including the use of one or two equivalents of m-peroxybenzoic acid (mCPBA) or 〇xone®, whether it is sulfoxide or Sulfone. The oxidation of this sulfide into a sub-stone or stone wind, and can also be used to oxidize 20 substances, hydrogen peroxide, other peracids, oxygen, ozone, and organic substances by 〇s〇4 and catalytic tertiary amines. Oxide, potassium permanganate is achieved with zinc, potassium persulfate and sodium hypochlorite. The replacement of stone wind 6_图I into the final product 7·pattern, often achieved with excess amine 'in N-decyltetrahydropyrrol (Barvian et al, j. Med. Chem. (2000), 4606 Ice 616). A wide range of primary amines carry out this reaction in superior yield. In — .........-—.........- ____ - 28 - This paper scale is universal China _ quasi (CNS) A4 specifications (21_ public love) - (please read first Precautions on the back side of this page) 丨装•线. 1298722 A7 B7 V. Invention description (27) 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 20 In some cases (in 0_ replacement or sulfonamide formation The anion of the nucleophile is prepared as a base (often sodium hydride 5 in dimethylformamide and then added to the sulfone. The yield of such reactions is usually very low. Similarly, the compounds herein Related sulfones and sulfoxides, which are also 3 〇-alkyl or s〇 2-alkyl, have been reported in the literature to be replaced by a wide variety of nucleophiles. Thus, the compounds herein wherein X is an alkyl sulfone Or an analog of Yalu, which can be replaced by a primary or secondary alkylamine without additional catalysis, preferably in a polar aprotic solvent such as, but not limited to, N-methyltetrahydropyridinium-2 Ketone (^〇&gt;), and at different temperatures, depending on the nucleophilicity of the amine. For example, a sulfone analog of the compound of formula 1, with ethanolamine, in NMP The substitution occurs at 6yc in 30 minutes, while the more hindered amine, such as ginseng (hydroxymethyl)-aminomethane, may require high temperatures and prolonged reaction time (80 ° C, 24 hours reaction time) The sulfone may also be substituted at a high temperature by aryl or heteroarylamine, and it is sometimes necessary to form an aryl or heteroarylamine anion in DMS by sodium hydride or other suitable base. A sulfoxide analog of a compound which can be readily substituted with an aluminum salt of an aryl or heteroarylamine, as previously described in the patent literature (W099/32121). Similarly, she, formula (I) The sulfone of (la) and the sulfoxide analog may be substituted with an aryl or heteroaryl group or an alkyl thiol, or a decyl or aryl or heteroaryl alcohol. For example, (I) containing a sulfone as an X substituent Alternatively, the sodium alkoxide may be substituted in the alcohol, or the reactive alkoxide or phenoxide nucleophile may be derived from an alcohol or a phenol with a suitable base such as sodium, NaH or sodium bistrimethyldecylamine. Produced in a polar aprotic solvent such as DMSO, or in a solvent-free reaction. Similarly, Formula 1 and (la) are associated with sulfones, such as carbon nucleophiles, such as aryl or alkyl -29. This paper scale applies to China National Standard (CNS) A4 specifications (210 X 297 public Chu) 90. 2,000 Read the back of the note page 1289872 A7 B7 V. Invention description (28)

Grignard reagent, or related organometallics such as organolithium, rhodium, tin or side replacement. In some cases, such reactions may require transition metal catalysis, such as the use of Pd or Ni catalysts. a substitution of a related 2-pyrimidine quinone, with a nitrogen, a malonate anion, an unactivated enol or a heterocyclic c nucleophilic 5 group, such as a 1-methylimidazolium anion, via NaH or other suitable There are also precedents for 'producing anions in THF' (see, for example, chem. Pharm Bull. I987, 4972-4976). For example, a compound of formula (1) and (10) wherein hydrazine is an analog of an alkyl sulfone may be substituted with an anion of 1-methylimidazole via a n-butyl group in a solvent such as THF at about -70. The product was produced at a temperature of 10 times, and 1-methylimidazole was treated to obtain a C-alkylated product substituted on the imidazole C-2. For the purposes herein, compounds of formula (I), (Ia), (II) and (Ha), wherein again &amp; or NHS(0)mR2, may be as defined by using formulas (1) and (Ia) The appropriate X functional group 'replacement' is derived from the 6-form I compound. To obtain a compound of formula 15 W, (Ia), (π) and (IIa) wherein X is S(0)mR2 and R2 is not methyl', the corresponding compound 6 is replaced by a thiol (3⁄4 SH) The difficulty of Formula I is then followed by oxidation if necessary followed by a suitable oxidizing agent such as MCPBA or ΚΜη04. Suitable oxidation methods for use herein include the use of an oxidizing agent, such as one or one, between the gas-peroxybenzoic acid or 〇x〇ne®, whichever is 20 hydrazine or sulfone. The oxidation of this sulfide to a sulfone can also be achieved by 〇s〇4 and a tertiary amine N-oxide for catalysis. Other methods for the oxidation of sulfides include the use of peracetic acid, other peracids, oxygen, ozone, organic peroxides, potassium permanganate and zinc, potassium persulfate and sodium hypocarbonate. 8-round I can also be applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) by trans ester 4_scheme j in alcohol at the corresponding alkanol ___- 30 - paper scale. (Please read the notes on the back and fill out this page)

T Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 90. 11. 2,000 1298722

V. Description of the invention (29) It is prepared by heating in the presence of sodium. The yield of this reaction is extremely high for the _-class alcohol, but it takes a longer reaction time for the secondary alcohol. The alkanoic acid can be readily prepared from the corresponding alcohol, such as sodium or sodium hydride. The transester 4-pattern I is reduced by SmI2 to obtain the reduced analog 11-circular I. This reduction can also be achieved in the presence of other reducing agents such as hydrogen, lithium in liquid ammonia, magnesium or sodium borohydride in a suitable organic solvent such as THF, ethanol or sulphur. The cyclization of ester 11 - Scheme I can be achieved with sodium methoxide in methanol to obtain the reduced analog round x. Other organic bases, such as sodium, sodium ethoxide or TEA, can be used in suitable organic solvents such as methanol, ethanol or dioxane. The product 12-Formula I can also be obtained by heating the ester n-pattern j in a suitable organic solvent such as toluene, xylene or isopropanol to discriminate it. Please read the note on the back first! 纩 page booked by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives -31 - 90. 11. 2,000 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1298722 A7 B7 V. Description of invention (3〇

[.R3NH2, DMSO

HCI, THF

1. OIBAL. OCM 2. HC(, THF, HaQ

N CliiLan嶋

Cl, N S

R2NHj. NMP Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing Figure ι 32- This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm). Off (please read the notes on the back and fill out this page)

90. 11. 2,000 1298722 A7 _B7_ V. DESCRIPTION OF THE INVENTION (31) Another aspect of the present invention is a novel (III) intermediate 0 R1 X R12 - 0^^^ and N persons/m where R! is a fang a heterocyclic ring or a heteroaryl ring. The ring is optionally substituted; the rule 3 is 〇1-1(), the base of the 3-7 ring, the 匸3-7 ring, the aryl group, the aromatic a 10-based Q i fluorenyl, heteroaryl, heteroaryl Q i fluorenyl, heterocyclic or heterocyclylalkyl moiety, which moiety is optionally substituted; and rule 12 is ¢^-12()alkyl, aryl, heteroaryl or aralkyl. Another aspect of the invention is a novel (Ilia) intermediate 15

S&quot; m Please read the notes on the back and fill out this page. Order the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Print 20, where &amp; is part of the group YRa; Y is C(Rb)(Rd), C(0 ), N(Rd), oxygen, 8(0) „1 or 8(0)111&lt;:(11€)(11&lt;1); Ra is an aryl or heteroaryl ring, which is optionally substituted ; 00(1^)(3⁄4) -33- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 A7 1298722 V. Description of invention (32)

Rb is hydrogen, Cm alkyl, NRe, hydroxy, thio, (^-2 alkoxy, ΧΟΧπΑ. alkyl;

Rc is hydrogen or &lt;^_2 alkyl; is nitrogen or Ci. 2 alkyl; 5 melon is 〇 or has an integer of 1 or 2; and R3 is alkyl, C: 3·7 cycloalkyl, (: a 7:7 cycloalkylalkyl, aryl, aryl C1M0 alkyl, heteroaryl, heteroaryl*Cl-1 decyl, heterocyclic or heterocyclic C1M0 alkyl moiety, this moiety The group is optionally substituted; and 10 R12 is C1-10 alkyl, aryl, heteroaryl or aralkyl. Preferably, formulas (III) and (Ilia) and (IV) and (IVa below) The substituent of the compound is a substituent according to the compound of the formula (I) or (11) in the following formula. Another aspect of the invention is a novel intermediate of the formula (IV), please read the notes on the back and then fill in the page. ) Order: 15

· Line. Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, where R!, R3 and Ri 2 are as defined above for formula (111). 20 Another aspect of the invention is a novel intermediate of formula (IVa)

90. 11. 2,000

15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1298722

V. Description of the invention (S3): nRi 2 is as defined in the text, and the other aspect of the U is the novel intermediate (V) Substituted heteroaryl ring; % is hydrogen - 'yl, C &gt; 7 cycloalkyl, c &gt; 7 cycloalkyl, aryl,", alkyl, (tetra), heteroaryl ~. a heterocyclic or heteropoly group q ??? 〇 alkyl moiety, the moiety being substituted as appropriate, provided that when hydrogen is present, &amp; is not chlorine. Preferably R1 is halogen More preferably, it is chlorine. Preferably, Ri is an optionally substituted aryl ring. Preferably, R3 is optionally substituted qi〇alkyl, cycloalkyl, lyophilized or aryl. The substituents are selected independently from Cii alkyl, halo substituted <^-10 alkyl, C2-10 alkenyl, c2-10 alkynyl, 〇3-7 cycloalkyl, c3 7 cycloalkyl c1M0 alkyl, ( :5·7 cycloalkenyl, c5-7 cycloalkenyl ei_1〇alkyl, halogen, (CRi〇R2〇)n〇R6, (CRi 〇R2 〇)n SH, (CR10R20)n S(0)mR7, (CR10R20)nNHS(O)2R7, (CR10R20)nNR4R14, (CR10R20)nCN, (CR10R20)nS(O)2NR4R14 '(CRwR ^nC^Z)!^,(CR10R20)nOC(Z)R6 -35 (Please read the precautions on the back and fill in this 1--.&gt;,

This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm). 90. 11. 2,000 Ϊ 298722 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Β7 Β7 V. Invention Description (34), (CR! 〇R2 〇)n yang team^ (CR10R2〇)nC(Z)NR4Ri4,(CR! 〇R2 〇)n NR10C(Z)R6,(CR10R20)nNR10C(=NR10)NR4R14 ^ (CR10R2〇)n- OC(Z) NR4R14, (CR10R20) nm1〇C(Z)NR4R14 or (CR10R20)nNR10^c(z)or7. More preferably, the substituent is independently selected from a halogen, an alkyl group, a hydroxyl group, an alkoxy group, an amine group or an alkyl group substituted with an i group. Exemplary compounds of the formula (v) include, but are not limited to, 4-lacyl-2-methylthio-6-phenylamino-mouth bite-5-staple; 4-methyl-6-(2, 6-Bism-phenylamino)-2-indolethio-pyrimidine-rebel acid: 10 4-chloro-6-(2-phenylphenylamino>2-methylthio-pyrimidine- 5-carboxyfurfural; 4-methyl-6-(2-fluorophenylamino)-2-indolethio-snack--5-staple; gas-based-6_(1·ethyl-propylamino) -2-methylthio-feeding&gt;5-retinoic acid; 4-chloro-6-isopropylamino-2-methylthio-5-carboxy decanoic acid; 4-chloro-6-ring Alanyl-2-methylthio-bense-5- sylvestre; 15 4-oxyl-6-(cyclopropylmethylamino)-2.methylthio-N-zincidine; 2-曱thio-*4-phenyl-6-phenylamine-mouth bite-5-Wei Jiajun; 4-(2-gasoyl)_6-(1-ethyl-propylamino)-2-methylthio Tf fixed j · Guanjia brewing; 4-(2-phenylphenyl)-6-(2_-phenylphenylamino)_2-methylthio-bearing carboxylic acid · 4-(2-fluorophenyl) - 6-(2-chlorophenylamino)-2-methylthio-pyrimidine-based retinoic acid; and 20 4-(2-fluorophenyl)-6-isopropylamino-2-methylsulfide The base of the invention is a novel intermediate of the following formula.

90. 11. 2,000 (please read the notes on the back and fill out this page)

-36- 1298722 A7 B7 V. Description of invention (35 of which

Ri is YRa; &quot; ¥ is 〇^)(3⁄4), C(0), N(Rd), NCR^CXF^XRd), oxygen, 0(:(1^)(3⁄4), SfC^S^mCdXRd );

Ra is an aryl or heteroaryl ring which is optionally substituted;

Rb is hydrogen, q-2 alkyl, N&amp;, hydroxy, thio, Cl-2 alkoxy, alkyl;

Rc is hydrogen or (^-2 alkyl;

Rd is hydrogen or (V2 alkyl; m is 0 or an integer having a value of 1 or 2; and &amp; is hydrogen, alkyl, c: 3·7 cycloalkyl, c3-7 cycloalkylalkyl, aryl , aryl Ci _ i 〇 基, heteroaryl, heteroaryl Ci M oxime, heterocyclic or heterobasic C! _ 〇 〇 部份 part of the group 'this part of the group as the case Substituted. 15 The Ministry of Economic Affairs' Intellectual Property Office employee's consumption contract is better printed. As mentioned above, the substituents of the compounds of formula (V) and (Va) are in accordance with the compounds of the last formula (I) and (II). Substituents of the formula (Va) include but are not limited to: -6-(2-phenylphenyl)-2-methylthio-mouth--5-indolecarboxylic acid; -6-(2-Phenylphenyl)-2-methylthio-. 密σ定-5-竣甲骏; 4-(1⁄4propylmercapto-amino)-6-(2-fluorophenyl曱-2-thiol-mouth 定 · carboxymethyl -4-; 4-(2,6-difluoro-phenylamino)-6-(2-fluorophenyl)_2-methylthio-°3⁄4 σ Wei Weijun; 4_(2-fluorophenyl)-6-(2-fluorophenylamino)&gt;2-methylthio-pyrimidine-5-carboxycarboxylic acid; 4-second·butylamino-6- (2-fluorophenyl)-2-indolethio-nodolinic carboxylic acid; M4-fluoro-2-methyl-phenyl)-6-isopropyl Aminomethyl-2-methylthio-pyrimidinecarboxylic acid; -37- 90. 11. 2,000 (Please read the notes on the back and fill in the 1--.1) This paper size applies to the Chinese National Standard (CNS) A4. Specification (210 X 297 mm) 1298722 A7 V. Description of invention (36) 4·Cyclopropylamino-6-(4-fluoro-2-methyl-phenyl)-2-methylthio, pyridine_5_ Carboxymethyl; 4-(cyclopropylmethyl-amino)-6-(4-fluoro-2-methyl-phenylmethylthio-mouth carboxycarboxaldehyde; 4_second-butylamino group- 6-(4-fluoro-2-methyl-styl)&gt;2-methylthio-pyrimidines-5 aldehyde; 4-amino-6-(2-fluorophenyl)-2.methylthio- Pyrimidine-5-staple; or 4-(2-random-based amino)-2-methylthio- 6-phenoxy" «Blowing _5_ 慢甲酿. 4-Amino-6 ·Gas-based 2-indole thiol bite "5-rebel formic acid; 4 · first · butylamino group · 6 chloro-2-methylthio group · feeding. _5_ carboxymethyl; Η) 4 -(2,6-difluoro-phenylamino)&gt;6-(4.fluoro-2-azyl-phenyl&gt; 2 thiol-pyrimidin-5 carboxyfurfural; and '4-(1 Ethyl propylamino)·6-(4-fluoro-2-methyl-phenyl)_2·methylthiopyrimidine carboxaldehyde. Another aspect of the invention is the novel intermediate of formula (VI). It Precautions to fill out this page &gt; IP: 11.15 set Ministry of Economic Affairs Intellectual Property Office employees consumer cooperatives printed which 〇-

The oxime is as defined above for the compound of formula 1, and &amp; is an optionally substituted aryl or heteroaryl moiety, as defined for the compound of formula (1). Another aspect of the present invention is a novel (VIa) intermediate. The paper size 剌 + customs standard; line - 90. 11. 2,000 -38 - 1298722 A7 B7 5. Invention description (37)

15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 where Rl is as defined above for the compound of formula (II) and r3 is an optionally substituted aryl or heteroaryl moiety such as The definition of a compound. Method of treating a compound of formula (I) and (la), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the prophylaxis or treatment of any disease state in a human or other mammal, by which Mammalian cells, such as but not limited to single cells and/or macrophages, are aggravated or caused by excessive or unregulated cytokine production. For the purposes herein, the compounds of formula (I) and (la) will be referred to collectively as compounds of formula 1, unless otherwise indicated. · The compounds of formula (I) are capable of inhibiting pre-inflammatory cytokines such as IL4, IL-6, IL-8 and TNF and are therefore useful in therapy. IL-1, L_6, IL_8 and the meeting will affect a wide variety of cells and tissues, and these cytokines and other white blood cells, and cytokines are important and critical for many disease states and symptoms. Inflammatory mediator. The inhibition of these pre-inflammatory cytokines is beneficial to control, reduce and alleviate many of these disease states. Accordingly, the present invention provides a method of treating a disease mediated by cytokines comprising administering an effective cytokine interference amount of a compound of formula 1 in an acceptable amount. 90. 11. 2,000 (Please read the notes on the back and fill in this! *-&gt;, Order: -Line -39 1298722

V. INSTRUCTIONS (38) 15 The Department of Intellectual Property's Intellectual Property Bureau, the Bayer Consumer Cooperative, printed 20 compounds of formula (1) capable of inhibiting inducible pre-inflammatory proteins, such as 'also known as many other names, such as prostaglandin intrinsic peroxide synthesis ^2 (PGHS-2), and therefore available for treatment. Cyclooxygenase (c〇) pathway: These pre-inflammatory lipid mediators are produced by the inducible c〇x_2 enzyme. Therefore, the regulation of COX-2, which is responsible for these products derived from arachidonic acid (such as prostaglandins), affects a wide variety of cells and tissues, which are important and critical inflammatory mediators for a wide variety of disease states and symptoms. body. The performance of coii is not affected by the compound of formula (1). This selective inhibition of c〇x_2 reduces or eliminates the tendency of ulcer formation associated with COX-1 inhibition, thus inhibiting the prostaglandins necessary for cytoprotection. Therefore, these pre-inflammations are beneficial to control, reduce and alleviate many of these diseases (4). It is worth noting that these inflammatory mediators, (iv) are prostaglandins, which are associated with pain, such as sensitization of pain receptors or edema. Therefore, this pain treatment includes treatment of nerve and muscle pain, headache, cancer pain and arthritis pain. The compound of the formula (1) or a pharmaceutically acceptable salt thereof can be used for prevention or treatment in human or other mammals by inhibiting the synthesis of the c〇x_2 enzyme. Accordingly, the present invention provides a method for inhibiting (3〇} (-2 synthesis, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is effective in the art. The present invention also provides a species in human or other A method for preventing treatment by a mammalian towel by inhibiting (10) 2 enzyme synthesis. In particular, a compound of the formula (I) or a pharmaceutically acceptable salt thereof can be used for preventing or treating any disease in humans or other mammals. = state, due to the cells of such mammals, such as but not limited to single cells and /

(Please read the notes on the back and fill out this page);p; line · 90. 11. 2,000 [298722

Excessive or unregulated 巨·^6,^8 or WF of macrophages is produced and aggravated or caused. ’ ‘ Therefore, on the other hand, the present invention relates to a kind of feeding in need? A method of inhibiting the production of E.1 -1 comprising administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt thereof. There are a number of disease states in which excessive or unregulated ILel production is associated with and/or causing the disease. It includes rheumatoid arthritis, osteoarthritis, meningitis, hemorrhagic and hemorrhagic stroke, nerve trauma / closed head injury, stroke, endotoxemia and / or toxic shock vine, two acute or chronic inflammatory Disease state, such as inflammatory reaction caused by endotoxin or inflammatory bowel disease, tuberculosis, atherosclerosis, muscle degeneration, multiple sclerosis, cachexia, bone loss, psoriatic arthritis, Lai's syndrome, gout Traumatic closure, inflammation, rubella arthritis and acute synovitis. Recent evidence is also linked to the activity of diabetes, pancreatic cell disease 15 and Alzheimer's disease. The use of CSAID to treat disease states mediated by CSBP may include, but is not limited to, neurodegenerative diseases such as Alzheimer's disease (as described above), Parkinson's disease, and multiple sclerosis.绖 部 犲 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( A method of inhibiting TNF production comprising administering to the mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Excess or unregulated TNF production, by medium or by exacerbation Diseases are associated with rheumatoid arthritis, rheumatic spondylitis, osteoarthritis, gouty arthritis and other arthritic symptoms, septicemia, septic shock,

The paper scale applies to the Chinese National Standard (CNS) A4 specification (21Q 297 297 public Chu) U· 2,〇〇〇

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, Printed 12,892,272 V. INSTRUCTIONS (4〇) Endotoxin Shock, Gram Negative Septicemia, Toxic Shock Syndrome, Adult Dyspnea Symptoms, Chronic Pneumonia Disease and Chronic Obstructive Pulmonary Disease, 矽Soil disease, pulmonary sarcoma disease, bone depletion disease (such as osteoporosis), heart, brain and kidney reperfusion injury, transplant response to host, allograft rejection, 5 fever due to infection with influenza Myalgia, brain infections' include encephalitis (including forms caused by HIV), cerebral malaria, meningitis, hemorrhagic and hemorrhagic stroke, infection or malignant recurrent cachexia, acquired immunodeficiency syndrome (AIDS) Sudden cachexia, AIDS, ARC (AIDS-related relapse), neoplasia, scar tissue formation, inflammatory bowel disease, Crohn's disease 10, ulcerative colitis and fever. The compounds of formula (I) are also useful in the treatment of viral infections, wherein such viruses are sensitive to upregulation by TNF or will be induced to be produced in vivo. The virus intended for treatment herein is either caused by the result of infection or is sensitive to inhibition, such as by directly or indirectly inhibiting replication by inhibiting the compound of formula 1 of TM17. Such viruses include, but are not limited to, HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus, and herpes group viruses such as, but not limited to, herpes zoster and herpes simplex. Thus, in another aspect, the invention relates to a method of treating a mammal having human immunodeficiency virus (HIV), comprising formulating an effective TMF inhibition amount for such a mammalian 20 (I) A compound or a pharmaceutically acceptable salt thereof. It is also clear that IL-6 and IL-8 are produced during rhinovirus (HRV) infection and can contribute to the onset of the common cold and worsen asthma associated with HRV infection (Turner et al. (I&quot;8 ), ciin_ Infec· Dis·, Vol. 26, p. 840; _— -42- The paper size is in Chinese National Standard (CNS) A4 specification (210 x 297 mm) 90. 11. 2,000 (please read first) A note on the back side of this page) a — — — — — — — I — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — ) Read the notes on the back and fill out this page.

Teren et al. (1997), AmJ Respir Crit Care Med, Vol. 155, p. 1362; Grunberg et al. (1997), AmJ^RespirCrit Care Med, 156: 609, and Zhu et al., J Clin Invest (I&quot;6), 97: 421) . It has also been demonstrated in vitro that infection of lung epithelial cells with HRV results in the production of IL-6 and IL-8 (Subauste et al., J. Clin. 5 Invest. 1995, 96: 549). The epithelial cell line represents the primary location of HRV infection. Accordingly, another aspect of the invention is a method of treatment to reduce inflammation associated with rhinovirus infection and does not necessarily have a direct effect on the virus itself. The compounds of formula (I) may also be combined with veterinary treatment in mammals other than humans in need of inhibition of TNF production. With regard to the treatment of TNF-mediated diseases in animals, either therapeutically or in a prophylactic manner, includes disease states as indicated above, but in particular viral infections. Examples of such viruses include, but are not limited to, lentiviral infections, such as equine infectious anemia virus, goat arthritis virus, sheep myelin shed virus or medivirus, or retroviral infection, such as but not limited to feline immunodeficiency virus (FIV), bovine immunodeficiency virus 15 or canine immunodeficiency virus, or other retroviral infections. The printed product of the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives, may also be used in a localized manner to treat or prevent local disease states that are mediated or exacerbated by excessive cytokine production, such as by individual IL-1 or TNF. Such as inflamed joints, eczema, psoriasis and other inflammatory skin conditions, such as sunburn; inflammatory eye symptoms, including conjunctivitis; 20 fever, pain and other symptoms associated with inflammation. Periodontal disease has also occurred in cytokine production in a local and systemic manner. Therefore, in such oral diseases such as gingivitis and periodontitis, the use of the compound of the formula (I) to control inflammation associated with cytokine production is another aspect of the present invention. -43 90. 11. 2,000 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives 1298722 V. INSTRUCTIONS (42) Compounds of formula (I) have also been shown to inhibit the production of IL-8 (interleukins, NAP). Thus, in another aspect, the invention relates to a method of inhibiting U production in a mammal in need thereof, which comprises administering to the mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. 5 There are a number of disease states in which excessive or unregulated IL-8 production is associated with exacerbation and/or causing the disease. These diseases are characterized by a large number of neutrophil immersion, such as psoriasis, inflammatory bowel disease, asthma, heart: brain and kidney reperfusion injury, adult dyspnea syndrome, thrombosis, and spheroid nephritis. All of these diseases are associated with increased work _8, which is responsible for the neutrophilic ball to the inflammatory site. In contrast to other inflammatory cytokines (IL-1, TNF, and IL-6), lL_8 has a unique property of promoting neutrophil tropism and activation. Therefore, inhibition of positive _8 production will result in a direct reduction of neutrophil erythrocyte immersion. The compound of formula (I) is administered in an amount sufficient to inhibit the production of cytokines, particularly ^^^ or 15 _), such that it is down-regulated to a normal level or, in some cases, to a level below normal, To improve or prevent the disease state. The abnormal content of IL-UL-MLA or TNF, for example, in the context of the present invention, constitutes: (I) free state (without cell binding or _ content, greater than or equal to 1 picogram per ml; (π) any Cells that bind to IL_i, IL· 20 6, IL·8 or TMF; or (in) IL_i, IL-6, IL-8 or TNF mRNA above the basal content present in cells or tissues, in which individual Produces sink-1, IL-6, IL-8 or TNF. The compound of formula (1) is a cytokine (especially a serotonin IL-8 and an inhibitor thereof, the discovery of which is based on the in vitro assay described herein)中,式(1) -44 - This paper scale applies to Chinese national standards (CNS dirty age gift) (Please read the note on the back and fill out this page) Order: Line 1129872 A7 B7 V. Invention Description (43 Ministry of Economics The property bureau's employee cooperative cooperative printed a compound for the production of IL-1, IL-8 and TNF. As used herein, the term 'inhibiting IL-1 (IL-6 JL-8 or TNF) production, the term means: Π a) Reduce the level of cytokine anal IL_6, IL_8 or excessive in vivo in humans to normal or normal levels by inhibiting Cytokines are released by all cells (including but not limited to single cells or macrophages); b) downregulate the excessive activity of cytokines (14^^ or TNF) in humans at genomic content Content, to normal or normal levels; c) down-regulation by inhibition of cytokine (IL1, IL-6, IL_8 or C. direct synthesis as a post-translational event; or d) at translational level, down Regulates cytokine (IL), H IL_8 or exogenous levels in humans to normal or normal levels. The term "disease or disease state" used in this article is used in this article. , in which TNF plays a role in any and all disease states, either by producing TNF itself, or by tnF causing another single-cell cytokine to be released, such as but not limited to sink-i, IL6 or IL-8 A disease state in which, for example, IL-1 is a major component, and its production or action is aggravated or secreted in response to TNF, and therefore, it is considered to be a disease by which it is mediated. The term "cytokine" means any being It is a 20-peptide that affects the function of cells and is a molecule that modulates the interaction between cells in immune, inflammatory or hematopoietic responses. Cytokines include, but are not limited to, monocytokines and lymphocytes. Cytokines, regardless of whether the cells are produced. For example, monocytokines are usually referred to as being produced and secreted by monocytes (such as macrophages and/or single cells). However, many other lines (please Read the precautions on the back and fill in this I.-). 15 45- No, I am using the China National Standard (CNS) A4 specification (210 X 297 public) 90. 11. 2,000 -- Line. 1298722 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention instructions (44) cells will also produce single-cell cytokines 'such as sputum killer cells' fibroblasts, basophils, neutrophils, endothelial cells, Brain astrocytes, bone marrow stromal cells, epidermal keratinocytes, and B-lymphocytes. Lymphocytes are usually referred to as being produced by lymphocytes. Examples of cytokines include, but are not limited to, interleukin-1 (IL-1), interleukokinin-6 (IL-6), interleukokinin-8 (IL-8), tumor necrosis factor. α (ΤΝρ_α) and tumor necrosis factor/5 (TNF-yS). As used herein, ''cytokine interference' or &quot; cytokine inhibition, the term, refers to an effective amount of a compound of formula (I) when administered to a patient for prophylaxis or treatment 10 over or under regulation When the cytokine is produced and aggravated or caused by a disease, it will cause a decrease in the in vivo content of the cytokine to a normal or normal level. As used herein, the cytokine referred to in the phrase "inhibition of cytokines for the treatment of HI v_infected humans" is a 15 cytokine associated with the following, (8) butyl activation Initiation and/or maintenance of action, and/or HIV gene expression and/or replication by activated T cells, and/or (9) problems associated with diseases mediated by any cytokine, such as cachexia or muscle deterioration. ' / The point (also known as lymphotoxin) has close structural homogeneity with TNF-α (also known as cachexia 2 scorpion toxin), and because it causes similar biological responses and binds to the same cellular receptor, TNF Both -α and TNF-/3 are inhibited by the compound of the present invention and are therefore collectively referred to herein as "TNF" unless otherwise specifically stated. Members of the MAP Kinase Group, or the 8 or version of CSBp, have been alone (please read the notes on the back and fill out this page).

