WO2023119210A1 - Novel compound as ripk1 inhibitor and pharmaceutical composition comprising same - Google Patents

Novel compound as ripk1 inhibitor and pharmaceutical composition comprising same Download PDF

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Publication number
WO2023119210A1
WO2023119210A1 PCT/IB2022/062655 IB2022062655W WO2023119210A1 WO 2023119210 A1 WO2023119210 A1 WO 2023119210A1 IB 2022062655 W IB2022062655 W IB 2022062655W WO 2023119210 A1 WO2023119210 A1 WO 2023119210A1
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c5alkyl
compound
mmol
reaction
independently
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PCT/IB2022/062655
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French (fr)
Korean (ko)
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이창석
공선주
용우순
이상욱
김태정
박성훈
박지선
이한창
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제일약품주식회사
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • Novel compounds as RIPK1 inhibitors and pharmaceutical compositions containing them ⁇ NOVEL COMPOUNDS AS RIPK1 INHIBITOR AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME ⁇
  • the present invention relates to compounds as RIPK1 inhibitors, stereoisomers, tautomers, pharmaceutically acceptable salts thereof, hydrates or solvates thereof, pharmaceutical compositions containing the same, and RIPK1 activity using the compounds. It relates to methods and uses thereof for the prevention or treatment of related diseases.
  • Protein kinase is an enzyme that catalyzes a phosphorylation reaction that transfers a gamma-phosphate group of ATP to a hydroxy group of tyrosine, serine, and threonine of a protein. Protein kinase is responsible for cell metabolism, gene expression, cell growth, differentiation and cell division, and plays an important role in cell signal transduction (Thomas A. Kami Iton, in Encyclopedia of Immunology (Second Edition) , 1998, 2028- 2033). Protein kinases are classified into tyrosine protein kinases ⁇ serine/threonine kinases, of which about 90 or more are tyrosine kinases.
  • Protein kinase is a molecular switch, and the transition between active and inactive states in cells must be smoothly regulated. If the active and inactive state When the transition between cells is abnormally regulated, intracellular signal transduction is excessively activated, leading to uncontrolled cell division and proliferation. In addition, abnormal activation by genetic mutation, amplification, and overexpression of protein kinase is related to the development and progression of various tumors, and thus plays a crucial role in the development of various diseases such as inflammatory diseases, degenerative brain diseases, autoimmune diseases, and cancer.
  • RIP1 kinase Receptor-interacting serine/threonine-protein kinase 1, RIPK1 belongs to the receptor-interacting serine/threonine kinase family (receptor-interacting ing Ser/Threonine-protein kinase family), and is involved in the TNFR1 signaling pathway. It is an important upstream kinase in the (Tumor necrosis factor receptor 1 si gna 1 ing pathway). RIPK1 is a key regulator of inflammation, apoptosis and necroptosis.
  • RIPK1 Activated RIPK1 induces inflammation and directly regulates programmed necrosis, and RIPK1 participates in a broader range of proinflammatory activities than is restricted to TNF. Since RIPK1 is an important regulator of apoptosis that plays a key role in inflammatory signaling related to tumor necrosis factor, inhibition of RIPK1 can block TNF-a-induced inflammation (Front. Cell Dev. Biol., 13 August 2019). Recent studies have demonstrated that the activity of RIPK1 controls a form of necroptosis, necrotic cell death traditionally thought to be passive and unregulated and characterized by a unique morphology. Additionally, RIPK1 is part of the pro-apoptotic complex that exhibits its activity in regulating apoptosis.
  • RIPK1 is subject to complex and esoteric regulatory mechanisms including ubiquitination, de-ubiquitination and phosphorylation. These controls determine whether cells survive, activate inflammatory responses, or die through apoptosis or necroptosis. comprehensively decide whether Studies have shown that dysregulation of RIPK1 signal transduction can induce excessive inflammation or apoptosis, and conversely, inhibition of RIPK1 can be an effective treatment for diseases involving inflammation or apoptosis.
  • RIPK1 Cell necrosis mediated by RIPK1 has been reported to be associated with various diseases such as inflammatory diseases, degenerative brain diseases, autoimmune diseases, and cancer. Engineered to completely block RIPK1-mediated programmed necrosis, RIP3 knockout mice have been shown to be resistant to inflammatory bowel disease (including ulcerative colitis and Crohn's disease), psoriasis, retinal-detachment-induced photoreceptor necrosis, and retinitis pigmentosa. ), cerulein-induced acute pancreatitis and sepsis/systemic inflammatory response syndrome (SIRS). In addition, RIPK1 has also been reported to mediate the microglial response in Alzheimer's disease.
  • inflammatory bowel disease including ulcerative colitis and Crohn's disease
  • psoriasis psoriasis
  • retinal-detachment-induced photoreceptor necrosis and retinitis pigmentosa.
  • RIPK1 has shown promise in animal models of diseases ranging from acute ischemic conditions to chronic inflammation and neurodegeneration.
  • RIPK1 plays a very important role in inflammation and apoptosis, and is a target material for neurodegenerative diseases and anti-cancer drugs as well as autoimmune-related diseases such as rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease (IBD).
  • RA rheumatoid arthritis
  • IBD inflammatory bowel disease
  • Patent Document 1 Korean Patent Publication No. 2018-0114910
  • Patent Document 2 Korean Patent Publication No. 2020-0088945
  • Patent Document 3 W0 2020/056074
  • Patent Document 4 Korean Patent Publication No. 2018-0023988
  • Non-Patent Document 1 Thomas A. Kami Iton, in Encyclopedia of Immunology (Second Edition), 1998, 2028-2033
  • Non-Patent Document 2 Front. Cel 1 Dev. Biol. , 13 August 2019
  • Non-Patent Document 3 Cell Death & Differentiation (2020) 27: 161-175
  • An object of the present invention is to provide a compound as a RIPK1 inhibitor, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.
  • Another object of the present invention is a compound as a RIPK1 inhibitor, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, and a hydrate thereof.
  • a pharmaceutical composition or kit containing a solvate thereof as an active ingredient is provided.
  • Another object of the present invention is to prevent RIPK1 activity-related diseases, including a compound as a RIPK1 inhibitor, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient. Or to provide a composition for treatment.
  • Another object of the present invention is related to RIPK1 activity, including administering a compound as a RIPK1 inhibitor, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof in a therapeutically effective amount. It is to provide a method for preventing or treating a disease.
  • Another object of the present invention is to use a compound, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as a RIPK1 inhibitor for the prevention or treatment of RIPK1 activity-related diseases.
  • Another object of the present invention is a compound as a RIPK1 inhibitor, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a compound thereof as a RIPK1 inhibitor for the preparation of a drug for preventing or treating RIPK1 activity-related diseases.
  • a compound thereof as a RIPK1 inhibitor for the preparation of a drug for preventing or treating RIPK1 activity-related diseases.
  • the present invention provides a compound according to any one of the following (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.
  • Z 2 and Z3 are each independently N, CR1 or CR2, but one of Z2 and Z3 is necessarily CRi,
  • Ri is a cyclic or non-cyclic functional group containing N directly linked to C in “CRi”,
  • R2 is H, halogen, CN or - 0- (Cl- C5 alkyl);
  • W2 is 0 or
  • A is aryl or heteroaryl
  • L is CH2, CH(CHs), CD 2 or 0;
  • B is aryl, heteroaryl ego,
  • R5 and R6 are each independently H, Cl-C5alkyl, CN, halogen, -(Cl-C5alkyl)-0-(Cl-C5alkyl) or heteroaryl, wherein at least one group of heteroaryl is each independently may be substituted with Cl- C5 alkyl;
  • R2 is halogen, CN or -0- (Cl-C5alkyl).
  • the cyclic functional group containing ni includes at least one cy, but the ring may consist of only a single bond or include at least one double bond,
  • a cyclic functional group containing ni can include Where, Z4 is CRcRd, 0, S or NR e ,
  • Ra, Rb, Rc, Rd and Re are each independently H, Cl- C5 alkyl, halogen, CF 3 , CH 2 F, (Cl- C5 alkyl)- OH or - 0- (Cl- C5 alkyl);
  • Z 5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a, b, and c are each independently an integer from 0 to 2, but n and m are simultaneously It cannot be 0, and a cannot be 0 at the same time.
  • the acyclic functional group containing Ni is an amino group (-NH2) or at least one of the two Hs of the amino group is substituted with a substituent that is not complementary.
  • e is an integer from 0 to 2
  • R7 is H or C1-C5 alkyl
  • R8 is H, Cl-C5alkyl, cycloalkyl, or heterocycloalkyl, wherein at least one group of Cl-C5alkyl is each independently CF 3 , halogen, N(C1-C5alkyl) 2, 0- (Cl-C5 Alkyl), OH, heterocycloalkyl, aryl or heteroaryl may be substituted, and at least one or more groups of the aryl or heteroaryl are each independently (Cl- C5 alkyl) or - 0- (Cl- C5 alkyl);
  • R9 is Cl-C5alkyl, 0-(Cl-C5alkyl), OH, CF 3 or (C1-C5alkyl)-CF3;
  • Rio can be Cl- C5 alkyl or cycloalkyl.
  • Z 2 and Z3 are each independently N, CR1 or CR2, but any one of Z2 and Z3 is necessarily CRi, , e high,
  • Z4 is CRcRd, 0, S or NR e ;
  • R a , Rb, Rc, Rd and Re are each independently H, Cl-C5alkyl, halogen, CF 3 ,CH 2 F, (Cl-C5alkyl)-OH or -0-(Cl-C5alkyl);
  • Z 5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a, b, and c are each independently an integer from 0 to 2, but n and m are simultaneously cannot be 0, a and cannot be 0 at the same time, e is an integer from 0 to 2,
  • R2 is H, halogen, CN or -O-(Cl-C5alkyl); R3 is H or CH3;
  • W2 is 0 or
  • A is aryl or heteroaryl
  • L is CH2, CH (CHs), CD 2 or 0;
  • B is aryl, heteroaryl or A
  • R5 and R6 are each independently H, Cl- C5alkyl, CN, halogen, -(Cl-C5alkyl)- 0-
  • R7 is H or C1-C5 alkyl
  • R8 is H, Cl-C5alkyl, cycloalkyl or heterocycloalkyl, wherein at least one group of Cl-C5alkyl is each independently CF 3 , halogen, N(C1-C5alkyl) 2, 0-(Cl-C5 alkyl), 0H, heterocycloalkyl, aryl or heteroaryl, and at least one group of the aryl or heteroaryl is each independently substituted with (Cl- C5 alkyl) or -0- (Cl- C5 alkyl) can be,
  • R9 is Cl-C5alkyl, 0-(Cl-C5alkyl), OH, CF 3 or (C1-C5alkyl)-CF3;
  • Rio is Cl-C5alkyl or cycloalkyl
  • R2 is halogen, CN or -0-
  • Z2 and Z3 are each independently N, CR1 or CR2, but either Z2 or Z3 is necessarily CRi, , e ,
  • Z4 is CRcRd, 0, S or NR e ;
  • Ra, Rb, Rc, Rd and Re are each independently H, Cl-C5alkyl, halogen, CF 3 , CH 2 F, (Cl-C5alkyl)-OH or -0-(Cl-C5alkyl);
  • Z 5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a, b, and c are each independently an integer from 0 to 2, but n and m are simultaneously cannot be 0, a and cannot be 0 at the same time, e is an integer from 0 to 2,
  • R2 is H, halogen, CN or -O-(Cl-C5alkyl);
  • R3 is H or CH3
  • W2 is 0 or
  • A is phenyl or a 5-membered or 6-membered heteroaryl containing at least one heteroatom selected from 0 and N;
  • L is CH2, CH (CHs), CD 2 or 0;
  • B is phenyl, a 6-membered heteroaryl containing 1 or 2 cy, or
  • R5 and R6 are each independently H, Cl- C5alkyl, CN, halogen, -(Cl-C5alkyl)-0-(Cl-C5alkyl) or 5- or 6-membered heteroaryl having 1 or 2 N atoms. , wherein at least one group of the heteroaryl is each independently substituted with Cl- C5 alkyl. can,
  • R7 is H or C1-C5 alkyl
  • R8 is H, Cl-C5alkyl, cycloalkyl having 3 to 6 carbon atoms, or 5- or 6-membered heterocycloalkyl containing at least one heteroatom selected from 0 and N, wherein at least one of Cl-C5alkyl
  • Each of the above is independently CF 3 , halogen, N (C1- C5 alkyl) 2, 0- (Cl- C5 alkyl), 5-membered or 6-membered hetero including at least one heteroatom selected from 0H, 0 and N It may be substituted with cycloalkyl, phenyl, or 5-membered or 6-membered heteroaryl containing at least one heteroatom selected from 0 and N, and at least one group of the phenyl or heteroaryl is each independently (Cl-C5alkyl ) or - 0- (Cl- C5 alkyl),
  • R9 is Cl-C5alkyl, 0-(Cl-C5alkyl), OH, CF 3 or (C1-C5alkyl)-CF3;
  • R2 may be halogen.
  • Z4 is CRcRd, 0, S or NR e ;
  • Ra, Rb, Rc, Rd and Re are each independently H, Cl-C5alkyl, halogen, CF 3 , CH 2 F, (Cl-C5alkyl)-OH or -0-(Cl-C5alkyl);
  • Z 5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a, b, and c are each independently an integer from 0 to 2, but n and m are simultaneously cannot be 0, a and cannot be 0 at the same time, e is an integer from 0 to 2,
  • R2 is H, halogen, CN or -O-(Cl-C5alkyl);
  • R3 is H or CH3
  • W2 is 0 or
  • A is phenyl or a 5-membered or 6-membered heteroaryl containing at least one heteroatom selected from 0 and N;
  • L is CH2, CH (CHs), CD 2 or 0;
  • B is phenyl, a 6-membered heteroaryl containing 1 or 2 cy, or
  • R5 and R6 are each independently H, Cl-C5alkyl, CN, halogen, -(Cl-C5alkyl)-0-(Cl-C5alkyl) or a 5-membered or 6-membered heteroaryl having 1 or 2 groups; ,
  • at least one group of heteroaryl may be each independently substituted with Cl- C5 alkyl,
  • R7 is H or C1-C5 alkyl
  • R8 is H, Cl-C5alkyl, cycloalkyl having 3 to 6 carbon atoms, or 5- or 6-membered heterocycloalkyl containing at least one heteroatom selected from 0 and N, wherein at least one of Cl-C5alkyl
  • Each of the above groups is independently CF 3 , halogen, N(C1-C5alkyl) 2, 0-(Cl-C5alkyl), 0H, 0, and 5-membered or 6-membered heteroatoms including at least one heteroatom selected from among It may be substituted with cycloalkyl, phenyl, or 5-membered or 6-membered heteroaryl containing at least one heteroatom selected from 0 and N, and at least one group of the phenyl or heteroaryl is each independently (Cl-C5alkyl ) or - 0- (Cl- C5 alkyl);
  • R9 is Cl-C5alkyl, 0-(Cl-C5alkyl), OH, CF 3 or (C1-C5alkyl)-CF3;
  • R2 may be halogen.
  • one of Z2 and Z3 may be CRi and the other may be N.
  • Z4 is CRcRd or 0;
  • Ra, Rb, Rc and Rd are each independently H, Cl- C5 alkyl, halogen, CH 2 F, (C1-
  • n, m and c are each independently an integer from 0 to 2, but n and m cannot be 0 at the same time;
  • R3 is H or CH3;
  • A is a 5- or 6-membered heteroaryl containing 1 to 4 cy,
  • B is phenyl
  • L is CH 2 or CD2
  • R4 is H, halogen, Cl- C5 alkyl or 0- (Cl- C5 alkyl);
  • Rs and R6 may each independently be H or halogen.
  • R6 may each independently be H or halogen.
  • Wi, W2, Rs, A, B, L, R 4 , RS and R6 is the same as defined in Formula I,
  • Ri is NR7R8;
  • R 7 and R 8 has the same definition as in formula (I).
  • Z4 is CRcRd, 0 or NRe
  • Rc, Rd and Re are each independently H, Cl-C5alkyl, halogen, or -O-(C1-C5alkyl);
  • Z 5 and Z6 are each independently CH or N, but at least one of Z 5 and Z6 is Si, n, m, a and are each independently an integer from 0 to 2, but n and m are 0 at the same time cannot be, and a and cannot be 0 at the same time,
  • R7 is H or C1-C5 alkyl
  • R8 is H, Cl- C5 alkyl, (Cl- C5 alkyl) - CF3 or 5-membered or 6-membered heterocycloalkyl including 0;
  • R9 is Cl-C5alkyl, CF 3 or (C1-C5alkyl)-CF3;
  • Rio is Cl- C5 alkyl or C3-C6 cycloalkyl
  • R3 is CH3
  • W2 is 0;
  • A is a 5- or 6-membered heteroaryl containing 2 to 4 N
  • R4 is visible, L is CH2;
  • B is phenyl
  • Rs and R6 may each independently be H or halogen.
  • the compound represented by Formula IV may be represented by Formula IVa below.
  • R c , Rd and Re are each independently H, Cl- C5 alkyl, halogen, or - 0- (C1- C5 alkyl);
  • Z 5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a and are each independently an integer from 0 to 2, but n and m can be 0 at the same time no, a and cannot be 0 at the same time, A may be a 5-membered heteroaryl group containing 2 to 4 N atoms.
  • One of Z2 and Z3 is CR1, the other is CR2,
  • Z4 is CRcRd, 0, S or NR e ;
  • Ra, Rb, Rc, Rd and Re are each independently H, Cl-C5alkyl, halogen, CF 3 or -0-(Cl-C5alkyl);
  • Z 5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a, b, and c are each independently an integer from 0 to 2, but n and m are simultaneously cannot be 0, and a and cannot be 0 at the same time,
  • R2 is H, halogen, CN or - 0- (Cl- C5 alkyl);
  • R3 is CH3
  • W2 is 0;
  • A is 5- or 6-membered phenyl or N or 1 to 4 containing 0 Heteroaryl, and is a phenyl, 6-membered heteroaryl containing 1 or 2 Ni, or
  • L is CH 2 , CH(CHS), or 0;
  • R5 and R6 are each independently H, Cl-C5alkyl, CN, halogen, -(Cl-C5alkyl)-0-(Cl-C5alkyl) or a 5-membered heteroaryl having at least one N, wherein the above At least one group of 5-membered heteroaryl may each independently be substituted with Cl-C5alkyl;
  • R2 can be halogen, CN or -0-(Cl-C5alkyl).
  • the formula I may be represented by the following formula Va or Vb.
  • W2, Z1, Z2, Z3, R1, Rs, L and R4 are each the same as defined in Formula I above,
  • A is phenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl or pyrizinyl; is phenyl, pyrazinyl, pyridinyl or U;
  • R5 and R6 are each independently H, Cl-C5alkyl, CN, halogen, -(Cl-C5alkyl)-0-(Cl-C5alkyl) or pyrazolyl, wherein at least one group of the pyrazole is each independently It may be substituted with Cl- C5 alkyl.
  • R5 and R6 are each independently H, Cl-C5alkyl, CN, halogen, -(Cl-C5alkyl)-0-(Cl-C5alkyl) or pyrazolyl, wherein at least one group of the pyrazole is each independently It may be substituted with Cl- C5 alkyl.
  • W2 is 0;
  • Z1 is One of Z2 and Z3 is CRi, the other is CR2,
  • Z4 is CRcRd or 0;
  • Rc and Rd are each independently seen, n and m are each independently an integer from 0 to 2, but n and m cannot be 0 at the same time,
  • R2 is H or halogen
  • R3 is CH3
  • A is phenyl or triazolyl
  • B is phenyl
  • L is CH 2 or 0
  • R 4 , RS and R6 can each appear independently.
  • W2 is 0;
  • One of Z2 and Z3 is CR1, the other is CR2,
  • Ri is Z4 is CRcRd, 0 or NR e ;
  • R c , Rd and Re are each independently H or C1-C5 alkyl, n and m are each independently an integer of 0 to 2, but n and m cannot be 0 at the same time;
  • R2 is H or halogen
  • R3 is CH3
  • A is phenyl or triazolyl
  • B is phenyl
  • L is CH 2 or 0
  • Wi is 0;
  • W2 is 0;
  • Z2 is CR1 or CR2
  • Z3 is N, CR1 or CR2, and either of Z' and Z3 is necessarily CRi;
  • Z4 is CRcRd, S or NR e ;
  • R a , R b , R c , Rd and Re are each independently H, Cl- C5 alkyl, halogen, CF 3 , CH 2 F,
  • Z5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a and are each independently an integer from 0 to 2, but n and m are simultaneously
  • R2 is H or halogen
  • R3 is CH3
  • R7 is H or C1-C5 alkyl
  • R8 is Cl-C5alkyl or (Cl-C5alkyl)-CF3;
  • A is phenyl, tetrazolyl or triazolyl
  • L is CH2, CD2 or 0;
  • B is phenyl
  • R4 is H, halogen or C1-C5 alkyl
  • Rs and R6 are each independently H or halogen
  • R2 can be halogen or -O-(Cl-C5alkyl).