90. 11. 2,000 1298722 A7 V. INSTRUCTIONS (45) 15 Printing by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives 20 The site was confirmed by several laboratories. This novel protein kinase is activated by double phosphorylation. It has been found in different cell systems when stimulated by a wide range of stimuli (such as physicochemical stress), and is expressed as lipopolysaccharide or pre-inflammatory cytokines, such as Interleukin hematostatin 4 and tumor necrosis factor treatment. The cytokine biosynthesis inhibitor of the present invention, a compound of formula 1, has been determined to be an effective and selective inhibitor of CSBP/p38/RK kinase activity. These inhibitors help to determine the signaling pathways involved in an inflammatory response. In particular, the first time, the explicit message transduction (IV) can be defined as the role of lipopolysaccharide in the production of cytokines in megatuber cells. In addition to the diseases already indicated, stroke, neurological trauma, cardiac and renal reperfusion injury, septic heart failure, coronary artery bypass graft (CABG) surgery, chronic renal failure, angiogenesis and related processes such as cancer, thrombosis, silk The treatment of spheroid nephritis, diabetes and pancreatic cells, multiple sclerosis, muscle degeneration, moist therapy, psoriasis, sunburn and conjunctivitis are also included. The CSBP inhibitor is then tested for anti-inflammatory activity in a number of animal models. The model system is selected to be relatively less sensitive to cyclooxygenase inhibitors to reveal the unique activity of the cytokine inhibitor. These inhibitors showed significant activity in many of these in vivo studies. Most notably, it is effective in the arthritis mode induced by collagen and inhibits TNF production in the endotoxin shock mode. In the later-mentioned study, the decrease in plasma content of _ was associated with survival and protection against endotoxin shock. It is also extremely important that the 7 compounds are effective in inhibiting bone loss in the long bones of the rat. Grisw〇ki et al. (19 Arthritis!^· 31 : 14〇6_1412; et al., (1989)^ 〇 〇 ^ 47- K paper-scale thorn towel @ @家标准(CNS)A4规格石〇χ 297 公爱)

tSI (Please read the notes on the back and then fill out this page | II - Suspect - Line - 90. Π. 2,000 1298722 ____ B7 V. Inventions (46) 15 20 61 ; Votta et al., (1994) in vitro. Bone 15, 533-538; Lee et al., (1993) · B Ann. NY Acad. Sd. 696, 149-170. Chronic disease with inappropriate angiogenic components, for various ocular neovascularization, such as diabetic patients Retinopathy and plaque degeneration. Other chronic diseases with excessive or increased vascular proliferation are tumor growth and metastasis, atherosclerosis, and certain arthritis symptoms. Therefore, CSBp kinase inhibitors block these. The vascular component of the disease state will be useful. The term "excessive or increased proliferation of vascular angiogenesis" is used herein, including but not limited to diseases characterized by hemangioma, and Department of Diseases. In this article, the term "inappropriate angiogenesis" includes, but is not limited to, diseases characterized by vesicle hyperplasia accompanied by tissue hyperplasia, such as cancer, metastasis, joints And atherosclerosis. = 'The present invention provides a method for treating a disease mediated by CSBP kinase in a mammal in need thereof, preferably =1, which comprises administering an effective amount to the animal. The compound of formula 1 or a pharmaceutically acceptable compound thereof is formulated into a pharmaceutical composition for use in the treatment of a compound of formula 1 or a pharmaceutical thereof - standard pharmaceutical practice. And comprising a compound of formula (I), and a pharmaceutically acceptable carrier or diluent, a pharmaceutically acceptable pharmaceutical composition, which may conveniently be deducted and deducted into the compound To administer drugs, for example, orally, for any means of administration, or by inhalation. (Please read the notes on the back and fill out this page) - -------- --- i line·

- I n n I ^ Zhang scale n n n I · 90. 11. 2,000 1298722 V. Description of the invention (47) Formal administration, which is carried out by combining the compounds of the formula (1). A parentally administrable compound, in a conventional dosage: 二: The procedure may involve mixing, granulating and combining the ingredients in a suitable manner to provide the desired preparation. It will be appreciated that the form and character of the pharmaceutically acceptable excipient or diluent will be governed by the activity, combination, and other conventional variables to be combined. The carrier must be "having" in the sense that it may be deleterious to the other ingredients of the formulation. The &lt;medicine carrier&apos; may be, for example, a solid or a liquid. For example, the solid interceptant is lactose. , kaolin, vegetable sugar, talc, gelatin, double fat, pectin, acacia, magnesium stearate, stearic acid, etc. Examples of liquid carriers are syrup, peanut oil, olive oil, water, etc. Similarly, _ or thin _ 15 20 may include the time-delayed substance of the art, such as glyceryl monostearate or glyceryl distearate, alone or accompanied by wax. It is known that a wide variety of f forms are used. If (4) is used, the preparation may be tableted, placed in a hard gelatin capsule in the form of a powder or pellets, or in the form of a lozenge or lozenge. The amount of solid carrier is varied widely, but preferably from about 25 mg to about 1 gram. When a liquid carrier is used, the preparation is in the form of a sugar feed, an emulsion, a soft gelatin capsule, a sterile injectable liquid such as an ampoule or a non-aqueous liquid suspension. The compound can be administered in a localized manner, meaning that it is This involves applying the compound of formula (1) to the epidermis or cheek cavity externally, and instilling the compound into the ear, eyes and nose, so that the compound-49- paper size is applicable to the Chinese National Standard (CNS). A4 size (210 X 297 public 90. 11. 2,000 1298722 A7

V. INSTRUCTIONS (48) I I I n 1 1 ϋ I _1 i_i ϋ mmm — ϋ · I mMM (please read the notes on the back and fill out this page) Do not enter the bloodstream significantly. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration. A formulation suitable for topical administration, including liquid or semi-liquid preparations suitable for penetration through the skin to an inflammatory site, such as a liniment, lotion, cream, ointment or 5 paste, and suitable for administration to the eyes, ears or nose. Agent. For topical two drugs, the active ingredient may comprise from 0.001% to 1% w/w, such as from 3% to 2% by weight of the formulation. However, it may constitute up to 1% w/w of the formulation, but preferably accounts for less than 5% w/w', more preferably 0.1% to. Lotions according to the present invention include those suitable for application to the skin or eyes. The eye 10 lotion may comprise a sterile aqueous solution, optionally containing a bactericide, and may be prepared by a similar method of preparing a drop. A lotion or 4 doses for application to the skin may also comprise an agent which accelerates drying and cools the skin, such as ethanol or acetone, and/or a wetting agent such as glycerin or an oil such as naring oil or peanut oil. Λ ^ / ♦ Ministry of Economic Affairs Intellectual Property Office Employees Consumption Cooperative Printed 15 The cream, ointment or paste according to the present invention is a semi-solid formulation of an externally applied active ingredient. It can be made by mixing the active ingredient in a finely divided or powder form, either alone or in a solution or suspension of an aqueous or non-aqueous fluid, by means of a suitable machine, with a greasy or non-greasy base. The base material may include hydrocarbons such as hard, soft or liquid paraffin, glycerin, bee bad 20, metal soap; pulp; oil of natural origin, such as almonds, corn, peanuts, hemp or withdrawal oil, sheep. A hair fat or a derivative thereof, or a fatty acid, such as stearic acid or oleic acid, and an alcohol such as propylene glycol or a macrogel. This formulation can be incorporated with any suitable surfactant, such as an anionic, cationic or nonionic surfactant, such as a phytosterol ester or its polyethylene oxide derivative-50 - This paper scale applies to the Chinese National Standard (CNS) ) A4 size (210 X 297 mm) '^ --- 90. 11. 2,0〇〇0 1298722 V. Description of invention (49 substances W float agent, such as sky ^ gum, cellulose derivatives, or inorganic substances For example, gluten-containing vermiculite, and other ingredients, such as lanolin, may also be added. According to the present day, _ may include water or oily impurities or suspensions, and may dissolve the active ingredient by bactericidal and / or a fungicide and / or any other suitable preservative and preferably in a suitable aqueous solution containing a surfactant. Then, the formed solution can be clarified by filtration, transferred to a suitable container 'then sealed and then Sterilize by performing the hot pot method or keeping it for half an hour. 2. Alternatively, the solution can be transferred to a container by sterilizing, and hunting, and the technology is suitable for adding bacteria to the drops. , 杈 ii ii (four) of the example ' It is mercury benzoate or phenylacetate (〇(8) attack), gasified benzylammonium oxide (〇.〇1%) and chlorhexidine acetate (〇〇1%). It is used to prepare suitable solvents for oily solutions. Including glycerin, dilute alcohol and propylene glycol. 15 The compound of formula (I) can be administered in a non-successful manner, that is, by intravenous, intramuscular, subcutaneous, intranasal, intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of administration are generally preferred. The appropriate form of such administration is in the form of T, and the compound of formula 1 can also be administered by inhalation, that is, by intranasal and oral administration. Appropriate dosage forms for such administration, such as aerosol formulations or metered dose inhalers, may be made by conventional techniques. hui Property Office staff consumption is for all methods of use of the compounds of formula (1) disclosed herein. Preferably, the daily oral dose is from about 01 to about 8 mg/kg body weight, preferably from about 0.2 to 30 mg/kg, more preferably from about 5 mg to about gram mg. The method of administration is about 1 to about 8 mg / kg 11. 2, 000 1 line This paper size applies to the Chinese standard (CNSM4 specification (10) x 29V^f

I 1298722 A7 B7 10 15 20 V. Description of the invention (50, body weight 2 is preferably from about 〇 to about 3 〇 mg/kg, and more preferably from about 5 gram to 15 mg/kg. Daily local dose service Preferably, the method is from 0.1 mg to 150 mg, administered daily to four times, preferably two or three times, daily inhaled dose, preferably from about 001 mg/kg to about ^mg/kg per day. It will also be apparent to those skilled in the art that the optimum amount and spacing of individual doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof, by the nature and extent of t, the form, route and location of administration, And treated; temple = disease, determined 'and this optimum value can be measured by conventional techniques. This artist should also understand that the most suitable treatment process, that is, the compound of the formula ω Or a pharmaceutically acceptable salt thereof, after a defined period of time = a conventional procedure in which a therapeutic assay can be used by the skilled artisan. The novel compound of formula (I) can also be used in combination with veterinary treatment, in a human (IV) or human Mammals are especially 疋 'in animals' by treatment or pre- Means for c:p/p38 vectors, including the disease states indicated in the treatment of J J, but especially viral infections. Two cases of this disease, including but not limited to lentivirus infection, such as = Transplanted enzymatic virus infection, such as rhinovirus (book =, / he; class 4, treatment due to human, parainfluenza virus, respiratory fusion cell virus or: disease paper size applicable to China National Standards (cns) A4 regulations * * * * 地11. 2,000 1298722 A7 Description of invention (51 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 sense: or respiratory virus infection 5 methods, the effectiveness of this method of CBSP / p38 inhibitor. / person The other side of the invention is a method for preventing pneumonia caused by influenza in need of human j. The human is administered an effective amount of a CBSP/p38 inhibitor. ΠΓΓ: ΠΓΓ / ρ38 kinase inhibitors in the treatment including prophylactic use 'the inflammatory line and human rhinovirus (_, other enterovirus, coronary disease 毋 sexy g virus, parainfluenza virus, respiratory fusion cell virus or adenovirus virus) Infection is associated In particular, the present invention is directed to the treatment of viral sensation in humans, and is a human 2 rhinovirus (HRV), other enterovirus, coronavirus, epidemic flu virus, parainfluenza virus, respiratory fused cell virus. Or adenovirus. In particular, the present invention is directed to respiratory viral infections, which aggravate asthma (because of this infection), chronic bronchitis, chronic obstructive pulmonary disease, otitis media, and sinusitis. Although inhibiting IL_8 or other Sputum cytokines may be beneficial in the treatment of rhinoviruses, which may be known, but the use of inhibitors of P38 kinase to treat HRV or other respiratory viral infections that cause general colds is novel. It should be noted that respiratory viral infections treated here may also be accompanied by secondary bacterial infections such as otitis media, sinusitis or pneumonia. For use herein, therapeutic treatment can include prophylaxis for use in a treatment group that is susceptible to such infection. It may also include reducing symptoms, improving symptoms, reducing severity, reducing the incidence, or any other change in the patient's symptoms, which may improve the outcome of the treatment. (Please read the precautions on the back and fill in this I.}.····'1 - Line · -53- This paper size applies to China National Standard (CNS) A4 specification (21Q X 297 mm) 90·11 2, 〇〇〇1298722 A7 V. Description of the invention (52 It should be noted that here the treatment is not aimed at eliminating or treating the virus organism itself, but for the treatment of respiratory virus infection, otherwise it will aggravate other diseases or diseases. Symptoms, such as asthma (caused by this infection), chronic bronchitis, chronic obstructive pulmonary disease, otitis media, and sinusitis. The best virus for treatment here is human rhinovirus infection (HRV) or respiratory fusion cell virus. The invention is described with reference to the following biological examples, which are merely illustrative, and are not intended to be construed as limiting the scope of the invention. Biological Examples The cytokine inhibition of the compounds of the present invention can be In vitro test: 15 20 A test for interleukolysin 1 (ΙΙ^ι), interleukocytokinin _8 (IL_8) and tumor necrosis factor (TNF) is used in this technique. Know, and can be found in many publications and patents A representative, suitable detection for use herein is described in Adams et al., U.S. Patent No. 5,593,992, the disclosure of which is incorporated herein in its entirety by reference in its entirety in Separation and purification of blood single cells, whether it is obtained from a fresh blood preparation of a volunteer supplier or a blood bank yellow layer, according to the procedure of c〇i〇tta et al., J Immunol, I32, 936 (Μ4). The cells were like ^), covering the 24-well plate at a concentration of 1-2 million/ml per well. The cells were allowed to adhere for 2 hours. After this time, the non-adherent cells were removed by gentle washing. Then, before adding the lipopolysaccharide (5 ng/g), add the test compound to the cells for 1 hour, and apply the culture to the Chinese National Standard (CNS) at 37 degrees. A4 size (210 X 297 mm) 90. 11. 2,000 A7 1298722 _ΕΤ_ V. Description of invention (53) 24 hours. At the end of this period, the culture supernatant is removed and the cells and all debris are removed. Clarification. Then, immediately test the IL-1 organism of the culture supernatant Activity, either by the method of Simon et al, J. Immunol. Methods, 84, 85 (1985) (based on IL-1 stimulation of interleukin-2 production cell line 5 (EL-4) to secrete IL-2 Ability, in combination with A23187 ionophore), or Lee et al, J. Immunol Therapy, 6 (1), 1-12 (1990) (ELISA). In vivo TNF detection: (1) Griswold et al., Drugs Under Exp, and Clinical Res.. XIX (6). 243-248 (1993); or 10 (2) Boehm et al., J. Med. Chem. 39, 3929-3937 (l&quot;6), the content of which is For reference herein. LPS-induced TNFa production in mice and rats To evaluate the inhibition of TNFα production by LPS- in vivo in rodents, mice and rats were injected with LPS. 15 The mouse method will be obtained from the males of the Charles River laboratory. “The mice are pretreated with compound or vehicle (30 minutes). After 30 minutes of pretreatment time, the rats are administered LPS intraperitoneally. (Lipopolysaccharide, obtained from E. coli serotype 〇55-85, Sigma Chemical Co., St Louis, MO) 25 μg/mouse in 25 μl of 20 phosphate buffered saline (pH 7.0). Two hours later, in C 〇 2 inhalation method to kill the mouse, and by bloodletting, collect the blood sample in the liver lipidated blood collection tube and store it on ice. Centrifuge the blood sample, collect the plasma and store at -20 ° C Until ELISA is used to detect TNFa as a soil. ___- - ____-- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 9〇. 11· 2,000 (please read the back Precautions Fill in this page again W-0 - Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1298922 A7 B7 V. Invention Description (54) Male Louise White Rats from Charles River Laboratory at different times Pretreatment with a compound or vehicle. After the pretreatment time, LPS (lipopolysaccharide Escherichia coli 055-85, Sigma Chemical Co., St Louis, M0) 3.0 mg/kg was administered intraperitoneally to the rats. The 5 C02 inhalation method was used. The dead rats were sacrificed, and 90 minutes after the LPS injection, the liver was collected from each of the rats by cardiac puncture, and the blood samples were centrifuged, and plasma was collected to analyze the TNFa content by ELISA. The ELISA method uses a sandwich ELISA to measure the TNF alpha content as described in Olivera et al, Circ. Shock 10 37, 301-306 (1992), the disclosure of which is incorporated herein by reference in its entirety, Mouse TNF Q (Genzyme, Boston, ΜΑ) was used as a capture antibody, and several rabbit anti-mouse TNFa (Genzyme) was used as a second antibody. For detection, a peroxidase-conjugated goat anti-rabbit antibody was added (Pierce, Rockford, IL), followed by the peroxidase (1 mg/ml 15 o-phenylenediamine, and 1% urea peroxide). The TNF a content in the plasma samples obtained from each animal was determined by the use of recombination. Produced by mouse TNF a (Genzyme) The standard curve is calculated. In the whole blood of humans, LPS-stimulated cytokine production is produced by the Ministry of Economic Affairs, Intellectual Property Office, and the Consumer Cooperatives. Printed test: The concentration of the test compound is made at a concentration of 10X, and the LPS is at 20 1 microgram. It was made at /ml (final concentration of 50 ng/ml LPS) and added to an L5 ml Eppendorf tube in a volume of 50 microliters. The human whole blood line of the liver liposuction was obtained from the healthy waist and distributed into the Eppendorf tube containing the compound and the volume of 0.4 ml, and the tube was cultured at 37 ° (: after 4 hours of culture) , the pipe fittings in the TOMY microcentrifuge, at -56- 90. 11. 2,000 (please read the notes on the back and then fill out this page) wide--line · This paper scale applies to China National Standard (CNS) A4 specifications (210 X 297 mm) 1298722 A7 B7 V. INSTRUCTIONS (55) Centrifuge at 5000 rpm for 5 minutes, extract plasma, and freeze at _80 ° C. Cytokines metric: standardized ELISA for sputum and / or TNF use Technical quantification. Use the ELISA kit for self-use to detect human IL-1 and TNF. Determine the IL-1 or TNF concentration from the standard curve of appropriate cytokines, and calculate the IC5 of the test compound by linear 5 regression analysis. Value (inhibition of 50% LPS-stimulated cytokine production). CSBP/p38 Kinase Assay: This assay measures 3 2 P from CSBP/p38-catalyzed transfer of [a-3 2 p]ATP to sulphate Residues, peptides of epidermal growth factor receptor (EGFR)-derived 10 with the following sequence (T669): KRELVEPLTPSGEAPNQALLR (residues 661-681) (see Gallagher et al., &quot;Pressure-induced cytokine production by regulation of bite-based feeding: inhibition of CSBP kinase”, BioOrganic & Medicinal Chemistry , 1997, 5, 49-64) The hydrazine reaction was carried out in a round bottom 96 well plate (available from Coming) in a volume of 30 ml. The reactant contained (expressed in final concentration): 25 mM Hepes, pH 7.5; 8 mM MgCl2; 0·17 mM ATP (Km[A τ p] of p38 (see Lee et al., Nature 300, n72, pp. 639-746 (December 1994)); 2.5 uCi of [g-32P] ATP; 0.2 mM sodium orthovanadate; ImMDTT; 0.1% BSA; 10% glycerol; 67.67mMT669 peptide; and 2_4 nM p38 expressed, activated and purified by yeast. Initiated by the addition of [r _ 20 32P]Mg/ATP The reaction was incubated for 25 minutes at 37° C. The inhibitor (dissolved in DMSO) and the reaction mixture were incubated on ice for 3 min before adding 32P-ATP. The final DMSO concentration was 0.16%. 1 〇 microliter of 0·3 Μ phosphoric acid, the reaction is terminated, and the phosphonylated peptide is isolated from the reactant by capturing it P81 cellulose phosphate filter on acyl. Apply the filter to the Chinese National Standard (CNS) A4 specification (21〇X 297 麓) on 57 paper scales. Read the notes on the back and fill out this page. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Employees' Consumption Cooperatives 90. 11. 2,000 15 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1297822 V. Inventive Note (56 75 mM phosphoric acid wash, and using the Lu scintillation counter, the incorporated 32p is set to 1. Under these conditions, the specific activity of p^8 It is 4〇(M5〇微微莫/微微摩尔酶, and the activity is linear. It reaches 2 hours of incubation period. The value produced when the substrate is not present (it is 1总数 of the total value) ] 5%) After subtraction, the kinase activity value was obtained. Representative final formulas (1) and (10) have been tested for examples 29, 31 to 35, 37 to 41, 43, 45 to 47, 60 to 65, 67 to 105, 107 to 109, 112 to 186, 188 to 193, 195 to 231, 233 to 239, 241 to 243, all of which have confirmed positive inhibitory activity in this binding assay, having Ι (: 5 〇 &lt; 1 〇 / ζΜ. Representative final formula (II) and (Ila) compound example m tested, here The positive inhibitory activity has been injected in the assay, with IC5() &lt;1〇"Μ. TNF_a in the detection of traumatic brain injury. This test is provided to experimentally induce lateral fluid to cause traumatic brain in rats. After TBI, check the expression of tumor necrosis factor mRNA in specific brain regions. Since TNF_a can induce nerve growth factor (NGF) and stimulate other cytokines to be released from activated astrocytes, In addition to post-injury changes in the expression of the TNF-[alpha] gene, it plays an important role in both acute and regenerative responses to CNS trauma. Suitable detection can be found in WO 97/35856, the disclosure of which is incorporated herein by reference. CNS damage pattern for IL-b mRNA This test will be performed in rats in the experimental lateral fluid after traumatic brain 4 (TBI), interleukin-1 (IL-1厶) in specific The regional manifestations in the brain region were characterized. The results from these tests showed that after TBI, the transient performance of IL-/5 mRNA was in the specific brain (please read the back of the note first. y·-. Order - 90. 1 1. 2,000 -58- 1298722 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (57 regional in a regional way $ stimuli. In the cytokines such as IL - call these regional changes, in Brain injury plays a role in post-traumatic pathology or regenerative sequelae. Suitable detection can be found in WO 9% 5%, the disclosure of which is incorporated herein by reference. Angiogenesis assay: The disclosure of WO 97/32583, the disclosure of which is hereby incorporated by reference, for the determination of inflammatory angiogenesis, which can be used to demonstrate that cytokine inhibition would cause excessive blood vessels or Tissue destruction of inappropriate proliferation stops. Rhinovirus/influenza test: Cell line rhinovirus serotype 39 and influenza virus a/PR/8/34 were purchased from the American Culture Type Collection (ATCC). The BEASJB cells were cultured according to the instructions provided by the ATCC using bEGM (branched tracheal epithelial growth medium) purchased from Ci〇netics. The HeLa cell culture for virus detection and titration is maintained in Eagle's minimal essential medium containing 10% fetal fetal serum, 2 mM 1-bromoamide, and 1 mM HEPES buffer (MEM).修正 A modification of this method, reported by Subauste et al. (supra), for the in vitro infection of human branch tracheal epithelial cells with rhinovirus, is used in these studies. BEAS-2B cells (2xl05 / well) were cultured in collagen coated wells for 24 hours prior to infection with rhinovirus. Rhinovirus serotype 39 was added to the cell culture, cultured at 34 ° C for one hour, then the inoculum was replaced with new medium, and the culture was incubated at 34 ° C for an additional 72 hours. The supernatant was collected 72 hours after infection, and the cytokine protein concentration 15 20 -59- was detected by ELISA using a commercially available kit (R&amp;D system) (please read the precautions on the back) Fill in this page 1) 1-SJ· ·-Line · This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 1298722 A7 B7 V. Description of invention (58) degrees. The virus yield was also determined from the supernatant of the culture using microtiter assays in HeLa cell culture (Subauste et al., supra, 1995). In cultures treated with the p38 kinase inhibitor, the drug was added 30 minutes prior to infection. A stock solution of the compound in DMSO (10 mM drug) was prepared and stored at -20 °C. To detect p38 kinase, cultures were cultured in minimal medium without growth factors and additives to reduce the endogenous content of activated p38 kinase. After the rhinovirus was added, cells were harvested at different time points. Phosphatidylinylation of tyrosine p38 kinase was detected by immunoabsorption, analyzed by commercially available kits, 10 and according to the manufacturer's instructions (PhosphoPlus p38 MAPK Antibody Kit: New England BioLabs). In some experiments, BEAS-2B cells were infected with an influenza virus (lines A/PR/8/34) instead of rhinovirus. At 48 and 72 hours post infection, culture supernatants were collected and tested for cytokines by ELISA as described above. 15 Cells and virus: Influenza A/PR/8/34 subtype HlNl (VR-95 American Culture Type Collection, Rockville, MD) was grown in the 10-day-old egg allantoic cavity. After incubating at 37 ° C and freezing at 4 ° C for 2 1/2 hours, the urinary fluid was collected, pooled and centrifuged (1, 〇〇〇rcf; 15 minutes; 4 ° C) to remove the cells. The supernatant was divided into several portions and stored at -70 °C. The titer of virus medium 20 was 1.0 x 101 G tissue culture infectious dose per milliliter (tcid50). Inoculation Procedures • Four- to six-week-old female Balb/cAnNcdBr mice were obtained from the Charles River (Raleigh, NC). Animals were infected intranasally. Glycolide (40 mg/kg; Fort Dodge Labs, Fort Dodge, la) was injected intraperitoneally with indole benzoquinone. Well (5 mg/kg; Miles, Shawnee Mission, Ks) makes the mouse paper 60 paper size applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). Please read the note on the back to order the Ministry of Economic Affairs Intellectual Property Bureau. Employees' Consumer Cooperatives Printed 90. 11. 2,000 A7 1298722 B7_ V. Inventions (59) (Please read the notes on the back and fill out this page.) Drunk and then dilute iPR821〇〇TCID5〇 in PBS to 2〇 Microliters were inoculated. Signs of infection were observed in each animal. All animal studies were approved by the Smith Kline Beecham Medical Society Animal Care and Use Committee. Virus Titration: Animals were sacrificed at different times after infection and collected in 5 sterile manners Lungs. Homogenize the tissue in a small vial containing 1 micron glass beads (Biospec product, Bartlesville, 0K) and 1 ml of Eagie's minimal essential medium. At l, 〇〇〇rcf, at 4 °C The cells were centrifuged for 15 minutes to remove cell debris, and the supernatant was continuously diluted on Madin_Darby canine kidney (MDCK) cells. At 37 ° C (5% c〇2), after 5 days of culture, 10 Add 50 μl of 0.5% chicken red blood cells per well and read the agglutination after 1 hour at room temperature. The virus titer is the tissue culture infection dose calculated by symbolic logic regression (TCID5〇) ELISA: cytokine content was quantified by Quantitative HLISA using commercially available kits. Ear samples were homogenized in PBS using small pieces of tissue. Line _ I5 Removed cell debris by centrifugation 5 minutes at 14, 〇〇〇 rpm. Determine the concentration and low limit of cytokines IL-6, IFN-r and KC (R&amp;D Systems, Minneapolis, MN) as described by the manufacturer. Department of Intellectual Property Office Staff Consumer Cooperative Printed Myeloperoxidase Assay: Myeloperoxidase (MPO) activity is measured kinetically as described by Bradley et al. (I982). In short, the rabbit angle 2 The ruthenium film was homogenized in hexadecyltrimethylammonium bromide (HTAB) (Sigma Chemical Co., St. Louis, Mo.), which was dissolved in Ο·5 Μ potassium phosphate buffer (JT Baker Scientific, Inc.). PhiUipsburg, NJ). After homogenization, the sample was subjected to freeze-thaw-sound vibration (Cole-Parmer 8853) , Cole-Parmer, Vernon Hills, II) 3 times. Then, under 12,5 〇 0 X g 'is 4 minutes at 4 c, by centrifugation, the suspension is ___-61 - 90. 2,000 paper scales are applicable to China National Standard (CNS) A4 specification (210 X 297 mm) A7 1298722 __ B7_ V. Invention description (6〇) &lt;Please read the notes on the back and fill in this paragraph 1.). Reacts with o-dianisamine dihydrochloride (ODI) 0.175 mg/ml (Sigma Chemical Co., St. Louis, Mo.) with 0.00〇2% hydrogen peroxide (Sigma Chemical Co., St. Louis, Mo.) During the period, the MPO enzyme activity was measured by a change in the colorimeter on the absorbance. The measurement was performed using a Beckman Du 5 640 spectrophotometer (Fullerton, Ca) equipped with a temperature control device. 50 microliters of the substance to be detected was added to 950 microliters of ODI, and the change in absorbance was measured at 460 nm for 2 minutes at 25 °C. Line - Whole body plethysmography: Influenza mice infected with influenza virus were placed in a whole body plethysmograph box with an internal volume of approximately 35 ml. A 10 liter/min bias air flow was applied to the box and the flow changes were recorded and recorded using the Buxco XA Data Acquisition and Respiration Analysis System (Buxco Electronics, Sharon, CT). Animals were acclimated to the environment in the plethysmograph box for 2 minutes prior to recording air flow data. Airway measurements are calculated using Penh (enhanced pause). Penh has previously been shown to be an index of airway obstruction and is associated with an increased 15 intrapleural pressure. The Penh calculation algorithm is as follows: Penh = [(expiration time / relaxation time) - 1] x (spike exhalation flow / spike inspiratory flow), where the relaxation time is required to 70% of the exhaled tidal volume The amount of time. The Ministry of Economic Affairs, Intellectual Property Office, and the Consumer Cooperatives printed the arterial oxygen saturation. The Nonin veterinarian with a tongue sensor was used to hold the 20-pulse oxygen meter 8500V (Nonin Medical, Plymouth MN), according to (Sidwell et al., 1992 Microbial agents and Chemotherapy 36: 473-476), daily measurements of arterial oxygen saturation % Sp02 〇 other data and test corrections, see PCT/USOO/25386 (WO 01 89322) filed on September 15, 2000 ), the content of which is based on its full text and is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) at this -62- 90. 11. 2,000 paper scale. 1298722 A7 k ( ___ B7_____ V. Description of invention ( 61) The following is a description of the present invention, which is intended to be illustrative only and is not intended to limit the scope of the invention. All temperatures are expressed in degrees Celsius, all solvents are The highest purity is obtained, and if necessary, all reactions are carried out in an anhydrous state and under Ar atmosphere. Mass spectrometry is operated in an open-channel LC-MS system using electrospray ionization. LC conditions Within 3.2 minutes, 4.5% to 90% CH3 CN (0·02 % TFA), 0.4 minutes of residence, and I·4 minutes of rebalancing; with MS, 10 UV at 214 nm, and light scattering detection Detector (ELS) detection. Column: Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative printed 1 X 40 mm Aquasil (C18) 1 H-NMR (hereinafter referred to as nNMRn) spectrum using a Bruker AM 400 spectrometer or Bruker AVANCE 400, recorded at 400 MHz. The multiplicity shown is: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br a broad signal. For preparation of 15 (prep) HPLC; approximately 5 mg of the final product was injected into 5 〇 0 μl of DMSO on a YMC CombiPrep ODS-A column with an internal diameter of 50 x 20 mm at 20 mL / At 10 minutes, use a 10 minute gradient from 10% CH3CN (0.1% TFA) to 90% CH3CN (0.1% TFA) in H2O (0.1% TFA) and stay for 2 minutes (unless otherwise stated). The chromatographic system is run on a Merck silicone 60 (230-400 mesh 20 mesh) in a solvent mixture containing different relative concentrations of di-methane and methanol, or EtOAc. And hexane, unless otherwise stated. Chromatotron chromatography (Desai, HK; Joshi BS; Panu, AM; Pelletier, SW J. Chromatogr. 1985 223-227) as previously described is available from Analtech (Wilmington). DE, USA) is operated on a chromatography plate. -63- 90. 11. 2,000 &lt;Please read the notes on the back and fill in the form!..&gt; One--Line - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) A7 1298722 B7______ V. INSTRUCTIONS (62) (Please read the notes on the back and fill out this page again w. satd = saturated; aq = aqueous solution; NMP = 1-methyl-2-tetrahydro 0 to 11 ketone; other abbreviations Both are described in the ACS Type Guidelines (American Chemical Society, Washington, DC, 1986).

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed 4-Nitro-2-methylthio-6-yl-amino----------------- </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> <RTIgt; Then, 4,6-dichloro-2-indolyl-pyrimidine-5-carboxaldehyde (1.11 g, 5 mmol) dissolved in anhydrous DMSO (20 ml) was added to the red solution [Santilli et al. 15 people, J. Heterocycl·Chem. 1971, 8, 445.45]. The reaction mixture turned yellow and was stirred at 23 ° for 2 h then EtOAc (250 mL). The liquid layer was separated; the organic layer was washed with a saturated aqueous solution of sodium chloride, dried (MgSO4) and filtered. The organic layer was evaporated, and the crude residue was crystalljjjjjjjjj The product was isolated by filtration and dried <RTI ID=0.0></RTI> tojjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1 H-NMR 5 2.59 (s, 3H), 7.21 (m, 1H), 7.44 (m, 2H), 7.68 (m, 2H), 10.37 (s, 1H), 11.38 (br s, 1H). LC MS (m/e) = 280 (MH+). Example 2 -64- 90. 11. 2,000 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1298722 A7 B7 V. Description of invention (63)

5 4- disordered-6-(2,6·dimer-phenylamino)-2-indolethio-p-denidine-5-nonanoic acid in 4,6-dichloroindolethio group- Pyrimidine _5. Carboxaldehyde (11.1 g, 5 〇 mmol) in CHCI3 (100 mL), 2,6-difluoroaniline (8.07 mL, 75 mmol, I·5 eq), This was followed by Et3N (10.43 mL, 75 mmol, 1-5 equivalent). The reaction mixture turned yellow and was heated to reflux for 10 hours, Η: Ο (5 mL) was added and the layers were separated. The organic layer was evaporated, and the crude product was recrystallized from 200 ml of decyl alcohol:H20 mixture (2:1) to obtain 12·3 g (76%) of pure 4-hydroxyl-6-(2,6-difluoro -Phenylamino>&gt;2-methylthio.pyrimidine-5-carboxaldehyde. 1 H-NMR: 5 2.21 (s, 3 Η), 6.91 (m, 2 Η), 7.24 (m, 1 Η), 10.29 (s , 1H), 10.35 (br s, 1H). LC MS (m/e) = 316 (MH+)· 15 Example 3 ·

(Please read the precautions on the back and fill out this page one). One-order.. Line - Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed 20 4-Methoxy-6-(2-chlorophenylamino)-2 - hydrazine-pyrimidine·5·carboxaldehyde was prepared as described in Example 1 above, starting with 4,6-dichloro-2·indolyl-pyrimidine-5-carboxyfurfural and 2-chloroaniline, and The title compound 4-isoyl-6-(2-chlorophenylamino)-2-methylthio-pyrimidine-5-carboxyfurfural was obtained. 1 H-NMR : 2.55 (s, 3H), 7.17 (m, 1H), 7.29 (m, 2H), 7.44 (m, 1H), 10.37 (s5 1H), 11.49 (br s, 1H). LC MS ( m/e) -65- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public) 90. 11. 2,000 A7 1298722 B7 V. Invention description (64) Example 4

izJL basal (2-gas _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The title compound 4-chloro-(2-fluorophenylamine 10-yl)-2-methylthio-pyridine-5-carboxyfurfural was obtained as the title compound. 1 H-NMR: 2·53 (s,3H),7 15 (4) 3H), 8.25 (m,lH), 7.44 (m,1H),10.31 (s,1H),11.35 (br s,1H)· LC MS (m/e ) =298 (MH+).

(Please read the notes on the back and then fill out this page. V Example 5

--Line - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 4 dichloro-6-(1-ethyl-propylamine V2-methyl-based-mouth α--5-propionic acid as in Example 2 above Preparation starting from 4,6-dichloro-t-methylthio-pyrimidine:carboxylic acid 20 aldehyde and 3·pentylamine to give the title compound 4-chloro-6-(1-ethyl-propylamino)- 2-Methylthiopyridine _5-carboxaldehyde. 1 H-NMR ·· 5 0·92 (t, 6H, J = 7.3 Hz), 1.50-1.74 (m, 4H), 2.52 (s, 3H), 4.22(m,lH), 9.21(brs,lH),10.33(s,lH)· LC MS (m/e) = 274 (MH+). Example 6 ___-66-___ ^The paper scale applies to the Chinese National Standard (CNS) ) A4 size (210 χ 297 mm) 90 n 1298722

V. Description of invention (65)

Aldehyde-pyrimidine-5., methylthio-field: starting from isopropylamine, the title compound 4: chloro-t-isopropylamino-carboyl-pyrimidine-5-carboxaldehyde was obtained. 1H-NMR: 3H)5 4.47 (m5 1H)5 9.16 (br s5 1H)5 i〇.25 (s, 1H). LC MS (m/e) = 246 (MH+). Example 7 (Please read the back first) Note the matter and fill in this I.--

Order: Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Alanine-pyrimidine _5_ Carboxylic Acid _ Prepared as described in Example 2 above, from 4,6-diox-2-indolethio-pyrimidine-5-carboxylate Starting with formic acid and cyclopropylamine, the title compound 4-chloro-cyclopropylamino-2-methylsulfanyl-5-carboxyfurfural was obtained.丨H_NMR: 5 〇68 machine 2H), 〇9 〇 machine 2H), 2.58 (s,3H), 3.07 (m,1H),9·20 (br s,1H),10.28 (s,1H)· LC MS (m/e) = 244 20 (MH+). Example 8 15

--Line · 67- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 90. 11. 2,000 1298722 V. Description of invention (66) Earth bis-butylamino thiol group - Pyrimidine-5-carbazide was prepared as described in Example 2 above, starting from the shirt, dioxin, thiomethyl-pyrimidine-methylcarboxaldehyde, and 2-butylamine, to give the title compound each second butylamine. Base gas base 2_methylthio-oroside _5_carboxaldehyde. 1 Η-ΝΜΚ ··占〇87 (m,3H), i 18 fine, 3H)9 1.20 (m? 2H), 2.51 (s5 3H), 4.24 (m, 1H)? 9.12 (br s, 1H)? 10.18 (s? 1H). LC MS (m/e) ~ 260 (MH+).

(Please read the precautions on the back and then fill in this section 1.&gt; One i. 15 4-Chloro-6-(cyclopropylmethyl-amine V2-methylthio) αα定_5_carboxy 曱Prepared as described in Example 2 above, starting from 4, bischlorochloroindolethioacridine ice carboxaldehyde and (aminomethyl)cyclopropane to give the title compound 1 chloro group (cyclopropylmethyl) -Amino)-2-methylthio" 唆5 曱5 曱 ,, 1 H-NMR: $ 〇32 (m, 2H), 0·59 (m, 2H), 1.12 (m, 1H), 2.55 (s, 3H), 3.46 (m, 2H), 9·35 (br s, 1H), 10.28 (s, 1H). LC MS (m/e) = 258 (MH+). Ministry of Economic Affairs Intellectual Property Office staff Printed by consumer cooperatives

H2n', n, s 4-amino-6-carbyl-2-methylthio-pyrimidine_5-carboxycarboxaldehyde in 4,6-diox-2-indolesulfanyl- mock. NHS gas was introduced in a solution of Ding-5-Jumbo (2 g, 7.36 mmol) in stupid (20 ml) for 30 minutes. Then, -68- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 9〇· 11. 2,000 1298722 V. Description of invention (67) Filter the solid formed: and from Et〇Ac (15 ml) was recrystallized to obtain 1.18 g (80%) of pure 4-aminosyl chloride·2·methylthio-pyrimidine^carboxyfurfural. Pupil NMR: (5 2.50 (s, 3H), 7·28 (t5 3H, J=45 Hz, D2 〇 exchangeable), 8 65 (d, 3H, J=41 Hz, D2 0 exchangeable), 10.11 (S, 1H)· 5 Example 11

(Please read the precautions on the back and fill in this I.).-·'·'' 15 Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Consumers' Cooperatives 20 2·Methylthio- 4-phenyl-6-phenylamino - Mouth bite - 5 - Born in 4-chloro-2-bromoindole-6-phenylamino-based Uscarboxaldehyde (3 mg, 1·〇7 mmol) in dioxane ( In a solution of 21 ml) and % Ο (7 ml), add anhydrous K: 2C03 (443 mg, 321 mmol, 3 equivalents) followed by phenyldihydroxyborane (196 mg, I·6 mmol) Ear,]j equivalent). The reaction mixture was degassed and hydrazine (triphenylphosphine) was added (61 mg, 〇 53 mmol, 0.05 eq.). Then, the reaction mixture was heated under reflux for 24 hours and cooled to 23. . The layers were separated, EtOAc (EtOAc)EtOAcEtOAc. Then, this yellow solution was evaporated. The product was purified by column chromatography or by crystallization from 10 mL of isopropanol:H20 (2:1) to give 24 mg (70% yield) of pure 2-methylthio-phenylphenyl-6-phenylamine. Base-pyrimidine-5_weicarboxylic acid. </ RTI> <RTIgt; e) = 322 (MH+). -69 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm). 90. 11. 2,000 - line. 1298722 A7 V. Description of invention (68) Example 12

Please read the instructions on the back of the preparation of 6-dioxo-phenylamine, ΗΙιΙΑ--2-methyl-stupyl V2-methyl hydrazine-pyrimidine carboxaldehyde, prepared as described in Example 11 above. Starting with a chloro group of (2,6-difluoro-phenylamino)-2-methylthio-pyrimidine-5-carboxyfurfural starting from 4-fluoro-l-methyl-phenyldihydroxyborane to give the title compound 4-(2,6-Difluoro-phenylamino)&gt;6-(4-fluoroylindoleyl-phenyl)-2-methylthio"melidine j carboxaldehyde. 1:6 by (s, Qiu ,Z25(5)3H),6·95 (m,4H),7.i8 (m,4H),9.54 (s,1H),10.29 (br s5 1H)· LC MS (m/e) re-fill in this page · 15 = 390 (MH+)· Ministry of Finance, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 20 Example 13

4-(1·By-propylamino)-6-(4-fluoro-2-methylindole-methyl)-2-methylthio-pyrimidine-5-carboxaldehyde was prepared as described in Example 11 above. From 4-chloro-6-(l-ethylpropylamino)-2-70- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 90· 11. 2,000 1298722 A7 B7 V. Inventive Note (69) Starting with thiol-pyrimidine·5-carboxaldehyde and 4-fluoro-furylphenyl dihydroxyborane, the title compound 4-(1-ethyl-propylamino)-6 was obtained. -(4-Fluoro-2-methyl-phenyl)-2-methylthiopyrimidine-5-carboxaldehyde. 1 H-NMR : 5 0·92 (m, 6H), 1.54-1.71 (m, 4H), 2.21 (s, 3H), 2·53 (s, 3H), 4.28 (m, 1H), 6.63-7.05 (m, 2H), 7.21 (m, 1H), 5 9.05 (br s9 1H), 10.50 (s, 1H). LC MS (m/e) = 348 (MH+). Example 14 &lt;Read the back Precautions Refill this I.〉. 15 4-(2-chlorophenyl)-6-(1-ethyl-propylamino V2-methylthio-pyrimidine-5-carboxaldehyde as described in Example 11 above Preparation starting from 4-chloro-(1-ethylpropylamino)&gt;2-methylthio-pyrimidine-5-carboxyfurfural and 2-chlorophenyldihydroxyborane to give the title compound 4-(2-chloro Phenyl)-6-(1-ethyl-propylamino)-2-sulfo-spray. D--5-decarbaldehyde. 1 H-NMR ·· 5 0.91 (m, 6H), 1.42-1.60 (m , 4H), 2.45 (s, 3H), 4.21 (m, 1H), 7.32 (m, 4H), 8.96 (br s, 1H), 9·44 (s, 1H)· LC MS (m/e) = 350 (MH+)· Example 15 Order: Line.

Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Cooperative, Printed 4-(2-Phenylphenyl)-6-(2-indolylamino)-2-methylthio-Binding-5-Lengjialing-71 - Ben The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) &quot;&quot;一·&quot; -- 9〇. 11· 2,〇〇〇1298722 A7 B7 V. Invention description (70) Prepared as described in Example 11, starting with 4-chloro-6-(2-phenylphenylamino)-2-methylthio-pyrimidine-5-carboxaldehyde and 2-phenylphenyldihydroxyborane, The title compound 4-(2-phenylphenyl)-6-(2-phenylphenylamino)-2-methylthio-pyrimidine-5-carboxaldehyde was obtained. 1 H-NMR : d 2.58 (s, 3H), 7.01 - 7.59 (m, 7H), 8.61 (d, 1H, J = 4.7 Hz), 9.65 (s, 1H), 11.48 (br s, 1H)· LC MS (m/e) = 390 (MH+). Example 16

($Read the back of the note and fill this IM in ml n- 15 4-(2-fluoromethyl)-6-(2-chlorophenylamino)-2-methylthio-pyrimidine-5-carboxaldehyde Preparation of 'from 4-gasyl-6-(2.sodium phenylamino)-2-methylthio-pyrimidine-5-carboxaldehyde and 2-fluorophenyldihydroxyboron as described in Example 11 above Starting from the alkane, the title compound 4-(2-fluorophenyl)-6-(2-chlorophenylamino)-2-methylsulfanyl-pyrimidine-5-carboxycarbox was obtained. 1 H-NMR: 5 2.60 ( s,3H),6.99-7.68 (m,7H),8.47 (d,1H,J=4.7 Hz), 9.78 (s,1H),11·59 (br s,1H)· LC MS (m/e) = 374 (MH+). Example 17 _ line. Printed by the Consumer Intellectual Property Office of the Ministry of Economic Affairs

4-Amino-6-(2-indolyl V2-methylthio-p-densin-5-rebellant was prepared as described in Example 11 above, from 4-amine gas base. Sulfur-pyrimidine-72- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 90· 11. 2, 〇〇〇1298722 A7 B7 V. Description of invention (71) Pyridin-5-carboxylate Starting from formaldehyde and 2-fluorobenzene; dihydroxyborane, the title compound amine group _6_(2-fluorophenyl)_2·decylthioguanidin-5-indenyl chain was obtained. 1 H-NMR : 5 2.59 ( s,3H), 5.78 (br s,1H),7.11-7.32 (m,2H),7.42-7.58 (m,2H),8.65 (br s, 1H),9.71 (s,1H)· LC MS (m /e) = 264 (MH+). 5 Example 18

4-(2-Acetyl-V6-isopropylamino-2-methylthio-p-dimethyl hydrazide, 5-boranate prepared as described in Example 11 above, from 4-chloroisopropylamine Starting from 2-ylthio-pyrimidinecarboxyfurfural and 2-fluorophenyldihydroxyborane, the title compound 4-(2-fluorophenyl)-6-isopropylaminosulfonylthio-pyrimidine was obtained. Carboxaldehyde. 1Η-15 NMR: 5 1.31 (d, 6Η, J=5.7 Ηζ), 2.56 (s, 3Η), 4·51 (m, 1Η), 7.05-7.31 (m, 2Η), 7·41- 7·55 (m, 2Η), 9·02 (br s, 1Η), 9·64 (s, 1Η). LC MS (m/e) = 306 (MH+). Example 19 (Please read the back note first) Please fill in this page again·0 Guang--Line. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print 20

±ΜΛΜΛ(2·Fluorophenyl)_2·Methylthio-pyrimidine-5-carboxaldehyde-73- 90. 11. 2,000 This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1298722 A7 B7 V. Description of the invention (72) Prepared as described in Example 11 above, from 4-a)-6-cyclopropylamino-2-methylthio-pyrimidine-5-carboxaldehyde and 2-fluorophenyl Starting from hydroxyborane, the title compound 4-cyclopropylamino-6-(2-fluorophenyl)-2-methylthio-pyrimidine-5-carboxyfurfural was obtained. 1 H-NMR : 5 0.66 (m, 2H), 0·92 (m, 2H) 2.60 (s, 3H), 3·11 (m5 1H), 7.10-7.30 (m, 2H), 5 7·41- 7·57 (m, 2H), 910 (br s, 1H), 9.66 (s, 1H)· LC MS (m/e) = 304 (MH+). Example 20

(Please read the precautions on the back and then fill out this page··-; - Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Print 4_(cyclopropyl decyl-amino)-6-(2-fluoromethyl V2_A Thio-pyrimidine-5-carboxaldehyde was prepared as described in Example 11 above, from 4-oxo-6-cyclopropylmethyl-amino-2-indolethio-pyrimidine-5-carboxaldehyde and 2 Starting with -fluorophenyldihydroxyborane, I5 title compound 4-(cyclopropylmethyl-amino)-6-(2-fluorophenyl)-2-methylthio-pyrimidine- 5-carboxyindole Aldehyde. 1 H-NMR : 3 0.34 (m, 2H), 0·61 (m, 2H), 1.19 (m, 1HX 2.56 (s, 3H), 3.51 (m, 2H), 7.11-7.27 (m, 2H) ), 7.31 - 7.52 (m, 2HX 9.22 (br s, 1H), 9·69 (s, 1H). LC MS (m/e) = 318 _+)· Example 21 20

74- This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 90. 11. 2,000 -- Line - 1298722 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description ( 73) 4-(2,6-difluoro-anthracene)-6-(2-fluoro-1yl)-2-methylthio-pyrimidine-5-carboxaldehyde

' &quot;&quot; ' I Prepared as described in Example 11 above, from 4-chloro-6-(2,6-difluoro-phenylamino)-2-methylthio-bend-5-carboxyl Starting with 2-fluorophenyl dipyridyl kiln, the super compound 4_(2,6--^ gas·n-ylamino)-6-(2_-phenylphenyl)-2·methylthiol was obtained.定定_ 5 5-carboxaldehyde. 1H-NMR: 3 .31 (s, 3H), 6.98-7.20 (m, 3H), 7.26 (m, 2H), 7.38-7.42 (m, 2H), 9·79 (s, 1H), 10.39 (br) s,1H)· LC MS (m/e) = 376 (MH+). Example 22

4_〇Fluorophenyl)-6-(2-Fluorophenylamino V2-oximethiotrim-5-weilic acid was prepared as described in Example 11 above, from 4-gasyl-6-(2 Starting from -fluorophenylamino)-2-15methylthio-pyrimidine-5-carboxaldehyde with 2-fluorophenyldihydroxydecane afforded the title compound 4-(2-fluorophenyl)-6-(2 -fluorophenylamino>&gt; 2-methylthio-pyrimidine-5-carboxaldehyde. 1 H-NMR: 5 .61 (s, 3H), 7.11·7·23 (m, 4H), 7.26 (m, 1H), 7.45-7.62 (m, 2H), 8.38 (m, 1H), 9·80 (s, 1H), 11.33 (br s, 1H). LC MS (m/e) = 358 (MH+). twenty three

-75- This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm). 90. 11. 2,000 words · (Please read the note on the back and fill in the page W-····'

A7 1298722 ____Β7 _ V. INSTRUCTION DESCRIPTION (74) 4-Second-butylamino-6-(2-fluorophenyl V2-oxime-pyrimidine-5-carboxyfurfural as described in Example 11 above Preparation starting from 4-second-butylamino-6-methyl-2-pyridyl-pyrimidine-5-carboxyfurfural with 2-fluorophenyldihydroxyborane to give the title compound 4-second- Butylamino-6-(2-fluorophenyl)-2.methylthiopyrimidine-5-carboxymethyl-5 aldehyde. 1 H-NMR : (5 0.96 (m, 3H), 1.30 (m, 3H), 1·67 (m, 2H), 2.58 (s, 3H), 4·38 (m, 1H), 7.11-7.31 (m, 2H), 7.42-7.58 (m, 2H), 9.07 (br s, 1H) , 9.63 (s, 1H). LC MS (m/e) = 306 (MH+). Example 24

4-(4-Actyl-2-methyl-phenyl)-6-isopropylamino-2-indolethio-p--5-tresonic acid 15 Prepared as described in Example 11 above Starting from 4_glycol-6--isopropylamino-2-methylthio-pyrimidin-5-carboxyfurfural with 4-fluoro-2-methylphenyldihydroxyborane to give the title compound 4-(4-Fluoro-2-indenyl-phenyl)-6-isopropylamino-2-methylthio-pyrimidine-5-carboxaldehyde. 1 H-NMR : (5 1.31 (d, 6H, J = 5.7 Hz), 2.21 (s, 3H), 2.59 (s, 3H), 4.52 (m, 1H), 7·90-7· 15 (m, 2H), 7.18-7.25 (m,1H), 9.06 (br s,1H), 20 9.50 (s,1H). LC MS (m/e) = 320 (MH+). Example 25 (Please read the note on the back first) Please fill out this page again b--·-* Order: --Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

1298722 A7 B7 V. INSTRUCTIONS (75) All-cyclopropylamino-6-(4-fluoro-2-methyl-phenyl)-2-methylthio-glycin-5-carboxaldehyde as in Example 11 above Prepared from 所 _ _6_cyclopropylaminomethylthio-pyrimidine-5-carboxaldehyde and 4-fluoropyridylphenyldihydroxyborane to give the title compound 4-cyclopropylamino _6_(4_Fluoro.2-decyl-phenylmethylthio-pyrimidine_ 5-retinoic acid. 1 H-NMR : 5 0·69 (m, 2 Η), 〇94 (m, 2 Η), 2 23 (s, 3Η), 2 62 (s, 3Η), 3.14 (m, 1Η), 6·98 (m5 2Η), 7.20 (m5 1Η), 9·09 (br s, 1Η), 9.49 (s, 1Η). LC MS (m/e) = 318 (MH+). Example 26

(Please read the notes on the back and then fill out this page|&gt;&gt; 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 Red Cyclopropylmethyl-Amine)-6-(4-Gu. -Methyl hydrazine-stupyl)-2-methylthio-pyrimidine-5-carboxaldehyde was prepared as described in Example 11 above, from 4-methoxy group of cyclopropylmethyl-amino _ 2 曱 thio -pyrimidine-5-carboxaldehyde and 4-fluoro-2-indenylphenyldihydroxyborane starting to give the title compound 4-(cyclopropylmethyl-amino)_6-(4-fluoro-2- Mercapto-phenyl)-2-indolethiopyridine _5_carboxyfurfural. 1 H-NMR : ά 0.30 (m, 2H), 0.60 (m, 2H), 1.18 (m, 1H), 2.24 (s, 3H), 2.55 (s, 3H), 3.50 (m, 2H), 6.98 ( m,2H), 7.18 (m,1H), 9.21 (br s,1H), 9.50 (s,1H)· LC MS (m/e) = 332 (MH+). Example 27 _-77- This paper size applies China National Standard (CNS) A4 Specification (210 x 297 mm) 90. 11. 2,000 - Line · [298722 A7 B7

Read First Note 1 ^ Page 4-(4·Fluoromethyl-phenyl•fluoromethylamino-K2-methylthio-pyrimidine Carboxaldehyde is prepared as described in Example 11 above, from 4·Chlorine Starting with 6-(2-fluorophenylamino)_2-methylthio-pyrimidine-5-carboxaldehyde and 4-fluoro-2-methylphenyldihydroxyborane, the title compound Μ4-1-based is obtained. 2-Methyl-phenyl)-6-(2-fluorophenylamino)-2-indolethio-pyrimidine-5-carboxaldehyde. 1 H-NMR : (5 2.28 (s, 3 Η)·59 (s, 3H), 7.01 (m, 2H), 7·18 (m, 3H), 7.24 (m, 1H)5 8.42 (m, 1H) , 9.63 (s, 1H), 11·30 (br s, 1H)· LC MS (m/e) = 372 (MH+). Example 28

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, printed 20 butylamino-6-(4-fluoro-2-methyl-phenyl)-2-indolesulfide _5_weicarboxylic acid as in Example 11 above Prepared as described in the title, starting from 4_second-butylaminochloro- 2 sulfonyl-pyrimidine-5-carboxaldehyde and 4-fluoro-2-methylphenyldihydroxyboron Compound 4-First butylamino-6-(4-carbyl-2-indenyl-phenyl)_2_-78- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 90 . 2,000 [298722

V. INSTRUCTIONS (77) Methylthiopyrimidine _5-carboxaldehyde. 1 H-Nmr : 丨〇 2 (m, 3H), 丨 3 〇 (m, 3H), 1·70 (m, 2H), 2·28 (m, 3H), 23⁄4 (s5 3H), 4.37 ( m,1H), 6.98 (m, 2H), 7.20 (m, 1H), 9.04 (br s, 1H), 9.50 (s, 1H)· LC MS (m/e) = 334 (MH+)· Example 29

U-thio-4,8-diphenyl·8Η-ρ ratio bite and r2,3_dlp close bite-7_ketone 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 make IS-crown-6 ether (422 mg,丨·6 mmol, 5 equivalents) with bis(2,2,2·trifluoroethyl X-methylmethylmethyl) sulphate g (81 μL, 〇·3 § millimoles, 丨 2 equivalents The solution in anhydrous THF (20 mL) was cooled to _78. To this solution was added potassium bis(dimethyl sulphate)amine (0.96 ml, 〇·48 mmol, 1.5 eq.) to make a 0.5 molar solution in toluene. This solution was taken at _7g. After stirring for an additional 3 minutes, 2-methylthiopiperidinyl phenylaminopyrimidine-5-carboxaldehyde (102 mg, 〇·32 mmol) in anhydrous THF (1 mL) was added dropwise. The reaction mixture was then stirred at -78 for 8 hours and warmed to 23. And stirred for 16 hours. A saturated aqueous solution of NI^Cl (5 mL) was added followed by diethyl ether (2 mL). Separate the liquid layer. The organic layer was washed with aq. aq. EtOAc (EtOAc EtOAc (EtOAc). Pure 2_Methylthio_4,8_diphenyl group _pyrazine and [2,3_d]pyrimidin-7-one. 1 H-NMR 6 2.19 (s, 3 Η), 6.70 (d, 1 Η, J=9.9 Ηζ), 7.26 (m, 2Η), 7.42-7.83 (m, 8Η), 7.88 (d, 1Η, J=9.9 Ηζ), LC MS (m/e) = 346 -79- This paper size applies China National Standard (CNS) A4 Specification (210 x 297 mm) 90. 11. 2,000 1298722 A# __ _ B7 V. Description of Invention (78) (MH+)· Example 30

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printing Sister-Difluoroi-Benzylamino)-6-Zhuangshiji 2,2-Methyl-Stupyl)_2_Methylthio-Minyl 10 pyridine_5_ Base 1-ethyl acrylate in a solution of triethyl sulfonate triacetate (8.18 ml, 41.3 mmol, 2 eq.) in 120 mL of dry THF, NaH (2 〇 5 g, in mineral oil) 60% dispersion, 5 L 4 mmol, 2.5 eq.) and the reaction mixture was stirred at 23 ° for 30 min. To this solution was added 4_(2,6-difluoro-phenylamino group μι5 (4-fluoro-2-methyl-phenyl)·2-methylthiol bite_5_carboxymethyl tour (8 g) , 20.65 mmol, which was prepared as a solution in 10 ml of anhydrous THF, and the reaction mixture was heated under reflux for 3 hours while being monitored by HPLC. After completion, 20 ml of a saturated aqueous solution of NH 4 C1 was added and the mixture was separated. The aqueous layer was washed with EtOAc (100 mL), and organic layer was combined. The organic layer was washed with &lt;RTI ID=0.0&gt;&gt; ML methanol: H20 (1:1) recrystallized to give 8. gram (88%) pure (E)-3-[4-(2,6-difluoro-phenylamino)-6-(4 Ethyl-fluoro-2-methyl-phenyl)-2-methylthio-pyrimidin-5-yl]-acrylate. LC MS (m/e) = 460 (MH+). Rt = 2.49 min. ___- 80-______ This paper size applies to the Chinese National Standard (CNS) A4 specification (210 297 297 mm) 90. 11. 2, 〇〇° 1298722 A7 V. Description of invention (79) Example 31

(6)-3-[4-(2,6-Difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylthio-pyrimidinyl]- Acrylic acid J (8 &gt; 1 g, 1 ? 6 mmol) was dissolved in % ml of anhydrous toluene. The reaction mixture was heated in a sealed tube at 22 ° C for 1 hour, and toluene was obtained, and the yellow residue was purified by flash chromatography to give 7 gram (%%) 8-(2,6- Fluorine-stupyl H-(4-fluoro-2-methylphenyl)_2-methylthio-8Η-15 pyridin. [2,3♦ 密-7-7. 1 Η-Chi (CDC13) 5 2·24 (s, 3Η), 2·29 (s, 3Η), 6.63 (d, 1Η, &gt;9·6 Ηζ), 7.03-7.20 (m, 4Η), 7·25 (m, 1Η) , 7.51 (m, 2Η); LC MS (m/e) = 414 (MH+). (Please read the notes on the back and then fill out this page j'-. I· -- Line. Ministry of Economic Affairs Intellectual Property Office staff consumption Cooperative printing example 32

Fluoryl)-2-methylthio-8H-pyridyl This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000

1298722 V. INSTRUCTIONS (8〇) in 4-(2-Phenylphenyl)-6-(2-phenylphenylamino)methylthiol_5-retinoic acid _ mg, 1.1€Moule) in bite ( In a solution of 2 ml), Ac2 (2 mL) was added, and the reaction mixture was heated under reflux for 48 hrs, solvent was evaporated, and the residue was dissolved in Et.sub.Ac (40 mL). The mixture was washed with H.sub.2 and saturated aqueous NaCl, dried (MgSO.sub.4), filtered and evaporated. The yellow residue was purified by flash chromatography to give pure bis(2-fluorophenyl)-2-methylthio-8H-pyrido[2,3-d]pyrimidinone (S2 〇 mg, %% ^ ^ H-NMR (CDC13) 5 2.21 (s, 3H), 6.76 (d, 1H, J = 9.6 Hz), 7.22-7.42 (m, 4H), 7,45-7.67 (m, 5H). LC MS (m/e) = 382 (MH+) 0 Example 33

(Please read the notes on the back and then fill out this page V i· 15

Cl

Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 M?-gas phenyl M-(2. fluorobenzene a V2_methylthio _8H-pyridinium hydrazine 2,3 ♦ pyridine ketone according to the above example 29 Prepared as described above, starting from ip fluorophenyl &gt; 6-(2-phenylphenylamino)-2-methylthio- cyano-5-carboxaldehyde, the title compound 8-(2- phenyl) 4-(2-Fluorophenyl)-2-methylsulfanyl-8H-indole. [2,3-φ-Bite-7-3⁄4.1 H-NMR δ 2.08 (s? 3H)? 6.61 ( d? 1H, J=9.7 Hz)? 7.11-7.51 (m5 9H). LC MS (m/e)- 399 (MH+) Example 34 ▲ 90. 11. 2,000 Paper Size Standards (CNS) A4 Specifications (210 X 2〗 7 K) 1298722 A7 B7 V. Invention Description (81) 15 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 20

H(2_lactophenyl- 8H) is pyridine and T2.3-dl azulene-7-_ prepared as described in Example 29 above, from hydrazine phenyl)_6_(2- phenylphenylamine Starting from 2-methylthio-pyrimidine_5-carboxaldehyde, the title compound 4,8_bis-(2-chlorophenyl)_2-methylthio-AH was obtained. Bisidine [2,3_d] shouts pyridine-7-one. 5ι·99 (s, 3Η), 6.50 (d, 1Η, J=9.7 Ηζ), 7·11·7·48 (m5 9Η)· LC MS (m/e) = 414 (ΜΗ+) Example 35

Gpropylmethyl-4-(2-indoleyl)-2-methylsulfanyl-8H-pyridoindole 2,3-dlpyrimidin-7-one was prepared as described in Example 29 above, from 4_( Starting with cyclopropylmethylamino)-6-(2-fluorophenyl)-2-methylsulfanyl-pyrimidine-5-carboxaldehyde, the title compound is obtained as the title compound </RTI> </RTI> <RTIgt; 2-Methylthio-8H-pyrido[2,3-d]pyrimidinone. 1沁NMR: 5 0.56 (m, 4H), 1·48 (m, 1H), 2.65 (s, 3H), 3.79 (s, 2H), 6.62 (d, 1H, J = 9.7 Hz), 7·19 -7.39 (m,3H)5 7.42-7.60 (m,2H). LC MS (m/e) = 342 (MH+) Example 36 -ft.?- This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 90. 11. 2,000 1298722 A7 B7 V. Description of invention (82

8-ring (2-fluorophenylpyridinium oxime 2&gt; dl pyrimidine-7-one was prepared as described in Example 29 above, from anthracycline _6_(2·fluorophenyl)_2_methylthio- Starting from pyrimidine-5-carboxaldehyde, the title compound 8_cyclopropyl_4-(2-fluorophenyl)_2·decylthio-8Η-π-pyridinium[2,3_d]^pyridine·7__.5〇. 98 (m, 2H), 1.35 (m, 2H) 2.69 (s, 3H), 3.02 (m, lH), 6.55 (d, lHJ = 9.6 Hz), 7.12 - 7.36 (m, 2H), 7.42 - 7.60 ( m,3H)· LC MS (m/e) = 328 (MH+)· Example 37 Please read the notes on the back and fill out this page. m 15

Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 8-second-butyl_4_(2_fluorophenyl)-:2-methylthio group than bite and 丨2,3-serving g-7-ketone Prepared as described in Example 29 above, starting from 4-bromo-butylamino-fluorophenyl)-2-methylsulfanyl-pyrimidine-5-carboxaldehyde to give the title compound. Winter fluorophenyl)-2-methylthio-8mb is precipitated [2,3-dp -7-嗣. 1 H-NMR : 6 0.91 (m, 3H), 1.67 (m5 3H), 2.00-2.42 (m, 2H), 2.69 (s, 3H), 5.85 (m, 1H), 6.79 (d, 1H, J = 9.7 Hz), 7.24-7.44 (m, 1H), 7.50-7.75 (m, 4H)· LC MS (m/e) = 328 (MH+) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297) 90. 11. 2,000 1298722 A7 B7 V. Description of invention (83) Example 38

Prepared as described in Example 29 above, starting from self-purity (2•fluorophenyl)_6•isopropylaminosyl-2-methylthio-pyrimidine j carboxaldehyde to give the title compound 'π fluorophenyl 8-iso Propyl-homylthio-8-pyrido[2,3_d]pyrimidinone. ! H-NMR : 5 (Please read the notes on the back and then fill in this 1&gt;-15.69 (m5 6H)? 2.60 (s, 3H)? 5.91 (m5 1H)5 6.52 (d5 13⁄4 J=9.6 Hz)? 7.16 -7.49 (m, 5H). LC MS (m/e) = 330 (MH+). Example 39

- Participated in the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, printed 20 propylmethyl-based _4-(4-fluoro-based, stupid, sulphate, sulphate, sulphate, pyridylpyrimidin-7-one, according to the above example Prepared as described in 29, starting from hydrazine cyclopropylmethylamino)-6(4-fluoro-2-methyl-phenyl)-2-methylthio-pyrimidinium carboxaldehyde, the title compound 8-ring Propylmethyl·4-(4-fluoro-2-methyl-phenyl>2_methylthio-cation-pyridyl[2&gt;d] This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 public) 90. 11. 2,000 15 1298722 B7 V. Description of the invention (84) Pyrimidine-7-one. 1 H-NMR : 6 0.55 (m, 4H), 1.56 (m, 1H), 2_23 (s , 3H), 2.67 (s, 3H), 4.40 (m, 2H), 6.60 (d, 1ΐΐ5 J=9.6 Hz), 7.05 (m, 2H), 7·22 (m, 1H), 7·39 (d , 1H? J=9.6 Hz). LC MS (m/e) = 356 (MH+). Example 40

10 β-cyclopropyl-4·(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl sigmaidine and “2 3_dl 碎口定-7-3⁄4)3⁄4 Preparation of 'from 4-3⁄4 propylamino-6-(4-carbyl-2-methyl-phenyl)-2-methylthio-N-butyl-5-carboxycarboxylic acid to give the title compound 8_ ring Propyl-4-(4-carbylmethyl-benzyl)-2-methylthio-8Η-σ ratio bite [2,3-d] mouth. -7-brist. 1 H-NMR : 5 0.99 (m, 2H), 1.40 (m, 2H), 2.21 (s5 3H), 2.71 (s5 3H), 3.06 (m, 1H), 6.61 (d, 1H, J = 9.6 Hz), 7.02 (m, 2H) ), 7·24 (m5 1H), 7.34 (d, 1H, J = 9.6 Hz), LC MS (m/e) = 342 (MH+). Example 41 (Please read the note on the back and fill out this page)一一--Line· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 20

8-Taxis.: Butyl ice (4-fluoro-2-indolyl-phenyl)-2-methylthio--8H-pyridyl and "2丄Η] -86 - 90. 11. 2,000 sheets of paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1298722 A7 B7 V. Description of the invention (85 pyrimidine-7-one prepared as described in Example 29 above, from the second butylamine in winter Starting from 6-(4-fluoro-indenyl-phenyl)-2-methylthio-pyrimidine: carboxaldehyde, the title compound 8-di-butyl-ice (4-fluorocarbomethyl-benzene) was obtained. Base&gt;2.Methylthio-8沁pyridino[2,3_d] shouting -7·_.1 Η·Ν]He: (4)·89 (m,3H),17〇(m,3H),2 Grab 2 42 (m, 2H), 2.21 (s, 3H), 2·65 (s, 3H), 5.80 (m, 1H), 6.61 (d, 1H, J = 9.7 Hz), 7.03 (m, 2H) , 7·24 (m, 1H), 7.39 (d, 1H, J=9.7 Hz) · LC MS (m/e) = 328 (MH+). Example 42 Read the back Φ note and fill out this page... w Set 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Print 4-(4-Fluoro-2-indenyl-phenyl)-8-isopropyl-2-indolyl-----bit and "2, 3-(1|. Miso--7-one) Prepared as described in Example 29 above, from 4-(4.fluoroindolyl) Starting from the title of isopropyl-6-isopropylamino-pyrimidine-5-carboxaldehyde, the title compound 4-(4-fluoro-2-methyl-phenyl)-isopropyl-2-yl Thioyl-8Η-pyrido[2,3-d] mouth bite 7-ketone. 1 H-NMR : 51.68 (m, 6H), 2.21 (s, 3H), 2.70 (s, 3H), 5.95 (m) , 1H), 6·60 (d, 1H, J = 9.6 Hz), 6.95-7.11 (m, 2H), 7.18-7.32 (m, 2H). LC MS (m/e 344 (MH+)· Example 43 line

-87- 90· 2, 〇〇〇 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1298722 V. Description of invention (86 A7 15

Difluorophenyl M-(2-fluorophenyl)_2-methylthio-8H-p is prepared as described in Example 29 above, from 4-(2,6). Starting with difluorophenylamino group &gt; 6-(2-fluorophenyl) 2-methylthio-pyrimidine-5-carboxaldehyde, the title compound 8_(2,6-fluoro-phenyl-M-(2-) was obtained. Fluorophenyl)-2-methylthio-8ίϋ σ定和[2,3-(1]°密定定-7-ketone. LC MS (m/e) = 400 (ΜΗ+)· Rt = 2.42 min Example 44

Read the note on the back and then I. Printed Li (2-chlorophenyl)-8-(1-ethyl-propyl)-2-indole--8H-吼 from the Intellectual Property Office of the Ministry of Economic Affairs 2.3 and "2.3-dl mouth bite-7-one was prepared as described in Example 29 above, from 4-(2-chlorophenyl&gt;6-(1-ethyl-propylamino)-2-methylthio Starting from pyrimidine-5-carboxaldehyde, the title compound 4-(2-chlorophenyl)-(1-ethyl-propyl)-2-methylthio-8H-pyrido[2,3-d]pyrimidine is obtained. -7 genera. 111-

NMR: 5 0.85 (m, 6H), 2·01 (πι, 4Η), 2·26·2·44 (m, 2H), 2.63 (s, 3H), 5.39 (m, 0·5Η), 5· 75 (m,0·5Η), 6.62 (br d,1H,J=9.6),7·31_7·60 (m,5H). LC MS (m/e) = 482 (MH+). Example 45 -88- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm). 90. 11. 2,000 1298722 A7 ——— _ B7 V. Description of invention (87)

1^-Fluoro 4methyl-phenyl V8··^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Starting from winter methyl phenyl)_6_(2-10 fluorophenylamino)&gt; 2-methylthio-pyrimidinecarboxaldehyde, the title compound 4_(4·fluoro-2-methyl-phenyl)-8-( 2-fluorophenyl)-2-methylthio-8H-pyrido[2,3-cy-mouth -7-one. 1 H-NMR (CDC13) 5 2.19 (s, 3H), 2.28 (s, 3H), 6.76 (d, 1H, J=9.6 Ηζ), 7·05 (m, 2H), 7.24-7.40 (m, 4H), 7·51 (m5 2H); LC MS (m/e 396 ( MH+) 15 Example 46 r (Please read the notes on the back and fill out this page) 1. Xiongding · Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative

2-methanesulfonyl-4-8-di-bump-8H_pyridine# f2.3-dl-pyrimidine-7-number in 2-indolethio-4,8-diphenyl-8H-pyridyl[2 ,3-d]pyrimidin-7-one C7〇mg, 0.2 ¢:mole) in a solution of dimethylacetate (5 ml), add 3-gas base over _____ -89-____ China National Standard (CNS) A4 Specification (21G X 297 public) A ' θΟίΓ^Τ -4. 1298722 A7 B7 V. Description of Invention (88) Oxybenzoic acid (109 mg, Oj millimol, 3 equivalents), and The reaction mixture was at 23. Stirring for 2 hours, evaporating the solvent, and purifying the yellow residue by flash chromatography to give 2-carbazinyl- 4,8-diphenyl-8H·吼 bite [2,3-d], Pyridin-7-one (55 mg, 71% yield). i H-NMMCDCU) 6 2.96(s,3H), 5 6·89 (d,1H,J==9·8 Hz), 7.26 (m,2H), 7.40-7.81 (m,8H),8.01 (d , 1H, J = 9.8 Hz), LC MS (m/e) = 378 (MH+). Example 47

<Please read the notes on the back and fill in this I..y •έ· Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed WAzigA Phenylmethane Hydrazine-based AH-pyridine and 2,3-dl-pyrimidin-7-one 4,8-bis-(2-hydroxyphenyl)-2-methylthio-8H-pyrido[2,3-d]pyrimidin-7-one (414 15 mg, 1 mmol) in CDC13 ( In a solution of 15 ml), 3_gas-based peroxybenzoic acid (549 mg, 3 mmol, 3 equivalents) was added, and the reaction mixture was at 23. After stirring for 5 hours, an aqueous solution of lMNa2CO3 (10 ml) was added, the layers were separated, and the organic layer was washed with EtOAc, dehydrated (MgS 〇 4), and solvent evaporated to give 4,8•bis-(2_ Phenylphenyl group &gt;2_methanesulfonyl-8H-pyridine and 20 [2,3_ά]σ^pyridin-7-one (550 mg, 89% yield). iH-NMRCCDCb) 6 3.15 (s? 3H) 5.96 (m? The weekly Chinese National Standard (CNS) A4 specification (21〇χ 297 mm) 90. 11. 2,000; line · 1298722