  • Wi CH2;
  • W2 is 0;
  • One of Z2 and Z3 is CRi, the other is 0,
  • Ri is Z4 is CRcRd
  • R c and Rd are each independently H, halogen or -0- (Cl- C5 alkyl), n and m are each independently an integer of 0 to 2, but n and m cannot be 0 at the same time,
  • R2 is H or halogen
  • R3 is CH3
  • A is tetrazolyl
  • L is CH2
  • B is phenyl
  • R4, Rs and R6 can each be seen independently.
  • Cm-Cn (where m and n are each independently an integer of 1 or more) means the number of carbon atoms, and for example, 'Cl-C5alkyl' represents alkyl having 1 to 5 carbon atoms.
  • alkyl means a straight-chain or branched-chain saturated hydrocarbon group. In the present invention, alkyl may have 1 to 5 carbon atoms. In one embodiment, an alkyl can have 1 to 3 carbon atoms.
  • alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, sec-pentyl, tert-pentyl, isopentyl, sec-isopentyl, neo-pentyl etc. are mentioned.
  • aryl includes monoaromatic or polycyclic aromatics, and refers to aromatic hydrocarbons having 6 or more carbon atoms.
  • Aryl has 6 to 6 carbon atoms can have 20
  • aryl can be phenyl, biphenyl, naphthalenyl, and the like.
  • heteroaryl refers to a monocyclic or polycyclic heterocyclic ring in which at least one or more carbon atoms in the aryl are replaced with nitrogen (N), oxygen (0), or sulfur (S). Heteroaryl may be 5-12 membered, for example, 5- or 6-membered. When two or more heteroatoms are included in heteroaryl, the types of heteroatoms may be the same as or different from each other. For example, when heteroaryl contains two or more heteroatoms selected from nitrogen, oxygen, and sulfur, when it contains two nitrogens, when it contains one nitrogen and one oxygen, two oxygens and one nitrogen It means various combinations, such as the case of including.
  • heteroaryl is pyridinyl, thiophenyl, triazolyl, tetrazolyl, benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindoleyl, benzofuranyl, benzopyrroyl, furanyl , Pyrroyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, benzooxazolyl, benzoimidazolyl, dihydrobenzothiophenyl, purinyl, indolizinyl, chromenyl, and the like.
  • cycloalkyl means a saturated hydrocarbon ring having 3 or more carbon atoms, and the saturated hydrocarbon ring includes both monocyclic and polycyclic structures.
  • Cycloalkyl can be a saturated hydrocarbon ring having from 3 to 12 carbon atoms.
  • Examples of cycloalkyl may be at least one selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • heterocycloalkyl is a ring of the cycloalkyl It means a cyclic functional group in which at least one carbon atom is substituted with a heteroatom.
  • heteroatom may be nitrogen (N), oxygen (0) or sulfur (S).
  • the heteroatom included in the ring of heterocycloalkyl may be one or two or more, one or one or more heteroatoms may be included, and at least one or more two or more heteroatoms may be included.
  • Heterocycloalkyls can be 3- to 12-membered rings. Examples of heterocycloalkyl include oxiranyl, oxetanyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyran work, etc.
  • alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl mean all of monovalent substituents or divalent or more polyvalent substituents in the chemical structure according to each definition.
  • alkyl may include monovalent alkyl or divalent alkyl (alkylene)
  • aryl may include monovalent aryl or divalent aryl (arylene).
  • halogen may be F, Cl, Br or I.
  • the compound according to the present invention may include the compounds listed in Table 1 below.
  • pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, and can be prepared by a conventional method known to those skilled in the art.
  • pharmaceutically acceptable salts include, for example, inorganic ion salts prepared with calcium, potassium, sodium or magnesium; Hydrochloric Acid, Nitric Acid, Phosphoric Acid, Bromic Acid, inorganic acid salts prepared with iodic acid, perchloric acid, or sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid organic acid salts prepared from acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, and the like; sul
  • the salt may be a hydrochloride salt.
  • “stereoisomer” includes diastereomers, optical isomers, and position isomers, and optical isomers include enantiomers as well as mixtures and racemates of enantiomers. including all body These isomers can be separated by conventional techniques such as column chromatography or HPLC resolution. Alternatively, each stereoisomer of the compound according to any one of (1) to (17) can be stereospecifically synthesized using optically pure starting materials and/or reagents of known configuration.
  • tautomer refers to a structural isomer that interconverts through a low energy barrier among the compounds according to any one of (1) to (17) above.
  • a compound may have, for example, an imino, keto, or oxime group. When containing or an aromatic substituent is included, atoms constituting the compound may be in the form of tautomerization.
  • structurally depicted compounds may be termed tautomers of the compounds of the present invention. It should be understood that references to named compounds or structurally depicted compounds are intended to encompass all tautomers of such compounds and any mixtures of tautomers thereof.
  • hydrate means a compound according to any one of (1) to (17) above, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a tautomer thereof, etc., in which water is bound by non-covalent intermolecular forces, It may contain stoichiometric or non-stoichiometric amounts of water.
  • the hydrate may include water in an amount of about 0.25 to about 10 moles based on 1 mole of the active ingredient.
  • solvate refers to a compound according to any one of (1) to (17) above, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a tautomer thereof, etc., in which a solvent other than water is bound by intermolecular force.
  • the solvent may be included in a stoichiometric or non-stoichiometric amount.
  • the solvate may include solvent molecules in an amount of about 0.25 to about 10 moles based on 1 mole of the active ingredient.
  • the compounds according to any one of (1) to (17) in the present invention may exist in various forms or derivatives, and may have different crystalline or polycrystalline forms, and active metabolites. can include
  • “prevention” refers to the compound according to any one of (1) to (17) above, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.
  • treatment refers to a compound according to any one of (1) to (17) above, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof. It refers to all activities that improve or beneficially change the symptoms of suspected or affected individuals by administration.
  • the compound according to any one of (1) to (17) of the present invention, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof prevents or prevents RIPK1 activity-related diseases It can be useful for treatment.
  • the compound according to any one of (1) to (17) of the present invention a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, inhibits RIPK1 or inhibits the RIPK1 signaling pathway.
  • the compound according to any one of (1) to (16), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof according to any one of the above (1) to (16) of the present invention is related to RIPK1 activity known in the art.
  • compositions comprising the compound according to any one of (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof as an active ingredient.
  • composition is provided.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of RIPK1 activity-related diseases. That is, a pharmaceutical composition comprising the compound according to any one of (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient. can be usefully used for the prevention or treatment of RIPK1 activity-related diseases.
  • the RIPK1 activity-related diseases include inflammation, autoimmune disease, cancer, infection, central nervous system disease, metabolic disease, cardiovascular disease, respiratory disease, liver disease, kidney disease, eye disease, skin disease, lymphatic condition, psychological disorder, and graft versus It may include host disease, allodynia, wounds, scars, and the like.
  • Inflammation refers to inflammation that occurs as a result of an inflammatory disorder, such as an autoinflammatory disease, inflammation that occurs as a symptom of a non-inflammatory disorder, inflammation that occurs as a result of infection, or inflammation that occurs as a result of infection or inflammation secondary to injury or autoimmunity. , sepsis, and systemic inflammatory response syndrome.
  • Autoimmune diseases include acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), antisynthetase antibody syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune infections, Autoimmune oophoritis, autoimmune glandular dysfunction, autoimmune thyroiditis, celiac disease, Crohn's disease, inflammatory bowel disease including ulcerative colitis, ulcerative colitis, type 1 diabetes (T1D), Goodpas Cher's syndrome, Grave's disease, Galambare syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenia, reduced purpura, Kawasaki disease, lupus erythematosus including systemic lupus erythematosus (SLE), primary progressive multiple sclerosis : PPMS), multiple sclerosis (MS) including secondary progressive multiple sclerosis (SPMS) and relapsing remitting multiple sclerosis (RR
  • Cancer as parenchymal organ malignancies, includes lung cancer, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia including acute lymphocytic leukemia (ALL) and acute myeloid leukemia (acute mye 1 oid leukemia: AML), adrenal cancer , Anal cancer, basal squamous cell skin cancer, cholangiocarcinoma, bladder cancer, bone cancer, cerebrospinal tumor, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrium Cancer, esophageal cancer, Ewing's series tumor, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumor, gas trointestinal stromal tumor (GIST), gestational trophoblastic disease, glioma, Hodgkin's lymphoma, Kaposi's sarcoma,
  • Infections include viral infections (eg, influenza virus, human immunodeficiency virus (HIV), alphaviruses (eg, Chikungunya and Ross River virus), flaviviruses (eg, dengue virus and Zika virus) viruses), herpes viruses (e.g., Epstein Barr virus, cytomegalovirus, varicella-zoster virus, and KSHV), poxviruses (e.g., vaccinia virus (modified vaccinia virus Ankara) and myxoma virus) , adenovirus (eg, adenovirus 5), or papillomavirus), Heliobacter pylori ( ⁇ Hel icobacter pylori'), Bacillus anthracis (fec7//w ant hr ads'), Bordatel la pertussis, Burcoholderia Pseudomallei ⁇ Burkholder la pseudomallei) , Corynebacterium diptheriae), Clos
  • Central nervous system diseases may include Parkinson's disease, Alzheimer's disease, dementia, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, cerebral aneurysm, traumatic brain injury and amyotrophic axial sclerosis, and the like.
  • Metabolic diseases may include type 2 diabetes (T2D), atherosclerosis, obesity, gout, pseudogout, and the like.
  • Cardiovascular disease includes hypertension, ischemia, reperfusion injury including ischemic reperfusion injury after MI, stroke including ischemic stroke, transient ischemic attack, myocardial infarction including recurrent myocardial infarction, congestive heart failure and ejection fraction heart failure.
  • Respiratory diseases can include chronic obstructive pulmonary disorder (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, nanoparticle induced inflammation, cystic fibrosis, idiopathic pulmonary fibrosis, and the like.
  • COPD chronic obstructive pulmonary disorder
  • Liver diseases include non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), including advanced fibrosis stage F3 and F4, and alcoholic fatty liver disease ( It may include alcoholic fatty 1 iver disease (AFLD) and alcoholic steatohepatitis (ASH).
  • Kidney disease may include chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, diabetic nephropathy, and the like.
  • Ocular diseases can include ocular epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infection, diabetic retinopathy, optic nerve damage, dry eye, glaucoma, and the like.
  • Skin disorders can include dermatitis, such as contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other cyst-causing skin disorders, acne vulgaris, and the like.
  • AMD age-related macular degeneration
  • HS hidradenitis suppurativa
  • Lymphatic conditions may include lymphangitis, Castleman's disease, and the like.
  • the disease associated with RIPK1 activity in the present invention is Crohn's disease, ulcerative colitis, ulcerative colitis, psoriasis, rheumatoid arthritis, spondyloarthritis, systemic onset juvenile idiopathic arthritis, psoriatic arthritis, osteoarthritis, ischemia-reperfusion of parenchymal organs injury, sepsis, systemic inflammatory response syndrome, multiple sclerosis, or parenchymal organ malignancies.
  • the pharmaceutical composition of the present invention in addition to the compound according to any one of (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, in addition to a pharmaceutical composition thereof It may include one or more types of generally acceptable carriers.
  • Pharmaceutically acceptable carriers are commonly used in the art, specifically lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, It may be polyvinylpyrrolidine, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, minerals, or oil, but is not limited thereto.
  • the pharmaceutical composition of the present invention in addition to the above components, lubricant, wetting agent, sweetener, A flavoring agent, an emulsifying agent, a suspending agent, a preservative, a dispersing agent, a stabilizing agent, and the like may be further included.
  • the pharmaceutical composition of the present invention can be formulated into oral formulations such as tablets, powders, granules, pills, capsules, suspensions, emulsions, solutions for internal use, emulsions, syrups, external preparations, and suppositories using pharmaceutically acceptable carriers and excipients.
  • it may be formulated in the form of a sterile injectable solution to be prepared in unit dose form or introduced into a multi-dose container.
  • the formulation may be prepared by a conventional method used for formulation in the art or a method disclosed in Remington's Pharmaceutical Science (19th ed., 1995), and may be formulated into various formulations according to each disease or component.
  • Non-limiting examples of formulations for oral administration using the pharmaceutical composition of the present invention include tablets, troches, lozenges, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, and soft capsules, syrups or elixirs; and the like.
  • a binder such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; excipients such as dicalcium phosphate and the like; disintegrants such as corn starch or sweet potato starch; Lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol wax may be used, and sweeteners, aromatics, syrups, and the like may also be used.
  • a liquid carrier such as fatty oil may be additionally used in addition to the above-mentioned materials.
  • Non-limiting examples of parenteral preparations using the pharmaceutical composition of the present invention include injection solutions, suppositories, powders for respiratory inhalation, aerosols for sprays, ointments, powders for application, oils, creams, and the like.
  • Parenteral administration of the pharmaceutical composition of the present invention In order to formulate for administration, sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, external preparations, etc. may be used, and the non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, Injectable esters such as ethyl oleate and the like may be used, but are not limited thereto.
  • the present invention includes administering the compound according to any one of (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof to a subject.
  • a method for preventing or treating a disease related to RIPK1 activity is provided.
  • “administration” means introducing a predetermined substance into a subject by an appropriate method.
  • “subject” refers to all animals such as rats, mice, livestock, etc., including humans who have or may develop RIPK1 activity-related diseases, and may specifically be mammals, including humans, but are not limited thereto no.
  • the method for preventing or treating a disease related to RIPK1 activity of the present invention is a compound according to any one of (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate thereof.
  • the solvate may be administered in a therapeutically effective amount.
  • therapeutically effective amount means an amount that is sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and does not cause side effects, which is a patient's sex, age, weight, health condition, type of disease, severity, activity of drug, sensitivity to drug, method of administration, time of administration,
  • a specific therapeutically effective amount for a particular patient can be determined by those skilled in the art depending on factors including route of administration, rate of excretion, duration of treatment, drugs used in combination or concomitantly, and other factors well known in the medical arts.
  • the present invention relates to a compound according to any one of (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a compound according to any one of (1) to (17) for the prevention or treatment of RIPK1 activity-related diseases.
  • the use of the solvate or composition comprising it is provided.
  • the present invention relates to the compound according to any one of (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof for the preparation of a drug for preventing or treating RIPK1 activity-related diseases.
  • a hydrate of or a solvate thereof, or a composition comprising the same is provided.
  • the compound according to any one of (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof is converted into a pharmaceutically acceptable compound according to any one of (1) to (17).
  • Auxiliaries, diluents, carriers, etc. may be mixed, and may have a synergistic effect by being prepared as a combined preparation with other active agents. Matters mentioned in the compounds, pharmaceutical compositions, treatment methods and uses of the present invention are equally applied unless contradictory to each other.
  • Step 2 Preparation of target compound A2 After dissolving compound A1 (9.5 g, 25.14 mmol) in methanol (251 mL), zinc and ammonium chloride were added. The mixture was stirred at 75 °C for 30 min. After completion of the reaction, the reaction mixture was filtered using celite and concentrated under reduced pressure to obtain the target compound A2 (8.7 g, 99%) as a purple solid. Step 3.
  • each of reactant 1 and reactant 2 is shown in Table 4 below.
  • Step B3 Preparation of target compound B1
  • Compound A4 400 mg, 1.16 mmo 1
  • Cui 90 mg, 0.47 mmo 1
  • potassium carbonate 482 mg, 3.49 mmo 1
  • azetidinone 99 mg, 1.40 mmol
  • toluene 5.8 mL
  • DMEDA 0.06 mL , 0.58 mmol
  • Step 2 Preparation of target compound B2 Compound B1 (126 mg, 0.38 mmol) was added and dissolved in dichloromethane (1.7 mL), and trifluoroacetic acid (0.51 mL, 6.66 mmol) was added at room temperature. The reaction was stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound B2 (93.0 mg, 98%) as an orange solid. Step 3.
  • Example 51 Example 51.
  • Example 50 in step 1 instead of azetidinone A compound according to Example 51 was prepared in substantially the same manner as in Example 50 for preparing Compound B3, except that pyrrolidin-2-one was used.
  • Example 50 1-(2-fluorobenzyl)-1H- 1,2,4-triazole-3-carboxylic acid was prepared in Example 50 in substantially the same manner as in Compound B3, except that carboxylic acid was used. A compound according to 52 was prepared. Example 53. (R)-2-benzyl-N-(5-methyl-4-oxo-8-(2-oxoazetidin-1-yl)-
  • Example 52 A compound according to Example 52 was prepared in substantially the same manner as in Example 50 for preparing Compound B3, except that 2-benzyl-2utetrazole-5-carboxylic acid was used.
  • the structure and compound name of each of the compounds obtained according to Examples 50 to 53, and NMR analysis results are shown in Table 6 below.
  • Step 1 Preparation of target compound C1 Under a nitrogen atmosphere, 4-amino-2-chloro-5-iodopyridine (1.0 g, 3.93 mmo 1 ), Pd(dba) 2 (56.4 mg, 0.10 mmo 1 ), Zantphos ( Xantphos , 113.6 mg, 1.96 mmo 1 ) ,
  • Target compound C2 Compound C1 (1.39 g, 4.00 mmol) was added to tetrahydrofuran (24 mL) to dissolve it, Isopropylethylamine (1.5 mL, 7.99 mmol), T 3 P (in
  • Step 3 Preparation of target compound C3 Compound C2 (570 mg, 1.73 mmol) > added to dimethylformamide (8.6 mL) to dissolve, potassium carbonate (263 mg, 1.90 mmol), methyl iodine (0.12 mL, 1.90 mmol) ) was added. The reaction was stirred for 2 hours at room temperature. After completion of the reaction, the mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate.
  • Step 4 Preparation of target compound C4 Compound C3 (103 mg, 0.30 mmol), Pd(0Ac) 2 (13.5 mg, 0.06 mmol), BI NAP (75 mg, 0.12 mmol), cesium carbonate (293 mg, 0.90 mmol) was diluted in toluene (1.3 mL) and pyrrolidine (0.04 mL, 0.45 mmol) was added. The reaction was stirred at 85 °C for 16 hours. After completion of the reaction, the reaction mixture was filtered using celite and concentrated under reduced pressure.
  • Step 5 Preparation of target compound C5 Compound C4 (116 mg, 0.31 mmol) was added to and dissolved in dichloromethane (2 mL), and hydrochloric acid (4> 1,4-dioxane solution; 0.77 mL, 3.07 mmol) was added. The reaction was stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture is reduced under reduced pressure. Concentration gave the desired compound C5 (51 mg, 47%) as a white solid. Step 6.
  • Target compound C6 Compound C5 (51 mg, 0.14 mmol), EDC (35.0 mg, 0.29 mmol), HOAt (39.0 mg, 0.29 mmol 1 ) , 1-benzyl-L ⁇ l, 2, 4 - Triazole-3-carboxylic acid (44 mg, 0.22 mmol) was diluted in dichloromethane (2.9 mL) and triethylamine (0.06 mL, 0.43 mmol) was added at 0 °C. The reaction was stirred at room temperature for 16 hours.
  • Step 2 Preparation of target compound D2 After dissolving compound D1 (38.0 mg, 0.01 mmol) in dichloromethane (0.48 mL), trifluoroacetic acid (0.08 mL, 0.1 mmol) was added at room temperature. The reaction was stirred at room temperature for 16 hours. After the reaction was terminated by adding water, basification was performed with an aqueous solution of potassium carbonate, and the organic layer was extracted using dichloromethane.
  • Examples 78 and 79 The reactants in Table 10 below instead of isobutylamide in step 1 of Example 75. Compound D3 of Example 75, except that 1 was used as reactant 2 in Table 10 instead of 1,2,4-triazole-3-carboxylic acid in Step 3 of Example 75. The compounds according to Examples 78 and 79 were prepared in substantially the same manner as the method for preparing
  • Step 3 Preparation of target compound E3 Compound E2 (1.25 g, 3.12 mmol) was added to and dissolved in dichloromethane (31.0 mL), then AlMes (2.0 M in toluene, 2.8 mL) was added at 0°C and stirred for 15 Stir for a minute. The reaction was stirred at room temperature for 1 hour and then at 45 °C for 3 hours.