Minutes 5. Description of invention (89)

Prepared as described in Example 47 above, from 8-(2,6-difluorophenyl)-4#·fluoroyl 1 methyl-phenyl)·2·methylthio-8H-acridine [2, Starting from 3-d]pyrimidinium, the title compound 8-(2,6-difluoro-phenyl&gt;4_(4-fluoroylmethyl-phenyl)_2-methanesulfonyl-8H-bite was obtained. [2,3-d]pyrimidin-7-one. LCMS(m/e) = 446(Mm:).Iltu3 Example 49 (Please read the notes on the back and fill out this page)1" 15

--Line _ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 thief - (2-fluorophenyl)-2- cough _7_ ketone prepared as described in Example 47 above, self-identified double like stupid base) 2 Sulfur-based Η 8Η-吼 bite open [2,3_(four) bite _7__ start 'obtained title compound μ fluorophenyl)-2-methyl lysine-8Η-bite and [2,3♦ dense bite_7_嗣. π 414 (MH+).Rt = 1.96 minutes. Example 50 -91 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) 90. 11. 2,000 1298722

9〇· 11. 2,000 1298722 A7 B7 V. Description of invention (91

Fluorophenyl was prepared as described in Example 47 above, from 4-(2.fluorophenyl)-8-isopropyl 1methylthio-8H-pyrido[2,3-d]pyrimidin-7-one Initially, the title compound '(a•fluorophenyl)_8_isopropyl-2·methanesulfonyl·8H_pyridopyrimidinone was obtained. LC MS (m/e) = 362 (MH+)· Rt = 1.85 min. Example 53 (Please read the notes on the back and fill out this page again. 15

Ιδι Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed more: ring _. propylmethyl-4-(4-fluoro-2-pyrylmyl-methyl)-2-methane 碏醯8H-pyridyl [2,3-dl pyrimidin-7-one was prepared as described in Example 47 above, from 8-cyclopropylmethyl-4-(4-fluoro-2-methyl-phenyl)-2 Starting from thiol-8H-pyrido[2,3-d]pyrimidin-7-one, the title compound 8-cyclopropylmethyl phenyl (4-fluoro-2-methyl-phenyl)-2 was obtained. - Methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one. LC MS (m/e) = 388 (MH+)· Rt = 2·13 min. Example 54 -93- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 1298722

V. Description of invention (92)

(Please read the precautions on the back and then fill out this page j - prepared as described in Example 47 above, self-centering propyl propyl (4_fluoro-.2 fluorenyl phenyl) 2-methylthio Starting with -8H-pyrido[^-pyrimidinone, the title compound 8-cyclopropyl-4-(4-fluoro-2-_2-methyl-phenyl)2-methane hydrazino-8 pyridine was obtained. [2'3-d] Pyrimidine-7-one. LC MS (m/e) = 374 _+)· Rt = 179 min. Example 55 15 20

The Ministry of Economic Affairs, the Intellectual Property Bureau, the employee consumption cooperative, printed according to Lu Wen, as described in Example 47, from 8 second butyl o-fluoro-based 2_, soil-based)-2-methylthio. 3_d] bite _7_ ketone starts, the standard is obtained as a chemical substance 8-first butyl ketone (4_fluoroyl-2-methyl-phenyl) 2 methane sulfonyl ketone And [2,3 threatening bite-7-ketone. LC Ms (m/e) = 39〇(mh+) along =2 〇5 minutes. 90. 11. 2,000 -94- 1298722 A7 V. Description of invention (93) Example 56

Prepared in the preparation of 4-(4 rhyme · 2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Base_2_f burnt base ratio = [2,3-_ d LC Ms (m/e) = 376 (mh+) == minutes. Example 57

(Please read the notes on the back and then fill out this page T 15

0 --Line - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

• 95-yl-8H-pyridine #"2 丄Γ 嘧 按 按 按 按 按 按 按 按 按 按 按 按 按 按 按 按 按 按 按 按 按 按 按 按 按 按 按 2 2 2 2 2 2 2 2 2 2 3 The core ketone starts, and the title compound &(2,6-di-phenyl-&gt;4-(2-fluorophenyl&gt;2_methanesulfonyl-qing_〇[2,3 bonetight] is obtained. Acridine_7_ ketone. LC MS (m/e) = 432 (MH+)_ Rt = 2 〇 4 minutes. This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 public) _ 90. 11. 2 , 〇〇〇A7 B7 1298722 V. Description of invention (94) Example 58

Ο Ο Read the injection on the back _(2-Phenylphenyl)-8-(1-ethyl-propyl)-2-methyl calcination base-8H-p ratio ρ定和定·7·ketone Prepared as described in Example 47 above, from 4-(2-chlorophenyl)-8-(1-ethyl-propyl&gt;10 2·decylthio-8H-pyrido[2,3-d] Starting from pyrimidine-7·one, the title compound 4_(2-chlorophenyl)-8·(1-ethyl-propyl)-2-indole-stone-yttrium-δΗ-吼 was obtained. D. 7-ketone. 1^:]\48(11^) = 406 (with 1^+).1^=2.15 minutes. Example 59 | i· Page·

Ministry of Finance, Intellectual Property Bureau, Staff and Consumers Cooperative, Printed 20 4·(4_Fluoro- 2 -decyl-phenyl), fluorenyl-2-ylmethanesulfonyl _8H-pyridine hydrazine 2.3-lead Mouth -7-_ was prepared as described in Example 47 above, from '(4-Fluoro-m-methyl-phenyl)-t-(2-fluorophenyl)-2-methylthio-8H-pyridino[ Starting with 2,3-d]pyrimidin-7-one, the title compound 4-(4-fluoro-2-indenyl-phenyl)-8-(2-fluorophenyl)_2-methanesulfonyl-8H_- 96- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 1298722 A7 B7 V. Description of the invention (95 pyridine and [2,3-d]pyrimidinone; !^]^(111 meaning)=428(]^11+). See =2.〇4 minutes' Example 60

Please read the back first

B 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 2-(2-diethylamino-ethylamine oxime)_4,8_diphenyl-8H-pyridine# "2,3-dl pyrimidine-7-M A solution of the product of Example 46 (1 mg, 0·5 5 m), NMP (5 mL), and N,N-diethylethylenediamine (28 mg, Ο·% mmol, 5 eq.) The mixture was heated to 50 ° C. After 1 h, H2 EtOAc (EtOAc) (EtOAc (EtOAc) Evaporation of the solvent. Purification of the yellow residue by flash chromatography to give 2-(2-diethylamino-ethylamino)-4,8-diphenyl-8H-pyrido[2,3-d]pyrimidine-7 -ketone (21 mg, 89% yield). h-NMF^CDCb) δ 0.74-0.98 (m9 6H)5 2.28-2.56 (m? 8H)5 2.98 (br s? 1H)5 6.32 (d? 1H3 J =9.8 Hz)? 7.26 (m, 2H), 7.09-7.88 (m, 11H), LC MS (m/e) = 414 (MH+)· Example 61

Item Refill Page Standard Paper Size Applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) 90. 11. 2,000 1298722 A7 __ B7_____^ V. Description of Invention (96) 2-(2-Diethylamine -ethylamino-based V8-(2.6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl V8H-pyrido- 2,3-dl-pyrimidine &lt; ketone

The title compound was reacted with N,N-diethylenediamine by the procedure of Example 60 to give the title compound 2-(2-diethylamino-ethylamino)-8-(2,6- Fluoro-phenyl)-5 4_(4.fluoro-2-oxa-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one. 1 H-NMR (CDC13) δ 0.96 (m? 6H)5 2.24 (s5 3H), 2.50 (m, 6H)5 3.14 (m5 2H), 6.02 (br s, 1H), 6.36 (d,1H,J= 9.6 Hz), 7.08 (m, 4H), 7.24 (m, 2H), 7.49 (m, 1H)· LC MS (m/e) = 482 (MH+). Example 62 (Please read the notes on the back and fill in again) This page) one by one

Order: 15 4,8-bis-(2-phenylphenyl)-2-(2-diethylamino-ethylamino)·8Η-pyridoindole (11 pyrimidine-7-one) The product of Example 47 N,N-diethylenediamine, the title compound 4,8-bis-(2-phenylphenyl)-2-(2-diethylamino-ethylamino)- 8H·pyrido[2,3-d]pyrimidin-7-one. 1 H-NMR (CDC13 ) (50.97 (m, 6H), 2.49 (s, 20 6H)? 3.12 (m? 2H)? 6.00 (br S5 1H)5 7.18-7.63 (m9 9H). LC MS (m/e) = 482 (MH+). Example 63 ___ - 98 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) --Line _ Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1298922 A7 B7 15 V. Invention Description (97)

5 M2-Phenylphenyl&gt;2-(2"diethylamino-ethylamine)-4-(2-fluorophenyl)-8Η·pyridine# H d~|唆唆-7·ketone a) 8 -(2-Phenylphenyl)-4-(2-fluorophenyl)-2-methanesulfonyl-8-H-pyrido[2,3-d]pyrimidin-7-one as in Example 47 above Prepared as described above, starting from the product of Example 33 to give the title compound. b) 8-(2-diphenyl)-2-(2-diethylamino-ethylamino) 4-(2-fluoro Phenyl)-8-pyrido[2,3-d]pyrimidin-7-one was prepared as described in Example 6 above, starting from the product of Example 63 (8) to give the title compound 8-(2-chlorophenyl). )-2-(2-diethylamino)ethylamino)-4-(2-fluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one. 1 h_NMR (CDCi3) 5 0· &quot; (m,6H),2_49 (s,6H),3.16 (m,2H),6·03 (br s,1H),7.13-7.63 (m,9H). LC MS (m/e) = 466 (MH+). (Please read the notes on the back and fill out this page again: • έ· Line· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 20 Examples 64

G-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-_2-methyl-methyl)-2-(2-yl-1-yl-methyl-A QQ-90. 11. 2,000 paper scales are applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1298722 A7 B7 V. Description of invention (98 fluorenyl)-8 pyridine pyridine 丨 2J-dl pyrimidine-7-one on 8 -(2,6-monofluoro-phenyl)-4-(4-lacyl-2-methyl-phenyl)_2-methyl-sinter 醯 σ σ-pyrido[2,3_d]pyrimidinone (8〇 〇mg, I·8 mmol) in a solution of μmethyl-2-tetrahydrofuranone (8 ml), add serinol (819 mg, 9 mM '5 equivalents) and The reaction mixture was heated to 5 Torr. After 1 hour, hydrazine (20 mL) was added, followed by Et.sub.2 (20 mL) and Et.sub.2 (2 mL). The layers were separated. Washing, dehydration drying (MgS04) 'Filter and evaporate the solvent. Then, purify the yellow residue by flash chromatography to give 8-(2,6-difluoro-phenyl) ice (4-amino-2·A) Phenyl)-2-(2-hydroxy-1-methyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (750 g, 92% yield). 1 H-NMR (CDC13) (5 2.30 (s, 3H), 3.67 (m, 1H) ), 3.88 (m, 4H), 6.30 buckle s5 1H), 6.41 (d? IK, J=9.6 Hz) 5 7.08 (m5 4H)? 7.24 (m? 1H)? 7.31 (d, 1H? J=9.6 Hz ), 7.49 (m, 1H). LC MS (m/e) = 457 (MH+). Example 65 Read the first page of the first page of the book. 15 Printed by the Intellectual Property Office of the Ministry of Economic Affairs

4,8· Shame.-(L gas phenyl)_2_(2_hydroxy_1-鼗methyl-ethylamino)-8H-pyridine and f2,3-dl mouth -7-_ The product was reacted with serine, by the procedure of Example 60 to give the title compound 4,8-bis-(2·-phenylphenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)- -100- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public) 90. 11. 2,000 1298722 A7 B7 V. Description of invention (99) 8H-pyrido[2,3-d]pyrimidine _ 7 diketone. 1H-NMR (CDC13) 5 3·44 (m, 1H), 3·68 (m, 4H), 6.30 (br s, 1H), 6.48 (d, 1H, J = 9.7 Hz), 7.24 - 7.65 (m , 9H). LC MS (m/e) = 457 (MH+). Example 66

10 4-(2-Fluorophenylethyl-propyl)-2-(2-heptyl-1-hydroxymethyl-ethylamine V8H-pyrene (please read the back of the note first and then fill in this page)广# 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 pyridine and 2,3-dl pyrimidine-7-one to 4-(2-fluorophenyl)-8-(1-ethylpropyl)-2 - methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one and a solution of the amine, by the procedure of Example 60 to give the title compound 4-(2-fluorophenyl)·8 -(1-ethyl-propyl)-2-(2-hydroxy-1-hydroxymethylethylamino)-8H-port ratio [2,3-d]N- 7-ketooxime 1 H -NMR: 3 0·◎ (m5 0H), 1·32 (m, 4H), 1.90 (m, 2H), 2·32 (m, 2H), 3.71 (m, 2H), 4.24 (m, 1H) , 5.38 (m, 0.5H), 5.69 (m, 0.5H), 5.71 (brs, lH), 6.30 (brd, lH, J = 9.6), 7.13 (d, lH, J = 9.6 Hz), 7.30 -7.55 (m, 4H). LC MS (m/e) = 401 (MH+) Example 67

Setting -101 90. 11. 2,000 This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1298722 A7 _____B7 ____ V. Description of invention (100) 4-(2·Chlorophenyl Mil· Ethyl hydroxy cyanomethylamino) _8 pyridine pyridine and f2,3-dl pyrimidine-7-one The product of Example 58 was reacted with the serine alcohol by the procedure of Example 6 to give the title compound 4-( 2-Phenylphenyl)_8-(1)ethyl-propyl)_2_(2-hydroxylhydroxymethyl-5ethylamine)-8Η_σpyridinyl[2,3_d]pyrimidinone. 1 H-NMR : 〇·84 (m,6H), ..t (Please read the notes on the back and fill out this page) 1.91 (m, 2H), 2.32 (m, 2H), 3·02 ( m, 2H), 3.95 (m, 4H), 4·14 (m, 1H), 5·30 (m, 0·5Η), 5.52 (m, 0·5Η), 6·28 (br d, 1H, J=9.6), 6.40 (br s, 1H), 7.12 (d, 1H, 9.6 Hz), 7.30-7.58 (m, 4H)· LC MS (m/e) = 417 (MH+). Example 68

15 4_(2-fluorophenyl)_2_(2-hydroxy-1-hydroxymethyl-ethylamino) isopropyl _8 乩pyridin and 2,3-dl pyrimidine-7-one gives Example 52 The title compound 4-(2-fluorophenyl)-2-(2-hydroxysuccinyl-ethylamino)-8-isopropyl was obtained by the reaction of the title compound with EtOAc. -8H-pyrido[2,3-d]pyrimidin-7-one. 1 H-NMR : 51.54 (m, 6H), 3.80 (m, 20 4H), 4·11 (m, 1H), 5.75 (m, 1H), 6·19 (d, 1H, J = 9.8), 6 · 38 (br s,1H), 7.01-7.21 (m,2H), 7.30-7.49 (m,3H)· LC MS (m/e) = 373 (MH+). Example 69 __ - 102- This paper size applies China National Standard (CNS) A4 Specification (210 x 297 mm) --Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1298922 A7 ______ B7 V. Invention Description (101)

F

(Please read the notes on the back and then fill out this page) 8-Cyclopropyl-4-(4-fluoroyl-2-methyl-containing a V242-M-based small methylol-ethylamine V 8H-pyridine And f2,3-dl-pyrimidine-7-_ The product of Example 54 was reacted with a solution of the title compound of the compound of Example 60 to give the title compound 8-cyclopropyl-4-(4.fluoro-2-? Benzyl-phenyl)_2·(2-carboxamide 10 methyl-ethylamino)-8-pyrido[2,3-d]pyrimidinone. 1 H-NMR : (5 0.85 (m, 2H) ),1·28 (m,2H),2·11 (m5 3H), 2.79 (m,1H), 3.89 (m,4H), 4.16 (m,1H), 6.18 (d,1H,J=9_8) , 6.31 (br s, 1H), 6.85-7.14 (m, 4H)· LC MS (m/e) = 385 (MH+). Example 70

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, printed 20 8-cyclopropylmethyl-4-(2-indolyl)-2-d-based-1-one-methyl-ethylamine)_附_口 ratio The title compound, 8-3⁄4 propyl fluorenyl-4-(2-, was obtained by reacting the product of Example 50 with the serine in the procedure of Example 6A. Fluorophenyl)-2-(2-amino-1-methyl-ethylamino)-8H-pyridyl and [2,3-d]-b. 7-ketone. 1 H-NMR : 5 〇.4〇(m, sister), _-103- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 297 297 mm) — 90. 11. 2,000 A7 1298722 _ B7 _ V. INSTRUCTIONS (102) 1.25 (m, 1H), 3.89 (m, 4H), 4.13 (m, 3H), 5.75 (m5 1H), 6.30 (d, 1H, J = 9.8 Hz), 6.59 (br s , 1H), 7·08-7·48 (m, 5H). LC MS (m/e) = 385 (MH+).

10 g-_第_二_-butyl-4-(4-fluoroyl-2-indolyl-phenyl)-2-(2-hydroxy-1.hydroxymethyl-ethylamino-V8H-pyrene 『2,3-d~|Naphthyl-7-_ The product of Example 55 was reacted with the serine alcohol by the procedure of Example 60 to give the title compound. 2-methyl-phenyl)-2-(2-hydroxysuccinyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1 H-NMR : δ 0.80 15 (m,3Η),1·37 (m,3Η), 2.21 (m,3Η),2·73 (m,2Η), 3.96 (m,4Η),4·20 (m,1Η), 5.52 ( m,1H), 6.29 (m,1H), 6.59 (br s,1H), 6.91-7.40 (m,4H)· LC MS (m/e) =401 (MH+). Example 72 ·ϋ n 1 1 ϋ ·1 1 _1 n Ml am- m§MW I i_i - &lt;Please read the notes on the back and fill out this page: • Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

F

___ -__-104- 90. 11. 2,000 This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1298722 A7 B7 V. Description of invention (103) 4: (4-Fluoro-based_2· Methylphenyl)-8-(2-fluorophenyl-V2-(2--K-K-methyl-ethylamino)-8H-pyrido- 2,3-dl-pyrimidin-7-one gives Example 59 The product was reacted with a solution of the title compound of the title compound to give the title compound 4-(4-fluoro-2-indolyl-phenyl)-8-(2-fluorophenyl)-2-( 2-Phenyl-1-methyl-ethylamino)-N-. Ratio to [2,3-d] mouth bite-7-ketone. 1 H-NMR : (5 2.24 (s, 3H), 2.68 (br s, 2H), 3.42 (m, 1H), 3.61 (m, 4H), 6.30 (br s, 1H), 6.38 (d, 1H, J = 9.7 Hz), 7·02 (m, 2H) ,7·27 (m,5H),7.46 (m,1H)· LC MS (m/e) = 439 (MH+). (Please read the notes on the back and fill out this page) Example 73

15 m_(2_Denylphenyl)-2:(2-hydroxy-1-methyl-ethylamine-based V8H-pyrazine mdl Order: Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printed shouting -7-ketone The title compound 4,8-bis-(2-fluorophenyl)-2-(2.hydroxy-indole-hydroxyindole) was obtained by reacting the product of Example 49 with a solution of the title compound. Ethylamino)_8H-pyridyl[2,3_d]glycine-7- _.1 H-NMR: 3 2.91 (br s,2H),3·39 (m, 20 1H),3·55 ( m,4H), 6.05 (br s,1H),6·33 (d,1H,J=9.7 Hz), 6.21 (m,5H),7·39 (m9 4H). LC MS (m/e) = 425 (MH+). Example 74 line!· This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public) 90. 11. 2,000 1298722 A7 B7 V. Description of invention (104)

8-(2,6-Difluoro-phenyl)-4-(2-fluorophenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyridoindole 2,3 - dl-pyrimidin-7-one The product of Example 57 was reacted with a solution of the title compound (m. 2-(2-Phosyl-1-methyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1 H-NMR: 52.52 (brs, 2H), 3·45 (m, 1H), 3·60 (m, 4H), 6·28 (br s, 1H), 6.34 (d, 1H, J = 9.7 Hz ), 6.98 (m, 2H), 7.19 (m, 3H), 7.42 (m, 3H). LC MS (m/e) = 443 (MH+). Example 75 Read the back Φ of the note page 15

Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed 20 8-cyclopropylmethyl ice (4-fluoro-2-methyl-phenyl)-ylamino-ethylamine)-8H-pyridine and f2 , 3-dl-pyrimidin-7-one The product of Example 53 was reacted with the serine in the procedure of Example 6 to give the title compound 8-cyclopropylmethyl ice (2-fluorophenyl &lt; (2. Hydroxy small hydroxymethyl _ ethylamine) · 8 Η · bite and [2, 3_d) feeding.定·7_ ketone. 1 H-NMR: 0.46 (m, 4H), 1.32 (m5 IK), 2.18 (s3 3H), 3.31 (br s, 52H)9 3.89 (m, 4H)5 4.15 (m? 3H), 6.30 (d , 1H, J=9.8 Hz), 6.59 (bi: s, 1H), 6.97 (m, 2H), 7.19 (m, 2H). LC MS (m/e) = -106 - This paper scale applies to Chinese national standards (CNS) A4 size (210 x 297 mm) 90. 11. 2,000 1298722 A7 B7 k V. Description of invention (105) 399 (MH+). Example 76

(Please read the notes on the back and then fill out this page) 4-(4_Fluoromethylguanidinium-phenyl)-2-oxoyl-1-hydroxymethyl-ethylamine v8_isopropyl·8H_ Pyridine&gt;2,3-dl-pyrimidin-7-one 10 The product of Example 56 was reacted with the serine in the procedure of Example 60 to give the title compound. 2-(2-hydroxysuccinomethyl-ethylamino) isopropyl _8H" pyridine [2,3 melamine _7·_. 1 H-NMR : $丨 (m, 6H), 2·15 (m, 3H), 3·45 (br s, 2Η) 5 3·85 (m, 5H), 5.74 (m, 1H), 6 · 21 (d, 1H, J = 9.8 Hz), 6.36 (br s, 1H), 6.91-7.20 (m, 4H). LC MS (m/e) = 387 (MH+). 15 Example 77 Ministry of Economics Intellectual Property Bureau employee consumption cooperative printing

20 4,8·bisphenyl)per(2-diamino-ethylamino)-8H-indole and pq-glycine-7-one The product of Example 47 and N,N-dimercaptoethylenediamine By the procedure of Example 6, the title compound 4,8-bis-(2-phenylphenyl)-2-(2-dimethylamino)-B 107- is used in the paper. The Chinese National Standard (CNS) ) A4 size (210 X 297 public) 9〇. 11. 2,00〇1298722 A7B7 V. Description of invention (106) Amino)-8H-pyrido[Hd]pyrimidin-7-one (396 mg, 84%) Yield). 1^ NMR (CDC13) δ 2.02-2.34 (m, 8H), 3.05 (m, 2H)5 6.02 (br s5 1H)? 6.39 (d? 1H5 J=9.8 Hz), 7.24-7.62 (m, 9H)· LC MS (m/e) = 455 (MH+). Example 78

10 Μ·bis-ochlorophenyl)K hexahydropyridin-4-ylamino)_8H-mouth pyridine and IZ3-C11 pyridinium 2 Please read the following notes on the back of the page and fill in this page)t: 15 7- The ketone was reacted with the product of Example 47 and hexahydropyridinylamine by the procedure of Example 6 to give the title compound 4,8-bis-(2-phenylphenyl)-2-(hexahydropyridyl) Base)-8H-pyrido[2&gt;d]pyrimidinone. 1 H-NMR (CDC13) 5 U1 (m, 2H), 1·84 (m, 2H), 2.38 (m, 2H), 3·01 (m, 2H), 3·30 (m, 1H), 5.36 (s, 1H), 6.40 (d, 1H5 J=9.8 Hz), 7.20-7.62 (m? 9H). LC MS (m/e) = 466 (MH+). Example 79 Customs Bureau of Intellectual Property Office Cooperative printing 20

This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm). 90. 11. 2,000 1298722 A7 ___B7 __ V. Description of Invention (107) The product of Example 47 is treated with 1-mercaptohexahydropyridine The title compound was reacted by the procedure of Example 60 to give the title compound 4,8-bis-(2-phenylphenyl)-2-(1-methyl-hexahydropyridinyl)-8H-pyridine. [2,3-d]pyrimidin-7-one. 1 H-NMR (CDC13) 5 1.42 (m, 2H), 1.79 (m, 4H), 2.25 (s, 3 Η), 2·75 (m, 2H), 3·15 (m, 1H), 5·33 (s, 5 1Η), 6.39 (d, 1Η, J=9.8 Ηζ), 7·24·7·59 (m, 9Η). LC MS (m/e) = 480 (ΜΗ+). Example 80

(Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Print 4,8-bis-(2-gas-based)-2·(2-hydroxy-1-hydroxyindolyl- 1-methyl-ethylamino)-8H-pyridine # "2,3-dl pyrimidine-7-one The product of Example 47 and 2-amino-2-methylpropane 1,3. The title compound was reacted to give the title compound 4,8-bis-(2-chlorophenyl)-2-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylamino)-8H- Pyrido[2,3-d]pyrimidin-7-one 1 H-NMR (CDC13) 5 1·01 (s5 3H), 3·43 (m, 2H), 3.62 (m, 2H), 6.03 (br s , 1H), 6.41 (d, 1H, J = 9.6 Hz), 7.27-7.65 (m, 9H). LC MS (m/e) = 471 (MH+)· Example 81

_ - 109- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm). 90. 11. 2,000 lines · A7 1298722 V. Description of invention (108) 4,8_double-(2-·gas "Stem base"·2-(2-hydroxy-ethylamino)·8Η·pyridine total “2 3 bepyrimidin-7-one. The product of Example 47 was reacted with f-aminoethanol by the procedure of Example 6〇. The title compound 4,8-bis-(2-chlorophenyl)-2-(2-hydroxyethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one was obtained. 1 H-NMR ( CDC13) δ 3.17 (m, 2H), 3.48 (m, 2H), 5 6.08 (br s, 1H), 6.45 (d? 1H? J = 9.6 Hz) 5 7.26-7.67 (m? 9H). LC MS ( m/e) = 427 _+)· Example 82 Please read the back note first

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, 2-(2-_Amino-ethylamino) V4,8-bis-(2-aero-methyl-V8H-pyrido- 2,3-dl-pyrimidin-7-one The product of Example 47 was reacted with 1,2-diaminoethane by the procedure of Example 60 to give the title compound 2-(2-amino-ethylamino)-4 bis-(2- Phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one. 1 H-NMR (CDC13 ) 5 2·59 (m, 2H), 3·11 (m, 2Η), 5· 91 (br s,1Η), 6.40 (d,1Η,J=9.6 Ηζ), 7.25-7.61 (m,9Η). LC MS (m/e) =426 (MH+). Example 83 20

Γ«Ύ __110- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 line 1298872 A7 ___B7___ V. Invention description (109) "4,8-double_(2-氦-)-7-keto-7,8-dihydropyridyl 2,3-pyrimidin-2-ylamino-1-ethyl acetate, the product of Example 47 and ethyl glycinate, by The title compound [4,8·bis-(2-chlorophenyl)-7-keto-7,8-dihydropyridine [2,3_d]5 pyrimidin-2-ylamino] -ethyl acetate. 1 H-NMR (CDC13) 5 1·21 (m, 3H), 3.59 (m, 2H), 4·12 (m, 2H), 5·91 (br s, 1H), 6· 41 (m, 2H), 7.25-7.62 (m, 9H). LC MS (m/e) = 469 (MH+). Rt = 2.12 min. Example 84 (Please read the note on the back and fill out this page)

•N Cl o 15 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 20

Ilg-bis-(2. p-phenyl)-7.yl-7,8-dioxinpyridinium [Z3-dl-pyrimidin-2-ylamine 1 acetic acid in the product of Example 83 (2 mg, 〇· To a solution of <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The reaction mixture was at 23. It was stirred for 1 hour, then neutralized with 1 EtOAc, EtOAc (5 mL) The organic layer was washed with η 2 、, a saturated aqueous solution of NaCl, and dried (M.s.). This solution was transferred and evaporated to give the title compound [4,8-bis-chlorophenyl)- keto- -7,8-dihydroindole and [2,3-d]pyrimidin-2-ylamino] -acetic acid. LC MS buckle / e) = 441 Rt = 1.85 minutes. Example 85 -111 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) 90. 11. 2,000 A7

1298722 (Please read the notes on the back and fill out this page) 4_(2•Oxygen 遂·碁amine-ethylamine)-8-(1-ethylpropyl)-8H-pyry^^ 『2, 3-dl-pyrimidin-7-one The product of Example 44 was reacted with N,N-diethylethylenediamine by the procedure of Example 6 to give 4-(2-chlorophenyl)-2-(2) -diethylamino-ethylamino)-8-(1•ethyl·propanyl 10-)--"pyridyl[Hd)pyrimidine_7 gram mg, 8 % yield). Lc Ms (m/e) = 442 (MH+). Rt $ 1.77 minutes. Example 86

15 2-(2diamino-ethylamino)-4-(2-arginyl)-8-(1-ethyl-propyl)-8H-indole and 13-dl Ministry of Economic Affairs Intellectual Property Office employees The consumer cooperative prints the seal -7-ketone 20 and the product of Example 44 is reacted with I,2-diaminoethane by the procedure of Example 6 and the 2(2-amino-ethylamine) 4-(2-chlorophenyl)_8_(1-ethyl-propyl)pyridinyl[2,3-d]pyrimidin-7-one. 1^1^(111义)=386 (1^讲).玢=1.54 minutes. Example 87 -11P- 90. 11. 2,000 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1298722

V. Description of the invention (Chuan)

- pyridine _7-_ The product of Example 44 was reacted with mercaptoethanol by the procedure of Example 6 to give the title compound 4-(2-phenylphenyl)-8-(1-ethyl-propyl 2-(2-hydroxy-ethylamino)·8Η-bite and [2,3_d]pyrimidine '7 ketone. LC MS (m/e) = tear Rt = i 94 10 min. ------------· I I (Please read the notes on the back and fill out this page) Example 88

Order·--Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1: (2-Chlorophenyl)-8-(1-ethyl-propyl-based sulfhydryl-ethylaminopyridine and f2, 3_dl-pyrimidin-7-one The product of the shell of Example 44 is reacted with (R)-2-aminopropanol by the procedure 20 of Example (9) to give the title compound M2-carbophenyl)-8-ethyl- Propyl)_2-((R&gt;2-transyl sulfhydryl-ethylamino)·8Η-pyrridine and [2,3-d] -7-ketone. 1 H-NMR: 0.81 ( m, 6H), 1.30 (m, 2H), 1.96 (m, 2H), 2·36 (m, 2H), 3.71 (m, 2H), 4.25 (m, 1H), 5.31 (m, 0.5H), 5·56 (m,0·5Η), 5.71 (br s,1H), 6.26 (br d,1H,J=9.6), 7.12 (d,1H,J=9.6 Hz), 7.30-7.54 (m,4H) LC MS (m/e) = 401 (MH+)· Rt = -113- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 ^ love): -- 90. 11. 2,000

1298722 A7 __B7 V. Description of invention (112) 2.07 minutes. Example 89 Pyridine IZ3-dl-pyrimidine-7-one 10 The product of Example 44 was combined with L-methyl hexahydropyridinylamine by the s. Propyl)(1-methyl-hexahydropyridin-4-ylamino)_8 乩pyridyl[2,3-d]-pyridone. LC MS (m/e) = 440 (MH+)· Rt = 1.67 min. Example 90 (Please read the note on the back and fill out this page again&gt;&gt;

• Line - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 twist-chlorophenyl) each group - propyl hydrazine. _7,8_ dipyrazepam p 3♦ dimethyl 0 _ 1 ylamine 1 -Acetyl acetate 83⁄4 The product of Example 44 was reacted with ethyl glycinate by the procedure of Example 6 to give a compound [4-(2·chlorophenyl)·8-(1-ethyl- Propyl keto-7-hydrogen acridine [2,3-d]pyrimidin-2-ylamino]-acetic acid B. LCMs (m/e) = 429 --- - 114-_ Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 1298722 A7 V. Invention description (113) (MH+). Rt = 2.49 minutes

Please read the following article 15 Secret 6-diqi-phenylphenyl V2-(2·蕤-ethylamine V8H·pyridinium 2.3-dl pyrimidine-7-one to make the product of Example 48 with 2- The title compound 8-(2,6-difluoro-phenyl)4-(4.6-fluoro-2-indenyl-phenyl) was obtained by the reaction of the title compound. -Ethylamino)-8-pyridyl-Od]pyrimidinone. 1h-NMR (CDC13) occupies 2.26 (s, 3H), 3.18 (m, 2H), 3.53 (m, 2H), 3.70 (br s, 1H ), 6.21 (br s, 1H), 6.40 (d, 1H, J = 9.7 Hz), 7.09 (m5 4H), 7.21 - 7.65 (m, 3H). LC MS (m/e) = 427 (MH+). Fill in this page again

Rt = 1.96 minutes. Line Example 92

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 90. 11. 2,000 1298722 A7 ______J7___ V. Description of invention (114) An amine-based V8H-pyridine hydrazine Z3-dl sulfonium-7- The ketone was reacted with the product of Example 48 and 1-methylhexahydropyridyl yl amide as the title compound (8-(2,6-difluoro-phenyl)-4-(4- Fluoro-2-methyl-phenyl)-2-mercapto-hexahydrou-butyt-4-ylamino)-8H-indeno[2,3-d] mp 5 pyridine. 1 H-NMR (CDC13) 51.45 (m, 2H), 1.85 (m, 4H), 2.40 (s, 3H), 2·72 (m, 2HX 3·30 (m, 1H), 5·41 (m, 1H),6·38 (d,1H,J=9.7 Hz), 7.05 (m,4H), 7.29 (m,3H)· LC MS (m/e) = 480 (MH+)· Rt = 1.67 min Example 93 Read the back note and fill out this page.

15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 N-(7.:fS base: 4,8_diphenyl·7,8·dihydropyridinium and 丨2,3_dl caidin-2_ base) Add a NaH (8 mg, 2 mmol) in a solution of methotrexate (2 〇 0 mg, 2 mmol, 4 eq.) in DMF (2 mL). 6% by weight of the dispersion in the mineral oil, 4 equivalents), and the reaction mixture was stirred at 23 ° for 30 minutes. Add 2·甲烧石黄醯基·4,8_ diphenyl to bite and [2,3_d] 〇定_ 7-ketone (190 mg, 〇·5 mmol) in DMF (1) The solution in cc) and heat the mixture to 50. . After 1 hour, add (1 mL), then Ε^Ο (10 mL). The liquid layer was separated, and the organic layer was washed with saturated aqueous Na Na. Then, the yellow residue is purified by flash chromatography to obtain N-(7-keto-4,8-diphenyl 8_di-116 - 90. 11. 2,000 paper scale for Chinese national standard (CNS) A4 size (210 X 297 mm) 1298722 A7 4 i B7 _____________ V. Description of invention (115) Hydropyrido[2,3-d]pyrimidin-2-yl)-methyl sulfonamide (101 mg, 5丨% yield). 1H-NMR (CDC13) δ ίη (s9 3H)5 6.69 (d, 1H, J-9.8 Hz)? 7.31 (m? 2H), 7.59 (m,8H), 7.91 (d,1H,J=9.8 Hz) , LC MS (m/e) = 393 (MH+). Example 94

l〇N-[4,8-bis-(2-indolyl)-7-keto-7.8-dihydropyrido[2,3-dl-pyrimidin-2-oxane碏15 decylamine gave Example 49 The product was reacted by the procedure of Example 9; 3 to give the title compound [4,8-bis-(2-fluorophenyl)-7-keto-7,8-dihydropyrido[2,3]. Pyrimidin-2-yl]-methanthroxanthin sulphate. 1 H-NMR (CDC13) 2.81 (s, 3H), 6.66 (d, 1H, J = 9.6 Hz), 7·24 (m, 4 Η), 7·48 (m, 4H), 7.87 (d, 1H, J = 9.8 Hz), LC MS (m/e) = 429 (MH+). Rt = 1.84 min. Example 95 (Please read the notes on the back and then fill out this page 5·, --Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 20

l[4-(2-Fluotyl y8-isopropyl ketone-7,8-dihydropyridyl 2,3-d]%. _2_ yl 1-methane 醯 醯 -117- The paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇X 297 mm). 90. 11. 2,000 1298722 A7 B7 V. Description of Invention (116) The product of Example 52 was obtained by the procedure of Example 93. The title compound N-[4_(2-fluorophenyl)-8-isopropylketo-7,8-dihydroindole[2,3_d] is sprayed. [Determining] methanesulfonamide. 1 H-NMR ( CDC13) δ 1.68 (m,6H),3,52 (s, (m,1H),6.68 (d,lH,J=9.6 Hz), 7,21-7.61 (m,5H)_ LC MS (m/ e) = 377 5 (MH+). Rt= 1·83 minutes e Example 96

(Please read the notes on the back and then fill out this page. Μ Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Print N48-(2,6-Difluoro-Stupid)-4-(2-1 Stupid)-7-_ -7-7,8-dihydroindenoin nd~| Carcinoxime-2-yl-1-yl-furanyl amine The product of Example 56 was reacted by the procedure of Example 93 to give the titled. -[8_(2,6-difluoro-phenyl)-4_(2_-phenylphenyl----yldihydropi-pyrene and [2,3-d]pyridin-2-yl]- A hospital sulphate. 1 H-NMR (CDC13) 5 3.08 (s5 3 Η), 6.72 (d, 1H, J = 9.6 Hz), 7.20 (m, 2H), 7 · 39 (m, 3H), 7.74 (m,3H). LC MS (m/e) =447 (MH+)· Rt = 1.84 min. Example 97 20 丄/*vFxrF' *118* This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 90. 11. 2,000 1298722

V. DESCRIPTION OF THE INVENTION (117) N-[8-(2?6·二H基)·4·(^·Fluoro-indenyl-methyl)_7·ketone _ into 8-dipyridinium and The title compound N-[8-(2,6-fluoro-phenyl) was obtained from the titled compound from m. - 4-(4-Fluoro-2-indenyl-phenyl)-7-yl-7,8-di-5hydropyrido[2,3-d]pyrimidin-2-yl]·methane. 1H-NMR (CDCl3) accounts for 2.29 (s, 3H), 3·04 (s, 3H), 6.69 (d, 1H, J = 9.6 Ηζ), 7·16 (m, 4H), 7·59 ( m 3H) LC MS (m/e) = 461 (MH+). Rt = 1.90 min. Example 98

15 8-(2,6_diox-phenyl-on-indole 4·fluoro-2-t-methyl-stupid vr-methoxy _8h_ mouth bh π gold and IZ3-dl pyrimidine-7-one economic ministry wisdom Printed by the property bureau employee consumption cooperative (please read the precautions on the back and fill out this page|&gt; 2 in the product of Example 3 (9 grams, 0. 2 millimoles) in sterol 0 ml) In the solution, sodium decoxide (1 ml, 25% w/w solution in methanol, excess) was added. The reaction mixture turned yellow and heated under reflux for 2 hours, steamed 20 times, and added H2 hydrazine (5 ml) , then EtOAc (20 mL). EtOAc (EtOAc)EtOAc. 71 mg (83% yield) 8-(2,6-difluoro-stupyl&gt;4_(4-fluoroyl 1 fluorenyl)&gt;2_methoxy-8H-port ratio. ] Mouthidine _7_ ketone. 1 HJNfMR (CDCl3) 5 2·3 〇 This paper scale applies to China National Standard (CNS) A4 specification (210 χ 297 -------- 90. 11. 2,〇〇 〇1298722 A7 _ B7 V. Description of invention (118) (s, 3H), 3.82 (s, 3H), 6.61 (d jH, J = 9.7 Hz), 7.01-7.18 (m, 4H), 7.25 (m, 1H), 7.52 (m5 2H);. LC MS (m / e) = 398 (MH +) Example 99

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10 — —Standyl V2-ethoxy-4-(4-fluoro-2-methyl-methyl)-8H-pyridine #『2,3-dl-pyrimidin-7-one prepared by the procedure of Example 98 Using sodium ethoxide to give the title compound 8-(2,6-difluorophenylethoxybenzene (4-fluoro-2-methyl-phenyl)-8H-pyrido[2,3-d]pyrimidine -7- _.1H-NMR (CDC13) δ 1.26 (m, 3H), 2.30 (s, 3H), 4.22 15 (8), 2H), 6·60 (d, ·1Η5 J=9.6 Hz), 6.98-7.20 (m, 4H), 7i5 (m, 1H), 7·51 (m, 2H), LC MS (m/e) = 412 (MH+). Example 100 &lt;Please read the notes on the back and fill out this page ·0.·'·' -Line - Ministry of Economic Affairs, Intellectual Property Bureau, Bayer Consumer Cooperative Printed

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1 butyl aryl-8-(26_士氟-笨基)-4_(4-fluoro-2-methyl-styl-α---_- 190- This paper scale applies to Chinese national standards ( CNS) A4 size (210 χ 297 mm) 90. 11. 2,000 1298722 A7 V. Inventive Note (119) "2,3-d| Pyrimidine-7-_ Prepared by the procedure of Example 98, using sodium butoxide The title compound 2-butoxy-8-(2,6-difluoro-phenyl) ice (4.fluoro-2-methyl-phenyl)-8H-pyrido[2,3-d ]. 唆-7-_. iH-NMR (CDCl3) (m7 (m, 3H), 1.31 (m, 2H), 1.65 (m, 2H), 2·27 (s, 3H), 4·16 ( m, 2H), 6·58 (d, 1H, J = 9.6 Hz), 6.95-7.21 (m, 4H), 7.25 (m, 1H), 7.52 (m, 2H), LC MS (m/e) = 440 (MH+). Example 101 (Please read the notes on the back and then fill out this page ^::.·' -

15 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 20 M·2·: Phenyl phenyl MO fluorophenyl V2-f oxy-8H-pyridine and 2,3-dl pyrimidine-7-one according to Example 98 above Prepared as described above, from (E)-3-[4-(2-chlorophenylamino)-6-(2-fluorophenyl)-2-pyrenethio-pyrimidin-5-yl]-acrylic acid Starting with the ester and sodium methoxide, the title compound 8·(2·Phenylphenyl)-(2-fluorophenyl)-2.methoxy-8H-pyrido[2,3-d]pyrimidin-7-one was obtained. 1H-NMR (CDC13) 6 3.70 (s, 3H), 6.59 (d, 1H, J = 9.7 Hz), 7.01-7.20 (m5 3H), 7.40 (m, 2H), 7.56 (m, 4H); LC MS (m/e) = 382 (MH+). Rt = 2.24 min. Example 102

-191 . -Line - This paper size applies to China National Standard (CNS) A4 specification (210 χ 297 public) 90. 11. 2,000 1298722 A7 _ B7__ V. Description of invention (120) iig: double helium phenyl _2-helium-based-8H-bite and f2,3-dl-pyridin-7-one were prepared as described in Example 98 above, from (6) each [4-(2-phenylphenylamino)_6· Starting with (2-chlorophenyl)-2-methylthio-pyrimidin-5-yl]-decyl acrylate and sodium decoxide to give the title compound 4,8-bis-(2-chlorophenyl) from methoxy _8H 比 pyridine [2,3 ♦ pyridine 5 -7-one. 1 H-NMR (CDC13 ) 6 3.71 (s, 3H), 6.55 (d, lH, J = 9.6 Hz), 7.24-7.60 ( m, 9H). LC MS (m/e) = 398 (MH+). Rt = 2·27 min.

(Please read the precautions on the back and fill out this page. - Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, 8-(2,6-Difluoro-Momo-Icing (2-Fluoro-methyl-2-carbyl) -8H-pyrido 2,3-dl pyrimidin-7-one was prepared as described in Example 98 above, from (E)_3_[4_(2,6-difluoro-phenylamino)-I5 6- Starting with (2-fluorophenyl)-2-methylsulfanyl-pyrimidin-5-yl]-decyl acrylate and sodium methoxide to give the title compound 8-(2,6-difluorophenyl) winter (2-fluoro Phenyl)-2-methoxy-8H-pyrido[2,3-d]pyrimidin-7-one. 1 H-NMR (CDC13) δ 3.82 (s, 3H), 6.56 (d, 1H, : Ν9 · 6 Hz), 7.08 (m, 2H), 7.26-7.59 (m, 6H). LC MS (m/e) = 384 (MH+). Rt = 2.22 min. 20 Example 104

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____-122- This paper size applies to China National Standard (CNS) A4 specification (210 x 297 mm) 90. 11. 2,000 - line. 1298722 A7 B7 V. Description of invention (121) Ethyl-propyl) ice ( 4-Fluoromethyl-phenyl)-2-methoxy-8H-pyridine and "upper dl-pyrimidin-7-one" were prepared as described in Example 98 above, from (6) each [4 serv. ) each (4-fluoromethyl-phenyl)_2·decylthio-pyrimidine. Tomb of Dingshi]·Acetyl acrylate and sodium methoxide 5 start 'to get the title compound HI-ethyl-propyl) 4 · (4_fluoro-2-indolyl-phenyl)-2_methoxy acridine And [nd]pyrimidine _7-ketone. 1 (CDCl3) 〇·89 (m, 6H), 2.02 (m, 2H), 2.22 (s, 3H), 2.33 (m, 2H), 3.39 (m, 2H), 4.09 (s, 3H), 5 · 35 (m, 0·5Η), 5.62 (m, 0.5H), 6.41 (br d, 1H, J = 9.6 Hz), 7.03 (m, 2H), 7.28 (m, 2H). LC MS (m/ e) = 356 (MH+). Rt = 2.50 minutes. 10 Example 105 (Please read the notes on the back and fill out this page 3-15

• Line· Ketone Economics Department Intellectual Property Bureau Staff Consumer Cooperative Printed 90. 11. 2,000 4,g_dichlorophenyl)-2-(2-yl-hexyl-aryl)-8H-indole 丨2, 3-d&gt; 唆-7 - was prepared as described in Example 98 above, from (E) _3_|; 4-(2-chlorophenylamino)-6-(2-chlorophenyl)-2- Methylthio-pyrimidin-5-yl]-methyl acrylate and sodium glycolate start 20 to give the title compound 4,1 bis-(2-chlorophenyl)-2-(2-hydroxy-ethoxy )-8H-pyrido[2,3_d]pyrimidin-7-one. 1 H-NMR (CDCl 3 ) 53.8 l (m, 2H), 4.23 (m, 2H), 5.62 (m, 0·5 Η), 6·65 (d, 1H, J = 9.6 Hz), 7.29-7.58 (9H LC MS (m/e) = 428 (MH+). Rt = 1.85 min. Example 106 _;_ 123- This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 public) 1298722 A7 B7 V. Description of invention (122)

Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 5 4_Amino-6_(2-1 stupid V2-methylthio-hard bite_5_ sharp armor in the product of Example 17 (2Πmg, 1.07 milli In a solution of dioxane (21 ml) and H2 (7 ml), anhydrous K2C〇3 (443 mg, 3.213⁄4 mol, 3 equivalents) was added followed by 2-fluorophenyl The mixture was degassed (218 mg, 1.6 mmol, 1-5 equivalents). The reaction mixture was degassed and added with hydrazine (tris- 10 phenylphosphine) (61 mg, 0.053 mmol, 〇·〇 5 equivalents) , and heating under reflux for 24 hours, cooling to 23 Torr. The layers were separated. EtOAc (5 mL), EtOAc (EtOAc) (MgS 〇 4 ), the solvent was evaporated and the solvent was evaporated. EtOAc mjjjjjjjjj -Fluorophenyl)-2-methylthio guanidine-5-drum awake: 1 H-NMR 5 2.58 (s 3 Η), 5.80 (br s, 1 Η), 7.16 (m, 1 Η), 7.28 ( m,1Η),7·59 (m,2Η), 8.68 (br s,1Η), 9·71 (s,1H) LC MS (m/e) = 264 (MH+)· Rt = 1.89 min. Example 107 20 4-(2-fluoromethyl-V2-methylthio-8H-pyridindole 2,3-d. Make 18_ crown (422 homes, 1.63⁄4 m, 5 equivalents) with double (2 2 2- 2 gas-124-

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 love) &lt;Please read the notes on the back and fill in this page y ·# -^1· •Line 90. 11. 2,000 1298722 A7 V. Description of the invention (123) Ethyl)(methoxycarbonylmethyl)phosphonate (81 μL, 0·38 mmol, i 2 eq.) in anhydrous THF (20 mL) solution cooled to -78 〇 To a solution of 〇·5 mol in toluene, potassium bis(tridecyl decyl)amine (Ο% ml, 〇牝 millimol, I·5 eq.) was added. This solution was taken at _78. Stir for another 3 minutes, and add 4_amino-6-(2-fluorophenyl)_2-methylthio-pyrimidine j carboxaldehyde (8S mg, 0.32 mmol) in anhydrous thF (1). Solution in milliliters). Then, the reaction mixture was stirred at -78 ° for 8 hours and warmed to 23. And stirred for 16 hours. A saturated aqueous solution of ΝΗβΙ (5 ml) was added followed by shame (2 ml). Separate the liquid layer. The organic layer was washed with a saturated aqueous solution of Na.sub.1, dried (MgSO.sub.4), filtered and evaporated. The yellow residue was purified by flash chromatography to give 100% (yield: 91% yield) of 4-(2-fluorophenylmethylthio)-pyridine-pyridine [2 3 d]- Ketone. 1 H-NMR 5 2.62 (s, 3H), 6·55 (d, 1H, J = 9.9 Hz), 7.26 (m, 3H), 7·52 (m, 2H), 8.99 (br s, 1H) LC MS (m/e) = 288 (MH+)· Rt = 1.75 minutes. Example 108 15

(Please read the precautions on the back and then fill out this page y·'···' Order: --Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 base-2: methylthio-criminal-definitely Position 3♦ pyridine 7-ketone in 4-(2-fluorobenzyl)-2-sulfonyl _8Η·吼. and [2,3_φ 唆-7-one (120 mg, 0.42 m) In a solution of 20 ml of anhydrous THF, add NaH (5 g, I·2 mmol, 60% dispersion in mineral oil, 3 equivalents) followed by methane iodide (74 μm)升, 1.2 mmol, 3 eq.) The reaction mixture was stirred at 23 ° for 1 hour to saturate the aqueous solution of ΝΗ4α (2 〇 ml) to make the reaction -125- paper scale applicable to the Chinese National Standard (CNS) A4 specification. (21〇X 297 mm) 90. 11. 2,000 1298722 A7 B7 V. Description of invention (124) Quenching 'Add Et2 0 (100 ml) and separate the liquid layer. Wash the organic layer with saturated aqueous NaCl solution. Dry (MgS 4), filter and evaporate. Then, the yellow residue was purified by flash chromatography to give 1 mg (92% yield) of 4-(2-fluorophenyl)methylmethylthio. · 8H^ than pyridine and [2,3_d]pyrimidinone. 1 Η · 5 NMR δ 2.68 (s, SB), 3.81 (s5 3H), 6.61 (d51H, J=9.8 Hz), 7.22 (m, 3H)5 7.50 (m,3H). LC MS (m/e) = 302 (MH+). Rt = 2.17 minutes. Example 109

Ethyl 4-(2-fluoromethyl)-2-indolyl _8H-pyridyl and "2,7 _ prepared as described in Example 1-8 above, from 4-(2-fluorophenyl) ) 2_Methylthio_8Η_ 15 ° ratio bite [2,3_d] mouth bite -7_ copper and Ethylene bromide start, • and the title compound 8_ ethyl-4-(2-phenylene)_2 _ 曱 曱 基 吼 并 and [2,3_d] 〇t _7_ ketone. Lc ms (m/e) = 316 (MH+). Rt = 2.29 minutes. Example 110 (Please read the note on the back and then fill out this page &gt; Set: --Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

4-(2-Chlorophenylamino)-2-indenylthio-6-indolyl mouth@ -126- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 90. 11 2,000 A7 1298722 V. Description of the invention (125) on 4-chloro-6-(2-chlorophenylamino)_2-methylthio. dense. _5_魏甲盘(3 Μmg '1 mmol) in a solution of 10 ml of anhydrous DMSO, add NaH (50 mg '1·2 耄 Moer' in 6% dispersion in mineral oil, 〖 2 equivalents) followed by phenol (II 2 mg, I·2 mmol, 12 equivalents). The reaction mixture was taken at 5 Z3. Stir under! The reaction was quenched with 4 Torr (2 mL), shame (1 mL) was added, and the layers were separated. The organic layer was washed with aq. sat. aq. EtOAc, dried (MgSO. Then, the yellow residue is purified by flash chromatography to give U0 mg (Μ% yield) 4-(2-carbylamino)·2·曱thiophenylphenoxy_feeding_5· Slow formic acid. 1 10 NMR 5 2.32 (s,3H), 7.01-7.49 (m,8H), 8.51 (d,1H,J==7.2 Hz), 10.49 (s,1H), 11.58 (br s,1H). LC MS (m/e) = 372 (MH+). Rt = 2.94 minutes. Example 111 (Please read the notes on the back and then fill out this page ^·

• Line Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing base)_2_Methylthiophenoxy-8H_pyridine and 2,3_dipyrimidinone 20 18-crown-6 ether (422 mg, l·6 mmol) Ear, 5 equivalents) with bis(2,2,2-trifluoroethyl)(methoxymethyl)phosphonic acid vinegar (81 μL, 0 J8 mmol, 丨 2 equivalent) in anhydrous THF (20 mL) The solution was cooled to -78 Torr. Potassium bis(trimethyldecyl)amine (〇96 ml, 〇48 mmoler equivalent) was added to this solution to make a solution of 5 mol in a sputum. This solution was at -π. Stir again - one - - - -127 - This paper size is suitable for the National Standard (CNS) A4 specification (210: 297 mm) ----------- 90· 11. 2,000 A7 1298722 _ -_ B7_ V. INSTRUCTIONS (126) Mix for 30 minutes and add 4-(2-phenylphenylamino)-2_indolyl-6-phenoxy-pyrimidine-5-carboxaldehyde (119) dropwise. </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Aqueous solution of NH4C1 (5 mL) was taken up in EtOAc (20 mL). The layer was separated. The organic layer was washed with saturated aqueous NaCI, dried (MgSCU), filtered, and solvent was removed in vacuo. The yellow residue was purified by flash chromatography to give 1 mg (yield: 91% yield) of pure 8-(2-phenylphenyl)-2-sulfonyl 4-phenoxy-8 Η-^. [2,3-〇1]. Midine-7-one. 1 H-NMR 5 1.89 (s, 3 Η), 6.55 (d, 1 Η J=9.9 Ηζ),7·18 (m,4Η), 10 7.28 (m,4Η), 7.44 (m,1Η),7·98 (d,1Η, J=9.9 Hz)· LC MS (m/e ) = 396 (ΜΗ+)·

Rt = 2.68 minutes. Example 112 (please read the notes on the back and fill out this page)

-- Line. Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, printed 2-amino-8-(2,6-difluoro-phenyl)-4-(2-fluorophenyl)-8沁pyridine and|~2 , 3-pyrimidin-7-one in 8-(2,6-difluoro-phenyl)-4·(2-fluorophenyl)-2-methanesulfonyl-8H-pyrido 2〇[2, 3 is called pyrimidinone (4) 2 mg, 1 mmol) in a solution of 丨methyl-2·tetrahydropyrrolidone (5 ml), add NaNH2 (195 mg, 5 mmol, 5 equivalents) and mix the mixture Heat to 50. . After 1 hour, Η2 Ο (20 ml) was added followed by Et20 (20 ml). Separate the liquid layer. The organic layer was washed with a saturated aqueous NaCI solution, dried (MgSO4), filtered and evaporated. However __ ___-128-___ This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 90 u. A7 1298722 __B7_ V. Invention description (127) Please read the notes on the back and fill in the form. After the page, 'purification of the residue of the coloring residue is subjected to flash chromatography to obtain 2-amino-8-(2,6-difluoro-phenyl)-4-(2-fluorophenylpyridin[2,3] -d]pyrimidin-7-one (100 mg, 53% yield). iH-NMR CCDClJ 5 5.51 (brs, 2H), 6.42 (d, lH, J = 9.8 Hz), 7.08 (m5 2H), 7.30 (m, 2H), 7.50 (m, 4H), LC MS (m/e) = 369 (MH+). Rt = 5 1.77 min.

15 8-(2,6-di-gas-based)-4-(4-carbyl-2-methyl-phenyl)-2-methylthio-5,8-di-rho-6H-pyridine and 2,3-dl-pyrimidin-7-one, a) 3-[4-(2,6-disorder-phenylamino)-6-(4-carbo-2-methyl-phenyl)-2 -Methylthio-pyrimidin-5-yl]-propionate Methyl Economist Intelligence Bureau Staff Consumer Cooperative Printed in Sml2 in THF (0.1M) (Aldrich) (15 ml, 1.5 mmol) with MeOH (3 The solution of Example 30 (100 mg, 0.22 mmol 20 s) was added to a solution in cc) and the reaction mixture remained blue. The presence of the new product and the disappearance of the starting material are indicated by HPLC. After 30 minutes, the reaction was diluted with H.sub.2 (10 mL) then EtOAc (EtOAc) The aqueous phase was washed with EtOAc (20 mL) EtOAc (EtOAc) (EtOAc) (210 X 297 mm) 1298722 A7 ___ V. Description of invention (128) 15 Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs 20 and crystallized the residue from i-Pr0H/H20 (1:1). 3_[4_(2,6-Difluoro-phenylamino)-6-(4-fluoro-2-methyltolan-phenyl)-2-methylthio-penetrating _5_yl]-propionic acid Methyl ester. LCMS (m/e) = 448.2 (MH+), Rt = 2.17 min. b) 8-(2,6-di-I-phenyl)-4Pentyl-2-indenyl-phenyl)-2-methylthio-5,8-dihydro-6H-pyrido[2, 3-d]pyrimidin-7-one in 3-[4·(2,6-di-I-phenylamino)-(4-carbyl-2-methyl-phenyl)-2-methylthio- a solution of pyridinium-5-yl]-propionate (45 mg, 0.1 mmol) in methanol (5 ml), a solution of sodium decoxide (〇·5 mL), and the reaction mixture Heat under reflux for 1 hour. The reaction mixture was then evaporated and EtOAc (20 mL) was then evaporated. The liquid layer was separated, and the organic layer was washed with saturated aqueous NaCI, dried (MgSO.sub.4), filtered and evaporated. Dichloromethane (5 ml) was added followed by 〇·5 ml of gasified hay, and 0.1 liter of EtsN. Then, the reaction mixture was at 23. The mixture was stirred for 2 hours, then H2 (5 mL) was added, followed by dichloromethane (15 mL). Separation of the liquid layer 'The organic layer was washed with a saturated aqueous solution of NaCl, dried (MgSO.sub.4), filtered and evaporated. The yellow residue was purified by flash chromatography to give 11.2 g (yield: 21%) of pure 8-(2,6-difluoro-phenyl) ice (4-fluoro- 2-methyl-phenyl) ) · 2~ methylthio _5,8-^ a mouse-book" than bite [2,3-d] pyridin-7-_. 1 H-NMR (CDC13 ) • (5 2.20 (s, 3H), 2.29 (s, 3H), 3·85 (m, 4H), 7·02 (m, 4H), 7·21 (m, 1H) , 7.42 (m,1Η)· LC MS (m/e) = 416.2 (ΜΗ+). Rt = 2·44 minutes. Example 114 -130 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297厘) 90. 11. 2,000 Please read the notes on the back and fill in the order on this page. A7 1298722 V. Description of invention (129)

2_(2_士-Ethylamino-ethylamine 棊&gt; 8-(2,6-^-fluoro-stupyl)-4彳4-fluoro-2-methyl-pen^)-5,8- - a rat - 6H-Pbb p fixed open f2, 3_d | mouth p -7 - 嗣 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed the product of Example II3 (8), by the procedure of Example 47 oxidized into 飒8-(2,6-Difluoro-phenyl)4-(4-fluoroylmethyl-phenyl)_2-indolesulfonyl-5,8-dihydro-6H-acridine[2, 3-d]pyrimidin-7-one, which was combined with n,N-diethylenediamine and reacted by the procedure of Example 6 to give the title compound 2-(2-diethylaminoethylamine)- 8-(2,6-Difluoro-phenyl)-4_(4.fluoro-2-methyl-phenyl)-5,8-dihydro-6H-吼°[[,3-d] Pyrimidine-7-ketone. 1 H-NMR (CDC13): 6 1.04 (m, 6H), 2.01-2.80 (m, 11H), 6·89·7·40 (m, 6H). LC MS (m/ e) = 484.2 (MH+). Rt = 1.80 minutes. Example 115

4-(4-Fluoro-2-indenyl-mosyl)-2-(2-hydroxy-ethylamino)-8-isopropyl-8H·pyrido-131 - This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) 90. 11. 2,000 1298722 A7 B7 V. Description of the invention (13〇) "2,3-dl pyrimidine-7-one makes the product of Example 56 with 2 aminoethanol, The title compound 4-(4-fluoro-2-indenyl-phenyl)-2-(2-hydroxyethylamino)-8-isopropyl-8H-indole was obtained by the procedure of Example 60. Pyrido[2,3-d]pyrimidin-7-one. 1 H_NMR(CDC13) : 5 1.78 (m,6H), 2.29 (s,3H),3_70 (br s5 2H),3.89 (br s,3H) , 5.81 (m, 1H), 6.02 (br s, 1H), 6.23 (d, 1H, J = 9.7 Hz), 7·00 (m, 2H), 7·11 (d, lH, J = 9.7 Hz) , 7.19 (m, 1H), LC MS (m/e) = 357.2 (MH+)· Rt = 1.80 min.

15 bis-fluoro-phenyl)-4-(4 climbing its 2-mercapto-phenyl-V7-ketone----------------------------------------------------- The Intellectual Property Office employee consumption cooperative printed the pyridine and "2,3-dl pyrimidine·2_yl 1-N-methyl-methane 碏醯 face in Ν·[8-(2,6-difluoro-phenyl)- 4-(4-Fluoro-2-methyl-phenyl)-7-keto-7,8-dif-azino[2,3-d]pyrimidin-2-yl]-methanesulfonamide In a solution of 92 mg, 〇2 mmol, in anhydrous DMF (2 ml), add NaH (80 mg, 60% dispersion in mineral oil, 2 mmol, 1 〇 equivalent) and react The mixture was stirred for 30 minutes at 23 <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (ml), and the reaction mixture was extracted with Et 〇Ac (2 χ 2 () ml). The organic layers were combined, washed with saturated aqueous NaC hydrazine, dehydrated dry-132- This paper scale General Chinese National Standard (CNS) A4 specification (210 X 297 public interest) 90. 11. 2,000 1298722 Α7 ________________ B7 V. Invention description (131) (MgS〇4), over And evaporating the solvent. Then, the yellow residue was purified by flash chromatography to give 80 m of pure Ν·[8_(2,6-difluoro-phenyl)-4-(4-denyl-2-methyl Phenyl H-keto-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]methyldecane. 1 H-NMR (CDC13): 5 2.22 (s, 3Η), 2.96 (s, 3Η), 3.30 (s, 3H), 6.68 5 (d, 1H? J=9.8 Hz), 7.02 (m, 4H). 7.213 (m, 1H), 7.42 (m, 2H) , LC MS (m/e) = 475.4 (MH+)· Rt = 2.25 min. Example 117

(Please read the notes on the back and then fill out this page. ^ Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Print N-[4-(4-Fluoro-2-methyl-phenyl)-8-isopropyl_7 -_Base·7,8-dihydrop ratio bite "2,3-(pyrimidin-2-yl-1-indole-methylmethanthine 15) Prepared as described in Example 115 above, self-producing -[4-(4-Fluoro-2-methyl-phenyl)-8-isopropyl-7-one-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl ]-Methanesulfonamide started to obtain the title compound N-[4-(4-fluoro-2-methyl-phenyl)-8-isopropyl-7-one-7,8-dihydropyridine [2,3_d]pyrimidine·2_yl]-N-methyl-methicillin xanthine. 1仏NMR (CDC13): 5 1.75 (d,6Η, J=6.9 Ηζ), 2.18 (s,3Η) , 3.39 (s5 3Η), 3·53 (s, 20 3Η), 5·81 (m, 1Η), 6·40 (d, 1Η, J=9.7 Ηζ), 6.96 (m, 2Η), 7.11 (m,1Η),7·21 (d, 1H, J=9.7 Hz), LC MS (m/e) = 405.4 _+)· Rt = 2·20 minutes. Example 118 -133- This paper scale applies to China National Standard (CNSU4 Specification (21〇χ 297 公爱〉 90. η. 2,000 -- Line · 1298722

V. Description of the invention (132)

Read the note on the back of the Department of Intellectual Property of the Ministry of Intellectual Property, the consumer cooperatives printed by the winter methyl-phenyl) winter hydroxyl - committed 4 pyrimidine ρ Μ shouting -7-ketone in 8 (2,6-a base)_4 ·(4-Fluoro-2,indenyl-phenyl)_2_曱 石石黄醯基·阳·10 pyrido[2,3-d]pyrimidin π-ketone pm.mg, 〇·5mmoler) In a solution of methyltetrahydropyrrole (5 ml), Et3N (0.1 mL) was added followed by 2-aminoethanesulfonic acid (200 mg, hexanes, 3 eq.) and the reaction mixture was heated to 50. ' After 12 hours. Then, 1 M HCl aqueous solution was added dropwise until pH 3. Then, the reaction mixture was extracted with Et 〇Ac (2 χ 2 〇 15 mL). The organic layers were combined, washed with a saturated aqueous NaCI solution, dried (MgSO.sub.4) and filtered. Then, the yellow residue was purified by flash chromatography to give an oily product, which was then recrystallized from methanol:H.sub.2 (3··1} to give 51 mg of pure 8-(2,6-difluoro-phenyl). _4 Well Fluoryl Winter Methyl Phenyl) Winter Hydroxyl -8H_ Pyrido[2,3-d]pyrimidin-7.one. 1 H-NMR (CDC13) : 6 20 2_24 (s, 3H), 6.31 (d, 1H, J = 9.8 Hz), 7.02 (m, 5H). 7.23 (m, 1H), 7.352 (m5 1H), LC MS (m/e) = 384.2 (MH+). Rt = 1.65 min. Example 119 Re-filling this page έ· 订 -134- This paper size applies towel@国标准(CNS)A4 specification (210 297 297 public) 90. 11. 2,000 1298722 A7

V. Description of invention (133)

Prepared as described in Example 32 above, starting from 4-(4-fluorocarbomethylphenyl)-2-methylsulfonyl-o-indolephenylaminopyrimidine-5-carboxyfurfural. The title compound 4-(4-fluoro-2-ylidene-phenyl)-2-methylthio-bu-tolyl-8-pyridyl[2,3_d] is a bit of bite winter. 1H-NMR ( CDC13) : 5 2.02 (s5 3H), 2·20 (s, 3H), 2·28 (s, 3H), 6.79 (d, 13⁄4 JN9.7 Ηζ), 7·02 (m, 2Η), 7· 17 (m,1Η),7·22 (m5 2Η),7·40 (m,2Η), 7_53 (d,1Η, J=9.7 Hz)· LC MS (m/e) = 392.2 (ΜΗ+)· Rt = 2.40 minutes. 15 Example 120,

Base-stupidyl-4-(4-meryl-2-methyl-phenyl)-2-methylthio-8!^ is determined by [2,3-d&gt;cough-7-one Prepared as described in Example 32, from 4-(2,6·dimethylphenylamino)-6_(4- _____________&quot;135 ~ 90. 11. 2,000 paper scales applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) 1298722 A7 B7 V. Description of the Invention (134) Fluoro-2-methyl-phenyl)-2-indolethio-pyrimidine-5-carboxaldehyde begins with the title compound 8-(2 ,6-dimercapto-benzenei)-4-(4.fluoroamino-2-indolyl-phenyl)-2-methylthio-8H-pyrido[2,3-d]pyrimidin-7-one . 1 H-NMR (CDC13) : 6 2.05 (s, 6H), 2.26 (s, 3H), 2.31 (s, 3H), 6.81 (d, lH, J = 9.7 Hz), 7.02 (m, 2H), 7.17 (m, 5H), 7.51 (d, 5 1H, J = 9.7 Hz). LC MS (m/e) = 406.4 (MH+). Rt = 2.55 min 〇 Example 121

(Please read the notes on the back and fill out this page again. &gt; A Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Print 4_(4_Fluoro-2-methyl-phenyl V2-methane fluorenyl-8-neighbor - 曱 基-8H-pyridine and 2,3-dl pyrimidine-7-one 15 was prepared as described in Example 47 above, from 4-(t-fluorophenyl-2-phenylphenyl)-2-methyl Starting from thio-n-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one, the title compound 4-(4-fluoro-2-methyl-phenyl)_2-methanesulfonate was obtained.各-o-phenyl-8H-acridino[2,3-d]pyrimidine; ketone. lC MS (m/e) = 424.2 (MH+). Rt = 2.02 min 0 - line - example 122

1298722 A7 B7 V. INSTRUCTIONS (135) 8 (2,6-Methyl-fundylmethyl-stupyl V2-carbstone xanthine-8H-pyridine and f2,3-dl pyrimidine&quot; Prepared as described above, from 8-(2,6-dimethyl-phenyl)_4_(4-fluoro]2-methyl-phenyl)-2-indolyl·8Η•pyridyl[2,3_d Starting from pyrimidine _7-ketone, the title compound 8-(2,6-dimethyl-phenyl) phenyl (4-fluorolmethyl-phenyl)_2-methanesulfonyl-8H-pyridine was obtained. , 3-d] pyrimidine. Lc MS (m/e) = 438 〇 (MH+) Rt = 2.07 min. Example 123

15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

Μ^6:·二暴phenyl H_(4_Fluoro-m-methyl-stupyl&gt;-2·(2-hydroxy--Ethyl 1 V 8Η-pyridinium 2,3-dl-pyrimidine-7- _ Prepared as described in Example 6 above, from 8_(2,6-dimethyl-phenyl)4-(4-fluoro-2-methyl-phenyl)-2-methyl 醯Starting from -2,3-dp, -7-one and 2-aminoethanol, the title compound 8-(2,6-dimercapto-phenyl)-4-( 4-decyl-2-mercapto-phenyl)_2_indoleyl-ethylamino)_crime" bite and [2,3-d]. dense. -7-ketone. 1!!-NMR (CDC13) : 5 1.92 (s, 6H), 2.12 (s5 3H)5 2.95 (br s? 2H) 3.30 (br s? 2H)? 3.45 (br s,1H)5 6.31 (d,1H,J=9.7 Hz), 6.92 (m, 2H), 7.17 (m5 5H). LC MS (m/e) = 419.4 (MH+)· Rt = 1.84 min. Example 124 -137 - 90. 11. 2,000 This paper size applies to China Standard (CNS) A4 specification (210 297 297 mm) 1298722 A7 B7 V. Description of invention (136)

8-(2,6-Di-methylphenyl)-4-(4•fluoro-2-(methyl-methyl)-V2-(2-hydroxysuccinyl-ethylamino)-8H-pyridine 『2.3-dl-pyrimidin-7-one The product of Example I22 was reacted with the serine, by the procedure of Example 60, to give the title compound 8-(2,6-dimethyl-phenyl)-4-(4) -Fluoroalkyl 4-methyl-phenyl)-2-(2-hydroxy-1-methyl-ethylamino)-8 Η-Bound and [2,3-d] sputum-7-one. 1 H- NMR (CDC13): 1.91 (s, 6H), 214 (s, 3H), 3.45 (br s, 4H), 3.93 (br s, 1H), 6.20 (br s, 1H), 6.31 (d, 1H, J=9.7 Ηζ),6·93 (m,2H),7.11 (m,5H). LC MS (m/e)= 449.0 (MH+). Rt = 1.62 min. 15 Example 125 · (Read first Note on the back of the page - - · Department of Economic Intelligence, Intellectual Property Bureau, Staff Consumer Cooperative, Printed 20

4-(4·基二f-hydroxyl-small-trans-methyl-ethylamino) each ortho-group g-opening 丨2,3-cT|p-density _7_ brewing | The product is reacted with serinol by the procedure of Example 6

90' 12· 2, 〇〇〇•线·1298722 A7 B7 V. Description of the invention (137) The title compound 4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1- Hydroxymethyl-ethylamino) o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one. 1 H-NMR (CDC13) : δ 2.09 (s, 3Η), 2·26 (s, 3Η), 3.73 (br s, 4H), 4.02 (br s, 1Η), 6.30 (br s, 1Η), 6 · 41 (d5 1H, J = 9.7 Hz), 7.05 (m, 2H), 7.24 (m, 6H). LC MS (m/e) = 435.2 (MH+). 5 Rt = 1.60 min. Example 126 ο

(Please read the notes on the back and then fill out this page)&gt; 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 and "2,3-dl-pyrimidin-7-one will be the product of example m (4 〇〇 mg 〇 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 The EtOAc was removed in vacuo and the residue was purified eluting elut elut The solvent was evaporated to give a residue which was crystallized to give the title compound 4-(4-fluoro-indolyl-phenyl)-2-(2-hydroxysuccinyl-ethylamine). Phenyl-p-pyridyl [2,3 flavonoid in -7-ketone' was a white solid (34 〇 mg, (10)%). lc_ms: (MH+, m/z), Rt = 1.85 min.