  • Target compound F2 After dissolving compound F1 (2.6 g, 5.96 mmol) in methanol (251 mL), Zinc (4.0 g, 59.6 mmol) and ammonium chloride (640 mg, 11.92 mmol) were added. The reaction was stirred at 75 °C for 16 hours. After completion of the reaction, the reaction mixture was filtered using celite and concentrated under reduced pressure to obtain the target compound F2 (1.9 g, 79%) as a gray solid. Step 3.
  • Target compound F3 Dilute compound F2 (1.9 g, 4.39 mmol), EDC (1.3 g, 10.99 mmol), and HOAt (1.5 g, 10.99 mmol) in dichloromethane (88.0 mL), Ethylamine (2.1 mL, 15.38 mmol) was added at 0 °C. The reaction was stirred at room temperature for 16 hours. After the reaction was terminated with an aqueous sodium bicarbonate solution, the mixture was washed with water and an aqueous sodium chloride solution, and the organic layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure.
  • Step 4 Preparation of target compound F4 After dissolving compound F3 (1.4 g, 3.65 mmol) in dimethylformamide (21.5 mL), cesium carbonate (1.4 g, 4.38 mmol) and methyl iodine (0.27 mL, 4.38 mmol) ) was added. The reaction was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate.
  • Target compound F4 (758 mg, 51%) as a white solid.
  • Step 5 Preparation of target compound F5 Compound F4 (300 mg, 0.74 mmol), Pd(0Ac) 2 (33 mg, 0.15 mmol), BI NAP (184 mg, 0.30 mmo 1 ), and cesium carbonate (482 mg, 1.48 mmol) were diluted in toluene (3 mL), and pyrrolidine (0.12 mL, 1.48 mmol) was added. The reaction was stirred at 85 °C for 16 hours. After completion of the reaction, the reaction mixture was filtered using celite and concentrated under reduced pressure.
  • Step 6 Preparation of target compound F6 After dissolving compound F5 (175 mg, 0.44 mmol) in dichloromethane (1 mL), hydrochloric acid (4> 1,4-dioxane solution; 0.55 mL, 2.21 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the product was concentrated under reduced pressure to obtain the target compound F6 (146 mg, 100%) as a white solid. Step 7.
  • Example 82 to 107 Reagent 1 in Table 12 was used as a compound corresponding to pyrrolidine in Step 5 of Example 81, 1-benzyl-1 in Example 81, Step 7, 1,2,4-Triazole- Compounds according to Examples 82 to 107 were prepared in substantially the same manner as the method for preparing compound F7 of Example 81, except that reactant 2 of Table 12 was used as a compound corresponding to 3-carboxylic acid.
  • target compound G2 After adding and dissolving compound G1 (630 mg, 1.49 mmol) in toluene (11 mL), Pd(0Ac) 2 (34 mg, 0.15 mmol), Zantphos (172 mg, 0.30 mmol) ), potassium carbonate (413 mg, 2.99 mmol) and pyrrolidine (0.18 mL, 2.24 mmol) were added. The mixture was stirred at 80 °C for 16 hours.
  • Target compound G3 was obtained by substantially the same process as in preparing compound F6 in step 6 of Example 81, except that compound G2 was used instead of compound F5. Then, the target compound G4 as a white solid according to Example 108 was obtained by substantially the same process as in Example 81 for preparing compound F7 in step 7 of Example 81, except that compound G3 was used instead of compound F6.
  • Step 2 and Step 3 Preparation of target compounds J2 and J3 Target compounds J2 to J3 were synthesized in the same manner as in the preparation process of F6 to F7. In each step through substantially the same process as described in Steps 6 and 7 of Example 81, except that Compound J1 was used instead of Compound F5 in Step 6 of Example 81, and Compound J2 was used instead of Compound F6 in Step 7. Target compound J2 and target compound J3 as white solids according to Example 112 were obtained.
  • Example 113 Process for preparing target compounds K2, K3, and K4 Using compound K1 instead of compound F4, substantially the same method as preparing compounds F5, F6, and F7 in steps 5, 6, and 7 of Example 81, respectively.
  • target compounds K2, K3 and target compound K4 according to Example 113 were obtained.
  • reactant 1 in Table 14 was used as a compound corresponding to pyrrolidine in step 1, and in step 3, 1-benzyl-L ⁇ l, 2,4-triazole-3-
  • Examples 114 to 162 were prepared in substantially the same manner as the compound K4 of Example 113, except that reactant 2 of Table 14 was used as a compound corresponding to carboxylic acid.
  • Step 4 Preparation of target compound P4 After dissolving compound P3 (77 mg, 0.32 mmol) in tetrahydrofuran (3.6 mL) and methanol (1.8 mL), lithium hydroxide (134 mg, 3.2 mmol) was added. The reaction was stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was diluted with water, and the concentration of the mixture was adjusted to pH 2-3 using 1 River HCl aqueous solution to precipitate a solid product.
  • Step 2 Preparation of reactant 2 (compound P8) for the preparation of Example 126 Step 1.
  • Preparation of target compound P5 Substantially the same process as for preparing compound P3 in step 3 of Preparation Example 1, except that methyl 4-nitro-1H-pyrazole-3-carboxylate was used instead of compound P2. Through this, the target compound P5 was obtained. Step 2.
  • target compound P6 After dissolving compound P5 (700 mg, 2.67 mmol) in methanol (16 mL) and water (5 mL), iron (447.4 mg, 8.01 mmol) and ammonium chloride (143 mL, 2.67 mmol) was added. The reaction was stirred at 80 °C for 5 hours. After completion of the reaction, the mixture was filtered using celite and concentrated under reduced pressure to obtain the target compound P6 (600 mg, 97%) as a brown solid. Step 3.
  • Target compound P8 was synthesized by substantially the same process as in preparing compound P4 in step 4 of Preparation Example 1, except that compound P7 was used instead of compound P3.
  • iH NMR 400 MHz, DMSO-d
  • 5 7.77-7.72 m, 4H
  • 7.62-7.58 m, 2H
  • 7.54-7.53 m, 4H
  • 1.48 s, 9H.
  • Table 15 The structure and compound name of each of the compounds obtained according to Examples 113 to 162, and NMR analysis results are shown in Table 15 below.
  • Example 163 (R)-l-Benzyl-N-(8-((3-chloropropyl)amino)-7-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydro
  • benzo [b] [1,4] thiazepin- 3 -yl) - 1H- 1,2,4- triazole -3 -carboxamide
  • Step 1 Preparation of target compound LI
  • Target compound L1 was synthesized through substantially the same process as in preparing compound F5 in step 5 of Example 81, except that azetidine was used instead of pyrrolidine. Step 2.
  • Target compound L2 After dissolving compound L1 (135 mg, 0.35 mmol) in dichloromethane (2.4 mL), hydrochloric acid (4> 1,4-dioxane solution; 0.89 mL, 3.50 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound L2 (148 mg, 98%) as a white solid. The obtained compound L2 was subjected to the next reaction without additional purification. Step 3. Preparation of target compound L3 Target compound L3 according to Example 163 was synthesized by substantially the same process as in preparing compound F7 in step 7 of Example 81, except that compound L2 was used instead of compound F6.
  • Step 1 Preparation of 1,2,4-triazole-3-carboxamide Step 2.
  • target compound Ml In step 4 of Example 113, 1-benzyl-1,2,4-triazole-3-carboxylic acid was replaced with 1-(2-bromobenzyl)-1, The target compound Ml was synthesized in substantially the same manner as in the preparation of compound K4, except that 2,4-triazole-3-carboxylic acid was used. Step 2.
  • the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure.
  • reaction concentrate was purified by silica gel column chromatography.
  • 1,2,4-Triazole-3 Preparation of carboxamide
  • step 2 of preparing Examples 166 and 167 (R)-1-benzyl-N-(7-fluoro- of Example 83 instead of Compound 01 5 -methyl- 8 -morpholino- 4 -oxo- 2,3, 4, 5 -
  • a white solid compound according to Example 168 was obtained in substantially the same manner as in Compound 02, except that azole-3-carboxamide was used.
  • Examples 169 and 170 In step 2 of preparing Examples 166 and 167, (R)-2-fluoro-N- of Example 84 instead of Compound 01 7 -Fluoro- 5 -methyl- 4 -oxo- 8-(pyrrolidin- 1-yl)-2, 3, 4, 5 - tetrahydrobenzo [b] [ 1 , 4] thiazepine- 3 -
  • the compounds of Examples 169 and 170 were obtained in substantially the same manner as the preparation of Compounds 01 and 02 of Examples 166 and 167, except that 1)-5-phenoxybenzamide was used.
  • the structure and compound name of each of the compounds obtained according to Examples 169 and 170, and NMR analysis results are shown in Table 17 below.
  • Example 173 (R)-1-benzyl-N-(7-fluoro-5-methyl-1,1 ⁇ Dioxido- 4 -oxo- 8- (pyrrolidin- 1-yl) - 2, 3, 4, 5 -tetrahydrobenzo [b] [1,4] thiazepin- 3 -yl) - 1H- 1 ,2,4-triazole-3-carboxamide
  • step 2 of preparing Compound 01 Compound F7 of Example 81 was used, except for using Compound 02 of Examples 166 and 167 and A beige solid compound according to Example 173 was obtained in substantially the same manner as for preparing 03.
  • Example 172 and 174 In step 2 of preparing Examples 166 and 167, (R)-1-benzyl-N-(5-methyl-4-oxo-7-(piperidine- 1-day)-2, 3, 4, 5 - The beige solid compound according to Example 172 and the white solid compound according to Example 174 were prepared in substantially the same manner as in preparing Compounds 02 and 03 of Examples 166 and 167, except that azole-3-carboxamide was used. Solid compounds were obtained respectively. The structure and compound name of each of the compounds obtained according to Examples 172 and 174, and NMR analysis results are shown in Table 18 below.
  • Step 2 Preparation of target compound Q2 After dissolving compound Q1 (163 mg, 0.58 mmol) and tritylchloride (195 mg, 0.70 mmol) in dichloromethane (5 mL), triethylamine (0.41 mL, 2.91 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography.
  • Step 4 Preparation of target compound Q4 After dissolving compound Q3 (152 mg, 0.30 mmol) in dichloromethane (5 mL), hydrochloric acid (4 River 1,4-dioxane solution; 0.38 mL) was added. did The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Q4 (102 mg, 100%) as a white solid. The obtained compound Q4 was subjected to the next reaction without further purification. Step 5.
  • hydrochloric acid 4 River 1,4-dioxane solution; 0.38 mL
  • Examples 176 to 190 Reactant 1 in Table 19 below was used as a compound corresponding to ethanolamine in step 3 of Example 175, and 1-benzyl-1-1,2,4-triazole-3-carboxyl in step 5 Compounds according to Examples 176 to 190 were prepared in substantially the same manner as the compound Q5 of Example 175, except that reactant 2 in Table 19 was used as a compound corresponding to the acid.
  • Step 1 Preparation of target compound R1 Object compound R1 in substantially the same manner as in preparing compound A5, except that tetrahydro-2opyran-4-amine was used instead of pyrrolidine in step 5 of Example 1. was synthesized. Step 2. Preparation of target compound R2 After dissolving compound R1 (100 mg, 0.25 mmol) in dimethylformamide (5 mL), cesium carbonate (160 mg, 0.49 mmol) and methyl iodine (0.24 mL, 0.37 mmol) )> After addition, the mixture was stirred at room temperature for 16 hours.
  • target compound R3 54 mg, 100%
  • the obtained compound R3 is further purified
  • the following reaction proceeded without Step 4.
  • Preparation of target compound R4 Compound R3 (54 mg, 0.15 mmo 1 ), EDC (37 mg, 0.30 mmo 1 ), HOAT (41 mg, 0.30 mmol), and 1-benzyl- 1,2,4
  • diluting -triazole-3-carboxylic acid 37 mg, 0.18 mmol
  • dichloromethane 5 mL
  • triethylamine 0.08 mL, 0.60 mmol
  • Step 2 Preparation of target compound T2 After dissolving compound T1 (3.19 g, 12.3 mmol) and tetramethylethylenediamine (8.35 mL, 55.6 mmoL) in dichloromethane (50 mL), at 0°C TMSI (7.92 mL) is added dropwise over 20 minutes.
  • target compound T3 After dissolving compound T2 (2.6 g, 6.77 mmol) in dimethylformamide (25 mL), sodium azide (530 mg, 8.13 mmol) was added and stirred at room temperature for 1 hour. while stirring. After completion of the reaction, the mixture was washed with water and aqueous ammonium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure.
  • target compound T4 After dissolving compound T3 (841 mg, 3.08 mmol) in isopropanol (10 mL), L-pyroglutamic acid (402 mg, 3.11 mmol) was added. The reaction was stirred at 70 °C for 30 min, then dissolved in isopropanol (14 mL) and 2-hydroxy-5- Nitrobenzaldehyde (16 mg, 0.092 mmol) was added sequentially and stirred at 70 °C for 3 days. After cooling the reactant to room temperature, the solid was filtered and washed with hexane and isopropanol. The solid was dried to obtain the pyroglutamate salt.
  • Step 6 Preparation of target compound T6 After dissolving compound T5 (391 mg, 1.08 mmol) in dimethylformamide (5 mL), potassium carbonate (180 mg, 1.29 mmol) and methyl iodine (0.067 mL, 1.08 mL) mmol) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure.
  • Step 7 Preparation of target compound T7 Compound T6 (201 mg, 0.52 mmol), Pd(0Ac) 2 (12.0 mg, 0.052 mmol), BI NAP (65 mg, 0.11 mmol), and cesium carbonate (677 mg, 2.08 mmol) were diluted in toluene (5 mL), then pyrrolidine (0.047 mL, 0.57 mmol) was added. The reaction was stirred at 90 °C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure.
  • Step 8 Preparation of target compound T8 After dissolving compound T7 (196 mg, 0.52 mmol) in dichloromethane (5 mL), hydrochloric acid (4> 1,4-dioxane solution; 0.65 mL) was added. did The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the product was concentrated under reduced pressure to obtain the target compound T8 (163 mg, 100%) as a white solid. The obtained compound T8 was subjected to the next reaction without additional purification. Step 9.
  • Target compound T9 Compound T8 (163 mg, 0.52 mmol), EDC (127 mg, 1.04 mmol), HOAt (142 mg, 1.04 mmol), and 2-benzyl-2woo 1,2, 3, 4 -Tetrazole- 5-carboxylic acid (117 mg, 0.57 mmol) was diluted in dichloromethane (5 mL), then triethylamine (0.29 mL, 2.08 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure.
  • Example 193 A compound according to Example 193 was prepared in the same manner.
  • Example 197 1-Benzyl-N-((S)-8-fluoro-7-((S)-3-methoxypyrrolidin-L-yl)-methyl-2-oxo-2, 3, 4, 5 -tetrahydro- 1H-benzo [b] azepin- 3 -yl)- 1H- 1,2, 4 - Preparation of triazole-3-carboxamides 7-Bromo-6-fluoro-3,4-dihydronaphthalen-1(2a)-one in step 1 of Example 194 is replaced with 6-bromo-7-fluoro-3,4-dihydronaphthalene - 1(2 ⁇ )-one as starting material, instead of pyrrolidine in step 7
  • step 1 of Example 194 7-bromo-6-fluoro-3,4-dihydronaphthalen-1(2a)-one is replaced with 6-bromo-7-fluoro-3, 4-dihydronaphthalen-1(2 ⁇ )-one as a starting material, instead of pyrrolidine in step 7
  • Example 198 A white solid compound according to Example 198 was synthesized in substantially the same manner as in Example 194 to prepare compound T9, except that (S)-methoxypyrrolidine was used.
  • iH NMR 400 MHz, DMS0-d 6 ) 5 8.86-8.81 (m, 1H), 7.39 (s, 5H), 7.23
  • Example 199 (S) -l-benzyl-N-(l-methyl-2-oxo-8-(pyrroly) of din-1-yl)-2, 3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide
  • step 1 of Example 194 7-bromo-6-fluoro-3,4- Instead of dihydronaphthalene-1(2a)-one, 7-bromo-3,4-dihydronaphthalene-1(using di-one, 2-benzyl-2 in step 7 1,2,3, Substantially the same as for preparing compound T9 of Example 194, except that 1-benzyl-1woo 1,2,4-triazole-3-carboxylic acid was used instead of 4-tetrazole-5-carboxylic acid.
  • Step 2 Preparation of target compound X2 Compound XI (7.04 g, 15.6 mmol) was dissolved in dimethylformamide (100 mL). Then, cesium carbonate (6.1 g, 18.7 mmol) and methyl iodine (0.981 mL, 15.8 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours.
  • Step 4 Preparation of target compound X4 Compound X3 (3.51 g, 10.1 mmol) and tritylchloride (3.12 g, 11.2 mmol) were added to chloroform (60 mL), followed by triethylamine (4.25 mL, 30.4 mmol). did The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure.
  • Step 5 Preparation of target compound X5 Compound X4 (4.19 g, 7.60 mmol) was added to dimethylsulfoxide (65 mL) followed by cesium carbonate (4.97 g, 15.2 mmol). The reaction mixture was stirred at 50 °C for 16 hours. After completion of the reaction, the solution was cooled to room temperature and then washed with ethyl acetate. After extraction and washing with water and aqueous sodium chloride solution, dried over sodium sulfate and filtered. The solvent was removed by concentration under reduced pressure.
  • Step 6 Preparation of target compound X6 Compound X5 (300 mg, 0.56 mmo 1 ), Pd(0Ac) 2 (12 mg, 0.056 mmo 1 ), BI NAP (70 mg, 0.112 mmo 1 ), and cesium carbonate (364 mg , 1.12 mmol) was added to toluene (2 mL) followed by pyrrolidine (0.07 mL, 0.85 mmol). The reaction mixture was stirred at 90 °C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent.
  • Step 7 Preparation of target compound X7 Compound X6 (250 mg, 0.48 mmol) was added to dichloromethane (2 mL), followed by 1,4-dioxane hydrochloric acid solution; 0.6 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure to obtain the target compound X7 (146 mg, 96%) as a white solid. The obtained compound X7 was subjected to the next reaction without additional purification. Step 8.
  • Target compound X8 Compound X7 (90 mg, 0.28 mmol), HATU (130 mg, 0.342 mmol), and 1-benzyl-1woo 1,2,4-triazole-3-carboxylic acid (58 mg, 0.28 mmol) in dimethylsulfoxide (1 mL), followed by diisopropylethylamine (0.1 mL, 0.57 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction is complete, After extraction with ethyl acetate, washing with aqueous sodium chloride solution, drying over sodium sulfate and concentration under reduced pressure.
  • Examples 204 to 214 Reactant 1 in Table 25 below was used as a compound corresponding to pyrrolidine in Step 6 of Example 203, 1-benzyl-1, 2, 4-triazole in Step 8 of Example 203.
  • Compounds according to Examples 204 to 214 were prepared in substantially the same manner as the method for preparing compound X8 of Example 203, except that reactant 2 of Table 25 was used as a compound corresponding to -3-carboxylic acid. did
  • Example 215. (S)-l-Benzyl-N-(8-fluoro-5-methyl-4-oxo-7-(pyrrolidin-1-yl)-2,3,4,5-tetrahydro Preparation of benzo [b] [1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide Steps 1 to 5 of Example 203 were followed except that 5-bromo-2,4-difluoroaniline was used instead of 4-bromo-2,5-difluoroaniline in Step 1 of Example 203.
  • Example 2115 The target compound Y4 was sequentially synthesized.
  • Examples 216 to 228 In the step of preparing compound Y2 in Example 215, reactant 1 in Table 27 was used as a compound corresponding to pyrrolidine, and in the step of preparing compound Y4 in Example 215, 1-benzyl-L ⁇ Carried out in substantially the same manner as in Example 215 for preparing compound Y4>, except that reactant 2 in Table 27 was used as a compound corresponding to ⁇ l,2,4-triazole-3-carboxylic acid.
  • Compounds according to Examples 216-228 were prepared.
  • target compound AB2 After dissolving compound AB1 (246 mg, 0.71 mmol) in dichloromethane (14 mL), EDC (173 mg, 1.42 mmol), HOAt (191 mg, 1.42 mmol), 1- Benzyl-1woo 1,2,4-triazole-3-carboxylic acid (159 mg, 0.78 mmol) and triethylamine (0.3 mL, 2.16 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 16 hours.