90. 11. 2,000 lines 1298722 A7 B7 V. Description of invention (138)

15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 twisted, 6-difluorophenyl) winter (4-fluoro^2·methyl jasmine V2_G methylthiopropane group V8H_ also pyridine and "2,3-dl Pyrimidine-7-one was added to a solution of 3-(methylthiopropanol (〇5 ml) in NaH〇 2 mg, 5·5 mmol), and the mixture was stirred at Ar and 23°. After 5 minutes, Stop releasing the gas' and add the product of Example 48 (Μ3 mg, 〇5 mmol) in one portion. The mixture was stirred for 30 minutes. Most of the excess 3_(methylthio)propanol was removed in vacuo and The residue is subjected to liquid separation between the crucible and the crucible. The organic phase is washed with hydrazine and a saturated aqueous solution of Na.sub.1, and dried over anhydrous EtOAc EtOAc. Chromatography, eluting with EtOAc / EtOAc / EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

90· 2, 〇〇〇 (Please read the notes on the back and then fill out this page) Ηδτ·-Line* A7 1298722 V. Description of invention (139) ^Phenyl)-4卄fluoroyl)·8Η_吼And |~2,3-d~l·密&lt;-7-Μ ~^ The product of Example I27 (100 mg, 0. U millimolar) in gas imitation (1 〇 ml, add 8〇%3 - Chloroperoxy benzoic acid (1) 5 mg ' 〇 63 mmoles). The mixture of 5 was stirred under Ar and 230 for 2 hours. After this time, the solvent was removed in vacuo and the residue was treated in two portions between &lt;RTI ID=0.0&gt; The organic phase is washed with 咏0, a saturated aqueous solution of NaCI, dried over EtOAc EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The title compound was obtained as a white crystalline solid. m.p. 16 s 162., LCMS m/z = 504 (MH+), retention time = 0.02 min.

15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 g; (2,6-one gas table base)-4-(4-fluoro-based: 2-mercapto-based)-: 2-(2-jing-based甲乙乙基基)-8H-pyridine and f2,3-dl pyrimidine _7-_ 1,3-o-benzylidene glycerol (100 mg, ο.% millimolar) dissolved in anhydrous THF (5 In ML), stir at Ari 23 °C. NaH (M mg, 0. 55 mmol) was added, and the mixture was stirred at 23 for a minute and then cooled to _78. . Add the product of Example 48 (222 mg, 〇.5 mmol) and mix -141 - 90. 11. 2,000 of this paper size to the Chinese National Standard (CNS) A4 specification (21 〇 X 297 mm)

1298722 A7 ______ B7 _ V. Description of the invention (140) The compound slowly warmed to 23°. The solvent was removed in vacuo <RTI ID=0.0>: </RTI> The mixture was heated to 60 ° C in an oil bath for three hours and then the solvent was removed in vacuo to give a crude material. The crude product was flash chromatographed twice eluted eluted elut elut elut elut elut elut elut elut elut elut elut 104-107 ° C, LC MS m/z = 458 (MH+), retention time = 1.88 min. Example 130

F 15 8-(2,6-di-phenyl)-4-(4-carbyl-2-methylphenyl)-2- 2; (second-butoxycarbon-based acetaminophen) Gas-based 1-8H-pyrido-f2,3-dl-pyrimidin-7-one The product of Example 48 (445 mg, 1 mmol) and BOC-aminoethanol (177 mg, U m. (10 ml), and cooled to -78 ° while stirring under Ar. NaH (28 mg, 1.1 mmol) was added in one portion. Allow the 20 mixture to slowly warm to 23. However, the reaction did not proceed to completion. Additional NaH (10 mg, 0.4 mmol) was added and the reaction proceeded to completion. The solvent was removed in vacuo and the residue was partitioned betweenEtOAc and H20. The organic phase was washed with aq. EtOAc (EtOAc)EtOAc. Rapid chromatography, 0-10 _-142-_ This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 (Please read the back note first and then fill out this page )一装. ;线· Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Ministry of Printing and Economy Ministry Intellectual Property Bureau Employees Consumption Cooperatives Printed 1297822 a7 _ , _ B7 ____ V, invention description (141) % EtOAc / hexane dissolved, obtained The title compound is a white amorphous solid. Melting point 103-105. , LC$lSm/z = 527 (MH+), residence time = 2.44 minutes. Example 131

8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-(2-aminoethoxy)-8H-pyridine and 2,3- The dl-pyrimidin-7-one was dissolved in ch2ci2 (8 mL) from EtOAc (1 g, EtOAc, EtOAc). Add 25% TFA in 15% of EtOAc: EtOAc (EtOAc) The organic phase is washed with H20, aq. EtOAc (aq. EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 20, a white amorphous solid. Melting point 96-99., LCMS m/z = 427 (MH+), retention time = 1.52 min. Example 132 - 143 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 (please read the notes on the back and fill out this page). Book 1 - Line · 1298722 A7 B7 V. Description of Invention (142)

15 MM-二敦苯_羞)-4_(4-Fluoro-m-methylmethyl phenyl) m· guanylamino 8 Η-pyridine and “2,3-dl pyrimidine-7-_ makes Example 1:31 The product (61 mg, 0. U mmol) was dissolved in CH.sub.2 C.sub.2 (2 mL) and stirred at 0 ° C and ar. Triethylamine (1 mL) was then added, then acetic anhydride (0. The mixture was slowly warmed to 23 and stirred for 18 hours. The solvent was removed in vacuo and the residue was purified eluting with EtOAc/EtOAc. The title compound was obtained as a white amorphous solid. Melting point 75_79 &lt;), LC MS m/z = 469 (MH+), retention time == 1.95 min. (Please read the note on the back and fill out this page) -Line - Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 20 Example 133

8-(2,6-Difluorophenyl)-4-(4-mercapto-2-methylphenyl)-2-(3-hydroxy-2-hydroxymethylpropaneoxy-144- This paper size applies China National Standard (CNS) A4 Specification (210&gt;&lt;297 mm) 90· 2,〇〇〇1298722 V. Description of Invention (143) Base)·8Η-Pyridin and DDL Azinc -7-Lion Face (15 Mg, 〇.6 ginger Mo) was added to a solution of 2_(methyl)tripropanediol in THF (5 liter). The mixture was scrambled at 23 Torr and under the heart and then cooled to -78. . At _78. A solution of the product from Example 48 (224 mg, 0.5 mmol) in THF (5 mL). And stirred for 2 hours. The solvent was removed in vacuo and the residue was partitioned between EtOAc and EtOAc. The organic phase was washed with aq. The title compound was obtained as a white amorphous solid by flash chromatography eluting with EtOAc (EtOAc). Melting point 77_81〇, LCMs she = 472 (MH+), residence time =; ι·79 minutes. Example 134 15 ▲ 20 difluorophenyl) bucket (4-fluoro-based phenyl-free) dyeing" oxy)-8H-g ratio bite [~2,3-cT|, 唆·7-_, The product of Example m (loo mg, ου millimol) was in 〇^% (4 ml), limb and (9) down (d). Triethylamine (〇J ml) was added, followed by the addition of methanesulfonate (293⁄4 g, 〇·25 mmol) in CH 2% ^ ml). 90. 11. 2,000 1298722 A7 V. Description of invention (144 ) , . The solvent was removed in vacuo and the residue was partitioned between EtOAc and EtOAc. The organic phase & H2 〇, saturated aqueous NaCl solution was washed, dried over anhydrous Na2SO4, filtered and evaporated to give crude. The title compound was obtained as a white compound, m.p. Refining point 95-&quot;. LC MS m/z = 5〇5 (MH+), retention time = 2.02 min. Example 135

Reading Back Φ Note Item Page 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 Fluorophenyl)-4-(4-fluoro-2-methyl-based)-2-(2-N-methane The product of the example (2 〇 mg, 〇·〇 4 mmol) is dissolved in acetone (2 ml) in the sulfonium-N-A basket s methoxy group-8H-pyridine and Qdl peptime-7-lion. Stir at Ar and 23 °. Potassium carbonate (7 mg, 毫 millimolar) was added followed by a solution of methane iodide (6.4 g, 〇·〇 45 mmol) in acetone (丨m). The mixture was stirred for 8 hours, the solution was removed in vacuo and residue was partitioned betweenEtOAc and EtOAc. The organic phase was washed with a saturated aqueous solution of EtOAc (EtOAc m. Flash-chromatography, 〇-5% Et〇Ac/CH2 (3⁄4 elution, the title compound was obtained as white amorphous solid. Hyun-146- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Line 90. 11. 2,000 A7 B7 1298722 V. Description of invention (145) 89-92. LC MS m/z = 519 (, +), residence time = 2 2 minutes / example 136

Iili fluoro-2-methyl._benzene_.. base.): 8-(2-fluoropenyl on the 2_ face of a △ amine V8H-pyrazine read the back of the note! Packing · 10 and "2 , 3-dl pyrimidin-7-one The product of Example 59 (2 〇 0 mg, 〇·47 mmol) was dissolved in THF (4 mL) and ethanolamine was added (115 g, 1.87 mmol) The solution was stirred in EtOAc (1 mL). Washed with H.sub.2.sub.2, EtOAc (aq.) (H.sub.HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Yellow amorphous solid. Melting point 120-124., LC MS m/z = 409 (MH+), retention time = i 84 min 0 Order---------

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 2〇 Example 137

90. 11. 2,000 1298722 A7 B7 V. INSTRUCTIONS (146) )-8-(2,6·Difluorophenyl&gt;24(1-xiang and -2-very$^48^product(2〇〇 Mg, 〇45 mmol) and (5) 1,3-aminopropanol I gram mol) in THF (丨〇 ml), and in Ar and 23 for 1 day. Remove in vacuum. The solvent was taken up and the residue was partitioned between EtOAe and H20. The organic phase was washed with H20HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The title compound was obtained as an off-white amorphous solid. m.p., </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Fill in this page' 15 Example 138

(εβ-(4m曱 difluoromethane m(1-hydroxypropanthoquinone m)]-8H-吼g and "2,3-d> 密喷·7-Xitong make the product of Example 48 (2 〇〇mg, 〇45mmol) and (8)1 amino-based gal alcohol (Pen's 1 'home) were dissolved in THF (10 ml) and mixed for IS for hours at Ar and 230. In vacuum The solvent is removed, and the residue is subjected to liquid separation between the mixture and the mixture. The organic phase is washed with h 2 〇, saturated aqueous NaC1 solution, dried over anhydrous Na. Rough production order --- Line - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 148- This paper scale applies China National Standard (CNS) A4 specification (210 X 297 public) 90. 11. 2,000 1298722 A7 V. Invention description (147) Rapid flash chromatography, eluting with 〇-15% Et0Ac/CH2Cl2, (MH+), retention time = 2 〇 9 min.

15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 乞 (4 gas 棊) _8-(2,6-difluoro phenyl Μ-Π·]-; methyl · 2__, its 丨 2,3-dl咭-7-ketone soil The product of Example 48 (2 mg, Ο# mmol) and Μ%2 amino 4-methyl propyl alcohol (94 mg, 1 mmol) were dissolved in THF (10 mL) The mixture was stirred for 3 days under Ar and 5 Torr. The solvent was removed in vacuo, and the residue was partitioned between the mixture and the mixture. The organic phase was treated with H20 and saturated aqueous solution of Na. The mixture was washed with EtOAc (EtOAc m. Heart = 455 (MH+), residence time = 219 minutes. Example 140 90. 11. 2,000 1298722 A7 V. Description of invention (148)

15 Amino·4-color private base_2·methylphenyl)_8·(2_Fluorophenyl)_"" is a product of Example 59 (2 〇〇 mg) than p 定2 pyridine pyridin-7-one , 〇·47 mmol, combined and stirred with 5 ml of a 2 Μ solution of ethylamine in THF. After 5 minutes, the solvent was removed in vacuo and residue was partitioned between EtOAc and EtOAc. The organic phase was washed with hydrazine, aq. sat. NaCI, and dried over anhydrous Na? The product was obtained as a pale-yellow crystalline solid, eluting with EtOAc/EtOAc (EtOAc) elute Melting point 176·17; 7 〇, LC MS m/z = 393 (MH+), retention time = 2.38 min. Example 141 For palm reading, read the back of the note, and then fill in this page. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives 20 〇

Benzene-2-A certain benzene V8_(2-fluorophenyl)-2-indolyl-hydroxypropan-2-yl)amine 1-8H· -150- This paper scale applies to China National Standard (CNS) A4 specification ( 21〇χ 297 mm) 90. 11. 2,000

1298722 V. INSTRUCTIONS (149) Also q and 丨 ^ ^ ^ 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 59 Dissolved in THF (10 mL) and stirred at <RTIgt; The solvent was removed in vacuo and the residue was partitioned between plaques. The organic phase was washed with aq. The title compound was obtained as a pale-white amorphous solid, eluting with EtOAc (EtOAc). The temperature of 114-12 〇. , LCMSm/z = 423 (MH+) 'Retention time = 2.0 minutes. (Please read the notes on the back and then fill out this page j. Example 142

i^T·-Line· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed phenyl)-8_(2·Fluoryl diazepam (1) Hydroxypropyl winter stealing pyrimidine-7-_ The product of Example 59 (2〇 0 mg, 〇·47 mmoles) and (R)_2-amino-indole-propanol (75 mg, 1 mmol) dissolved in THF (10 mL) and mixed with 18 hours. The solvent was removed in vacuo and the residue was partitioned between EtOAc & EtOAc (EtOAc). The crude product was obtained by flash chromatography, eluting with 〇-2〇% EtOAc/CH2C12 to obtain the title----_-151-____ The National Standard for Time (CNS) A4 specification (210) X 297 mm) ' 90. 11. 2,000 1298722 Description of the invention (15〇) The mouthpiece is an off-white amorphous solid. Melting point 116_122〇, LCMSm/z = 423 (MH+), retention time = 2.04 min.

(Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Cooperative, Printed 1 ))) (4-Fluoro-2-L-based stupid) _8-(2_ fluoro-mumophilic yang - Pyridopyrimidine-7-one The product of Example 59 (2 mg, 〇·47 mmol) and 2-amino-2-methylpropanol (94 mg, 1 mmol) were dissolved. Stir in THF (1 mL) and stir for 3 days under hydrazine and 5 Torr. The solvent was removed in vacuo and the residue was partitioned between EtOAc and EtOAc. The mixture was washed with aq. EtOAc (EtOAc EtOAc (EtOAc). Mass solid. Melting point 106_112 〇, LCMS m/z = 437 (MH+), retention time = 1.94 min. 20 Example 144

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). Order 90. 11. 2,000 1298722 A7

暴-4-(4-yl-2-yl^yl)·8_(2_flutylpyridin[23.Midine-7-one^] The far more polar product formed in Example 143, The ruthenium was eluted from a flash column using 5% MeOH/CH.sub.2.sub.2. The reaction of h2〇 was formed. Melting point &gt; 280., LCMSm/z = 366_+), residence time = 17 minutes. Example 145

(Please read the note on the back and then fill out this page.) The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed 15 and f2,3-dl pyrimidine-7-one to make the product of Example 59 (200 mg, ο.47 m Mole) was combined with cyclohexylamine (just mg, 1 mmol) in THF (10 mL) and combined with &amp; Stir under 18 hours. The solvent was removed in vacuo and the residue (4) was taken up in flash chromatography eluting with 5 -1 -1% CH2Cl2 /hexanes. Recrystallization from CH2%/hexane gave the title compound as a white crystalline solid. Melting point (8)-182 〇, ° LCMSm/z = 447 (MH+), retention time = 2.71 min. Example 146 20 9〇· 11· 2, 〇〇〇 line -153 - 1298722 A7 \ 5, invention description (152)

The product of Example 59 (2 〇 0 mg, 〇 47 mmol) was combined with 4-aminotetrahydropyran (102 mg, 1 mmol) in THF (1 mL) and &quot ; and 23. Mix for 18 hours. The solvent was removed in vacuo and the residue was purified eluting elut elut Recrystallization from CH.sub.2Cl.sub.2/hexanes gave the title compound as pale yellow crystalline solid. Melting point 211_212 〇, LCMSm/z = 449 (MH+), retention time = 2.21 min. Example 147 --------------3⁄4--- (Please read the notes on the back and fill out this page) · · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 20

2. Ethylamine Shiki Shimi 2·methylphenyl)-8-(2,6-difluoro-based)-8H4 p-densified dl. Ding-7-ketone makes the product of Baye 48 (2〇〇家克 ' 0·45 house Moule) and ethylamine in Thf -154- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm); Line. 90. 11. 2,000 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1297872 __B7________ V. Description of Invention (153) 5 ml of 2 Μ solution were combined and stirred together. After 5 minutes, the solvent was removed in vacuo and the residue was partitioned between EtOAc and EtOAc. The organic phase was washed with hydrazine, saturated aqueous NaCl, dried over anhydrous Na.sub.2SO.sub. The product was obtained as a white crystalline solid. EtOAc EtOAc: EtOAc (EtOAc) Melting point 195-1960, LCMSm/z = 411 (MH+), retention time = 2.4 min. Example 148

15 Cyclohexylamine-2·indolyl methane, m2,6-difluoromethane V8H-pyrimidine^2,3_dl-pyrimidin-7-one The product of Example 48 (2〇0 mg, 〇45 mmol) ) and cyclohexylamine (1 mg, 1 mmol) in THF (10 mL), and mp. Stir under 18 hours. The solvent was removed in vacuo and the residue was flash chromatographed using 20-100% CH2 C12 /hexane. Recrystallization from CH 2 Cl 2 /hexane gave the title compound as a white crystalline solid. Melting point 218_2in:, LCMSm/z = 465 (MH+), retention time = 2 8 minutes. Example 149 -- —_ -155- This paper scale applies to Chinese national standard specifications (210 X 297 public)------- 90. U. 2, 〇〇〇 (please read the notes on the back and fill in This page ^ one

1298722 V. Description of invention (彳54)

1·(tetrahydropyranylbutyl L歴.yl)-each (4-fluoromethylbenzoquinone vg-(2,6-difluoromethyl V 8H-pyrido and f2,3-dl pyrimidine-7-) The ketone was combined with the product from Example 48 (2 EtOAc, EtOAc, EtOAc, EtOAc) The mixture was stirred at rt EtOAc (3HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Crystalline solid. Melting point 231-232., LC MS m/z = 467 (MH+), retention time = 2.27 minutes. 15 Example 150 (please read the notes on the back and fill out this page) 0 · Ministry of Economic Affairs Intellectual Property Office Printed by employee consumption cooperatives

St. (2,2,2-trifluoroethylamino)-4-(4-fluoro-based gastric 2-methylphenyl)-8-(2-fluoro-based)-8Η-pyridine bite (Z3-dl Pyrimidine-7-one The product of Example 59 (2 〇 0 mg, 〇·47 mmol) and trifluoroethylamine (2 〇〇 milli-156----- This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 90. 11. 2,000 1298722 V. Description of the invention (155) gram, 2 mmol) dissolved in Na (7 ml). The mixture was heated to 6. After 4 days == solvent was removed, and the residue was subjected to flash chromatography using EtOAc EtOAc EtOAc (EtOAc) 187-1880, ϊ Γ 1UQ / ΑΛη / , ° 227 minutes. LCMSm/z=447(MH+), residence time = example 151 set 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption company printed reverse 2·(4-hydroxystar ^基笨基V8-仏孝笑基)--off-吼g fixed "2,3-d| mouth pH ah to make the product of example 59 (200 mg, 〇·47 mmol), trans-amylamine Cyclohexanol hydrochloride (151 mg, 1 mmol) and triethylamine (0.283⁄4 L, 2 mmol) Add to THF (10 liters), and stir for 2 days at the bottom of the mixture. Remove the solvent in vacuo and leave the residue between Et EtOAc and EtOAc. After washing with a saturated aqueous solution of EtOAc (Na2SO4), EtOAc EtOAc (EtOAc) The product 'is a pale yellow crystalline solid. The melting point is 148-151 〇, LC MS m/z = 463 (MH+), and the residence time = 2 〇 minutes. 157- This paper scale applies to the Chinese National Standard (CNS) A4 specification (21 〇χ 297 mm 90. 11. 2,000 1298722

Example 152

Twisted base V8-r2-huang phenyl V8H-pyridoxine 2,3-dl-pyrimidin-7^ 10 The product of Example 59 (200 mg, 〇·47 mmol) and 2-aminocarbazone The base 1,3-propanediol (1 〇 5 mg, 丨 millimol) was combined in ΤΗρ (1 〇 ml) and was in Ar and 5 〇. Stir for 3 days. The solvent was removed in vacuo and EtOAcqqqqqm Melting point 16〇_162. , 15 LCMSm/z = 453 (MH+), retention time = 1.75 minutes. (Please read the notes on the back and fill out this page) έ· Set: Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing Instance 153

K2,2,2·trifluoroethylamino>&gt;4-(4-Fluoro-:2-indolyl)·8-(2,6-di-phenyl)·8η·pyridindole 2, 3-dl pyrimidine-7-one-158- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 A7 1298722 V. Description of invention (157) The product of Example 48 ( 30 (^ mg, 0.67 mmol) and trifluoroethylamine (3 mg mg 3 mM) were dissolved in THF (10 mL) and sealed in a small broken bottle under Ar. Heat in the bath to 60 °C for 4 days. Remove the solvent in vacuo and allow the residue to be flash chromatographed, using 9 〇% CH2d2 / 5 hexanes. Obtain the title from CH2 (3⁄4 / hexane recrystallized) The compound was obtained as a white crystalline solid. m.p. 195-1960, LC MS m/z = 465 (MH+), s.

------·丨L· (Please read the notes on the back and fill in this IW 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 2-(1-hydroxy-1-methyl-2-hydroxyethyl) Amino)-4-(4-fluoro-π-methylphenyl)·8_α6_difluoro-powderyl V8H-indole and 2,3-dl mouth bite 7-ketone make the product of Example 48 (3〇0 Mg, 〇·67 mmol) and aminomethyl 1,3-1,3-propanediol (1% 3⁄4 g, I·5 mmol) combined with kthf (1 () mL) and given at Ar and 50 The mixture was stirred for 3 days. The title compound was crystalljjjjjjjjjjj 16〇., LC MS m/z = 471 (MH+), retention time = 175 minutes. Example 155 -159- -- Line one

90. 11. 2,000 paper scales are applicable to China National Standard (CNS) A4 specification (210 X 297 male cage) 1298722 A7 __B7 V. Invention description (158)

1-Formula-2-(4-hydroxydecylamino) Winter (4.Fluoro-2-carboxamide) v_5^2 6•Difluorocapry&gt;8H-pyridine# ddl-pyrimidin-7-one makes an example The product of 48 (3 mg, 〇67 mmol), trans-haamine ring 10 hexanol hydrochloride (226 mg, 1. 5 mmol) and triethylamine (0.42 ml, </ RTI> </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Washed with %0, sat. &lt;(1) aqueous solution, dried over anhydrous NazSO4, filtered and evaporated to give a crude product. EtOAc EtOAc EtOAc Recrystallization gave the product as a white crystalline solid. m.p. 158 - 16 s., LCMS m/z = 481 (MH+), retention time = 2 〇 8 min. (Please read the note on the back and fill out this page) #. --Line - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing example 156

_—— -160- This paper scale applies to China National Standard (CNS) A4 specification (2) “Novogong Love” 90. 11. 2,000 A7 1298722 _____B7_ V. Invention Description (159) } Ethoxy-4-(4-乱Benzyl-2-methylphenyl)-8-(2_fluorophenyl)&gt;~81^ 〇 莽丨 2,3-(11 密 0 0 -7-ketone^ The product of Example 59 (2 〇0homek, 〇·47 mmol) was placed in Et〇H (1 mL), and the mixture was stirred under Ar. About 2 mL of ethanol was distilled off to dry the mixture at 5. When the mixture was cooled to 23 At the time, a part of the starting material was crystallized and crystallized. NaH (11.5 mg, 0.46 mmol) was added. The reaction was not completed, so another NaH (4 mg, 〇·16 mmol) was added. The solvent was removed and the residue was flash chromatographed on silica gel eluting with EtOAc EtOAc (EtOAc) Crystalline solid. Melting point 137-1390, LC MS m/z = 394 (MH+), retention time = 2.32 min. Example 157 (Please read the notes on the back and fill out this page) t·

--Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 90. 11. 2,000 20 difluoro phenyl)-4-(4-fluoro-2-methyl phenyl group V2-indole (2-aminoethyl) The amine 1- ML-pyrido-Odl pyrimidine-7-one The title compound of Example 48 [8-(2,6-difluorophenyl)4-(4-fluoro-2-methylphenyl) -2-Methanesulfonyl-8Η-pyrido[2,3_d]pyrimidin-7-one] (0.89 g, 0. 〇〇2 mol) in anhydrous THF, stirred at 23 and under Ar, Diamine (668 μl, -161 - This paper scale applies to China National Standard (CNS) A4 specification (21〇x 297 mm) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1298922 A7 __B7_ V. Invention Description (16〇 0.01 mol) treatment. The color turned orange. After 5 minutes, LC MS showed no starting material. The reaction was stripped to dryness; the residue was dissolved in Et0Ac-H20. The aqueous phase was adjusted to pH 10.5 with EtOAc. EtOAc (EtOAc m. MS (m/e) = 426 (MH+)· Rt = 1.52 Example 158

F

1-"248-(2,6-difluorophenyl) ice (4-fluoroyl-2-indenyl]&gt;7-keto-7,8-dihydropyridinium 15 and "2,3· (Τ|Pyridine-2-ylamino 1 ethyl 1-3-ethylurea The product of Example 157 (42.5 mg··········· After stirring, treat with a portion of ethyl isocyanate (9.6 mg, 0.0001 mol). After 30 minutes, the red solution formed was stripped to dryness; dissolved in dioxane (5 ml) and applied to Chromatotron T M 20 rotor plate (1000 micron thickness); this plate was dissolved in a dioxane-nonanol gradient (〇% to 2% MeOH) to give 30 mg (60.4%) of .) 'LC MS (m/e) = 497 (MH+).Rt = 2.04 minutes. Example 159 __-162-_ This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 90. 11 2,000 (Please read the note on the back and fill out this page) - -- Line · 1298722 A7 B7 V. Description of invention (161)

Li^8-(2,6-二华.phenylhydrazine) ice (4_Fluoro.2·methyl phenyl group V7-keto group _7,8_二^^ degree and 2,3-dl -2-Aminoamine 1ethyl 1-3-phenylidene 10 The title compound from Example I57 (42·3 mg, 0.0001 mol) was obtained as phenyl isocyanate (1 L 9 mg, 0.0001 mol) Treated in the same manner as described in Example 158. Purified to give 43 mg (yield: EtOAc: EtOAc: 2.34 minutes. Example 160 15 (Please read the notes on the back and then fill out this page) Order ·· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 〇

1-|~2_"8-(2,6-Difluorophenyl)-4·(4-fluoromethyl-based V7-ketodihydrop-pyridyl 2,3-dl-pyrimidine-2-amine Base 1 B 1-3-cyclohexene will be obtained from the title compound of Example 57 (42·3 mg, 0.0001 mol) with iso-163 - --- - 90. 11. 2,000 paper size for Chinese countries Standard (CNS) A4 size (210 X 297 mm) 1298722 A7 V. Description of the invention (162) Cyclohexyl cyanate (12.5 mg, 0.00011 mol) was treated in the same manner as described in Example 158. Purification was obtained. The title compound was obtained as a red solid (yield: 178-1830) LC MS (m/e) = 551 (MH+). Rt = 2.38 min.

Fluorophenyl V4-(4-fluoro-2-methylphenyl)-7-one a -7,8-di-If pyridin-2-ylamine 1 ethyl 1-3-丨3-fluoromethane The title compound (42. 3 mg, 〇〇〇〇 1 mol) from Example I57 was obtained in the same manner as described in the example of 3·fluorophenyl isocyanate (12 mg, 0.0001 mol). deal with. The title compound was obtained as a pale yellow solid (m.p. 131-1440). LC MS (m/e) = 563 (ΜΗ+)· Rt = 2.22 min. Example 162 » (Please read the note on the back and fill out this page) 15 - Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 20

-164- 90. 11. 2,000 This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) A7 1298722 _._B7_ V. Invention description (163) (Please read the notes on the back and fill in the form) Page) 8-(2,6-Difluorophenyl)-4-(4-fluoroyl-2-methylphenyl)-2-"H2-aminoethyl)-3-indolylurea 1- 8H·pyridine&gt; 2,3-dl^f-pyridine-7-one The title compound from Example 157 (150 mg, 0.00035 mol) was obtained from decyl isocyanate (22 μL, 21.6 mg, 0.00035 mol) This was treated in the same manner as described in Example 158. The title compound was obtained as a pale red solid (yield: 124-133.) LC MS (m/e) = 452 (MH+)· Rt = 1.85 minutes. Example 163

Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, 8-(2,6_二气笨基)-4-(4-carbyl-2-methylphenyl)_2-[N_(2-aminoethyl) Benzyl benzylamino 1-8H-pyridyl 2,3- </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> <RTIgt; Triethylamine (78.8 mg, 20 109 microliters, 0.00078 moles) was then stirred with Ar and then treated with gasified phenylhydrazine (119 mg, 99 microliters, 0.00085 moles). The mixture was stirred at 23 ° for 18 hours; stripped to dryness, then dissolved in dichloromethane (5 mL) and applied to a Chromatotron T M rotor plate (2000 micron thickness); The alcohol gradient (〇% to 2% MeOH) was dissolved. This gave 141 mg (37.5%) of the title -165- 90. 11. 2,000 paper scales applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1298722 A7 _-_B7_ V. Inventive Note (164) Compound, It is an off-white solid (melting point 246-2480). LC MS (m/e) = 530 (MH+). Rt = 2.25 min. Example 164

8-(2,6-Difluorophenyl V4-(4•Fluoro-2-methylmethyl)-2_ΓΝ·(2-Aminoethyl ethanoate)1·8Η-pyridine hydrazine 2, 3-dlpyrimidin-7-one The title compound (3 mg, 〇·〇〇〇 71 Mo) from Example I57 was used in the same manner as described in Example 163, using ethyl chloroformate (91·8) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; m/e) = 4.98 (MH+).Rt = 2.09 minutes. Example 165 ------------ - - ^ · II <Please read the notes on the back and fill out this page) --Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

__________ 1298722 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing (please read the notes on the back and then fill in this page ^: Order: V. Invention description (165)

Mg,6-difluorophenyl)ice (4-fluoro-2-methylphenyl)·2·ΓΝ-(2-aminoethyl)propanylamino)1-8Η-pyridine and DJ-dl 'Pyridin-7-one will be obtained from the title compound of Example I57 (3 mg, 〇·〇〇〇 71 Mo) in the same manner as described in Example 163, using propionic anhydride (110 mg, u 〇 micro 5) L, 〇·〇〇〇85 mol) is treated as a thiolation reagent. Purification of the crude product <RTI ID=0.0></RTI> </RTI> <RTIgt; LC MS (m/e) = 482 (ΜΗ+). Rt = 1.95 min. Example 16ό

Μ2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)_2-ΓΝ_(2-facial acetyl hydrazinopyridine and 2,3-dl pyrimidine- The 7-ketone will be obtained from the title compound of Example I57 (3 〇 0 mg, 〇·〇〇〇7ι Mo) in the same manner as described in Example 163, using 2,2-dimethyl chlorinated chloride ( 1 〇 2 20 20 g, 1 〇 4 μl, 〇·〇〇〇 85 摩尔) was treated as the thiolation reagent. Purification of the crude product afforded EtOAc (m. -133〇).1^:1^18(111义)=510(]\411+). Dressing = 2.14 minutes. Example 167 ___·_-167-_ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) &quot; ----------- 90· 11. 2, 〇〇〇1298722 A7 B7 A7 V. Description of invention (166)

8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-(N-(2-amine-ethylamine) Vinegar) 1-8H-pyridine and "2,3-d"pyrimidin-7-one 10 The title compound (300 mg, 0.00071 mol) from Example 57 was used in the same manner as described in Example 163. Di-tert-butyl dicarbonate (185 mg '0.00085 mol) was treated as a reagent for the formation of urethane; triethylamine was omitted from this reaction. Purification of the crude product gave 2 mg (56%) The title compound is an off-white solid (m.p. 106- 119.) LC MS (m/e) = 526 15 (MH+). Rt = 2.30 min. Example 168 (Please read the back note and fill out this page). ; Line - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20

8-(2,6-dioxin)-4-(4-fluoroyl-2-methylphenyl)-2-(anthracene-amine urinary ρ-g-butyl-5-yl)-8H-pyridine And "2,3-dl-pyrimidin-7-one_-168- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 1298722 A7 ___ B7 V. Invention description (167 The title compound of Example 48 [8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-methanesulfonyl-8H-pyridin[2] , 3-d]pyrimidin-7-one] (100 mg, 0.000225 mol) and 5-aminouracil (70 mg, 0.00〇55 mol) dissolved in anhydrous DMSO (1.5 ml) under Ar The mixture was stirred and warmed to EtOAc (EtOAc). It is then evaporated to a brown glassy material. The glassy material is crystallized from a small amount of MeOH to give crystals to give crystals of the title compound (yield &gt; 300). m/e) = 493 (MH+). Rt = 1.82 minutes. Example 169 ---------- - -- Install i ! .--. (Read first Note on the back page Fill in this page again 0 15

Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, 8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-N-(2-aminoethyl) - Ν'-(T-Butoxycarbonylglycinemethyl-)-8-pyridyl-f2,3-dl-pyrimidin-7-one gave the title compound from Example 157 (168 mg, 0.0004 m) THF (2 ml) with tri-butoxycarbonylglycine (70 mg, 0.0004 mol) in dicyclohexylcarbodiimide (82·4 mg, 0.0004 mol) in anhydrous THF (2 mL) Processing. The solution was stirred at 23 ° for 16 hours; filtered and -169 - This paper scale was applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 90. 11. 2,000 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1298722 _______ B7 ___ V. Description of invention (168) Stripping to dryness. The residue was dissolved in dichloromethane (5 mL) and applied to a ChrOmatotrcnTM rotor plate (1000 micron thickness); the plate was dissolved in dichloromethane-methanol gradient (〇% to 3% MeOH). This gave 122 mg (52%) of the title compound as a pale red solid. LC MS (m/e) = 583 (MH+). Rt = 2.12 min.

8-(2,6-Difluorophenyl)-4-(4-fluoroyl-2-indolyl)-2-"-(2-aminoethyl)-:-------- 1-8H-Pyridinium 2,3-dl-pyrimidin-7-one The title compound of Example 169 (80 mg, 0.000137 m) was dissolved in dioxane (2 mL); The solution was stirred at <RTI ID=0.0># </RTI> for <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The title compound is bis-trifluoroacetate as an off-white solid, 60 mg (62%). LCMS (m/e) = 483 (MH+). Rt = 1.55 min. Example 171 - 170 - The paper scale applies to the Chinese national standard ( CNS) A4 size (210 X 297 mm) 90. 11. 2,000 (please read the notes on the back and fill out this page) νδΊ· -- Line _ 1298722 A7 B7 V. Description of invention (169)

Please read the back Φ Note. Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Print 8-(2,6-Difluoro-phenyl)-4-(4-fluoroyl-2-indenyl)-2-indole- 22,2-Dimercapto-2-hydroxylethylamine) 1-8 Η-pyridine and 2,3-dlpyrimidin-7-one 10 The title compound of Example 48 (150 mg, 0.000337 m) In THF (5 ml), 2,2·dimethylethanolamine (5 mg, 50 μl, 0·00〇67 mol) [by Bijaya L. Rai et al., J. Med. Chem. I&quot Process prepared by the method of 8, 41, 3347], stirred at 23°; progress of the reaction was monitored by LCMS. The reaction was stripped to dryness; the residue was dissolved in dichloromethane (5 mL), 15 And applied to a Chromatotron T M rotor plate (2000 micron thickness); this plate was dissolved in a dioxane-methanol gradient (〇% to 1.5% MeOH) to give 116 mg (69%) of LCMS(m/e) = 455 (MH+)· Rt = 1.99 minutes. Example 172 20 F Pair of palms

This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 items and then fill in this page - yc." 1289872 A7 B7 V. Invention Description (170) S-(+)- 8-(2,6-difluorophenyl) ice (4_fluoro-2-(methyl) pheno-V2-[N-(1_amine-2-py!)1-8H-pyridine and f2,3 - </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Mg, 79 μl, 0.00098 mol), and stirred at 23. The progress of the reaction was monitored by 1^^^8. The reaction was stripped to dryness; the residue was dissolved in dichloromethane (5 mL) ) and applied to a ChromatotronTM rotor plate (2000 micron thickness); this plate was dissolved in a di-methane-methanol gradient (〇% to 1.5% MeOH). This gave 76 mg (51%) of the title compound as pale white Solid (MH+).Rt = 1.94 min. Example 173

For the palm of the 15 Ministry of Economic Affairs Intellectual Property Bureau staff consumption A company printed f please read the back of the note before you fill out this page) II I stupid) bucket (4-fluoro-2-methyl stupid)-2 - "N-(l-amine-2-)1-8Η·pyridine and 2,3-dl azoxypyrimidine The title compound of Example 48 (jo mg, 〇〇〇〇337 mol) in anhydrous THF (5 house liters), treated with r7) amino-2-propanol (5 〇 $ mg, % liter, 0·00067 mol), and at 23. Stirring; reaction development was monitored by LCMS. The reaction was extracted into dry wine; the residue was dissolved in two gas (5 ml)

90. 11. 2,00 A7 1298722 ___B7 __ V. Description of the invention (171) (Please read the note on the back and then fill out this page &gt;.々 and apply it to the ChromatotronTM rotor plate (2000 micron thickness); This was eluted with a methylene chloride-methanol gradient of EtOAc (m/e). = 1.94 minutes. 5 Example 174

Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative (R)-8-(2,6-digas-based)-4-(4- disordered base_2·曱 basic amino group-2-yl group_ 2- Phenylethyl)1-8-pyridyl- 2,3-dl-pyrimidin-7-one 15 The title compound from Example 48 (150 mg, EtOAc, EtOAc) -Amino-1-phenylethanol (93 mg, 0.00067 mol) was treated and stirred at 23 °; the progress of the reaction was monitored by LCMS. The reaction was stripped to dryness; the residue was dissolved in di-methane (5 mL) and applied to a ChiOmatotronTM rotor plate (2000 micron thickness); this plate was dichloro 20 decane-methanol gradient (0 Dissolved from % to 1.5% MeOH). This gave 108 mg (64%) of the pure title compound as light orange gum. LC MS (m/e) = 503 (MH+)· Rt = 2.20 min. Example 175 -173- This paper scale applies to China National Standard I (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 1298722 A7 ___B7 V. Description of invention (172)

Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, 8-(2,6-diphenyl)-4-(4-fluoroyl-2-methylphenyl)-2-indole-triyl-decylamino Methyl 1-8 hydrazine-pyrido- 2,3-dl-pyrimidin-7-one 10 The title compound of Example 48 (15 mg, 0·00 〇 337 m) and s (trimethylolmethylamine) 121 mg, 0.0001 mol) in Ν-methyltetrahydropyrrolidone (1.5 ml) at 300 watts using MARS 5tm microwave (CEM) at 18 Torr. Microwave for 2 minutes (excitation in 3 minutes). When monitored by LCMS, no starting material remained. The solvent was stripped under vacuum, and the residue was dissolved in 15 methylene chloride (5 mL) and applied to Chromatotron T M rotor plate (2000 micron thickness); this plate was chromato-methanol gradient The solution (〇% to 1.5% MeOH) was dissolved. This gave 42 mg (26%) of the title compound as a pale brown solid. LC MS (m/e) = 487 (MH+). Rt = 1.55 min. Example 176

-174- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm). 90. 11. 2,000 (Please read the note on the back and fill out this page) Line · 1298722 A7 B7 V. Description of invention ( 173) 8-(2-Fluorophenyl)-4_(4-fluoro-2-methylphenyl)-2-indole-(丨2,2-dimethyl-2-hydroxy-2-hydroxyl-B The title compound (144 mg, 0.000337 mol) of Example 59 in anhydrous THF (5 mL). Ethanolamine (50 mg, 50 μl, 5 0.00067 mol) [manufactured by Bijaya L. Rai et al., J. Med. Chem. 1998, 41, 3347] and stirred at 23°; Progress is monitored by LCMS. The reaction was stripped to dryness; the residue was dissolved in dichloromethane (5 mL) and applied to Chromatotron T M rotor plate (2000 micron thickness); this plate was taken in dichloromethane-methanol gradient (0% Dissolve to 1.5% MeOH). This gave 106 mg (72%) of the title compound as pale white solid. LC MS (m/e) = 437 (MH+). Rt = 1.92 min. Example 177

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, 20 (S)-(+)-8-(2-Phenylphenyl)-4-(4-carbyl-2-methylphenyl)-2-[N- (f2-mercapto-2-yl 1 ethylamine Π-8 Η-pyridine and 2,3-dl pyrimidine-7-one The title compound of Example 59 (I 44 mg, 0·00 〇 337 m) In anhydrous THF (5 ml), take S-(1)-1-aminopropanol (76 mg, 79 μl, -175- 90. 11. 2,000 (please read the note on the back and fill out this page) Paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1298722 A7 B7 _ V. Invention description (174) ----I------------ (Read first Precautions on the back side. Fill in this page) 0.00098 mol) and stir at 23. The progress of the reaction is monitored by LCMS. The reaction is stripped to dryness; the residue is dissolved in dichloromethane (5 mL) And applied to a Chromatotron T M rotor plate (2000 micron thickness); this plate was dissolved in a dichloromethane-nonanol gradient (0% to 1.5% MeOH). This gave 132 5 mg (93%) of the title compound as Light yellow solid. LCMS (m/e) = 423 (MH+). Rt = 1 · 82 min.

-•Line·15 (RV(_)-8-(2-Fluorophenyl)-4-(4-fluoroyl-2-methylphenyl)-24Ν-(『2-mercapto-2-hydroxyl 1 Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printing ethylamine) 1-8 Η-pyridine and f2,3-dl pyrimidine-7-one The title compound of Example 59 (150 mg, 0.000337 mol) in anhydrous THF (5 mL In the process, R-(I)-1-amino-2-propanol (50.5 mg, 54 μl, 0.00067 mol) was treated and stirred at 23. The progress of the reaction was controlled by LCMS. Stripped to dryness; the residue was dissolved in dichloromethane (5 mL) and applied to a Chromatotron T M rotor plate (2000 micron thickness); this plate was taken in dichloromethane-methanol gradient (〇% to 1.5% MeOH) This was obtained by dissolving 151 mg (quantitatively) pure title compound as a pale yellow gum. LC MS (m/e) = 423 (MH+). Rt = 1.84 min. -176- 90. 11. 2,000 paper scale for China National Standard (CNS) A4 Specification (210 X 297 mm) 1298722 A7 · B7 V. Description of Invention (175) Example 179

15 4-Alkyl-2-indolethio-6-d-hexylamine-based thiophene-5-nonanoic acid 4,6-dichloro-2-indolylpyrimidin-5-carboxaldehyde (4.0 g, 0.018 mol) was treated with cyclohexylamine (3.76 g, 4.3 mL, 0.038 mol) in acetonitrile (65 mL) over 1 min and stirred rapidly. The reaction was stirred for 16 hours and then diluted with 3 volumes of hydrazine. The precipitated solid was collected, washed with EtOAc EtOAc (EtOAc) LC MS (m/e) = 286 (ΜΗ+)· Rt = 2·85 min. , Example 180 (Please read the notes on the back and fill out this page) i Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 20

2-曱thio-4-(2-mercapto-4-fluorophenyl)-6-cyclohexylaminopyrimidine-5·carboxycarboxaldehyde-177 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 1298722 A7 ___ B7 _ V. Description of the invention (176) The title compound from Example 180 (5.1 g, 0.018 mol), 2-methyl-4-fluorodihydroxyboron Alkane (5·54 g, 〇·〇36 mol), Na2C03 (3.82 g, 0. 〇36 mol), hydrazine (triphenylphosphine) palladium (0), dioxane (100 ml) and H20 ( A mixture of 5 ml) was stirred under Ar and warmed to 65. And stirred for 16 hours. 5 Allow the reaction to cool to 23. Diluted with EtOAc, and the mixture was washed sequentially with H20, aqueous NaHCO3 and saturated aqueous NaCI. The organic phase was dried (Na2SO4) and then stripped to a thick syrup. The slurry was crystallized from a small amount of MeOH and subjected to sonication and mild warming. This gave 5.5 g (86%) of title compound as a white solid. LCMS (m/e) = 360 (MH+). Rt = 3.00 min. 10 Example 181 (Please read the notes on the back and fill out this page)

Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 90. 11. 2,000 8-Cyclohexyl-4-(4-fluoroyl-2-indolyl)-2-methylthio-8H-pyridine and "2 , 3-dl pyrimidine-7-oxime triethyl phosphonate acetate (3.87 ml, 0.01953 mol) in anhydrous THF 20 (56 mL), NaH (60% in mineral oil) (967.5 mg, The mixture was stirred for 30 minutes to give a clear solution. </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; The solution was gently refluxed for 72 hours. After cooling to 23 °, the reaction mixture was diluted with diethyl ether and then saturated with ___ 178 - paper size applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1298722 A7 _ B7 ___ V. Description of the invention (177) NH4C1 aqueous solution and H20 washing. The organic layer is dehydrated and dried (Na2S04), and then evaporated to a thick slurry, which is in a di-methane-hexane gradient (20% to 0% hexane). The 920 mg (19%) of the title compound was obtained as a white solid. LC MS (m/e) = 384 (MH+) . Rt = 2.79 minutes. 5 Example 182 〇

8-cyclohexyl-4-(4-fluoro-2-indolyl)-2-ethoxy-8H-pyrido[2,3-dl-pyrimidine-7-indole The title compound was obtained as a white solid. LCMS (m/e) = 382 (MH+)· Rt = 2.67 min. Example 183 (Please read the note on the back and fill out this page). 15 - Line · Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Print 20 0

〇-179- 90. 11. 2,000 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1298722 A7 B7 V. Invention description (178) 8-玉哀己基-4-(4-气Benzyl-2-methylphenyl)-2-methyl calcination base-8H-Pbb σ cleave f2,3-dl Mouth -7-one will be obtained from the title compound of Example 181 (850 mg, 0.0022 Mol) was stirred in dichloromethane (100 mL) and treated with m-chloroperbenzoic acid (77%) (992 mg. This solution was at 23. Stir under overnight. LC MS showed about 90% conversion to the title compound, therefore, an additional 120 mg of m- benzene benzoic acid was added to the reaction. After 1 hour, the reaction was washed successively with 5% Na.sub.2CO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. The title compound is a white solid. LC MS (m/e) = 416 (MH+). Rt = 2.24 min. Example 184 (Please read the note on the back and fill out this page)

Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed 20 8-cyclohexyl-4-(4-fluoroyl-2-methylphenyl)-2-indole-2,2-dimercaptoethanolamine 1-8H-pyridine The title compound of Example 183 (150 mg, 0.00036 mol) was taken in anhydrous THF (2.5 mL) with 2,2-dimercaptoethanolamine (64 mg, 64) Microliter, 0.00072 Moh) [by Bijaya L. Rai et al., J. Med. Chem. 1998, 41, 3347-180- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 A7 1298722 __B7_ V. Description of invention (179) Method made] treated, and at 23. Stir for 16 hours; the progress of the reaction was monitored by LC MS. The reaction was stripped to dryness; the residue was dissolved in dichloromethane (5 mL) and applied to ChromatotronTM rotor plate (2000 micron thickness); this plate was taken in a methane-methanol gradient (0% to 2) % MeOH) was dissolved, and 5 of 107 mg (70%) of pure title compound was obtained as colorless glass. LC MS (m/e) = 425 (MH+)· Rt = 2.22 min. Example 185

15 (SM+V8-cyclohexyl-4-(4fluoro-2-methylphenyl V24N-1-amino-2-hydroxypropylhydrazine-8 Η-pyridyl r2,3-d|pyrimidine-7- The title compound (150 mg, 0.00036 mol) from EtOAc (EtOAc: EtOAc) Treated and stirred at room temperature; progress of the reaction was monitored by LCMS 20. The reaction was allowed to warm at 90 ° for 15 hours. The reaction was stripped to dryness; the residue was dissolved in dichloromethane (5 mL) And applied to a Chromatotron T M rotor plate (2000 μm thickness); this plate was dissolved in a dichloromethane-methanol gradient (0% to 2% MeOH) to give 118 mg (80%) of the title compound as colorless gum. LC MS (m/e) = 411 (MH+). Rt = 2.10 minutes -181 - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) &lt;Please read the notes on the back first. Fill in this page again) Order: Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 90. 11. 2,000 1298722 A7 B7 V. Invention Description (18〇) Example 186 〇

For the palm of the hand 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed (R)-(a)-8-cyclohexyl-4-(4-fluoroyl-2-mercaptoalkylamino-2-hydroxypropyl 1-8H - Pyridyl 2,3-dl-pyrimidin-7-one The title compound of Example 183 (150 mg, 0.00036 mol) in anhydrous THF (2.5 mL). 54 mg, 58 μl, 0.00072 mol), and stirred for 16 hours at 23. The progress of the reaction was monitored by LCMS. The reaction was stripped to dryness and the residue was dissolved in dichloromethane (5 mL) And applied to a Chromatotron T M rotor plate (2000 micron thickness); this plate was dissolved in a dichloromethane (methanol to 0% MeOH) to give 158 mg (quant.) pure title compound as colorless. Colloid. LC MS (m/e) = 411 (MH+).Rt = 2.12 minutes. Example 187 (Please read the note on the back and fill out this page) Order _ · -- Line · 20 〇

_ -182- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 A7 1298722 _B7 V. Description of invention (181) 8·Cyclohexyl-4-(4-fluoro group) -2-N-dihydroxymethyl decyl 1-8H-acridine 2,3-dl pyrimidine-7-one The title compound of Example 183 (150 mg, 0.00036) Treatment with serine (62 mg, 0.000674 mol) in anhydrous 5 THF (2.5 mL) and warming at 90 ° for 16 hours; progress of the reaction was monitored by LC MS. To dryness; the residue was dissolved in dichloromethane (5 mL) and applied to ChrematotiOnTM rotor plate (2000 micron thickness); this plate was dissolved in dichloromethane-methanol gradient (〇% to 2% MeOH) This gave 163 mg (quantitative) of pure 10 title compound as colorless gum. LC MS (m/e) 427 (MH+). Rt = 1.75 min. Example 188 (Please read the back note first and then fill out this page)

--Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 20 8-(2,6-Difluorophenyl)-4-(4-fluoroyl-2-indenyl)-2-indole-(2 -Chloroethylaminopyridine and f2,3-dl-pyrimidin-7-one The title compound from Example 48 (890 mg, 0.002 mol) in anhydrous DMF (18 mL) (345 mg, 0.003 mol) and K2CO3 (207 mg, 0.0015 mol) are treated and stirred. The mixture is at 23. -183 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 A7 1298722 ____B7_ V. Stirring for 16 hours under the invention (182). Strip the reaction to a residue; dissolve in EtOAc; wash with H20 (2X); dehydrate the organic extract (Na2S04) Then, it was evaporated to a brown gum. This residue was dissolved in dichloromethane (5 ml) and applied to a Chromatotron T M rotor plate (2000 micron thickness); this plate was dissolved in dichloromethane. This gave 510. The title compound has a modified purity. The compound is then dissolved in acetonitrile (2 ml) and spurred to give a white crystalline solid. 280 mg (31.5%) of the title compound. mp (m/e) = 445 (MH+)· Rt = 2.44 min.

1^-"2-"丨8-(2,6-difluorophenyl)-4-(4-fluoroyl-2-indolyl)-7,8-dihydro-7-ketopyridine [ ~2,3-dl-pyrimidin-2-yl 1amino 1 ethyl 1-decanesulfonamide The product of Example 157 (250 mg, 0.58 mmol), diisopropylethylamine (111 dl, 0.64) A solution of millimolar) and CH2C12 (10 ml), cooled to -5 ° 20 and added decanesulfonium chloride (50 μL, 0.64 mmol), and the resulting solution was warmed to 23 ° After stirring for 15 minutes, it was diluted with EtOAc EtOAc (EtOAc)EtOAc. Chromatotron chromatography (CH2C12/CH30H), and crystallization from Et20 afforded a pink solid. Melting point __-184-___ This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 9〇. 11. 2,000 (please read the notes on the back and fill out this page). Line _ Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1298922 A7 B7 V. Invention Description (183) =105-115. (decomposition); LC MS (m/e) = 504.2 (MH+)· Rt = 1.94 minutes Example 190

15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed Ν-[8_(2,6-difluorophenyl) ice (4-fluoromethyl I methyl stupyl)-in 8_dihydro·7__ curtain noisy 2 , 3-dl shouting 唆-2-yl 1 methyl glycinate, the product of Example 48 (2·25 mg, 5.0 mmol), glycine acid g hydrochloride (3·13 g ' 25.0 house) Mohr), anhydrous K2C〇3 (3.45 g, 25 〇 mmol) and NMP (25 liters) were stirred at 60 ° for 1 hour. The reaction was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The resulting brown residue was filtered through a pad of silica gel (35 mL) (dichloromethane / methanol) to afford a brown foam. The title compound N-[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)7 mustard dihydrodione oxime was obtained. [2,3-d] Mouth-2-yl]glycinate as a white solid. Melting point = 212-2130. ” Example 191 (Please read the back note and fill out this page) -185- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 90. 11. 2,000 1298722 A7 B7 V. Description of invention (184)

p jHg-.(2,6-difluorophenyl)-4-(4.fluoro group:j:^stupyl η·8·二急工岬芊4 says "2,3-pyrimidin-2-yl 1 Glycine The product of reaction 190 is reacted by the procedure of the example, and the title compound is obtained (2,6-di-phenyl phenylprotonyl j-methylphenyl pentane I hydrazide [2, 3-d]pyrimidin-2-yl]glycine, as a white solid. Melting point = 26 〇 261. Example 192 (Please read the notes on the back and fill out this page again 15

-·Line· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 2·[[8·(2,6·difluorophenyl) winter (4·fluoromethylmethyl) _7,8_二氤_7_j | Shame on the bite [2,3-d~|, p-but-2-yl 1amino 1-N-ethylamine to give the product of Example 191 (5 mg, 〇.11 mmol) , 1^_Phenylbenzo: 嗤 (2 丨 mg ' 〇 · 34 mmol), μ methyl whf (19 μL, 〇 172 mmol), Ν-methyl tetrahydropyrrolidone ( 2. 5 millimolar) dissolved together, then added 1-(3-diodinopropyl)-3-ethylcarbodiimide hydrochloride (66 mg, -186- this paper size applies to China Standard (CNS) A4 specification (210 X 297 mm) 9〇· 11. 2,000 1298722 A7 B7 V. Description of invention (185) 〇·34 tmol) 'Stir for 1 hour, then add ethylamine (2 Μ, at THF) (1 ml, 2.0 mmol), and the mixture was stirred at <RTI ID=0.0></RTI> </RTI> <RTIgt; ML) and saturated aqueous NaC1 (2 mL), dehydrated and dried 5 (MgS04). Concentration and Chromatotron chromatography (CH2Cl) Purification of 2 /CH3 OH) gave 35 mg of the title compound 2-[[8-(2,6-difluorophenyl&gt; 4-(4-fluoro-2-methylphenyl H,8-dihydro) Ketopyridine [2,3-d]pyrimidin-2-yl]amino]ethylacetamide as a white powder. Melting point = 250-253 (dec.) LC MS (m/e) = 468.2 (MH+). = 1.87 minutes. (Please read the notes on the back and fill out this page) - 济例193

• Line· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed M2,6-difluoro-phenyl) winter (4-fluoro-based 2-methyl-Momo-Imfu _4_某_?) -ethylamine)·8Η-吼 bite and 丨2,3_dl, spray -7-Μ under Ar, 吗福咁 (58 mg, 〇.66 mmol) and trimethylaluminum (2 % 20 , A solution of (0. 33 ml, mil. of millimolar) in dichloromethane was stirred for 10 min. A solution of the product (100 mg, 〇 22 mmol) in dichloromethane (2 mL). The resulting mixture was stirred for 16 h, diluted with EtOAc EtOAc EtOAc. Purification by flash chromatography on silica gel with Et0Ac / hexane / triethylamine (70 / 3 〇 / 2, ν / ν / ^ dissolved 90. 11. 2,000 -187 - 1298722 A7 V, invention description (186) The product was recrystallized from dichloromethane (hexane) to give the desired product (35 mg, &lt;RTI ID=0.0&gt;&gt; Palm

(Please read the precautions on the back and fill out this page) 10 ϋ4·: Fluoryl 1 methyl-phenyl)_2_((RV2-hydroxymethylethylethylamine)-o-methyl-m--gH- Oral ratio and "2,3-dl啼 -7-_ according to the general procedure outlined in Example U6, the product of Example (2) (2 〇〇 mg '0·47 mmol) and (8)-(I) The title compound was obtained as a white solid. EtOAc (EtOAc: EtOAc: EtOAc: Minutes. . . Example 195 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 20

4-(4-Fluoro-2-methyl-methyl-V2-(4-hydroxy-cyclohexylamino)-o-indolyl-8H-pyrido- 2,3-dl-pyrimidin-7-one- 188 - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 1298722 A7 V. Invention description (187) &lt;Please read the notes on the back and fill in this page) Trans-glasylcyclohexanol hydrochloride (27 mg, 235 mmol), NMp (1 mL) and triethylamine (0.33 mL, 2.35 mmol) were stirred at 23 ° for 10 min. The product of Example 121 (2 mg, 0. 47 mmol) was added and the mixture was stirred for 2 hr, diluted with EtOAc and EtOAc. The organic phase 5 was separated and the solvent was evaporated to give a crude material, which was purified from &lt LC-MS: 459.4 (ΜΗ+, m/z), 2.21. (Rt, min). Example 196

15 4: ί4-fluoro-indolyl-styl)-2-((SV2-hydroxy-1-indolyl-ethylamine V8-o-methyl-1-yl-8H-pyrido-f2.3-dl-pyrimidine- 7-Ketone Economics Department Intellectual Property Office Staff Consumer Cooperative Printed according to the general procedure outlined in Example I26, the product of Example 121 (200 mg, 〇·47 mmol) and (SH+)-2-amino-1- Propanol (0.18 mL, 2.36 mmol) gave the desired product 185 mg (94%). LC-MS: 419.2 (MH+, m/z), 20 1.96 (Rt, min). The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 90· U· 2, 〇〇〇1298722 A7 —--; ___B7 V. Description of invention (188)

4-(4-hydroxy-2-bromo-2-methylbenzene)-2-(2-hydroxydimethylhydrazine-ethylamino)-8-o-quinolyl-8Η-pyridine and 2,3-dl-pyrimidine The product of Example 丨21 (222 10 mg, 〇·52 mmol) and 2·Amino-2-methyl-1-propanol (0.25 ml) were prepared according to the general procedure outlined in Example 126. , 2.62 mmol, reaction, to give a crude material. Purified by flash chromatography, eluted with dioxane / ethanol / triethylamine (100 / 1/2, v / v / v), then prepared HPLC, eluted with acetonitrile / 112 〇 (10 / 90 </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 2.10 (Rt, 15 minutes) · (Please read the notes on the back and fill out this page) i Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Example 198

2. Ethylamine base (4) Fluoro-2-methyl·Methyl V8-o-methyl-phenyl--8H-pyridine hydrazine 2 氺 喊 定 -7-7-ketone-190- This paper scale applies to Chinese national standards (CNS) A4 size (210 X 297 mm) 90. 11. 2,000 1298722 A7 B7 V. INSTRUCTIONS (189) According to the general procedure outlined in Example I26, the product of Example 121 (2 〇〇 mg' 〇 · 47 millimoles) reacted with ethylamine (118 ml, Z36 mmol) and 4 in bulk. Purification by flash chromatography, eluting with Et EtOAc / hexane / triethylamine (30/70/2, v/v/v), then recrystallized from dichloromethane and hexane to give the desired product 150 mg. (82%). LC_MS ·· 389 2 (MH+, 2 39 (Rt, minutes) 〇 Example 199

&lt;Please read the notes on the back and then fill out this page.) Order -· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed giM hexylamine·4·(4_fluoromethyl stupyl)-8_邻_甲芡_8H-pyridinium ρ 15 15 dl pyrimidine-7-one is known: according to the general procedure outlined in Example 126, the product of Example (2) (2 mg, 〇·47 mmol) and cyclohexane The amine (0. 27 mL, 236 mmol) was reacted and the crude material was purified <RTI ID=0.0># </ RTI> </ RTI> as described in Example I98 to give the desired product 100 mg (48%). LC-MS: 443.4 (MH+, m.). 2〇 Example 200

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 90, 11· • Line. 1298722 A7 -------B7 ------~------- V. Description of the invention (19〇)-phenyl)-2_(tetraoxane H-based amine V8-o-p-styl--8 team ^L^A『2,3-dl. Miha-7-_ The product of Example 121 (15 mg, 〇·35 mmol) was reacted with 4-aminotetrahydrofuran, G. g., 177 mmol, 5 according to the general procedure outlined in Example 126. The crude material was purified and purified to give the desired product (140 mg). LC_MS: 445.4 (MH+, m/z), 2.27 (Rt, min). Example 201

(Please read the notes on the back and fill out this page; &gt; Printed by the Intellectual Property Office of the Ministry of Economic Affairs, 15 i=(4_Fluoroalkyl-stupyl)-8-o-tolyl-2- α:2·2-Trifluoro-ethylamino V8H-pyridine and 2,3-dlpyrimidin-7-one The product of Example 121 was obtained according to the general procedure outlined in Example I26 (15 mg, 〇.35 Milliol), 2,2,2-trifluoroethylamine (Π6 mg, 177 mmol) was reacted to give a crude material which was purified as described in Example I98 to give the desired product 130 mg. (84%) LC-MS: 443.0 (MH+, m/z), 2.27 (Rt, min). Example 202 -192- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 90 11. 2, 〇〇〇1298722 A7 ____ B7 V. Description of invention (191)

4·(4_Fluoro- 2~-methyl-hydroxyl-hydroxyl-a-methyl-methyl-ethylamine)_8_o-tolyl·8Η·pyridinium 2,3-dl-pyrimidine -7-_ The product of Example 121 (2〇〇10 mg, 〇·47 mmol) and 2-amino-2-indolyl-i,3-propanediol according to the general procedure outlined in Example 6 (494 mg, 4.7 mmol) was reacted to give a crude material, which was purified from &lt;RTIgt; LC-MS: 449.0 (MH+, m/z). (Please read the notes on the back and fill out this page.) Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs.

20-Methyl-methyl-phenyl-terihydropyridinyl 1-indene-dimethyl-acetamidine dimethylamine (11 ml, 2.23⁄4) was prepared according to the general procedure outlined in Example 193. Moer), trimethylmex] ml, 2·2 millimoles) and examples of production&quot;—·--丨~ · ~ 193 - This paper scale applies to the cap national standard (CNS) A4 specification (21G X Move) ------- - Line · 90. 11. 2,000 1298722 A7 B7 V. Invention Description (192) The substance (_mg '0.22 mAh #耳) reacts and obtains the desired product brother mg (54 %). LC-MS: 468·2 (MH+, m/z). Example 204 〇

(Please read the precautions on the back and then fill out this page) 15 卜 卜 from difluoro-phenyl) hopper (4-fluoro ketone -2- -4-yl-ethylamine) · 8 Η - ρ 唆 『 and 2,3-dl 唆-7-ketone according to the general procedure outlined in Example 193, to make the tetrahydro σ ratio slightly (〇·ι8 ml, 2·2 mmol), trimethyl Aluminium (L1 mL, 22 mmol) and the product of Example 19 (100 <RTIgt; LC-MS ·· 494.4 (MH+, m/z), 2_10 (Rt, min). Example 205 Hydropyrazole Order: --Line - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

2m6_difluoro-phenyl)-4-(4-fluoro-2-indenyl-phenyl)-7-one a certain -7,8-dipyridinium. Pre-based amine-based ι-Ν_α-naphthoquinone-fluorenyl)-acetamide-194- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 1298722 A7 V. Description of the Invention (彳93) The general procedure outlined in Example 193 is such that 2-methoxyethylamine (〇17 liters '2.2 mmol), trimethylaluminum (U ml '2.2 mmol) and An example of the product (200 mg, 〇. 44 mmol) was obtained and the desired product was 145 g (66%). LC_MS : 498 2 _+, _, i 9〇 (10), minute b Example 206

(Please read the precautions on the back and fill out this page) 15 HH2,6-Difluoro-phenyl M-(4-fluoro-2-methyl-mosa)-7-keto-7,8•2 Hydropyrido[2,3-dl-pyrimidin-2-ylamine]&gt; and _ know: according to the general procedure outlined in Example 6, the product of Example 48 (5 〇〇 mg 'I 2 mM) and 3-Aminopropionitrile (〇·41 ml, 5.6 mmol) was reacted to give the desired product 270 mg (55%). LC-MS: 436.0 (MH+, m/z). -Line· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 207

_-195- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public I) 90. 11. 2,000 1298722 A7 B7 V. Invention description (194) 4·(4: 虱基冬methyl-菜Shame 咁 基 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Tg, 0·22耄莫耳), 福福σ林 (9) mg, vermiculite 6 mmol) and trimethylaluminum (0.33 house liter, 0.66 mmol), and the desired product 01 mg ( 64%) LC-MS: 431.2 (MH+, m/z), 2.46 (Rt, min).