  • Example 241 The solvent was removed through concentration under reduced pressure to obtain the target compound AB3 (3 mg, 6%) as a beige solid according to Example 240.
  • target compound AQ2 After dissolving compound AQ1 (7.1 g, 30 mmol) in toluene (200 mL), Pd(dba) 2 (431 mg, 0.75 mmo 1 ) and Zantphos (867 mg, 1.5 mmo 1 ) , AHBoc-L-cysteine (7261 mg, 33 mmol) and diisopropylethylamine (10.3 mL, 60 mmol) were added under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 2 h. After completion of the reaction, the mixture was filtered using celite and concentrated under reduced pressure.
  • Step 3 Preparation of target compound AQ3 After dissolving compound AQ2 (10.46 g, 31.56 mmol) in dichloromethane (310 mL), diisopropylethylamine (11 mL, 63.12 mmol) and T 3 P (50% ethyl acetate) solution; 27.6 mL; 63.12 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature.
  • Step 4 Preparation of target compound AQ4 After dissolving compound AQ3 (1212 mg, 3.87 mmol) in dimethylformamide (30 mL), potassium carbonate (1069 mg, 7.74 mmol) and methyl iodine (0.24 mL, 3.87 mmol) were added. added. The reaction mixture was stirred for 1 hour at room temperature.
  • Step 6 Preparation of target compound AQ6 After dissolving compound AQ5 (733 mg, 2.44 mmol) and tritylchloride (816 mg, 2.928 mmol) in dichloromethane (3 mL), triethylamine (1.7 mL, 12.2 mmol) ) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure.
  • Step 7. Preparation of target compound AQ7 After adding compound AQ6 (438 mg, 0.94 mmol) to 4-methoxybenzylamine (2 mL), the mixture was stirred at 60°C for 16 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, washed with water and aqueous sodium chloride solution, dried over magnesium sulfate, and filtered. The concentrate was purified by silica gel column chromatography.
  • Step 8 Preparation of target compound AQ8 After dissolving compound AQ7 (493 mg, 0.84 mmol) in dichloromethane (2 mL), hydrochloric acid (4> 1,4-dioxane solution; 1.1 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure to obtain the target compound AQ8 (319 mg, 99%) as a white solid. The obtained compound AQ8 was subjected to the following reaction without further purification. Step 9.
  • Example 242 Compound AQ11 of Example 242 was prepared, except that reactant 1 in Table 33 was used as a compound corresponding to 3,3,3-trifluoropropionyl chloride in step 11 of Example 242. Compounds according to Examples 243 to 246 were prepared in substantially the same manner as the preparation method.
  • reaction solution was extracted with dichloromethane, washed with aqueous sodium bicarbonate solution and aqueous sodium chloride solution, dried over magnesium sulfate, and filtered. The solvent was removed through concentration under reduced pressure to obtain the target compound AC2 (41 mg, 37%) as a yellow solid.
  • the obtained compound AC2 was subjected to the following reaction without further purification.
  • reaction solution was extracted with dichloromethane, washed with aqueous sodium bicarbonate solution, water, and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure.
  • Examples 248 to 252 Reactant 1 in Table 35 below was used as a compound corresponding to azetidinone in step 1 of Example 247, and 1-benzyl-1-1,2,4-triazole-3-carboxyl in step 3 Compounds according to Examples 248 to 252 were prepared in substantially the same manner as the method for preparing compound AC3 of Example 247, except that reactant 2 in Table 35 was used as a compound corresponding to the acid.
  • Step 2 Preparation of target compound AE2 Compound AE1 (13.4 g, 31.8 mmol) was added to methanol, followed by MeOH (318 mL), zinc (20.8 g, 318 mmol) and ammonium chloride (3.4 g, 63.6 mmol). . The reaction mixture was stirred at 75 °C for 16 hours. After completion of the reaction, the reaction mixture was filtered using Celite. The concentrate was concentrated under reduced pressure to obtain a beige target compound AE2 (12.4 g, 99%). Step 3.
  • Step 4 Preparation of target compound AE4 After dissolving compound AE3 (3.8 g, 10.11 mmol) in dimethylformamide (60 mL), cesium carbonate (4.9 g, 15.17 mmol) and methyl iodine (0.76 mL, 12.13 mmol) were added. added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, washed with water and aqueous sodium chloride solution, dried over magnesium sulfate, and filtered. The solvent was removed through concentration under reduced pressure to obtain the target compound AE4 (2.4 g, 60%) as a white solid. Step 5.
  • Step 6 Preparation of target compound AE6 After adding compound AE5 (262 mg, 0.69 mmol) to dichloromethane (4.6 mL), hydrochloric acid (4> 1,4-dioxane solution; 0.87 mL, 3.47 mmol) was added. did The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure to obtain the target compound AE6 (67 mg, 31%) as a white solid. The obtained compound AE6 was subjected to the following reaction without further purification. Step 7.
  • reaction solution was extracted with dichloromethane, washed with aqueous sodium bicarbonate solution, water, and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure.
  • Example 254 (R)- 1-Benzyl- N- (5 -methyl- 8 -morpholino- 4 -oxo- 2, 3,4,5- tetrahydrobenzo [b] [ Preparation of 1,4]thiazepin-3-yl)-1H-imidazole-4-carboxamide
  • Target compound AG2 Compound AG1 (807 mg, 3.03 mmol) and tritylchloride (1.02 g, 3.64 mmol) were added to and dissolved in dichloromethane (10 mL), and triethylamine (2.12 mL,
  • Step 4 Preparation of target compound AG4 After dissolving compound AG3 (97 mg, 0.19 mmol) in dichloromethane (5 mL), hydrochloric acid (4 River 1,4-dioxane solution; 0.24 mL) was added. . The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction concentrate was concentrated under reduced pressure to obtain the target compound AG4 (57 mg, 100%) as a white solid. Step 5.
  • Target compound AH1 Compound Q2 (100 mg, 0.21 mmol) was dissolved in cyclopentylamine (1 mL) and stirred at 100°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound AH1 (70 mg, 100%) as a pale yellow solid. Step 2. Preparation of target compound AH2 After dissolving compound AH1 (70 mg, 0.21 mmol) in dichloromethane (5 mL), hydrochloric acid (4> 1,4-dioxane solution; 250 uL, 0.0011 mmol) was added. The reaction was stirred at room temperature for 16 hours.
  • Step 3 Preparation of target compound AH3 Compound AH2 (67 mg, 0.21 mmo 1 ) , EDC (51 mg, 0.41 mmo 1 ) , HOAt (56 mg, 0.41 mmol), and 1-benzyl-1woo 1,2,4-triazole-3-carboxylic acid (51 mg, 0.25 mmol) were diluted in dichloromethane (5 mL) and triethylamine (0.12 mL, 0.82 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure.
  • Step 4 Preparation of target compound AH4 To compound AH4 (46 mg, 0.093 mmol) were added formic acid (45 ⁇ L, 1.17 mmol) and formaldehyde aqueous solution (5 mL), and the mixture was stirred under reflux conditions for 16 hours. After completion of the reaction, the reaction mixture was basified with an aqueous solution of sodium bicarbonate and washed with water and an aqueous solution of sodium chloride. The organic layer was extracted using ethyl acetate.
  • iH NMR 400 MHz, DMSO—d6) 5 8.74 (s, 1H), 8.15 (s, 1H), 7.34-7.25 (m, 5H), 6.83 (s, IH) , 4.57 (m, IH), 4.11 ( s, 2H), 3.44-3.38 (m, 3H), 3.31-3.25 (m, 4H), 2.39-2.35 (m, 2H), 1.79 (m, 2H); LRMS (electrospray) m/z (M+H) ) + 520.
  • Step 2 Preparation of target compound AK2 Compound AK1 (8.3 g, 51.8 mmol) was dissolved in methanol (259 mL), and then Pd/C (1.3 g, 12.4 mmol) was added. The reactants were stirred for 2 hours at room temperature under a hydrogen atmosphere at a pressure of 40 psi. After completion of the reaction, the reaction mixture was filtered using celite and concentrated under reduced pressure to obtain the target compound AK2 (6.7 g, 99%) as a brown solid. Step 3.
  • Step 8 Preparation of target compound AK8
  • Compound AK7 (1.3 g, 2.8 mmol) and potassium carbonate (1.5 g, 11.3 mmol) were added to 1,4-dioxane (5.6 mL) to dilute, pyrrolidine (0.92 mL) , 11.3 mmol) was added.
  • the reaction was stirred for 16 hours under reflux conditions. After completion of the reaction, the reaction mixture was washed with water, and the organic vapor was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure.
  • Step 9 Preparation of target compound AK9 Compound AK8 (1.3 g, 2.6 mmol) was dissolved in dichloromethane (12.8 mL), and then hydrochloric acid (4 River 1,4-dioxane solution; 6.4 mL) was added. . The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound AK9 (900 mg, 98%) as a white solid. Step 10.
  • Step 3 Preparation of target compound AL3 Compound AL2 (14 mg, 0.05 mmo 1 ), EDC (11 mg, 0.09 mmo 1 ), HOAt (12 mg, 0.09 mmol), and 1-benzyl- 1,2,4 -Triazole-3-carboxylic acid (14 mg, 0.07 mmol) was diluted in dichloromethane (0.9 mL) and triethylamine (0.02 mL, 0.14 mmol) was added at 0°C. The reaction was stirred at room temperature for 16 hours.
  • Target compound AM2 After dissolving compound AM1 (347 mg, 0.591 mmol) in dichloromethane (5 mL), hydrochloric acid (4> 1,4-dioxane solution; 740 uL, 0.296 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound AM2 (225 mg, 91%) as a pale yellow solid. Step 3. Preparation of target compound AM3 Compound AM2 (225 mg, 0.591 mmol) and 5-benzyl-1woo 1,2,4-triazole-3-carboxylic acid (133 mg, 0.65 mmol) were mixed with dichloromethane.
  • Step 2 Preparation of target compound A02 After dissolving compound A01 (100 mg, 0.202 mmol) in dichloromethane (2 mL), hydrochloric acid (4 River 1,4-dioxane solution; 0.25 mL) was added. . The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound A02 (36 mg, 62%) as a white solid. Step 3.
  • Step 4 Preparation of target compound AP4 Compound AP3 (21 mg, 0.06 mmol) and 5-benzyl-1woo 1,2,4-triazole-3-carboxylic acid (17 mg, 0.08 mmol) were mixed with dichloromethane. (0.33 mL), Diisopropylamine (0.02 mL, 0.11 mmol) and T 3 P (50% ethyl acetate solution; 0.07 mL, 0.11 mmol) were added at 0°C. The reaction was stirred at room temperature for 16 hours.
  • Target compound AU5 Compound AU4 (60 mg, 0.11 mmol) was added to and dissolved in dichloromethane (2 mL), then hydrochloric acid (4> 1,4-dioxane solution; 0.13 mL, 0.53 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound AU5 (42 mg, 99%) as a brown solid. Step 6.
  • Reactant 1 in Table 41 below was used as a compound corresponding to 4-aminotetrahydropyran in step 1 of Example 279, and 5-[(2-fluorophenyl)methyl]-4 in step 6
  • Example 280 and Example 280 in substantially the same manner as the compound AU6 of Example 279, except that reactant 2 in Table 41 was used as a compound corresponding to 1,2,4-triazole-3-carboxylic acid.
  • Compounds according to 281 were prepared. [Table 41] The structure and compound name of each of the compounds obtained according to Examples 279 to 281, and the results of NMR analysis are shown in Table 42 below.
  • Step 2 Preparation of target compound AV2 Compound AV1 (885 mg, 3.62 mmol) was added to ethanol (10 mL) and water (13 mL), followed by AHBoc-L-cysteine (800 mg, 3.62 mmol) and hydrogen carbonate. Sodium (910 mg, 10.9 mmoL) is added. The reaction mixture is refluxed for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and then water was added and washed with diethyl ether.
  • Step 3 Preparation of target compound AV3 Compound AV2 (1.24 g, 2.78 mmol) was dissolved in methanol (28 mL), and then zinc (1.82 g, 27.81 mmol) and ammonium chloride (297 mg, 5.56 mmol) were added. . The mixture was stirred at 75 °C for 3 hours.
  • Step 4 Preparation of target compound AV4 Compound AV3 (1.19 g, 2.78 mmol), EDC (679 mg, 5.56 mmol), and HOAt (757 mg, 5.56 mmol) were diluted in dichloromethane (19 mL), ethylamine (1.16 mL, 8.34 mmol) was added. The reaction was stirred at room temperature for 16 hours.
  • the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure.
  • RPMI medium Hyclone containing Streptomycin and Hyclone.
  • RPMI medium without phenol red was used, and 15,000 cells/well of U937 cells and L929 cells were placed in a 96-well plate (ViewPlate-96, white 96-well, PerkinElmer). After dispensing at a concentration of 5,000 cells/well, respectively, 5% C02, and incubated for 5 to 6 hours at 37 °C conditions.
  • each of the compounds of the present invention was given a 10-fold concentration gradient in the concentration range of 0.01 nM to 1 uM for U937 cells and 0.lnM to 10 uM for L929 cells, 5% C0 2 , 1 hour at 37 °C. treated during. Then, after adding TNF-a (lOOng/mL, Sigma) and Q-VD-Oph (50uM, Selleckchem), they were incubated for 19 to 21 hours at 5% C0 2 and 37 °C.
  • TNF-a lOOng/mL, Sigma
  • Q-VD-Oph 50uM, Selleckchem
  • Example compounds of the present invention have excellent cell protection effects under apoptosis inducing conditions. That is, the compounds of the present invention provide an apoptosis inhibitory effect, and thus can be usefully used for the treatment of RIPK1 activity-related diseases.
  • Experimental Example 2 In vivo biological analysis The compounds of the present invention were tested in vivo by TNF-a (Tumor Necrosis Factor- alpha) was confirmed through an acute mouse model ( lethal shock mouse model). In this model, infusion of TNF combined with the caspase inhibitor zVAD induces a systemic inflammatory response characterized by hypotension, hepatitis, hypothermia and intestinal necrosis.
  • TNF-a Tumor Necrosis Factor- alpha
  • Efficacy can be measured by the ability of RIPK1 inhibitors to prevent loss of body temperature.
  • a total of 5 C57BL/c mice per group were orally administered with vehicle (a mixture of DMSO, cremophor EL and DW) or compounds at a dose of 10 mg/kg, and after 15 minutes, mouse TNF-a (30 doses/mouse) and z -VAD-fmk (0.4 mg/mouse) was administered intravenously.
  • vehicle a mixture of DMSO, cremophor EL and DW
  • mouse TNF-a (30 doses/mouse) and z -VAD-fmk (0.4 mg/mouse) was administered intravenously.
  • body temperature loss mouse body temperature 2 hours after intravenous administration - mouse body temperature before oral administration
  • CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 were analyzed using Invitrogen (P2863, P3019, PV6141, P2861, P2864, P2972, P2858) kits.
  • Invitrogen kit the example compounds were prepared by diluting in Vivid CYP450 reaction buffer (IX) to 2.5X of the final experimental concentration, and the P450 BACULOSOMES sample and the Regenerate ion system (100X) It was prepared by diluting the concentration suitable for the type of CYP450 in Vivid CYP450 reaction buffer (1> ⁇ ).
  • Example compounds were orally administered to BALB/c mice at a dose of 10 mg/kg.
  • For blood collection 200 uL of blood was collected from the orbital vein using a capillary tube coated with sodium-heparin at fixed times (5 minutes, 30 minutes, 1 hour, 3 hours, 5 hours, and 8 hours after administration). The collected blood was transferred to a 1.7mL tube, and plasma was separated by centrifugation at 6,000g, 4°C, and 5 minutes.
  • Example compounds in plasma were pretreated by protein precipitation, and quantitative analysis was performed using an LC-MS/MS system.

Abstract

The present invention relates to a compound as an RIPK1 inhibitor, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and a pharmaceutical composition comprising at least one thereof as an active ingredient, which can be effectively used in the prevention or treatment of diseases associated with RIPK1 activity. The compound according to the present invention may be represented by chemical formula I below. [Chemical Formula I]

Description

【명세서】 【Specification】
【발명의 명칭】 【Name of Invention】
RIPK1 저해제로서의 신규한 화합물 및 이를 포함하는 약학적 조성물 {NOVEL COMPOUNDS AS RIPK1 INHIBITOR AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME} Novel compounds as RIPK1 inhibitors and pharmaceutical compositions containing them {NOVEL COMPOUNDS AS RIPK1 INHIBITOR AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME}
【기술분야】 본 발명은 RIPK1 저해제로서의 화합물, 이의 입체 이성질체, 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물 및 이를 포함하는 약학적 조성물, 그리고 상기 화합물을 이용한 RIPK1 활성 관련 질환의 예방또는 치료를 위한방법 및 이의 용도에 관한 것이다. [Technical Field] The present invention relates to compounds as RIPK1 inhibitors, stereoisomers, tautomers, pharmaceutically acceptable salts thereof, hydrates or solvates thereof, pharmaceutical compositions containing the same, and RIPK1 activity using the compounds. It relates to methods and uses thereof for the prevention or treatment of related diseases.
【배경기술】 단백질 키나아제는 ATP의 감마-인산기를 단백질의 타이로신, 세린 및 트레오닌의 하이드록시 그룹에 전달하는 인산화 반응을 촉매하는 효소이다. 단백질 키나아제는 세포의 대사, 유전자 발현, 세포 성장, 분화 및 세포 분열 작용을 담당하고, 세포 신호 전달에 중요한 역할을 한다 (Thomas A. Kami Iton, in Encyclopedia of Immunology (Second Edition) , 1998, 2028-2033) . 단백질 키나아제는 타이로신 단백질 키나아제오} 세린/트레오닌 키나아제로 분류되는데, 그 중 약 90종 이상은 타이로신 키나아제이다. 단백질 키나아제는 분자 스위치로 세포 내에서 활성과 비활성 상태 사이의 전이가 원활하게 조절되어야 한다. 만약, 상기 활성과 비활성 상태 사이의 전이가 비정상적으로 조절되면 세포 내 신호 전달을 과도하게 활성화시켜 통제불능의 세포 분열 및 증식을 유도하게 된다. 또한, 단백질 키나아제의 유전자 변이 , 증폭 및 과발현에 의한 비정상적인 활성화는 다양한 종양의 발생 및 진행과 관련이 있어 염증성 질환, 퇴행성 뇌질환, 자가면역 질환, 암 등 다양한 질병의 발병에 결정적인 역할을 하게 된다. 키나아제 중 , RIP1 kinase (Receptor-interact ing ser ine/ threonine- protein kinase 1 , RIPK1)는 수용체-상호작용 세린/트레오닌 키나아제 패밀리 (receptor- interact ing Ser/Thr kinase fami ly)에 속하고 , TNFR1 신호 경로 (Tumor necrosis factor receptor 1 s i gna 1 i ng pathway)에서 중요한 상위 효소 (upstream kinase)이다. RIPK1은 염증 , 아폽토시스 및 네크롭토시스의 핵심 조절제이다. 활성화된 RIPK1는 염증을 유발하여 프로그램된 괴사를 직접 조절하고 , RIPK1은 TNF에 제한되는 것보다 더 광범위한 염증 유발 활동에 참여한다. RIPK1은 종양괴사인자와 관련한 염증성 신호전달에서 핵심적인 역할을 하는 세포괴사의 중요한 조절인자이므로, 이를 억제할 경우 TNF- a 에 의한 염증을 차단할 수 있다 (Front . Cel l Dev. Biol . , 13 August 2019) . 최근의 연구는 , RIPK1의 활성이 전통적으로 수동 및 비조절적이라고 생각되었고 독특한 형태학을 특징으로 하는 네크롭토시스 , 괴저성 세포 사멸 형태를 제어한다고 입증하였다. 추가로, RIPK1는 아폽토시스 조절에 있어서 그 활성을 나타내는 프로-아폽토시스 복합체의 일부이다. [Background Art] Protein kinase is an enzyme that catalyzes a phosphorylation reaction that transfers a gamma-phosphate group of ATP to a hydroxy group of tyrosine, serine, and threonine of a protein. Protein kinase is responsible for cell metabolism, gene expression, cell growth, differentiation and cell division, and plays an important role in cell signal transduction (Thomas A. Kami Iton, in Encyclopedia of Immunology (Second Edition) , 1998, 2028- 2033). Protein kinases are classified into tyrosine protein kinases} serine/threonine kinases, of which about 90 or more are tyrosine kinases. Protein kinase is a molecular switch, and the transition between active and inactive states in cells must be smoothly regulated. If the active and inactive state When the transition between cells is abnormally regulated, intracellular signal transduction is excessively activated, leading to uncontrolled cell division and proliferation. In addition, abnormal activation by genetic mutation, amplification, and overexpression of protein kinase is related to the development and progression of various tumors, and thus plays a crucial role in the development of various diseases such as inflammatory diseases, degenerative brain diseases, autoimmune diseases, and cancer. Among kinases, RIP1 kinase (Receptor-interacting serine/threonine-protein kinase 1, RIPK1) belongs to the receptor-interacting serine/threonine kinase family (receptor-interacting ing Ser/Threonine-protein kinase family), and is involved in the TNFR1 signaling pathway. It is an important upstream kinase in the (Tumor necrosis factor receptor 1 si gna 1 ing pathway). RIPK1 is a key regulator of inflammation, apoptosis and necroptosis. Activated RIPK1 induces inflammation and directly regulates programmed necrosis, and RIPK1 participates in a broader range of proinflammatory activities than is restricted to TNF. Since RIPK1 is an important regulator of apoptosis that plays a key role in inflammatory signaling related to tumor necrosis factor, inhibition of RIPK1 can block TNF-a-induced inflammation (Front. Cell Dev. Biol., 13 August 2019). Recent studies have demonstrated that the activity of RIPK1 controls a form of necroptosis, necrotic cell death traditionally thought to be passive and unregulated and characterized by a unique morphology. Additionally, RIPK1 is part of the pro-apoptotic complex that exhibits its activity in regulating apoptosis.
RIPK1는 유비퀴틴화, 탈-유비퀴틴화 및 인산화를 포함하는 복잡하고 난해한 조절 메커니즘의 지배를 받는다. 이들 조절의 경우는 세포가 생존하고 염증성 반응을 활성화하고 또는 아폽토시스 또는 네크롭토시스를 통해 죽을지 여부를 종합적으로 결정한다. RIPK1의 신호전달 조절 장애는 과도한 염증 또는 세포 사멸을 유도할 수 있고, 반대로, RIPK1의 저해는 염증 또는 세포 사멸을 수반하는 질환에 대한유효한치료가 될 수 있다고 연구결과 밝혀졌다. RIPK1 is subject to complex and esoteric regulatory mechanisms including ubiquitination, de-ubiquitination and phosphorylation. These controls determine whether cells survive, activate inflammatory responses, or die through apoptosis or necroptosis. comprehensively decide whether Studies have shown that dysregulation of RIPK1 signal transduction can induce excessive inflammation or apoptosis, and conversely, inhibition of RIPK1 can be an effective treatment for diseases involving inflammation or apoptosis.
RIPK1에 의해 매개되는 세포괴사는 염증성 질환, 퇴행성 뇌질환, 자가면역 질환, 암 등 다양한 질병과 관련이 있음이 보고되어 왔다. RIPK1-매개 프로그램화된 괴사가 완전히 차단되도록 설계된 RIP3 녹아웃 마우스는 염증성 장 질환 (궤양성 결장염 및 크론병 포함), 건선 (Psoriasis), 망막-박리-유도된 광수용체 괴사, 색소성 망막염 (Retinitis pigmentosa) , 세룰레인-유도된 급성 췌장염 및 패혈증/전신 염증 반응 증후군 (SIRS)에서 보호성인 것으로 확인된 바 있다. 또한, RIPK1은 알츠하이머병 (Alzheimer ' s disease)에서 소교 반응 (microglial response)을 매개하는 것으로보고된 바도 있다. 최근에는, 류마티스 관절염 환자의 활막 조직 샘플에서 인산화된 RIPK1이 증가하는 것이 확인되었다 (Cell Death & Differentiation (2020) 27： 161- 175). RIPK1 Knock-In 류마티스 관절염 동물모델에서 RIPK1 신호 경로 저해로 인해 염증이 완화되고, Genent ech 사에서 비임상 개발 중에 있는 RIPK1 저해제 GNE684가 TNFR2- Fc를 이용해 TNF에 의한 신호전달을 차단하는 것과 비슷한 수준으로 관절염을 완화시키는 것이 확인되었다. Cell necrosis mediated by RIPK1 has been reported to be associated with various diseases such as inflammatory diseases, degenerative brain diseases, autoimmune diseases, and cancer. Engineered to completely block RIPK1-mediated programmed necrosis, RIP3 knockout mice have been shown to be resistant to inflammatory bowel disease (including ulcerative colitis and Crohn's disease), psoriasis, retinal-detachment-induced photoreceptor necrosis, and retinitis pigmentosa. ), cerulein-induced acute pancreatitis and sepsis/systemic inflammatory response syndrome (SIRS). In addition, RIPK1 has also been reported to mediate the microglial response in Alzheimer's disease. Recently, it was confirmed that phosphorylated RIPK1 is increased in synovial tissue samples from patients with rheumatoid arthritis (Cell Death & Differentiation (2020) 27: 161-175). In the RIPK1 Knock-In rheumatoid arthritis animal model, inhibition of the RIPK1 signal pathway relieves inflammation, and Genentech's RIPK1 inhibitor GNE684, which is under non-clinical development, blocks TNF-induced signal transduction using TNFR2-Fc. It has been confirmed to alleviate arthritis.
RIPK1의 약리학적 억제 또는 유전적 비활성화는 급성 허혈성 상태 , 만성 염증 및 신경변성에 이르는 질병의 동물 모델에서 가능성을 보여주고 있다. 이처럼, RIPK1가 염증, 세포사멸 등에 있어서 매우 중요한 역할을 수행하고, 류마티스 관절염 (RA), 건선 (Psoriasis), 염증성 장질환 (IBD)과 같은 자가면역 관련 질환은 물론 신경 퇴행성 질환 및 항암 치료제 표적물질로도 많은 관심을 받고 있으므로, 신규한 구조의 단백질 키나아제 억제제에 대한 개발이 요구되고 있다. Pharmacological inhibition or genetic inactivation of RIPK1 has shown promise in animal models of diseases ranging from acute ischemic conditions to chronic inflammation and neurodegeneration. As such, RIPK1 plays a very important role in inflammation and apoptosis, and is a target material for neurodegenerative diseases and anti-cancer drugs as well as autoimmune-related diseases such as rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease (IBD). also a lot of attention Therefore, development of a protein kinase inhibitor having a novel structure is required.
［선행기술문헌］ [Prior art literature]
［특허문헌］ [Patent Documents]
（특허문헌 1） 한국공개특허 제 2018- 0114910호 (Patent Document 1) Korean Patent Publication No. 2018-0114910
（특허문헌 2） 한국공개특허 제 2020- 0088945호 (Patent Document 2) Korean Patent Publication No. 2020-0088945
（특허문헌 3） W0 2020/056074 (Patent Document 3) W0 2020/056074
（특허문헌 4） 한국공개특허 제 2018- 0023988호 (Patent Document 4) Korean Patent Publication No. 2018-0023988
［비특허문헌］ [Non-patent literature]
（비특허문헌 1） Thomas A. Kami Iton, in Encyclopedia of Immunology （Second Edition）, 1998, 2028-2033 (Non-Patent Document 1) Thomas A. Kami Iton, in Encyclopedia of Immunology (Second Edition), 1998, 2028-2033
（비특허문헌 2） Front . Cel 1 Dev. Biol . , 13 August 2019 (Non-Patent Document 2) Front. Cel 1 Dev. Biol. , 13 August 2019
（비특허문헌 3） Cell Death & Differentiation （2020） 27： 161-175 (Non-Patent Document 3) Cell Death & Differentiation (2020) 27: 161-175
【발명의 상세한설명】 【Detailed description of the invention】
【기술적 과제】 본 발명은 RIPK1 저해제로서의 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물을 제공하는 것을 목적으로 한다. 본 발명의 또 다른 목적은, RIPK1 저해제로서의 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물을 유효성분으로서 포함하는 약학적 조성물 또는 키트를 제공하는 것이다. 본 발명의 또 다른 목적은, RIPK1 저해제로서의 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물을 유효성분으로서 포함하는, RIPK1 활성 관련 질환의 예방 또는 치료를 위한조성물을 제공하는 것이다. 본 발명의 또 다른 목적은, RIPK1 저해제로서의 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물을 치료학적 유효량으로 투여하는 것을 포함하는 RIPK1 활성 관련 질환의 예방또는 치료를 위한방법을 제공하는 것이다. 본 발명의 또 다른 목적은, RIPK1 활성 관련 질환의 예방 또는 치료를 위한 RIPK1 저해제로서의 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물의 용도를 제공하는 것이다. 본 발명의 또 다른 목적은, RIPK1 활성 관련 질환의 예방 또는 치료용 약제의 제조를 위한, RIPK1 저해제로서의 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물의 용도를 제공하는 것이다. [Technical Problem] An object of the present invention is to provide a compound as a RIPK1 inhibitor, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. Another object of the present invention is a compound as a RIPK1 inhibitor, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, and a hydrate thereof. Or to provide a pharmaceutical composition or kit containing a solvate thereof as an active ingredient. Another object of the present invention is to prevent RIPK1 activity-related diseases, including a compound as a RIPK1 inhibitor, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient. Or to provide a composition for treatment. Another object of the present invention is related to RIPK1 activity, including administering a compound as a RIPK1 inhibitor, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof in a therapeutically effective amount. It is to provide a method for preventing or treating a disease. Another object of the present invention is to use a compound, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as a RIPK1 inhibitor for the prevention or treatment of RIPK1 activity-related diseases. is to provide Another object of the present invention is a compound as a RIPK1 inhibitor, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a compound thereof as a RIPK1 inhibitor for the preparation of a drug for preventing or treating RIPK1 activity-related diseases. To provide a use for the solvate.
【기술적 해결방법】 이하, 본 발명을 보다구체적으로 설명한다. 본 발명에서 개시된 다양한 요소들의 모든 조합은 본 발명의 범주에 속한다. 또한, 하기의 구체적인 서술에 의하여 본 발명의 범주가제한된다고 볼수 없다. 화합물 본 발명은 하기 (1) 내지 (17) 중 어느 하나에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화을 제공한다. [Technical Solution] Hereinafter, the present invention will be described in more detail. All combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, in the detailed description below It cannot be seen that the scope of the present invention is limited by Compound The present invention provides a compound according to any one of the following (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.
(1) 하기 화학식 I로 표시되는 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물; (1) a compound represented by the following formula (I), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof;
<화학식 1>
Figure imgf000007_0001
화학식 I에서, <Formula 1>
Figure imgf000007_0001
In Formula I,
Zi은 CH또는시이고, Zi is CH or Si,
Z2 및 Z3은 각각독립적으로 N, CR1또는 CR2이되 , Z2 및 Z3중 어느 하나는 반드시 CRi이고, Z 2 and Z3 are each independently N, CR1 or CR2, but one of Z2 and Z3 is necessarily CRi,
Ri은 “CRi” 에서의 C와 직접 연결된 N을 포함하는 고리형 또는 비고리형 작용기이고, Ri is a cyclic or non-cyclic functional group containing N directly linked to C in “CRi”,
R2는 H, 할로겐, CN또는 - 0- (Cl- C5알킬)이고, R2 is H, halogen, CN or - 0- (Cl- C5 alkyl);
R3은 H또는 CH3이고, Wi은 CH2, S, 0, 8(=0) 또는 S(=0)2이고, R3 is H or CH3; Wi is CH2, S, 0, 8(=0) or S(=0)2;
W2는 0또는으이고, W2 is 0 or
A는 아릴 또는 헤테로아릴이고, A is aryl or heteroaryl;
L은 CH2, CH(CHs), CD2 또는 0이고, L is CH2, CH(CHs), CD 2 or 0;
B는 아릴, 헤테로아릴
Figure imgf000008_0001
이고, B is aryl, heteroaryl
Figure imgf000008_0001
ego,
R4는 H, 할로겐, NH2, Cl- C5알킬, NHC（=O）O-（Cl- C5알킬） 또는 0-（Cl- C5알킬）이고, R4 is H, halogen, NH 2 , Cl-C5alkyl, NHC(=O)O-(Cl-C5alkyl) or 0-(Cl-C5alkyl);
R5 및 R6은 각각 독립적으로 H, Cl- C5알킬, CN, 할로겐, -（Cl- C5알킬）- 0- （Cl- C5알킬） 또는 헤테로아릴이고, 여기서 헤테로아릴의 적어도 1 이상의 보는 각각 독립적으로 Cl- C5알킬로치환될 수 있고, R5 and R6 are each independently H, Cl-C5alkyl, CN, halogen, -(Cl-C5alkyl)-0-(Cl-C5alkyl) or heteroaryl, wherein at least one group of heteroaryl is each independently may be substituted with Cl- C5 alkyl;
Zi 내지 Z3가 N을 포함하지 않고 Wi이 0일 때, R2는 할로겐, CN 또는 - 0- （Cl- C5알킬）이다. When Zi to Z3 do not contain N and Wi is 0, R2 is halogen, CN or -0- (Cl-C5alkyl).
（2） 상기 （1）에 있어서, 상기 화학식 I의 Ri에서, 니을 포함하는 고리형 작용기는 적어도 1개 이상의 시을 포함하되, 고리는 단일결합만으로 이루어지거나 적어도 1 이상의 이중결합을 포함할 수 있고, 고리를 형성하는 탄소는 C（=0） 구조를 가질 수 있으며 , 단환또는 이중환일 수 있다. 예를 들어, 니을 포함하는 고리형 작용기는
Figure imgf000008_0002
Figure imgf000009_0001
포함할 수 있다. 여기서 , Z4는 CRcRd, 0, S또는 NRe이고, (2) In the above (1), in Ri of Formula I, the cyclic functional group containing ni includes at least one cy, but the ring may consist of only a single bond or include at least one double bond, The carbon forming the ring may have a C(=0) structure, and may be monocyclic or bicyclic. For example, a cyclic functional group containing ni
Figure imgf000008_0002
Figure imgf000009_0001
can include Where, Z4 is CRcRd, 0, S or NR e ,
Ra, Rb, Rc, Rd 및 Re는 각각독립적으로 H, Cl- C5알킬, 할로겐, CF3, CH2F, (Cl- C5알킬)- OH 또는 - 0- (Cl- C5알킬)이고, Ra, Rb, Rc, Rd and Re are each independently H, Cl- C5 alkyl, halogen, CF 3 , CH 2 F, (Cl- C5 alkyl)- OH or - 0- (Cl- C5 alkyl);
Z5 및 Z6은 각각 독립적으로 CH 또는 N이되, Z5 및 Z6 중 적어도 어느 하나는 시이고, n, m, a, b, c 및 거는 각각 독립적으로 0 내지 2의 정수이되, n과 m은 동시에 0일 수 없고, a와으는 동시에 0일 수 없다. Z 5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a, b, and c are each independently an integer from 0 to 2, but n and m are simultaneously It cannot be 0, and a cannot be 0 at the same time.
(3) 상기 (1) 또는 (2)에 있어서, 상기 화학식 I의 Ri에서 , 니을 포함하는 비고리형 작용기는 아미노기 (- NH2) 또는 아미노기의 2개의 H 중 적어도 하나 이상이 보가 아닌 치환기로 치환된 구조를 가질 수 있다. 예를 들어, 니을 포함하는 비고리형 작용기는 NR7R8, NH(CH2)e-C(=O)-R9 또는 NHS(=O)『 Rio 일 수 있다. 여기서, e는 0 내지 2의 정수이고, (3) In the above (1) or (2), in Ri of Formula I, the acyclic functional group containing Ni is an amino group (-NH2) or at least one of the two Hs of the amino group is substituted with a substituent that is not complementary. can have a structure. For example, an acyclic functional group containing Ni may be NR 7 R 8 , NH(CH 2 ) e -C(=O)-R 9 or NHS(=O)"Rio. Here, e is an integer from 0 to 2,
R7은 H또는 C1-C5알킬이고, R7 is H or C1-C5 alkyl;
R8은 H, Cl- C5알킬, 사이클로알킬 또는 헤테로사이클로알킬이고, 여기서 Cl- C5알킬의 적어도 1 이상의 보는 각각 독립적으로 CF3, 할로겐, N(C1- C5알킬) 2, 0- (Cl- C5알킬), 0H, 헤테로사이클로알킬, 아릴 또는 헤테로아릴로 치환될 수 있으며, 상기 아릴 또는 헤테로아릴의 적어도 1 이상의 보는 각각 독립적으로 （Cl- C5알킬） 또는 - 0-（Cl- C5알킬）로치환될 수 있고, R8 is H, Cl-C5alkyl, cycloalkyl, or heterocycloalkyl, wherein at least one group of Cl-C5alkyl is each independently CF 3 , halogen, N(C1-C5alkyl) 2, 0- (Cl-C5 Alkyl), OH, heterocycloalkyl, aryl or heteroaryl may be substituted, and at least one or more groups of the aryl or heteroaryl are each independently (Cl- C5 alkyl) or - 0- (Cl- C5 alkyl);
R9는 Cl- C5알킬, 0-（Cl- C5알킬）, OH, CF3 또는 （C1-C5알킬）- CF3이고,R9 is Cl-C5alkyl, 0-(Cl-C5alkyl), OH, CF 3 or (C1-C5alkyl)-CF3;
Rio은 Cl- C5알킬 또는사이클로알킬일 수 있다. Rio can be Cl- C5 alkyl or cycloalkyl.
（4） 상기 （1） 내지 （3） 중 어느하나에서 , 화학식 I에서 , (4) in any one of (1) to (3) above, in formula I,
Zi은 CH또는시이고, Zi is CH or Si,
Z2 및 Z3은 각각독립적으로 N, CR1또는 CR2이되 , Z2 및 Z3중 어느 하나는 반드시 CRi이고,
Figure imgf000010_0001
, e 고,Z 2 and Z3 are each independently N, CR1 or CR2, but any one of Z2 and Z3 is necessarily CRi,
Figure imgf000010_0001
, e high,
Z4는 CRcRd, 0, S 또는 NRe이고, Z4 is CRcRd, 0, S or NR e ;
Ra, Rb, Rc, Rd 및 Re는 각각독립적으로 H, Cl- C5알킬, 할로겐, CF3, CH2F, （Cl- C5알킬）- OH 또는 - 0-（Cl- C5알킬）이고, R a , Rb, Rc, Rd and Re are each independently H, Cl-C5alkyl, halogen, CF 3 ,CH 2 F, (Cl-C5alkyl)-OH or -0-(Cl-C5alkyl);
Z5 및 Z6은 각각 독립적으로 CH 또는 N이되, Z5 및 Z6 중 적어도 어느 하나는 시이고, n, m, a, b, c 및 거는 각각 독립적으로 0 내지 2의 정수이되, n과 m은 동시에 0일 수 없고, a와으는 동시에 0일 수 없으며 , e는 0 내지 2의 정수이고, Z 5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a, b, and c are each independently an integer from 0 to 2, but n and m are simultaneously cannot be 0, a and cannot be 0 at the same time, e is an integer from 0 to 2,
R2는 H, 할로겐, CN또는 - 0-（Cl- C5알킬）이고, R3은 H또는 CH3이고, R2 is H, halogen, CN or -O-(Cl-C5alkyl); R3 is H or CH3;
Wi은 CH2, S, 0, 8（=0） 또는 S（=0）2이고, Wi is CH2, S, 0, 8(=0) or S(=0)2;
W2는 0또는으이고, W2 is 0 or
A는 아릴 또는 헤테로아릴이고, A is aryl or heteroaryl;
L은 CH2, CH（CHs）, CD2 또는 0이고, L is CH2, CH (CHs), CD 2 or 0;
0 자 0 characters
B는 아릴 , 헤테로아릴 또는 A 이고, B is aryl, heteroaryl or A;
R4는 H, 할로겐, NH2, Cl- C5알킬, NHC（=O）O-（Cl- C5알킬） 또는 0-（C1- R4 is H, halogen, NH2, Cl-C5alkyl, NHC(=O)O-(Cl-C5alkyl) or 0-(C1-
C5알킬）이고, C5 alkyl),
R5 및 R6은 각각 독립적으로 H, Cl- C5알킬, CN, 할로겐, -（Cl- C5알킬）- 0- R5 and R6 are each independently H, Cl- C5alkyl, CN, halogen, -(Cl-C5alkyl)- 0-
（Cl- C5알킬） 또는 헤테로아릴이고, 여기서 헤테로아릴의 적어도 1 이상의 보는 각각 독립적으로 Cl- C5알킬로치환될 수 있고, (Cl-C5alkyl) or heteroaryl, wherein at least one member of the heteroaryl may each independently be substituted with Cl-C5alkyl;
R7은 H또는 C1-C5알킬이고, R7 is H or C1-C5 alkyl;
R8은 H, Cl- C5알킬, 사이클로알킬 또는 헤테로사이클로알킬이고, 여기서 Cl- C5알킬의 적어도 1 이상의 보는 각각 독립적으로 CF3, 할로겐, N（C1- C5알킬） 2, 0-（Cl- C5알킬）, 0H, 헤테로사이클로알킬, 아릴 또는 헤테로아릴로 치환될 수 있으며, 상기 아릴 또는 헤테로아릴의 적어도 1 이상의 보는 각각 독립적으로 （Cl- C5알킬） 또는 - 0-（Cl- C5알킬）로치환될 수 있고, R8 is H, Cl-C5alkyl, cycloalkyl or heterocycloalkyl, wherein at least one group of Cl-C5alkyl is each independently CF 3 , halogen, N(C1-C5alkyl) 2, 0-(Cl-C5 alkyl), 0H, heterocycloalkyl, aryl or heteroaryl, and at least one group of the aryl or heteroaryl is each independently substituted with (Cl- C5 alkyl) or -0- (Cl- C5 alkyl) can be,
R9는 Cl- C5알킬, 0-（Cl- C5알킬）, OH, CF3 또는 （C1-C5알킬）- CF3이고,R9 is Cl-C5alkyl, 0-(Cl-C5alkyl), OH, CF 3 or (C1-C5alkyl)-CF3;
Rio은 Cl- C5알킬 또는사이클로알킬이고, Rio is Cl-C5alkyl or cycloalkyl;
Zi 내지 Z3가 니을 포함하지 않고 Wi이 0일 때, R2는 할로겐, CN 또는 - 0- When Zi to Z3 do not contain nickel and Wi is 0, R2 is halogen, CN or -0-
（Cl- C5알킬）일 수 있다. (5) 상기 (1) 내지 (4) 중 어느 하나에서, 상기 화학식 I로 표시되는 화합물은, 하기 화학식 II로 표시될 수 있다. (Cl- C5 alkyl). (5) In any one of (1) to (4) above, the compound represented by the formula (I) may be represented by the following formula (II).
<화학식 11>
Figure imgf000012_0001
상기 화학식 II의 Z2, Z3, W1, W2, Rs, A, B, L, R4, RS 및 R6 각각은, 상기 화학식 I에서 정의한 것과 동일하다. <Formula 11>
Figure imgf000012_0001
Each of Z2, Z3, W1, W2, Rs, A, B, L, R 4 , RS and R 6 in the above formula (II) is the same as defined in the above formula (I).
(6) 상기 (1) 내지 (4) 중 어느 하나에서 , 상기 화학식 I에서 , (6) In any one of (1) to (4) above, in the above formula (I),
Zi은 이이고, Zi is y;
Z2 및 Z3은 각각 독립적으로 N, CR1 또는 CR2이되 , Z2 및 Z3 중 어느 하나는 반드시 CRi이고,
Figure imgf000012_0002
, e , Z2 and Z3 are each independently N, CR1 or CR2, but either Z2 or Z3 is necessarily CRi,
Figure imgf000012_0002
, e ,
Z4는 CRcRd, 0, S 또는 NRe이고, Ra, Rb, Rc, Rd 및 Re는 각각독립적으로 H, Cl- C5알킬, 할로겐, CF3, CH2F, （Cl- C5알킬）- OH 또는 - 0-（Cl- C5알킬）이고, Z4 is CRcRd, 0, S or NR e ; Ra, Rb, Rc, Rd and Re are each independently H, Cl-C5alkyl, halogen, CF 3 , CH 2 F, (Cl-C5alkyl)-OH or -0-(Cl-C5alkyl);
Z5 및 Z6은 각각 독립적으로 CH 또는 N이되, Z5 및 Z6 중 적어도 어느 하나는 시이고, n, m, a, b, c 및 거는 각각 독립적으로 0 내지 2의 정수이되, n과 m은 동시에 0일 수 없고, a와으는 동시에 0일 수 없으며 , e는 0 내지 2의 정수이고, Z 5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a, b, and c are each independently an integer from 0 to 2, but n and m are simultaneously cannot be 0, a and cannot be 0 at the same time, e is an integer from 0 to 2,
R2는 H, 할로겐, CN 또는 - 0-（Cl- C5알킬）이고, R2 is H, halogen, CN or -O-(Cl-C5alkyl);
R3은 H또는 CH3이고, R3 is H or CH3;
Wi은 CH2, S, 0, 8（=0） 또는 S（=0）2이고, Wi is CH2, S, 0, 8(=0) or S(=0)2;
W2는 0또는으이고, W2 is 0 or
A는 페닐 또는 0 및 N 중에서 선택된 적어도 1 이상의 헤테로원자를 포함하는 5원 또는 6원의 헤테로아릴이고, A is phenyl or a 5-membered or 6-membered heteroaryl containing at least one heteroatom selected from 0 and N;
L은 CH2, CH（CHs）, CD2 또는 0이고, L is CH2, CH (CHs), CD 2 or 0;
B는 페닐, 1 또는 2개의 시을 포함하는 6원의 헤테로아릴 또는
Figure imgf000013_0001
B is phenyl, a 6-membered heteroaryl containing 1 or 2 cy, or
Figure imgf000013_0001
R4는 H, 할로겐, NH2, Cl- C5알킬, NHC（=O）O-（Cl- C5알킬） 또는 0-（Cl- C5알킬）이고, R4 is H, halogen, NH 2 , Cl-C5alkyl, NHC(=O)O-(Cl-C5alkyl) or 0-(Cl-C5alkyl);
R5 및 R6은 각각 독립적으로 H, Cl- C5알킬, CN, 할로겐, -（Cl- C5알킬）- 0- （Cl- C5알킬） 또는 1 또는 2개의 N을 갖는 5원 또는 6원의 헤테로아릴이고, 여기서 헤테로아릴의 적어도 1 이상의 보는 각각 독립적으로 Cl- C5알킬로 치환될 수 있고, R5 and R6 are each independently H, Cl- C5alkyl, CN, halogen, -(Cl-C5alkyl)-0-(Cl-C5alkyl) or 5- or 6-membered heteroaryl having 1 or 2 N atoms. , wherein at least one group of the heteroaryl is each independently substituted with Cl- C5 alkyl. can,
R7은 H또는 C1-C5알킬이고, R7 is H or C1-C5 alkyl;
R8은 H, Cl- C5알킬, 탄소수 3 내지 6을 갖는 사이클로알킬 또는 0 및 N 중에서 선택된 적어도 1 이상의 헤테로원자를 포함하는 5원 또는 6원의 헤테로사이클로알킬이고, 여기서 Cl- C5알킬의 적어도 1 이상의 보는 각각 독립적으로 CF3, 할로겐, N（C1- C5알킬） 2, 0-（Cl- C5알킬）, 0H, 0 및 N 중에서 선택된 적어도 1 이상의 헤테로원자를 포함하는 5원 또는 6원의 헤테로사이클로알킬, 페닐 또는 0 및 N 중에서 선택된 적어도 1 이상의 헤테로원자를 포함하는 5원 또는 6원의 헤테로아릴로 치환될 수 있으며, 상기 페닐 또는 헤테로아릴의 적어도 1 이상의 보는 각각 독립적으로 （Cl- C5알킬） 또는 - 0-（Cl- C5알킬）로치환될 수 있고, R8 is H, Cl-C5alkyl, cycloalkyl having 3 to 6 carbon atoms, or 5- or 6-membered heterocycloalkyl containing at least one heteroatom selected from 0 and N, wherein at least one of Cl-C5alkyl Each of the above is independently CF 3 , halogen, N (C1- C5 alkyl) 2, 0- (Cl- C5 alkyl), 5-membered or 6-membered hetero including at least one heteroatom selected from 0H, 0 and N It may be substituted with cycloalkyl, phenyl, or 5-membered or 6-membered heteroaryl containing at least one heteroatom selected from 0 and N, and at least one group of the phenyl or heteroaryl is each independently (Cl-C5alkyl ) or - 0- (Cl- C5 alkyl),
R9는 Cl- C5알킬, 0-（Cl- C5알킬）, OH, CF3 또는 （C1-C5알킬）- CF3이고,R9 is Cl-C5alkyl, 0-(Cl-C5alkyl), OH, CF 3 or (C1-C5alkyl)-CF3;
Z2 및 Z3가 N을 포함하지 않고 Wi이 0일 때 , R2는 할로겐일 수 있다. 일 실시예에서 , 상기 화학식 II에서 ,
Figure imgf000014_0001
Z4는 CRcRd, 0, S 또는 NRe이고, When Z 2 and Z3 do not contain N and Wi is 0, R2 may be halogen. In one embodiment, in Formula II,
Figure imgf000014_0001
Z4 is CRcRd, 0, S or NR e ;
Ra, Rb, Rc, Rd 및 Re는 각각독립적으로 H, Cl- C5알킬, 할로겐, CF3, CH2F, （Cl- C5알킬）- OH 또는 - 0-（Cl- C5알킬）이고, Ra, Rb, Rc, Rd and Re are each independently H, Cl-C5alkyl, halogen, CF 3 , CH 2 F, (Cl-C5alkyl)-OH or -0-(Cl-C5alkyl);
Z5 및 Z6은 각각 독립적으로 CH 또는 N이되, Z5 및 Z6 중 적어도 어느 하나는 시이고, n, m, a, b, c 및 거는 각각 독립적으로 0 내지 2의 정수이되, n과 m은 동시에 0일 수 없고, a와으는 동시에 0일 수 없으며 , e는 0 내지 2의 정수이고, Z 5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a, b, and c are each independently an integer from 0 to 2, but n and m are simultaneously cannot be 0, a and cannot be 0 at the same time, e is an integer from 0 to 2,
R2는 H, 할로겐, CN 또는 - 0-（Cl- C5알킬）이고, R2 is H, halogen, CN or -O-(Cl-C5alkyl);
R3은 H또는 CH3이고, R3 is H or CH3;
Wi은 CH2, S, 0, 8（=0） 또는 S（=0）2이고, Wi is CH2, S, 0, 8(=0) or S(=0)2;
W2는 0또는으이고, W2 is 0 or
A는 페닐 또는 0 및 N 중에서 선택된 적어도 1 이상의 헤테로원자를 포함하는 5원 또는 6원의 헤테로아릴이고, A is phenyl or a 5-membered or 6-membered heteroaryl containing at least one heteroatom selected from 0 and N;
L은 CH2, CH（CHs）, CD2 또는 0이고, L is CH2, CH (CHs), CD 2 or 0;
B는 페닐, 1 또는 2개의 시을 포함하는 6원의 헤테로아릴 또는
Figure imgf000015_0001
B is phenyl, a 6-membered heteroaryl containing 1 or 2 cy, or
Figure imgf000015_0001
R4는 H, 할로겐, NH2, Cl- C5알킬, NHC（=O）O-（Cl- C5알킬） 또는 0-（Cl- C5알킬）이고, R4 is H, halogen, NH 2 , Cl-C5alkyl, NHC(=O)O-(Cl-C5alkyl) or 0-(Cl-C5alkyl);
R5 및 R6은 각각 독립적으로 H, Cl- C5알킬, CN, 할로겐, -（Cl- C5알킬）- 0- （Cl- C5알킬） 또는 1 또는 2개의 시을 갖는 5원 또는 6원의 헤테로아릴이고, 여기서 헤테로아릴의 적어도 1 이상의 보는 각각 독립적으로 Cl- C5알킬로 치환될 수 있고, R5 and R6 are each independently H, Cl-C5alkyl, CN, halogen, -(Cl-C5alkyl)-0-(Cl-C5alkyl) or a 5-membered or 6-membered heteroaryl having 1 or 2 groups; , Here, at least one group of heteroaryl may be each independently substituted with Cl- C5 alkyl,
R7은 H또는 C1-C5알킬이고, R7 is H or C1-C5 alkyl;
R8은 H, Cl- C5알킬, 탄소수 3 내지 6을 갖는 사이클로알킬 또는 0 및 N 중에서 선택된 적어도 1 이상의 헤테로원자를 포함하는 5원 또는 6원의 헤테로사이클로알킬이고, 여기서 Cl- C5알킬의 적어도 1 이상의 보는 각각 독립적으로 CF3, 할로겐, N(C1- C5알킬) 2, 0- (Cl- C5알킬), 0H, 0 및 N 중에서 선택된 적어도 1 이상의 헤테로원자를 포함하는 5원 또는 6원의 헤테로사이클로알킬, 페닐 또는 0 및 N 중에서 선택된 적어도 1 이상의 헤테로원자를 포함하는 5원 또는 6원의 헤테로아릴로 치환될 수 있으며, 상기 페닐 또는 헤테로아릴의 적어도 1 이상의 보는 각각 독립적으로 (Cl- C5알킬) 또는 - 0- (Cl- C5알킬)로치환될 수 있고, R8 is H, Cl-C5alkyl, cycloalkyl having 3 to 6 carbon atoms, or 5- or 6-membered heterocycloalkyl containing at least one heteroatom selected from 0 and N, wherein at least one of Cl-C5alkyl Each of the above groups is independently CF 3 , halogen, N(C1-C5alkyl) 2, 0-(Cl-C5alkyl), 0H, 0, and 5-membered or 6-membered heteroatoms including at least one heteroatom selected from among It may be substituted with cycloalkyl, phenyl, or 5-membered or 6-membered heteroaryl containing at least one heteroatom selected from 0 and N, and at least one group of the phenyl or heteroaryl is each independently (Cl-C5alkyl ) or - 0- (Cl- C5 alkyl);
R9는 Cl- C5알킬, 0- (Cl- C5알킬), OH, CF3 또는 (C1-C5알킬)- CF3이고,R9 is Cl-C5alkyl, 0-(Cl-C5alkyl), OH, CF 3 or (C1-C5alkyl)-CF3;
Z2 및 Z3가 N을 포함하지 않고 Wi이 0일 때 , R2는 할로겐일 수 있다. When Z 2 and Z3 do not contain N and Wi is 0, R2 may be halogen.
(7) 상기 (1) 내지 (4) 및 (6) 중 어느하나에서 , 상기 화학식 I에서 , 어은이이고, Z2 및 Z3중 어느 하나는 CRi이고 다른 하나는 N일 수 있다. (7) In any one of (1) to (4) and (6) above, in the above formula (I), one of Z2 and Z3 may be CRi and the other may be N.
(8) 상기 (1) 내지 (4) 및 (6) 중 어느 하나에서, 상기 화학식 I에서,(8) In any one of (1) to (4) and (6) above, in the above formula (I),
Z1은 이이고, Z2 및 Z3 중 어느 하나는 CR1이고, 다른 하나는 CR2일 수 있다. (9) 상기 (1) 내지 (4) 중 어느 하나에서, 상기 화학식 I로 표시되는 화합물은, 하기 화학식 II la으로 나타낼 수 있다. Z1 is 2, one of Z2 and Z3 is CR1, and the other can be CR2. (9) In any one of (1) to (4) above, the compound represented by the formula (I) can be represented by the following formula (IIa).
<화학식 IIIa>
Figure imgf000017_0001
상기 화학식 II la의 RI, Wi, W2, Rs, A, B, L, R4, RS 및 R6 각각은, 상기 화학식 I에서 정의한 것과 동일하다. 일 실시예에서, 상기 화학식 Illa에서,
Figure imgf000017_0002
<Formula IIIa>
Figure imgf000017_0001
Each of RI, Wi, W 2 , Rs, A, B, L, R 4 , RS and R 6 in Formula IIa is the same as defined in Formula I. In one embodiment, in Formula Illa above,
Figure imgf000017_0002
Z4는 CRcRd 또는 0이고, Z4 is CRcRd or 0;
Ra, Rb, Rc 및 Rd는 각각 독립적으로 H, Cl- C5알킬, 할로겐, CH2F, (C1-Ra, Rb, Rc and Rd are each independently H, Cl- C5 alkyl, halogen, CH 2 F, (C1-
C5알킬)- 0H 또는 - 0- (Cl- C5알킬)이고, n, m 및 c는 각각 독립적으로 0 내지 2의 정수이되, n과 m은 동시에 0일 수 없고, C5alkyl)-0H or -0-(Cl-C5alkyl), n, m and c are each independently an integer from 0 to 2, but n and m cannot be 0 at the same time;
R3는 H또는 CH3이고, A는 1 내지 4의 시을 포함하는 5원 또는 6원의 헤테로아릴이고, R3 is H or CH3; A is a 5- or 6-membered heteroaryl containing 1 to 4 cy,
B는 페닐이고, B is phenyl;
L은 CH2또는 CD2이고, L is CH 2 or CD2;
R4는 H, 할로겐, Cl- C5알킬 또는 0- (Cl- C5알킬)이고, R4 is H, halogen, Cl- C5 alkyl or 0- (Cl- C5 alkyl);
Rs 및 R6은 각각독립적으로 H또는 할로겐일 수 있다. 일 실시예에서, 상기 화학식 Illa에서, Rs and R6 may each independently be H or halogen. In one embodiment, in Formula Illa above,
Wi, W2, Rs, A, B, L, R4, RS 및 R6 각각은 화학식 I에서 정의한 것과 동일하고, Each of Wi, W2, Rs, A, B, L, R 4 , RS and R6 is the same as defined in Formula I,
Ri은 NR7R8이고, Ri is NR7R8;
R7 및 R8각각은 화학식 I에서 정의한 것과 동일하다. Each of R 7 and R 8 has the same definition as in formula (I).
(10) 상기 (1) 내지 (4) 중 어느 하나에서, 상기 화학식 I로 표시되는 화합물은 하기 화학식 IV로 나타낼 수 있다. (10) In any one of (1) to (4) above, the compound represented by the formula (I) may be represented by the following formula (IV).
<화학식 IV>
Figure imgf000018_0001
상기 화학식 IV에서 , Ri, W1, W2, Rs, A, B, L, R4, R5 및 R6각각은 화학식<Formula IV>
Figure imgf000018_0001
In Formula IV, each of Ri, W1, W2, Rs, A, B, L, R 4 , R5 and R 6 is represented by the formula
I에서 정의한 것과 동일하다. 일 실시예에서 , 상기 화학식 IV에서 ,
Figure imgf000019_0001
, NR7R8, NHC(=O)-R9 또는 NHS(=0)2-Same as defined in I. In one embodiment, in Formula IV,
Figure imgf000019_0001
, NR 7 R 8 , NHC(=0)-R 9 or NHS(=0)2-
Rio°l고 , Rio°l High ,
Z4는 CRcRd, 0 또는 NRe이고, Z4 is CRcRd, 0 or NRe;
Rc, Rd 및 Re는 각각 독립적으로 H, Cl- C5알킬, 할로겐, 또는 - 0-（C1- C5알킬）이고, Rc, Rd and Re are each independently H, Cl-C5alkyl, halogen, or -O-(C1-C5alkyl);
Z5 및 Z6은 각각 독립적으로 CH 또는 N이되, Z5 및 Z6 중 적어도 어느 하나는 시이고, n, m, a 및 으는 각각 독립적으로 0 내지 2의 정수이되, n과 m은 동시에 0일 수 없고, a와으는 동시에 0일 수 없으며 , Z 5 and Z6 are each independently CH or N, but at least one of Z 5 and Z6 is Si, n, m, a and are each independently an integer from 0 to 2, but n and m are 0 at the same time cannot be, and a and cannot be 0 at the same time,
R7은 H또는 C1-C5알킬이고, R7 is H or C1-C5 alkyl;
R8은 H, Cl- C5알킬, （Cl- C5알킬）- CF3 또는 0를 포함하는 5원 또는 6원의 헤테로사이클로알킬이고, R8 is H, Cl- C5 alkyl, (Cl- C5 alkyl) - CF3 or 5-membered or 6-membered heterocycloalkyl including 0;
R9는 Cl- C5알킬, CF3 또는 （C1-C5알킬）- CF3이고, R9 is Cl-C5alkyl, CF 3 or (C1-C5alkyl)-CF3;
Rio은 Cl- C5알킬 또는 C3-C6사이클로알킬이고, Rio is Cl- C5 alkyl or C3-C6 cycloalkyl;
R3은 CH3이고, R3 is CH3;
Wi은으이고 Wi is
W2는 0이고, W2 is 0;
A는 N을 2 내지 4개 포함하는 5원 또는 6원의 헤테로아릴이고, A is a 5- or 6-membered heteroaryl containing 2 to 4 N,
R4는보이고, L은 CH2이고, R4 is visible, L is CH2;
B는 페닐이고, B is phenyl;
Rs 및 R6은 각각독립적으로 H또는 할로겐일 수 있다. 일 실시예에서 , 상기 화학식 IV로 나타내는 화합물은 하기 화학식 IVa로 나타낼 수 있다. Rs and R6 may each independently be H or halogen. In one embodiment, the compound represented by Formula IV may be represented by Formula IVa below.
<화학식 IVa>
Figure imgf000020_0001
<Formula IVa>
Figure imgf000020_0001
Rc, Rd 및 Re는 각각 독립적으로 H, Cl- C5알킬, 할로겐, 또는 - 0-（C1- C5알킬）이고, R c , Rd and Re are each independently H, Cl- C5 alkyl, halogen, or - 0- (C1- C5 alkyl);
Z5 및 Z6은 각각 독립적으로 CH 또는 N이되, Z5 및 Z6 중 적어도 어느 하나는 시이고, n, m, a 및 으는 각각 독립적으로 0 내지 2의 정수이되, n과 m은 동시에 0일 수 없고, a와으는 동시에 0일 수 없으며 , A는 N을 2 내지 4개 포함하는 5원 헤테로아릴일 수 있다. Z 5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a and are each independently an integer from 0 to 2, but n and m can be 0 at the same time no, a and cannot be 0 at the same time, A may be a 5-membered heteroaryl group containing 2 to 4 N atoms.
(11) 상기 (1) 내지 (4) 중 어느하나에 있어서 , 상기 화학식 I에서 ,(11) In any one of (1) to (4) above, in the above formula (I),
Zi은이이고, Zi is
Z2 및 Z3중 어느 하나는 CR1이고, 다른하나는 CR2이고,
Figure imgf000021_0001
One of Z2 and Z3 is CR1, the other is CR2,
Figure imgf000021_0001
Z4는 CRcRd, 0, S 또는 NRe이고, Z4 is CRcRd, 0, S or NR e ;
Ra, Rb, Rc, Rd 및 Re는 각각 독립적으로 H, Cl- C5알킬, 할로겐, CF3 또는 - 0- (Cl- C5알킬)이고, Ra, Rb, Rc, Rd and Re are each independently H, Cl-C5alkyl, halogen, CF 3 or -0-(Cl-C5alkyl);
Z5 및 Z6은 각각 독립적으로 CH 또는 N이되, Z5 및 Z6 중 적어도 어느 하나는 시이고, n, m, a, b, c 및 거는 각각 독립적으로 0 내지 2의 정수이되, n과 m은 동시에 0일 수 없고, a와으는 동시에 0일 수 없으며 , Z 5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a, b, and c are each independently an integer from 0 to 2, but n and m are simultaneously cannot be 0, and a and cannot be 0 at the same time,
R2는 H, 할로겐, CN 또는 - 0- (Cl- C5알킬)이고, R2 is H, halogen, CN or - 0- (Cl- C5 alkyl);
R3은 CH3이고, R3 is CH3;
Wi은 CH2, S, 0, 8(=0) 또는 S(=0)2이고, Wi is CH2, S, 0, 8(=0) or S(=0)2;
W2는 0이고, W2 is 0;
A는 페닐 또는 N 또는 0를 1 내지 4개 포함하는 5원 또는 6원의 헤테로아릴이고, 으는 페닐, 니을 1 또는 2개 포함하는 6원의 헤테로아릴 또는
Figure imgf000022_0001
A is 5- or 6-membered phenyl or N or 1 to 4 containing 0 Heteroaryl, and is a phenyl, 6-membered heteroaryl containing 1 or 2 Ni, or
Figure imgf000022_0001
L은 CH2, CH(CHS), 또는 0이고, L is CH 2 , CH(CHS), or 0;
R4는 H, 할로겐, NH2, Cl- C5알킬 또는 NHC（=O）O-（Cl- C5알킬）이고, R4 is H, halogen, NH 2 , Cl-C5alkyl or NHC(=O)O-(Cl-C5alkyl);
R5 및 R6은 각각 독립적으로 H, Cl- C5알킬, CN, 할로겐, -（Cl- C5알킬）- 0- （Cl- C5알킬） 또는 적어도 1 이상의 N을 갖는 5원의 헤테로아릴이고, 여기서 상기 5원의 헤테로아릴의 적어도 1 이상의 보는 각각 독립적으로 Cl- C5알킬로 치환될 수 있고, R5 and R6 are each independently H, Cl-C5alkyl, CN, halogen, -(Cl-C5alkyl)-0-(Cl-C5alkyl) or a 5-membered heteroaryl having at least one N, wherein the above At least one group of 5-membered heteroaryl may each independently be substituted with Cl-C5alkyl;
Wi이 0일 때 R2는 할로겐, CN 또는 - 0-（Cl- C5알킬）일 수 있다. 이때, 상기 화학식 I는 하기 화학식 Va또는 Vb로 나타낼 수 있다. When Wi is 0, R2 can be halogen, CN or -0-(Cl-C5alkyl). In this case, the formula I may be represented by the following formula Va or Vb.
<화학식 Va>
Figure imgf000022_0002
<Formula Va>
Figure imgf000022_0002
<화학식 Vb>
Figure imgf000023_0001
<Formula Vb>
Figure imgf000023_0001
(12) 상기 (1) 내지 (4) 중 어느하나에 있어서 , 상기 화학식 I에서 ,(12) In any one of (1) to (4) above, in the above formula (I),
W1는 S, 8(=0) 또는 S(=0)2이고, W1 is S, 8(=0) or S(=0)2;
W2, Z1, Z2, Z3, R1, Rs, L 및 R4는 각각 상기 화학식 I에서 정의한 것과 동일하고, W2, Z1, Z2, Z3, R1, Rs, L and R4 are each the same as defined in Formula I above,
A는 페닐, 피라졸일, 이미다졸일, 트리아졸 일, 테트라졸일, 아이소옥사졸일 또는 피리진일이고,
Figure imgf000023_0002
이 으는 페닐, 피라진일, 피리딘일 또는 으이고, A is phenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl or pyrizinyl;
Figure imgf000023_0002
is phenyl, pyrazinyl, pyridinyl or U;
R5 및 R6은 각각 독립적으로 H, Cl- C5알킬, CN, 할로겐, - (Cl- C5알킬)- 0- (Cl- C5알킬) 또는 피라졸일이고, 여기서 피라졸의 적어도 1 이상의 보는 각각 독립적으로 Cl- C5알킬로치환될 수 있다. 일 실시예에서, 상기 화학식 I에서, R5 and R6 are each independently H, Cl-C5alkyl, CN, halogen, -(Cl-C5alkyl)-0-(Cl-C5alkyl) or pyrazolyl, wherein at least one group of the pyrazole is each independently It may be substituted with Cl- C5 alkyl. In one embodiment, in Formula I above,
V1는 S(=0)이고, V1 is S(=0),
W2는 0이고, W2 is 0;
Z1은이이고, Z2 및 Z3중 어느 하나는 CRi이고, 다른하나는 CR2이고, Z1 is One of Z2 and Z3 is CRi, the other is CR2,
Ri은
Figure imgf000024_0001
이고, Ri is
Figure imgf000024_0001
ego,
Z4는 CRcRd 또는 0이고, Z4 is CRcRd or 0;
Rc 및 Rd는 각각독립적으로보이고, n 및 m은 각각 독립적으로 0 내지 2의 정수이되, n과 m은 동시에 0일 수 없고, Rc and Rd are each independently seen, n and m are each independently an integer from 0 to 2, but n and m cannot be 0 at the same time,
R2는 H 또는 할로겐이고, R2 is H or halogen;
R3은 CH3이고, R3 is CH3;
A는 페닐 또는 트리아졸일이고, A is phenyl or triazolyl;
B는 페닐이고, B is phenyl;
L은 CH2또는 0이고 L is CH 2 or 0;
R4, RS 및 R6은 각각독립적으로보일 수 있다. R 4 , RS and R6 can each appear independently.
(13) 상기 (1) 내지 (4) 중 어느하나에 있어서 , 상기 화학식 I에서 ,(13) In any one of (1) to (4) above, in the above formula (I),
Wi는 S(=0)2이고, Wi is S(=0)2,
W2는 0이고, W2 is 0;
Zi은 이이고, Zi is y;
Z2 및 Z3중 어느 하나는 CR1이고, 다른하나는 CR2이고, One of Z2 and Z3 is CR1, the other is CR2,
Ri은
Figure imgf000024_0002
Z4는 CRcRd, 0 또는 NRe이고, Ri is
Figure imgf000024_0002
Z4 is CRcRd, 0 or NR e ;
Rc, Rd 및 Re는 각각독립적으로 H또는 C1-C5알킬이고, n 및 m은 각각 독립적으로 0 내지 2의 정수이되, n과 m은 동시에 0일 수 없고, R c , Rd and Re are each independently H or C1-C5 alkyl, n and m are each independently an integer of 0 to 2, but n and m cannot be 0 at the same time;
R2는 H또는 할로겐이고, R2 is H or halogen;
R3은 CH3이고, R3 is CH3;
A는 페닐 또는 트리아졸일이고, A is phenyl or triazolyl;
B는 페닐이고, B is phenyl;
L은 CH2또는 0이고, L is CH 2 or 0;
Rs 및 R6은 각각독립적으로보일 수 있다. Rs and R6 can each be seen independently.
(14) 상기 (1) 내지 (4) 중 어느하나에 있어서 , 화학식 I에서 , (14) In any one of (1) to (4) above, in formula I,
Wi는 0이고, Wi is 0;
W2는 0이고, W2 is 0;
Z1은 이이고, Z1 is 2,
Z2는 CR1 또는 CR2이고, Z3은 N, CR1 또는 CR2이되, Z』 및 Z3 중 어느 하나는 반드시 CRi이고,
Figure imgf000025_0001
Z2 is CR1 or CR2, Z3 is N, CR1 or CR2, and either of Z' and Z3 is necessarily CRi;
Figure imgf000025_0001
Z4는 CRcRd, S 또는 NRe이고, Z4 is CRcRd, S or NR e ;
Ra, Rb, Rc, Rd 및 Re는 각각독립적으로 H, Cl- C5알킬, 할로겐, CF3, CH2F,R a , R b , R c , Rd and Re are each independently H, Cl- C5 alkyl, halogen, CF 3 , CH 2 F,
（Cl- C5알킬）- OH또는 - 0-（Cl- C5알킬）이고, Z5 및 Z6은 각각 독립적으로 CH 또는 N이되, Z5 및 Z6 중 적어도 어느 하나는 시이고, n, m, a 및 으는 각각 독립적으로 0 내지 2의 정수이되, n과 m은 동시에(Cl-C5alkyl)-OH or -0-(Cl-C5alkyl); Z5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a and are each independently an integer from 0 to 2, but n and m are simultaneously
0일 수 없고, a와으는 동시에 0일 수 없으며 , cannot be 0, and a and cannot be 0 at the same time,
R2는 H또는 할로겐이고, R2 is H or halogen;
R3은 CH3이고, R3 is CH3;
R7은 H또는 C1-C5알킬이고, R7 is H or C1-C5 alkyl;
R8은 Cl- C5알킬 또는 (Cl- C5알킬)- CF3이고, R8 is Cl-C5alkyl or (Cl-C5alkyl)-CF3;
A는 페닐, 테트라졸일 또는 트리아졸일이고, A is phenyl, tetrazolyl or triazolyl;
L은 CH2, CD2 또는 0이고, L is CH2, CD2 or 0;
B는 페닐이고, B is phenyl;
R4는 H, 할로겐 또는 C1-C5알킬이고, R4 is H, halogen or C1-C5 alkyl;
Rs 및 R6은 각각독립적으로 H 또는 할로겐이며 , Rs and R6 are each independently H or halogen,
Z3이 N이 아닌 경우, R2는 할로겐 또는 - 0- (Cl- C5알킬)일 수 있다. When Z3 is not N, R2 can be halogen or -O-(Cl-C5alkyl).
(15) 상기 (1) 내지 (4) 중 어느하나에 있어서 , 화학식 I에서 , (15) In any one of (1) to (4) above, in formula I,
Wi는 CH2이고, Wi is CH2;
W2는 0이고, W2 is 0;
Zi은이이고, Zi is
Z2 및 Z3중 어느 하나는 CRi이고, 다른하나는 0여이고, One of Z2 and Z3 is CRi, the other is 0,
Ri은
Figure imgf000026_0001
Z4는 CRcRd이고, Ri is
Figure imgf000026_0001
Z4 is CRcRd;
Rc 및 Rd는 각각독립적으로 H, 할로겐 또는 - 0-（Cl- C5알킬）이고, n 및 m는 각각 독립적으로 0 내지 2의 정수이되, n과 m은 동시에 0일 수 없고, R c and Rd are each independently H, halogen or -0- (Cl- C5 alkyl), n and m are each independently an integer of 0 to 2, but n and m cannot be 0 at the same time,
R2는 H또는 할로겐이고, R2 is H or halogen;
R3은 CH3이고, R3 is CH3;
A는 테트라졸일이고, A is tetrazolyl;
L은 CH2이고, L is CH2;
B는 페닐이고, B is phenyl;
R4, Rs 및 R6은 각각독립적으로보일 수 있다. 본 발명에서 “Cm- Cn” （여기서 m, n은 각각 독립적으로 1 이상의 정수）는 탄소의 개수를 의미하며, 예를 들면, ‘Cl- C5알킬’ 은 탄소수가 1 내지 5 인 알킬을 나타낸다. 본 발명에서 “알킬” 은 직쇄형 또는 분지쇄형인 포화탄화수소기를 의미한다. 본 발명에서 알킬은 1 내지 5의 탄소수를 가질 수 있다. 일 실시예에서 , 알킬은 1 내지 3의 탄소수를 가질 수 있다. 알킬의 예로서는, 메틸 , 에틸, n-프로필, 아이소프로필, n-뷰틸, sec-뷰틸, tert-뷰틸, 아이소뷰틸, n- 펜틸, sec-펜틸, tert-펜틸, 아이소펜틸, sec-아이소펜틸, neo-펜틸 등을 들 수 있다. 본 발명에서 “아릴” 은 일환 방향족 또는 다환 방향족을 포함하는 것으로, 탄소수 6 이상의 방향족 탄화수소를 의미한다. 아릴은 탄소수 6 내지 20을 가질 수 있다. 예를 들어, 아릴은 페닐, 바이페닐, 나프탈렌일 등일 수 있다. 본 발명에서 “헤테로아릴” 은 상기 아릴에서 적어도 1 개 이상의 탄소원자가 헤테로원자인 질소 (N), 산소 (0) 또는 황 (S)으로 치환된 일환 또는 다환의 헤테로 고리를 의미한다. 헤테로아릴은 5원 내지 12원일 수 있고, 일례로, 5원 또는 6원일 수 있다. 헤테로아릴에 2 이상의 헤테로원자가 포함하는 경우, 헤테로원자의 종류는 서로 동일하거나 다를 수 있다. 예를 들어, 헤테로아릴이 질소, 산소 및 황으로부터 선택된 이종원자를 2 이상 포함하는 경우는, 2개의 질소를 포함하는 경우, 1개의 질소와 1개의 산소를 포함하는 경우, 2개의 산소와 1개의 질소를 포함하는 경우 등의 다양한 조합을 의미하는 것이다. 예를 들어, 헤테로아릴은, 피리딘일 , 티오펜일 , 트리아졸일 , 테트라졸일 , 벤조티아졸일 , 벤조티오펜일 , 퀴놀린일 , 인돌일 , 아이소인돌일 , 벤조퓨란일 , 벤조피롤일 , 퓨란일, 피롤일, 티아졸일, 아이소티아졸일, 이미다졸일, 피라졸일, 옥사졸일, 아이소옥사졸일 , 피라진일 , 피리다진일 , 피리미딘일 , 아이소퀴놀린일 , 벤조옥사졸일 , 벤조이미다졸일 , 디하이드로벤조티오펜일 , 퓨린일 , 인돌리진일 , 크로멘일 등을 포함할수 있다. 본 발명에서 “시클로알킬” 은 3 이상의 탄소원자를 갖는 포화탄화수소 고리를 의미하고, 포화탄화수소 고리는 일환 및 다환고리 구조를 모두 포함한다. 시클로알킬은 3 내지 12의 탄소수를 갖는 포화탄화수소 고리일 수 있다. 시클로알킬의 예로서는 , 사이클로펜틸 , 사이클로헥실 , 사이클로헵틸 및 사이클로옥틸 등으로부터 선택되는 1종 이상일 수 있다. 본 발명에서 “헤테로시클로알킬” 은 상기 시클로알킬의 고리를 이루는 적어도 1개 이상의 탄소원자가 이종원자로 치환된 고리형 작용기를 의미한다. 상기 이종원자의 예로서는, 질소 (N), 산소 (0) 또는 황 (S)일 수 있다. 이때, 헤테로시클로알킬의 고리에 포함되는 이종원자는 1종 또는 2종 이상일 수 있고, 1종의 이종원자가 1개 또는 1개 이상 포함될 수 있으며, 2종 이상의 이종원자들이 각각 적어도 1개 이상 포함될 수도 있다. 헤테로시클로알킬은 3원 내지 12원 고리일 수 있다. 헤테로시클로알킬의 예로서는, 옥시란일 , 옥세탄일 , 모포린일 , 피롤리딘일 , 피페리딘일 , 피페라진일 , 테트라하이드로퓨란일 , 테트라하이드로티오펜일 , 테트라하이드로피란일 , 테트라하이드로티오피란일 등을 들 수 있다. 본 발명에서, 알킬, 아릴, 헤테로아릴, 시클로알킬 및 헤테로시클로알킬은 각각의 정의에 따른 화학 구조의 1가의 치환기 또는 2가 이상의 다가 치환기를 모두 의미하는 것이다. 예를 들어, “알킬” 은 1가 알킬 또는 2가 알킬 (알킬렌)을 포함할 수 있고, “아릴” 은 1가 아릴 또는 2가 아릴 (아릴렌)을 포함할 수 있다. 본 발명에서 “할로겐” 은 F, Cl, Br 또는 I일 수 있다. R4, Rs and R6 can each be seen independently. In the present invention, "Cm-Cn" (where m and n are each independently an integer of 1 or more) means the number of carbon atoms, and for example, 'Cl-C5alkyl' represents alkyl having 1 to 5 carbon atoms. In the present invention, "alkyl" means a straight-chain or branched-chain saturated hydrocarbon group. In the present invention, alkyl may have 1 to 5 carbon atoms. In one embodiment, an alkyl can have 1 to 3 carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, sec-pentyl, tert-pentyl, isopentyl, sec-isopentyl, neo-pentyl etc. are mentioned. In the present invention, “aryl” includes monoaromatic or polycyclic aromatics, and refers to aromatic hydrocarbons having 6 or more carbon atoms. Aryl has 6 to 6 carbon atoms can have 20 For example, aryl can be phenyl, biphenyl, naphthalenyl, and the like. In the present invention, “heteroaryl” refers to a monocyclic or polycyclic heterocyclic ring in which at least one or more carbon atoms in the aryl are replaced with nitrogen (N), oxygen (0), or sulfur (S). Heteroaryl may be 5-12 membered, for example, 5- or 6-membered. When two or more heteroatoms are included in heteroaryl, the types of heteroatoms may be the same as or different from each other. For example, when heteroaryl contains two or more heteroatoms selected from nitrogen, oxygen, and sulfur, when it contains two nitrogens, when it contains one nitrogen and one oxygen, two oxygens and one nitrogen It means various combinations, such as the case of including. For example, heteroaryl is pyridinyl, thiophenyl, triazolyl, tetrazolyl, benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindoleyl, benzofuranyl, benzopyrroyl, furanyl , Pyrroyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, benzooxazolyl, benzoimidazolyl, dihydrobenzothiophenyl, purinyl, indolizinyl, chromenyl, and the like. In the present invention, "cycloalkyl" means a saturated hydrocarbon ring having 3 or more carbon atoms, and the saturated hydrocarbon ring includes both monocyclic and polycyclic structures. Cycloalkyl can be a saturated hydrocarbon ring having from 3 to 12 carbon atoms. Examples of cycloalkyl may be at least one selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. In the present invention, "heterocycloalkyl" is a ring of the cycloalkyl It means a cyclic functional group in which at least one carbon atom is substituted with a heteroatom. Examples of the heteroatom may be nitrogen (N), oxygen (0) or sulfur (S). At this time, the heteroatom included in the ring of heterocycloalkyl may be one or two or more, one or one or more heteroatoms may be included, and at least one or more two or more heteroatoms may be included. . Heterocycloalkyls can be 3- to 12-membered rings. Examples of heterocycloalkyl include oxiranyl, oxetanyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyran work, etc. In the present invention, alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl mean all of monovalent substituents or divalent or more polyvalent substituents in the chemical structure according to each definition. For example, “alkyl” may include monovalent alkyl or divalent alkyl (alkylene), and “aryl” may include monovalent aryl or divalent aryl (arylene). In the present invention, “halogen” may be F, Cl, Br or I.
(16) 본 발명에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물은 하기 표 1에 기재된 화합물을 포함할 수 있다. (16) The compound according to the present invention, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof may include the compounds listed in Table 1 below.
[표 1]
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
[Table 1]
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
(17) 본 발명에 따른 화합물은 하기 표 2에 기재된 화합물일 수 있다. (17) Compounds according to the present invention may be compounds listed in Table 2 below.
[표 2]
Figure imgf000040_0002
Figure imgf000041_0001
본 발명에서 “약학적으로 허용 가능한 염” 은 의약업계에서 통상적으로 사용되는 염을 의미하며 , 당업계 통상의 기술자에게 공지된 통상적인 방법에 의해 제조될 수 있다. 본 발명에서 약학적으로 허용 가능한 염은, 예를 들어 칼슘, 칼륨, 나트륨 또는 마그네슘 등으로 제조된 무기이온염 ; 염산, 질산, 인산, 브롬산, 요오드산, 과염소산, 또는 황산 등으로 제조된 무기산염; 아세트산, 트라이플루오로아세트산, 시트르산, 말레인산, 숙신산, 옥살산, 벤조산, 타르타르산 , 푸마르산 , 만데르산 , 프로피온산 , 젖산 , 글리콜산 , 글루콘산 , 갈락투론산 , 글루탐산 , 글루타르산 , 글루쿠론산 , 아스파르트산 , 아스코르브산 , 카본산, 바닐릭산, 하이드로 아이오딕산 등으로 제조된 유기산염; 메탄설폰산, 에탄설폰산, 벤젠설폰산, P-톨루엔설폰산 또는 나프탈렌설폰산 등으로 제조된 설폰산염, 글리신, 아르기닌, 라이신 등으로 제조된 아미노산염; 또는 트리메틸아민, 트리에틸아민, 암모니아, 피리딘, 피콜린 등으로 제조된 아민염 등이 있으나, 열거된 이들 염에 의해 본 발명에서 의미하는 염의 종류가 제한되는 것은 아니다. 본 발명의 일 실시예에 있어서 , 상기 염은 염산염일 수 있다. 본 발명에서 “입체 이성질체 (stereoisomer)” 는 부분 입체 이성질체 (diastereomer ) , 광학 이성질체 (enantiomer) 및 위치 이성질체 (posit ion isomer)를 포함하는 것으로, 광학 이성질체는 거울상 이성질체뿐만 아니라 거울상 이성질체의 혼합물 및 라세미체까지 모두 포함한다. 이러한 이성질체는 종래기술, 예를 들어 관 크로마토그래피 또는 HPLC 등의 분할에 의해 분리가 가능하다. 또는, 상기 (1) 내지 (17) 중 어느 하나에 따른 화합물 각각의 입체 이성질체는 공지된 배열의 광학적으로 순수한 출발 물질 및/또는 시약을 사용하여 입체 특이적으로 합성할수 있다. 본 발명에서 “호변 이성질체 (tautomer , 토토머)” 는 상기 (1) 내지 (17) 중 어느 하나에 따른 화합물 중 낮은 에너지 장벽을 통해 상호전환되는 구조 이성질체를 의미하는 것이다. 화합물이, 예를 들어 이미노, 케토, 또는 옥심기를 포함하거나 방향족 치환기를 포함하는 경우 화합물을 구성하는 원자가 토토머화의 형태일 수 있다. 특정 경우에 구조적으로 도시된 화합물을 본 발명의 화합물의 호변이성질체로서 명명할 수 있음을 통상의 기술자는 인지할 것이다. 명명된 화합물 또는 구조적으로 도시된 화합물에 대한 언급은 이러한 화합물의 모든 호변이성질체 및 그의 호변이성질체의 임의의 혼합물을 포괄하는 것으로 의도됨을 이해해야 한다. 본 발명에서 “수화물” 은 상기 (1) 내지 (17) 중 어느 하나에 따른 화합물 , 이의 약학적으로 허용 가능한 염 , 이의 광학 이성질체 또는 이의 호변 이성질체 등과 물이 비공유적 분자간 힘으로 결합되어 있는 것으로, 화학양론적 또는 비화학양론적의 양의 물을 포함하는 것일 수 있다. 예를 들어 , 상기 수화물은 활성성분 1 몰을 기준으로 물을 약 0.25몰 내지 약 10몰 비로 포함할 수 있다. 본 발명에서 “용매화물” 은 상기 (1) 내지 (17)중 어느 하나에 따른 화합물 , 이의 약학적으로 허용 가능한 염 , 이의 광학 이성질체 또는 이의 호변 이성질체 등과 물이 아닌 용매가 분자간 힘으로 결합되어 있는 것으로, 용매를 화학양론적 또는 비화학양론적 양으로 포함할 수 있다. 구체적으로는 , 상기 용매화물은 활성성분 1 몰을 기준으로 용매분자를 약 0.25몰 내지 약 10몰 비로 포함할 수 있다. 염 , 입체 이성질체 , 호변 이성질체 , 수화물 또는 용매화물 이외에도 본 발명에서 상기 (1) 내지 (17) 중 어느 하나에 따른 화합물은 다양한 형태 또는 유도체로 존재할 수 있고 , 상이한 결정형 또는 다결정형 , 및 활성 대사산물을 포함할 수 있다. 본 발명에서 “예방” 은 본 발명의 상기 (1) 내지 (17) 중 어느 하나에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물의 투여에 의해 질환의 발병을 억제시키거나 지연시키는 모든 행위를 의미한다. 본 발명에서 “치료” 는 본 발명의 상기 (1) 내지 (17) 중 어느 하나에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물의 투여에 의해 질환의 의심 및 발병 개체의 증상이 호전되거나 이롭게 변경되는 모든 행위를 의미한다. 본 발명의 상기 (1) 내지 (17) 중 어느 하나에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물은 RIPK1 활성 관련 질환의 예방 또는 치료에 유용하게 사용될 수 있다. 본 발명의 상기 (1) 내지 (17) 중 어느 하나에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물은 RIPK1의 억제 또는 RIPK1 신호 경로를 억제할수 있다. 본 발명의 상기 (1) 내지 (16) 중 어느 하나에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물은 종래에 알려져 있는 RIPK1 활성 관련 질환의 예방 또는 치료를 위한 약물과 유사하거나 실질적으로 동일한 수준 또는 보다 우수한 수준으로 RIPK1 활성 관련 질환의 예방또는 치료효과를 나타낼 수 있다. 조성물 본 발명은 상기 (1) 내지 (17) 중 어느 하나에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물을 유효성분으로포함하는 약학적 조성물을 제공한다. 또한 본 발명은, 상기 (1) 내지 (17) 중 어느 하나에 따른화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물을 유효성분으로 포함하는, RIPK1 활성 관련 질환의 예방 또는 치료를 위한 약학적 조성물을 제공한다. 즉, 상기 (1) 내지 (17) 중 어느 하나에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물을 유효성분으로 포함하는 약학적 조성물은 RIPK1 활성 관련 질환의 예방또는 치료에 유용하게 사용될 수 있다. 상기 RIPK1 활성 관련 질환은, 염증, 자가면역 질환, 암, 감염, 중추신경계 질환, 대사 질환, 심혈관 질환, 호흡기 질환, 간 질환, 신장 질환, 안구 질환, 피부 질환, 림프 병태, 심리 장애, 이식편대숙주 질환, 이질통, 창상, 반흔 등을 포함할수 있다. 염증은, 염증성 장애의 결과로서 일어나는 염증, 예컨대, 자가염증성 질환, 비-염증성 장애의 증상으로서 일어나는 염증, 감염의 결과로서 일어나는 염증, 또는 손상또는 자가면역에 부차적인 감염 또는 염증의 결과로서 일어나는 염증, 패혈증, 전신 염증 반응 증후군 등을포함할수 있다. 자가면역 질환은, 급성 파종성 뇌염, 애디슨병, 강직성 척추염, 항인지질항체 증후군 (ant iphosphol ipid antibody syndrome： APS) , 항합성효소항체 증후군, 재생불량성 빈혈, 자가면역 부신염, 자가면역 감염, 자가면역 난소염 , 자가면역 뭇샘성 기능상실 , 자가면역 갑상선염 , 셀리악병 , 크론병, 궤양성 대장염, 궤양성 결장염 등을 포함하는 염증성 장질환, 제 1형 당뇨병 (type 1 diabetes： T1D), 굿파스처 증후군, 그레이브병 , 갈랑바레 중후군 (GBS), 하시모토병, 특발성 혈소판, 감소성 자색반증, 가와사키병, 전신 홍반 루푸스 (SLE)를 포함하는 홍반성 낭창, 1차 진행성 다발성 경화증 (primary progressive multiple sclerosis： PPMS) , 2차 진행성 다발성 경화증 (secondary progressive multiple sclerosis： SPMS) 및 재발 완화형 다발성 경화증 (relapsing remitting multiple sclerosis： RRMS)을 포함하는 다발성 경화증 (MS), 중증 근무력증, 안구간대경련 근간대경련 증후군 (opsoclonus myoclonus syndrome： OMS) , 시신경염 , 오드 갑상선염 , 천포창, 악성 빈혈 , 다발성 관절염, 원발성 담즙성 경변증, 류마티스 관절염 (rheumatoid arthritis： RA), 척추 관절염, 건선성 관절염, 소아 특발성 관절염 또는 스틸병 , 골관절염, 난치성 통풍성 관절염, 라이터 증후군, 쇼그렌 증후군, 다발성 경화증 전신 결합조직 장애, 타카야수 동맥염, 측두 동맥염, 온난 자가면역 용혈성 빈혈, 베게너 육아종증, 전신성 탈모증, 베체트병, 샤가스병, 자율신경실조증, 자궁내막증, 화농성 한선염 (hidradenitis suppur at iva： HS) , 간질성 방광염, 신경근육긴장증, 건선, 사르코이드증, 피부경화증, 울혈성 결장염, 슈니츨러 증후군, 대식세포 활성화 증후군, 블라우 증후군 (Blau syndrome) , 백반증 또는 외음부 통증 등을 포함할수 있다. 암은, 실질 기관 악성 종양으로서, 폐암, 췌장암, 위암, 골수이형성 증후군, 급성 림프구성 백혈병 (acute lymphocytic leukaemia： ALL) 및 급성 골수성 백혈병 (acute mye 1 o i d leukaemia： AML)을 포함하는 백혈병 , 부신암, 항문암, 기저 편평세포 피부암, 담관암, 방광암, 골암, 뇌척수종양, 유방암, 자궁경부암, 만성 림프구성 백혈병 (CLL), 만성 골수성 백혈병 (CML), 만성 골수단핵구 백혈병 (CMML), 결장직장암, 자궁내막암, 식도암, 유잉 계열 종양, 눈암, 담낭암, 위장 유암종, 위장관 기질 종양 (가스 trointestinal stromal tumour : GIST), 임신융모질환, 신경교종, 호지킨 림프종, 카포시 육종, 신장 암, 하인두암, 간암, 폐유암종, 피부 T세포 림프종을 포함하는 림프종, 악성 중피종, 흑색종 피부암, 머켈 세포 피부 암, 다발성 골수종, 비강 및 부비강암, 비인두암, 신경모세포종, 비호 ■지킨 림프종, 비소세포 폐암, 구강 및 구인두암, 골육종, 난소암, 음경암, 뇌하수체 종양, 전립선암, 망막모세포종, 횡문근육종, 침샘암, 피부 암, 소세포 폐암, 소장 암, 연조직 육종, 위암, 고환암, 흉선암, 미분화 갑상선암을 포함하는 갑상선암, 자궁육종, 질 암, 외음부 암, 발텐스트롬 마크로글로불린혈증, 윌름스 종양등을 포함할수 있다. 감염은, 바이러스 감염 (예컨대 , 인플루엔자 바이러스, 인간 면역결핍 바이러스 (HIV), 알파바이러스 (예컨대, 치쿤구니야 및 로스 리버 바이러스 (Chikungunya and Ross River virus) ) , 플라비바이러스 (예컨대 , 댕기 바이러스 및 지카바이러스), 헤르페스 바이러스 (예컨대, 엡스타인 바 바이러스, 거대세포바이러스, 수두-대상포진 바이러스, 및 KSHV) , 폭스바이러스 (예컨대 , 백시니아 바이러스 (변형된 백시니아 바이러스 안카라 (Ankara)) 및 점액종 바이러스), 아데노바이러스 (예컨대 , 아데노바이러스 5), 또는 유두종바이러스),
Figure imgf000047_0001
헬리오박터 파 ■알로리 (、Hel icobacter pylori') , 바실러스 안트라시스 (fec7//w ant hr ads') , 보르다텔라 퍼투八스 {Bordatel la pertussis) , 부르코홀데리아 슈도말레이 {Burkholder la pseudomallei) , 코리네박테륨
Figure imgf000048_0001
diptheriae) , 클로스트리듐 테타니 ( Clostridium tetani〉 , 클로스트리듐 보툴리눔 ( Clostridium botulinum) , 스트렙토코커스
Figure imgf000048_0002
pyogenes) , 리스테리아 모노사이토게네스 (Z/s*r/스 monocytogenes ) , 헤모필루스 인플루앤자 (Hemophi lus influenzae) , 파스퇴 렐라 멀티시주다 (Pasteurel la multicida) , 시 겔라 디 센테리 애 (5方/ v/比 dysenteriae) , 마이코박테륨
Figure imgf000048_0003
레프래
Figure imgf000048_0004
leprae) , 마이코플라즈마 뉴모니 애 (Mycoplasma pneumoniae) , 마이코플라즈마 호미니스 (Mycop 1 asma hominis) , 네 이세리아 메닌기티丁]스 (Neisseria meningi tidis) , 네이세리아 고노르호애 (Neisseria gonorrhoeae) , 리 케트시아 리 케트시 이 (Rickettsia rickettsii) , 레지오네라 뉴모필라 (Zem'a*/比 pneumophila) , 클레브시 엘라 뉴모니 애 (Klebsiella pneumoniae) , 슈도모나스 아에루기노사 ■{Pseudomonas aeruginosa) , 프로피오니박테륨 아크네스 (Propionibacteriiim acnes) , 트레포네마 팔리둠 ( Tr eponema pallidum) , 클라미디아 트라코마티스 (6方/ ⑦ gy(7北 trachomatis) , 비브리오 콜레라
Figure imgf000048_0005
살모넬라 티피무륨 (5% /WT*//日 typhi murium) , 살모넬라 리피 ( Sahnonel la typhi) , 보렐리아 부르그도르페리 (及 zrre/7日 burgdorferi) 또는 에르시니아 페스티스 ( Jfers/刀/刀 pest is) , 진균 감염 (예컨대 , 캔디다 (Candida)종 또는 아스퍼 질러스 (Aspergi 1 lus)종 유래 ) , 원생동물감염 (예컨대 , 말라리아원충 , 바베시아 (Babesia) , 기아르디아 (Giardia) , 엔타모에바 (Ent amoeba) , 리슈마니아 (Leishmania) 또는 트리파노소마 (Trypanosome) 유래 ) , 연충 감염 (예컨대 , 주혈흡충, 회충, 촌충 또는 흡충류 유래), 프리온 감염 등을 포함할수 있다. 중추신경계 질환은, 파킨슨병, 알츠하이머병, 치매, 운동 뉴런 질환, 헌팅턴병, 뇌 말라리아, 폐렴 구균성 수막염으로부터의 뇌 손상, 뇌동맥류, 외상성 뇌손상 및 근위축성 축삭 경화증 등을 포함할수 있다. 대사 질환은, 제 2형 당뇨병 (type 2 diabetes： T2D) , 죽상경화증, 비만, 통풍, 가성 통풍 등을 포함할수 있다. 심혈관 질환은 고혈압, 허혈, MI후 허혈성 재관류 손상을 포함하는 재관류 손상, 허혈성 뇌졸중을 포함하는 뇌졸중, 일과성 허혈성 발작, 재발성 심근경색증을 포함하는 심근경색증, 울혈성 심부전 및 심박출계수보존 심부전을 포함하는 신부전, 색전증, 복부 대동맥류를 포함하는 동맥류, 또는 드레슬러 증후군을 포함하는 심낭염 등을 포함할수 있다. 호흡기 질환은, 만성 폐쇄성 폐 장애 (COPD), 천식, 예컨대, 알러지 천식 및 스테로이드-내성 천식, 석면증, 규폐증, 나노입자 유도염증, 낭성 섬유증, 특발성 폐 섬유증 등을 포함할수 있다. 간 질환은, 진행성 섬유증 제 F3기 및 제 F4기를 포함하는 비알코올성 지방간 질환 (non- alcohol ic fatty 1 iver disease： NAFLD) 및 비알코올성 지방간염 (non- alcohol ic steatohepatitis： NASH) , 알코올성 지방간 질환 (alcoholic fatty 1 iver disease： AFLD) , 알코올성 지방간염 (alcohol ic steatohepatitis： ASH)을 포함할수 있다. 신장 질환은, 만성 신장 질환, 옥살레이트 신장병증, 신장석회증, 사구체신염 , 당뇨성 신장병증 등을 포함할수 있다. 안구 질환은, 안구 상피 , 연령-관련 황반 변성 (age- related macular degeneration： AMD) (건성 및 습성), 포도막염, 각막 감염, 당뇨성 망막병증, 시신경 손상, 안구 건조증, 녹내장등을 포함할수 있다. 피부 질환은, 피부염, 예컨대, 접촉성 피부염 및 아토피 피부염, 접촉 과민증, 일광화상, 피부 병변, 화농성 한선염 (HS), 기타 낭종-초래 피부 질환, 집족성 여드름 등을 포함할수 있다. 림프 병태는, 림프관염 , 캐슬만병 등을 포함할수 있다. 일 실시예에서 , 본 발명에서의 RIPK1 활성 관련 질환은 크론병 , 궤양성 대장염, 궤양성 결장염, 건선, 류마티스 관절염, 척추관절염, 전신 발병 소아 특발성 관절염, 건선성 관절염, 골관절염, 실질 기관의 허혈 재관류 손상, 패혈증, 전신 염증 반응 증후군, 다발성 경화증, 또는 실질 기관 악성종양을 포함할 수 있다. 본 발명의 약학적 조성물은 상기 (1) 내지 (17) 중 어느 하나에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물 외에 추가로 약학적으로 허용 가능한 담체를 1종 이상 포함할 수 있다. 약학적으로 허용 가능한 담체는 당업계에서 통상적으로 이용되는 것으로, 구체적으로 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알지네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로오스, 폴리비닐피롤리딘, 셀룰로오스, 물, 시럽, 메틸 셀룰로오스, 메틸 히드록시벤조네이트, 프로필 히드록시벤조네이트, 활석 , 스테아르산 마그네슘, 미네랄, 또는 오일일 수 있으나, 이에 제한되는 것은 아니다. 본 발명의 약학적 조성물은 상기 성분들 외에 윤활제, 습윤제, 감미제, 향미제 , 유화제 , 현탁제 , 보존제 , 분산제 , 안정화제 등을추가로 포함할수 있다 . 또한, 본 발명의 약학적 조성물은 약학적으로 허용 가능한 담체 및 부형제를 이용하여 정제, 산제, 과립제, 환제, 캡슐제, 현탁액, 에멀젼, 내용액제, 유제, 시럽 등의 경구용 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제제화하여 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 제제는 당업계에서 제제화에 사용되는 통상의 방법 또는 Remington's Pharmaceutical Science(19th ed. , 1995)에 개시되어 있는 방법으로 제조될 수 있으며 , 각 질환또는 성분에 따라다양한 제제로 제제화될 수 있다. 본 발명의 약학적 조성물을 이용한 경구 투여용 제제의 비제한적인 예로는, 정제, 트로키제 (troches), 로젠지 (lozenge), 수용성 현탁액, 유성 현탁액, 조제 분말, 과립, 에멀젼, 하드 캡슐, 소프트 캡슐, 시럽 또는 엘릭시르제 등을 들 수 있다. 본 발명의 약학적 조성물을 경구 투여