Read the back note and fill in this page. 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 Enterprise (2,6-Fluoro-phenyl)·4-(4-Fluoro-2-methyl-phenyl -2-(lSRJ!SR)-2-transyl- Wang Qinhexylamine V8H-pyridine and "Z3-dT pyrimidine-7-one" The product of Example 48 was obtained according to the general procedure outlined in Example I95 ( 2〇〇克克' 〇·45 house Moer), trans-mercapto-1-cyclohexylamine hydrochloride (Ml mg ' 2.25 mmol) and triethylamine (OJi ml, 2 · 25 mmol) The reaction was afforded to give EtOAc (md. Example 209 196- ▲ 9〇· 11. 2,000 This paper scale applies to China National Standard (CNS) A4 specification (21〇x 297 mm) 1298722

The product of Example 2〇5 (9) mg, (U millimolar) in di-methane (2 ml) 10 solution, added 1 Μ boron tribromide in dichloromethane (〇·5 ml, 〇·5 Millions of ears). The mixture was stirred at 23 ° for 2 hours, η 2 〇 was added, and the organic layer was dehydrated to dryness (Na; 2SO4) and concentrated to give a crude material. Recrystallization from trichloromethane and hexanes gave the title product (3 mg, 62%). LC-MS ·· 484.2 (MH+, m/z), 1.59 (Rt, min). 15 Example 210 (Please read the note on the back and then fill out this page) Ί^τ· Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

8-(2,6-disorder-phenyl)-4-(4.fluoro-2-t-methyl-phenyl)·2_丨2_(出-四〇坐-5-ethylamine; ^ 1- 8H-pyrido 2,3-dl pyrimidine-7-one The product of Example 206 (2〇0 mg, 0·46 mmol), triethylamine hydrochloride-197- This paper scale applies to Chinese national standards (CNS) A4 size (210 X 297 mm) 9〇· 11. 2, 〇〇〇-line - 1298722 A7 ___- B7______ V. Description of invention (196) (63〇mg, 4.6mmol) and NaN3( A suspension of 299 mg, 4.6 mmol (20 mL) in toluene (20 liters) was heated to reflux with toluene over 6 hrs to give the title compound 1 〇〇 </ br> (45 % LC. 0 (MH+, m/z), 1.82 (Rt, minutes). 5 Example 211

Manic propyl hydrazine 2,6·: fluoro-mosquito) ice (4-fluoromethyl-methyl-styl V7-keto-7,8-pyridine and 2,3-dl-pyrimidin-2-ylamino 1- Acetamide The cyclopropylamine (〇·23 mL, 3.3 15 mmol), trimethylaluminum (丨7 mL, 3 3 mmol) and Example 19〇 were obtained according to the procedure outlined in Example 193. The product (15 mg of 〇·33 mmol) was reacted to give the desired product 2 mg (13%). LC-MS: 480·0 (ΜΗ+, m/z), 1.89 (Rt, min. Example 212 (Please read the notes on the back and then fill out this page -;

-I t»J· . Line · Ministry of Finance, Intellectual Property Bureau, employee consumption cooperation, printing

1298722

----------------- (Please read the notes on the back and fill out this page) 1^. -· Line · A7 --------—_—— _____ --------- V. Description of invention (197)

Hg-(2,6-difluorophenyl)-4-(4-fluoroyl-2-indole-stupid•four-punch_&lt;;•莘methyl)amine-based VSH-pyrobite#『2.3- Dl shout bite 7-ketone a) [8_(2,6-di-I-phenyl)-4-(4-1-yl-2-methyl-phenyl)-7-fluorenyl-7,8-di Hydropyrido[2,3-d]pyrimidin-1ylamino]-acetonitrile 5 The product of the example was obtained according to the general procedure outlined in Example 195 (500 克 ' 1.12 mmol), amin acetonitrile hydrosulfuric acid Salt (I·% g, V mmol) and triethylamine (0.78 mL, 5.6 mmol) at 65. The reaction was carried out for 2 hours to obtain 46 mg of crude material. LC-MS: 421·8 (MH+, m/z), 2. 〇8 (Rt, min). b) 2·[8-(2,6·Difluoro-phenyl)-4_(4-decyl-2-methyl-phenyl)-2·((1Η-tetrazol-5-ylmethyl 10yl) Amino)-8Η-pyrido[2,3-d]pyrimidin-7.one The crude product of Example 2丨2(4) was obtained according to the procedure outlined in Example 210 [8_(2,6--fluoro· Benzo-(4.fluoroylindenyl-phenyl)-7-yl-7,8-dihydroindole [2,3_d]pyrimidin-2-ylamino]-acetonitrile (46 mg), Triethylamine hydrochloride (1·54 g, 11.2 mmol) and NaN3 (728 mg, II·2 mmol) were reacted to give 50 mg (9.6%) of desired product. LC-MS : 465.2 (MH+,m/z), 1.79 (Rt, minutes). Example 213 Printed by the Intellectual Property Office of the Ministry of Economic Affairs

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 90. 11. 2,000 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 90. 11. 2,000 1298722 A7 _____B7________ V. Description of Invention (198) a Trans-2-azido-cyclopentanol in oxidized cyclopentene (2.0 g, 23.8 mmol) in CH3〇H and H20 (4 mL) (4/l, v/v) NaN3 (7.7:3 g, 119 mmol) and 1^ (:1 (3.17 g, 59.2 mmol) were added to the solution. The resulting mixture was heated to reflux 5' for 18 hours, then The mixture was cooled to 23. The mixture was evaporated. EtOAcjjjjjjjjjjjjjjj : 5 4.10 (m,1H), 3.72 (m,1H),2·10 (m,2H),1.72-1.60 (m,4H)· b) trans-2-amino-cyclopentanol hydrochloride 1 〇 10% Pd/C (0.5 g) was added to a solution of trans-1 azido-cyclopentanol (Ig, 7.87 mmol) in Et0Ac. The mixture was flooded with Ar and then admixed for 2 hours at 40 psi and 23 ° on a Parr apparatus. The mixture was filtered through celite and the celite was washed with Et0Ac. The filtrate was acidified with 3 ml of 4NHC1 in M-dioxane, and a white solid precipitated. The mixture 15 was filtered and the solid was collected to give the desired product &quot; (0.76 g, 99%). 1 H NMR (MeOD_d4) : 6 4.09-4.04 (m,1H), 3.29-3.25 (m,1H), 2.18 (m,1H), 2.03 (m,1H),1.83-1.80 (m,2H),1.65 -1.58 (m,2H)· c) 2-[8-(2,6-Difluoro-phenyl&gt;4PFC--2-phenyl)phenyl)_2_(1SR,2SR) 4-hydroxycyclopenta Aminoamine &gt; 8H-Pyridine[2,3-d)-pyrimidin-7-one 20 The product of Example 48 (200 mg, 0. 45 mmol) was obtained according to the general procedure outlined in Example 195. , trans 1 amino-cyclopentanol hydrochloride (227 mg, 2.25 mmol) and triethylamine (〇·31 ml, 2·25 mmol) were reacted for 2 hours to obtain the desired product 63 mg. (3〇%). LC-MS ·· 467.0 (ΜΗ+, m/z), 2.09 (Rt, min). —_______-200- This paper size is applicable to China National Standard (CNS) A4 specification (21〇x 297 mm) (Please read the notes on the back and fill out this page again) gt; Wide order -·-Line· 1298722 A7 B7 d V. Description of the Invention (199) Example 214

2-[8-(2,6-&gt;mono-n-yl)-4-(4-diyl-2-indenyl-enyl)-2-(3-methylthio-propylamino)-8H Pyridine and f2,3-dlpyrimidin-7-one The product of Example 48 (2 mg, 〇·44 mmol) and 3-(methylthio)propylamine were obtained according to the general procedure outlined in Example l26. 231 mg, 2.2 mmol (m.). LC-MS: 471.2 (ΜΗ+, m/z), 2.37 (Rt, min). _____________^«" (Please read the notes on the back and fill out this page first), - 15 Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Consumers' Cooperatives Example 215

--Line · 20 Diqi-Phenylfluoro-2-methyl-stupyl V2-(3-decanesulfonyl-propan-1)-8H-bite and "2,3-d~| Ha-7-M In a solution of the product of Example 2U (12 mg, 〇·26 mmol) in dioxane (5 mL), m-chloroperbenzoic acid (13 mg, 〇 52 millimoles) -201 - 90· 11. 2,000 1298722 A7 B7 V. Description of invention (200). The mixture was at 23. Under the #丨.5 hours. The mixture was diluted with Et 〇Ac and washed with % ’ to give a crude material. Purification by column chromatography eluting with EtOAc /EtOAc (EtOAc /EtOAc) LC-MS: 503.2 (MH+, m/z). Example 216

(Please read the notes on the back and then fill out this page. Θ Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed 248-(?.Cold:_Difluoro·Fungi)·4_(4·Fluoromethyl-Phenyl) _2·(3·keto-hexahydroindole_·1-yl-Vethylamine-based V8H-bite and f2,3-d~|° 唆-7-one 15 is generally as outlined in Example 193. The procedure is to make the hexahydro-sigma ratio. Well (165 pg 'I·65 house Moule), dimethyl meme (〇83 ml, 1 65 mmol) and the product of Example 190 (15 mg, 0J3 mmol) The reaction was carried out to obtain a crude material. Prepared HPLC was eluted with acetonitrile / Η 2 〇 (ΙΟ / %, v / v to 9 〇 / 1 〇, ν / ν 1 〇 minutes), followed by dichloromethane and hexane Recrystallization, to obtain the desired product, 20 g (29%). LC-MS: 523.2 (ΜΗ+, m/z) 5 1.68 (Rt, min). Example 217 -202- This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) 90. 11. 2,000 - line. 1298722 A7 Qin V_ B7 V. Invention description (201)

MH2,6·difluoro-benzoic acid ice (4_fluoro-2-_2-methyl-chyl ν2-Γ(5_methyl_4H 十 2 41 兰; salvage A V 脍 1_8H_P pyridine) [~2 3-dl-pyrimidine-7-one The product of Example 48 (15 mg, 〇·34 mmol) and (5-methyl 10-triazol-3-yl)-methylamine (190 mg, 1.7 Milliol) solution in NMP (2 ml) was stirred at 100 ° for 16 hours to give a crude material. Prepare HPLC, acetonitrile / 112 〇 (1 〇 / 90, 〜~~9 〇/10, ¥/¥, after 1 minute), dissolve to obtain the desired product 23 mg (14%). LC-MS: 478.2 (MH+, m/z), 1.70 (Rt, min) 15 or, the desired product can be borrowed Purification by flash chromatography, eluting with EtOAc / triethylamine (100/2, v/v), then recrystallised from EtOAc and methanol to the hydrochloride salt. Example 218 (Read the back I.) ιδ]·. --Line. Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative

M8-(2,6-difluoro-phenyl)ice (4fluoro-2-methyl-methyl)-2-((1,1-dione-tetra-203- this paper scale applies to China) Standard (CNS) A4 size (210 X 297 mm) 90. 11. 2,000 1298722 A7 B7 Jade, invention description (2〇2) 口口塞--3·-ylmethyl)-aminopyridine hydrazine 2· 34 唆 -7-嗣 According to the general procedure outlined in Example 217, the product of Example (10) (1 〇〇 mg '0·22 mmol) and 3 胺 曱 环 环 ( (Mg mg, The reaction was carried out to give a crude material, which was purified by flash chromatography, eluting with EtOAc / 5 hexane / triethylamine (65/35/2, v/v/v) to give the desired product 25 Mg (22%). LC-MS ·· 515.4 (MH+, m/z), 1.97 (Rt, min).

15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 8-(2.,_6-difluoro-phenyl)-4-(4-fluoro-based methyl group with a V2-"3-methyl-iso-lt; Benz-5-ylmethyl)amino)·8Η·pyridine and 2J-dl pyrimidine-7-one, according to the general procedure outlined in Example 217, the product of Example 48 (1 〇〇 mg ' 0.22 mM The ear is reacted with (3-mercapto-isoxazole·5-yl)·guanamine (125 mg, 1.12 mmol) to give the desired product 5 mg (see).]^!^ ·· 478.2 (ΜΗ+, m/z), 2.20 (Rt, minutes). Example 220 -204- 90. 11. 2,000 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public)

1298722 Α7 Β7 V. Description of invention (2〇3) For palmity 2-[8-(2,6-difluoro-phenyl&gt;4-(4-fluoro-2-methyl-菜-V2-( (3S,4S)-4.Phenyl-1,1-dione-tetrahydroammonium)-8H-pyridoxin-2·3-(Γ|N--7-one as outlined in Example 217 The general procedure for reacting the product of Example 48 (100 mg, 0.22 mmol) with 3(S)-amino-4(S)-hydroxysulfolane (169 mg, 1.12 mmol) gave the desired The product was 50 mg (44%). LC-MS: 517.0 (MH+, m/z), 1.87 (Rt, min). Example 221 ----I---------i ! Please read this page on the back of the reading page.

i line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed j-[8-(2,6-difluoro-phenyl)-4-(4-carbyl-2-mercapto-phenyl ketone-2, 3-Dihydro-bromo-4-ylamino>&gt;8-pyridyl-Z3-dl-pyrimidin-7-one The product of Example 48 was obtained according to the general procedure outlined in Example 217 (100 mg, 0.22 mmol) The ear is reacted with cytosine (I24 mg, I" 2 mmol) to obtain the crude material. The preparative HPLC is obtained as the title compound: 27 mg (20%) - 205 - The paper size is applicable to the Chinese National Standard (CNS) A4 specification. (210 X 297 mm) 90. 11. 2,000 1298722

V. Description of the invention (2〇4). LC-MS: 477.2 (MH+, m/z). Example 222

-milk: phenyl hydrazine-(4. fluoro-2-methyl-carbyl group 0), amine group V8H-pyridine and (2,3-dl pyrimidine-7-one (1H-imidazole) 2_yl)-guanamine dihydrochloride (184 mg, u mmol), NMP (1 ml) and triethylamine (〇 ji ml, μ mmol) were given for 1 min in μ. The product of Example 48 (100 mg, EtOAc: EtOAc (EtOAc) (MeOH) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH MS: 463.2 (MH+, m/z), 1.42 (Rt, minutes). Example 223 (please read the notes on the back and fill out this page) Scales · Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print 20

VNH 2-[8-(2,6-Difluoro-phenyl)4-(4-fluoroyl_2.methyl-phenyl)-2-(lH-"U,41 triazole_3_yl-206 · This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 [298722 A7 B7 V. Description of invention (2〇5) Amine)-8H-pyridine# ddl pyrimidine according to κ The general procedure outlined in Example 217 gave the product of the example (15 〇 mg '〇·33 mmol) to the 3-amino-1,2,4_three sigma (141 mg, 丨68 mmol) The reaction was carried to give a crude material. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;

I

15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 2_[8 two (?> two I-phenylfluoro-4-methyl-benzene V2-(1H-tetrazol-5-ylamine)-8H - Pyridyl-~2,3-d|Azulidine-7-M The product of Example 48 (15 mg < 0.33 mmol) and 5-amino-1H was obtained according to the general procedure outlined in Example 217. - tetrazole (ία mg, I.68 mmol) was obtained as a crude material. m. m. z), 2·04 (Rt, minutes). Example 225

-207- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 90. 11. 2,000 [298722 A7 B7 V. Description of invention (2〇6) Methoxy-ethylamine h8H_ Compared with the mouth [~2,3_dl, sprayed, 7-_ will be the product of Example 48 (丨5〇 mg, 〇34 mmol) and 2 (〇·〇9 ml, UU millimolar) in DMF ( The solution in 2 ml) was stirred for 16 hours. The mixture was diluted with Et.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. LC-MS: 441·2 (MH+, m/z), 2.10 (Rt, min). Example 226

(Please read the notes on the back and then fill out this page) 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 ii2,.^rr-Fluorine-shame 1^(4·乱基phenyl)·2·(four n __3_ a face of it&gt;8Η-pyridine and f2,3-dl uracil-7-one a) (tetrahydrofuran I group)-amine methyl acid third butyl ester under Ar, (Extra-tetrahydrofurancarboxylic acid (5 mg, 43 mmol) in a solution of DMF (2 mL), add triethylamine (〇66 ml, 4 mM) to $ Nitridate a base plate S (1.02 ml, 4 J4 mmol). The mixture was heated to 80. After 3 hours, cooled to 23. Then add a second-butanol (33⁄4 liter) and The resulting mixture was stirred for π hr. The mixture was diluted with EtOAc and washed with EtOAc.

90. 11. 2,000 • Line - 1298722 A7 V. Description of invention (207) b) Tetrahydro-furan·3-ylamine hydrochloride -------------- Install I (please Read the instructions on the back and fill out this page) Add 2 to the solution of the crude (tetrahydro-furan-3-yl)-amine methyl acid, the third-butyl ester (46 mg) in EtOAc (10 mL) The milliliter is in 4NHC1 in dioxane. The mixture was at 23. After stirring for 16 hours, it was concentrated to give a crude material (240 mg). c) 8-(2,6-fluoro-based)-4-(4.fluoro-2-oxa-phenyl)·2·(tetrahydro-furanylamino)-811-11 ratio唆弁[2,3-dp 喘 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _Likeamine hydrochloride (24 mg) 10 and triethylamine (〇·27 ml, I·9 mol) were reacted to give a crude material. Purification by flash chromatography eluting EtOAc / EtOAc / EtOAc (EtOAc (EtOAc) LC-MS: 453.2 (MH+, m/z). Example 227

• Line· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 8-(2,6-di-I-phenyl H_(4_fluoromethylmethyl phenyl) hydroxy-ethylcarbamamine 1-8H- Pyridinium "2·3-(Γ|pyrimidin-7-one) The product of Example 48 (1〇〇家克 '0.22 house mole), Ν-methylethanolamine (〇) according to the general procedure outlined in Example U6 ·〇5 ml, 〇66 mmol) ______ - 209 - 90. 11. 2,000 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1298722 A7 B7 V. Invention Description (2〇8 The reaction was allowed to proceed for 2 hours to give a crude material, which was taken from the purified HpL (purified to give the title compound 26 mg (27%). Lc-Ms: 2 (MH+, ring, 2 W (Rt, min)). Example 228

M2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-momium V2-"2-rm-mouth 岫-4-, its fe base ratio g 定定ρ定-7 - The product of Example 48 (15 mg, 〇.34 mmol) was reacted with histamine (187 mg, 丨.68 mmol) according to the general procedure outlined in Example 217. Product 50 mg (31%). LC-MS: 477.0 (MH+, m/z), 1.59 (Rt, min). (Please read the note on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Office, Staff Cooperatives System 20 example 229

[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl-7-keto-7,8-dihydroanthracene). 90. 11. 2,000 paper scales are applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1298722 A7 B7 V. Description of invention (2〇9) f2,3-dl feeding 11--2 amino group 1-Ethylamine in a solution of dimercaptoaluminum (3.3 ml, 6.6 mmol) in di-methane, foamed with NH3 gas for 30 minutes, then add the product of Example 19 (5 (8) mg, 1·1 The mixture was stirred for 16 hours. The mixture was diluted with EtOAc and washed with EtOAc EtOAc EtOAc EtOAc , ν / ν), the desired product (263 mg, 54%). LC-MS: 440.0 (MH+, m/z), 1.75 (Rt, min). Example 230 Read I page I

〇 经济 经济 经济 经济 智慧 智慧 智慧 智慧 智慧 智慧 智慧 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 Ketooxime-7,8-dihydroanthraquinone and "2,3-dl-mouth-2-yl 1-nonanamine a) 2-amino-8-(2,6-difluoro-phenyl)-4 The product of (4. fluoro-2-methyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one in Example 48 (1.0 g, 2.2 min) Triethylamine (1 ml) was bubbled with NH3 gas in a solution of 2 ml of NMP at 23. It took 30 minutes. The mixture was diluted with EtOAc and washed with EtOAc EtOAc. Purification by flash chromatography with EtOAc / hexanes / triethylamine (5 〇 / / / / / / / / / / / / / / / / / / / / / / / Mg, 43%). LC-MS: 383.0 (MH+, m/z). -211 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 1298722 A7 V. Invention description (21〇) b) Cyclopropanol acid [8·(2, 6-Difluoro-phenyl&gt; 4-(4-fluoro-2-methyl-phenyl)-7. keto. 7,8-dihydropyrido[2,3-d]pyrimidine_2_ ] 醯 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于(1 mg, 〇% mmol) NaH (19 mg, ο" mmol) was added to a solution of 3 5 liters of tetrahydrofuran. The mixture was stirred at 23 ° for 2 min, cyclopropane was added. a solution of carbonyl chloride π mg ' 〇 · 26 mmoles in tetrahydrofuran (1 mL). The resulting mixture was heated to reflux with solvent for 10 hr to give crude material which was purified by preparative HPLC. Get 25 mg (21%. LC_MS: 451 2 10 (MH+, m/z), 2·14 (Rt, minutes). (Please read the note on the back and fill out this page) Pack 15 Example 231

Order: • Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 alkyl carboxylic acid (1-cyclopropyl-methyl hydrazine V "8-(2.6-dioxin _ stupid H-(4-fluoro-2) -Methyl-phenyl)-7-keto-7,8-dihydropyridyl and "2,3-(11-pyrimidin-2-yl 1-decylamine) was obtained from the reaction of Example 230, after purification by HPLC The second compound, the title compound was purified, 33 mg (24%). LC-MS: 519·0 (ΜΗ+, m/z), 2.37 (Rt, min). Example 232 -212- The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 90. 11. 2,000 1298722 A7 _____ B7 V. Description of invention (211)

Difficulty-ethylamino)-8H-indole- and f2,3-d|pain _7-ketone according to the general procedure outlined in Example 193, thio-fufu oxime (〇·22 mil 10 liters) , 2·2 millimolar), tridecyl aluminum (U ml, 2.2 mol) and the product of Example 19 (200 mg, 0.44 mol), and the desired product 2 mg (86%). LC-MS: 526.0 (ΜΗ+, m/z), 2.07 (Rt, min). Example 233

(Please read the note on the back and then fill out this page) Binding: --Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 8-(2,6-two-stupid)-4-(4- _ 2-methyl-stupyl V2-"tetrahydrofuran-2-ylindenyl)-amino 1 - appended - 吼 g 弁 "2,3-dl ^ -7 -7---the general procedure outlined in Example 225 The product of Example 48 (100 mg, 0. 22 mmol) and THF (EtOAc, EtOAc (EtOAc) (MH+,m/z), __-213:_ ____ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 9〇. 11· 2,000 1298722 A7 j _____ B7 V. Description of invention (212 ) 2.22 (Rt, minutes).

Example 234 F

(Please read the precautions on the back and fill out this page) έ·1〇8-(2,6-一乱-笨基)-4-(4-Alkyl-2-methyl-stupyl)-2 - "2-(3-Acyl-one gas to the same 1-yl V2-keto-ethylamino 1-8H-pyridine and "2.3-dl pyrimidine-7-one a) - azatetraindole-3-ol Add 10% Pd/C (1.0 g) to a solution of 1-diphenylhydrazine-nitrotetradecyl-3-ol (1.0 g, 4.16 mmol) in methanol (2 mL) And 4NHC1 (2 ml) in I,4·dioxane 15 . The mixture was flooded with Ar and then on a Parr apparatus at 40 psi H2 and 60. Stir under 6 hours. The mixture was allowed to cool to room temperature and filtered through celite. The filtrate was concentrated, and the solid was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted , 3.91 (m, 2H). 2〇b) 8-(2,6-one gas-based)-4_(4-carbyl-2-methyl-phenyl)-2-[2-(3- [-(4-,6-di-I)-phenyl) ice (4.Fluoromethyl-phenyl)^7-based _7,8-dihydroindole sigma-[2,3-d] sputum-2-ylamino]-acetic acid (1 mg, 〇23 mM), nitrous tetrahydrazide hydrochloride (37 mg, 0.34 mmol), hexafluoroantimony benzophenone 214- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Order-· Line· Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Ministry of Printing and Economy Ministry Intellectual Property Bureau Employees Consumption Cooperatives Printed 1297822 A7 ___B7 _ V. Invention Description (213) Triazole Small Group-N,N, Mixture of Nf, N'-tetramethyl sulphate (129 mg, 0.34 mmol) and N-methyl-folamine (0.12 mL, 1.133⁄4 mol) in DMF (2 mL), stirring at 23. 16 hours, getting crude material, making it The preparatory HPLC purification to give the title compound 56 mg (49%) .LC-MS: 496.2 5 _ +, m / z), 1.69 (Rt, min). Example 235

4-(4-Fluoro-2-indenyl-phenyl)-2-((R)-2-hydroxy-propylamino)-8-o-indoleyl-8H-pyrido-f2,3-dl-pyrimidine -7- Ketone 15 The product of J21 (120 mg, 0.28 mmol) and R (-)-l-amino-2-propanol (0.064 mL, 0.85 mmol) according to the general procedure outlined in Example 225. Ear) reacts to get a crude substance. Purification by flash chromatography, eluting with EtOAc / hexane / triethylamine (50/50/2, v/v/v), then recrystallised from dichloromethane and hexanes to give the desired product 110 mg. %). LC-MS: 419.0 (MH+, m/z), 20 1.83 (Rt, min). Example 236 -215-, the paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 (please read the note on the back and fill out this page again) Η - Install 1298722 Ministry of Economics Property Bureau employee consumption cooperative printing 5, invention description (214)

4_(4·乱基-2-methyl-jamolyl)-2-(2·ylaminomethyl-propylamino-methyl-l- 8H-pyrido- 2,3-dl-pyrimidin-7-one The general procedure outlined in Example 225, the product of Example m (12 〇 10 mg, 〇·% mmol) and 1-aminomercapto-2-propanol (?6 mg, ο·% mmol) The reaction is a crude material. It is purified by flash chromatography and dissolved in Et〇Ac / hexane/difefe (50/50/2, v/v/v), followed by two gas and calcined Recrystallization <96 mg (79%) of desired product. LC-MS: 433.4 (MH+, m/z), 1.87 (Rt, min).

Fluorosyl-2-methyl-phenyl) -7 ketones 一 一 一 一 一 一 2 2 2 2 2 2 2 2 2 ι ι ι ι ι ι ι 按照 按照 按照 按照 按照 按照 按照 按照 按照 按照 按照 按照 按照 按照 按照 按照 按照 按照 按照 按照 按照Product (15〇-216 - This paper size applies to China National Standard (CNS) A4 specification (21G X 297 public)------ 90. 11. 2,000 (Please read the back note first and then fill out this page ) .线. 〇

1298722 A7 B7 V. Description of the invention (215) mg, 〇·34 mmol) reacted with a 2-amino-5-cyclopentane carboxamide (139 mg, 1.02 mmol) to give a crude material. . Purification by flash chromatography, eluting with EtOAc / hexane / diethylamine (5 〇 / / / / / / / / / / / / / / / / / / / / / / / / / Mg (52%). 1^-1^8: 494.0 (ΜΗ+, m/z), 2.00 (Rt, minutes). Example 238 for the palm of the genus Fluoryl-2-mercapto-phenyl)-2-((S)-2-hydroxy--3⁄4 face-based V8-o----------------------------- ---------装-------Book· (Please read the notes on the back and fill in this Iy

15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 pyridine and f2,3-dl pyrimidine-7-one according to the general procedure outlined in Example 225, the product of hydrazine (22 〇 mg '0.52 mmol) and (S)-(+)-l-Aminopropanol (〇丨2 ml, 1 brother millimolar) reacted to give a crude material. Purification by flash chromatography, eluting with Et EtOAc / hexane / triethylamine (50/50/2, v/v/v), then recrystallized from dichloromethane and hexanes to give the desired product 135: 3⁄4 grams (62%). LC-MS: 419.2 (MH+, m/z). Example 239 Line -217- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 1298722 A7 _—_— B7 V. Description of invention (216)

15 2^8-(2?6-Difluoro-phenyl): 4·(4-Fluoro-I-methyl-phenyl)·2-methylamino _8H-pyridinium and 2,3-dl Pyrimidine-7-one The product of Example 48 (1 g, 2.24 mmol) was reacted with decylamine (5. 6 mL, π 2 mmol) according to the general procedure outlined in Example 225. Get crude material. Purification by flash chromatography, eluting with Et EtOAc / hexane / triethylamine (30 / 7 /2 / / / / / / / / / / / / / / / / / / / / / / Mg (48%). LC-MS: 397.2 (ΜΗ+, m/z), 2.14 (Rt, min.). Example 240 (Please read the note on the back and fill out this page) • Install ιδι· Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative 20

Package 2,6-di-phenyl)_2_丨2_(y^keto-_n6_thiophene oxime-based V2_ketone _ 1 cleavage group] (4_fluoromethyl V8H-pyridine #『Z3-dl-pyrimidin-7-one The product of Example 232 was obtained according to the procedure outlined in Example 215. 8_(2,6-two&quot;218- This paper was used on the m-scale of the dry country (CNS) A4 Specification (21〇X 297 male cage) 90. 11. 2,000 •-line · 1298722 A7 __ B7_____ V. Description of invention (217) Fluoro-phenyl &gt; 4·(4-Fluoro-2·methyl·benzene 2-(2-keto-2-thiophene π linyl · ethylamine)-8H-pyrido[2,3-d]pyrimidin-7-one (I64 mg, 0.31 mmol) Reaction with m-benzoic acid (156 mg, 0.62 mmol) to give the desired product 165 mg (95%). LC-MS ·· 558.2 (MH+, m/z), 1.77 (Rt, Minutes. 5 Example 241

----I--I--IIII ^ ! (Please read the precautions on the back and fill out this page first) Printed by the Ministry of Commerce, Intellectual Property Office, Consumers' Cooperatives 2-[8-(2?6-,^ --本基)_4-(4-Alkyl-2-methyl-phenyl)-2-(3-(2-Amino-tetraoxylpyrrolidine-1-yl-V-propylamine-based V8H-pyridine#" 2,3-dl-pyrimidin-7-one The product of Example 48 was obtained according to the general procedure outlined in Example 225 (1 〇〇I5 gram 〇 22 莫 Mo) and N-(3'-Aminopropyl propyl ) _2 四 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc 2, v/v/v) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 20 Example 242

____ -219- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 90. 11. 2,000 --Line · 1298722 Α7 Β7 V. Invention description (218) HM2,6·Dimorph-benzene H-(4_Fluoro.2_indolyl-phenylhydrazine V7-keto-7,8·2j.pyrazine [2,3-〇11-Butyl-2-ylamino-l-^ - a solution of hydroxylamine hydrochloride (119 mg, 172 mmol) and triethylamine (0.26 ml, 1.893⁄4 mol) in 53⁄4 L of J3MS0 under a base-C. Stir at 5 ° for 5 minutes, add the product of Example 206. [8-(2,6-Difluoro-phenylfluoroindolyl-phenyl keto-7,8-dihydropyridinium [2,3_ (ΐ]pyrimidine_2_ylamino]propionitrile (150 mg, 0·34 mmol). The resulting mixture was heated to 8 〇0 over 16 hours. Prepared HPLC followed by ethanol and The alkane was recrystallized to give the desired product 80 mg (45%). LC-MS: 469.2 (?+, m/z), 1.52 (Rt, 10 min). Example 243 (Please read the notes on the back and fill in the form) page)

--Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed Μ?,6·II I-benzene 1&gt; 4-(4-carbyl-2-methyl-phenyl-V2-r2-d4,5-dihydrogen 〇_, 2, 41-5 di-salt-peak_ethylamino)_8H_pyridine total "2,3_pyrimidine_7·醎20 under the armpit, the product of Example 242 3-[8-(2, 6-Difluorophenyl)ice (4-fluoro-2-methyl-phenyl)-7-keto-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino Add 2-ethylhexyl chloroformate to a solution of pyridine-hydroxyl-propionate (100 mg, 0·20 mmol) and pyridine (0. 〇 48 ml, 〇·6 mmol). · 039 ml, 〇·2 mmol.) Stir the mixture at room temperature for 2 hours, then dilute with % ,, and apply the Chinese National Standard (CNS) A4 to the paper size of -----__ 220 Specifications (21〇χ 297 mm)----- 9〇· 11. 2,000 1298722 A7 __ B7 V. Description of invention (219)

Extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was diluted with a liter of hexanes and heated to reflux. mp was obtained over 18 hrs to afford crude material, which was purified by preparative HPLC and 28 mg (28%) of desired product. LC-MS ·· 495.0 (ΜΗ+, m/z), 1.96 (Rt, 5 minutes). All publications cited in this patent specification, including but not limited to patents and patent applications, are hereby incorporated by reference in their entirety as if individually individually individually individually individually For general reference. The above description is complete to reveal the invention, including its preferred embodiments. Modifications and improvements of the specific embodiments disclosed herein are within the scope of the following claims. Those skilled in the art will be able to use the present invention to its fullest extent without further elaboration. Therefore, the examples herein are to be construed as merely illustrative, and the scope of the invention is not limited in any way. In the embodiment of the invention, the excluded nature or specific interest claimed is defined as follows. — — — — — — — — I l· (Please read the notes on the back and fill out this page again) - Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print this paper scale Guanjia Standard (CNS) A4 Specifications 221 221 - χ2^Γ 「" 90. 11. 2,000

Claims (1)

‘!] 乂 f Patent Application No. 90125987 ROC Patent Appln. N〇.90125987 After the amendment, there is no scribe line, the text of the patent is attached to one (3) Sixth, the scope of application for patents (submitted on December 2, 1996, Republic of China) (Submitted on December l\, 2007) ^98722 1·Compound 8-(2,6-difluoro-phenyl)-4-(4-fluoro- 2-indenyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidinone or a pharmaceutically acceptable salt thereof. 5 2. A pharmaceutical combination for treating a disease mediated by CSBP/P38 kinase, comprising an effective amount of 8-(2,6-difluoro-phenyl MH2_methyl-phenyl)_2-(2- Hydroxyl-hydroxymethyl-ethylamino)_8H-pyrido[2,3_d&gt; pyridine-7-- or a pharmaceutically acceptable salt thereof, as an active ingredient, and a pharmaceutically acceptable carrier or Thinner. 10 3·-8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)_2-(2-aryl-1-hydroxymethyl-ethylamino) The use of-8H-pyrido[2,3-d]pyrimidin-7-one or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease mediated by CSBP/RK/p38 kinase in a mammal. 4. According to the application of the third paragraph of the patent application scope, csBp/RK/p38 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed clothing 15 (4) The media is psoriatic arthritis, Lai's syndrome, gout, trauma Arthritis, rubella arthritis, acute synovitis, 'rheumatoid arthritis, rheumatic spondylitis, osteoarthritis, gouty arthritis and other arthritis symptoms, septicemia, septic shock, endotoxin shock, leather Blue-negative septicemia, toxic shock syndrome, cerebral malaria 20 brain f [hemoptysis and hemorrhagic stroke, nerve trauma/closed head injury, asthma, adult dyspnea syndrome, chronic pneumonia disease, chronic obstructive pulmonary disease, Shiyue soil disease, pulmonary sarcoma disease, bone depletion disease, osteoporosis, restenosis, heart, viscera and cerebral palsy and renal reperfusion injury, septic heart failure, coronary artery bypass graft (cabg) surgery, 25 thrombosis , spheroid nephritis, chronic renal failure, diabetes, sugar-222 - This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 90509B-connected 2 Ϊ 298722 A8 B8 C8 D8 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing, application for patent area Retinopathy of patients with urinary disease, speckle degeneration, transplant response to host, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, Neurodegenerative diseases, muscle deterioration, tumor growth and metastasis, angiogenic diseases, pneumonia caused by influenza, moist therapy, contact 5 dermatitis, psoriasis, sunburn or conjunctivitis. 5. The use according to item 3 of the scope of the patent application, wherein 8-(2,6-difluoro-phenyl)-4-(4-gas-2-methyl-phenyl)-2-(2-3⁄4yl) -1-3⁄4 benzyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating inflammation in a mammal. -223 - This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm)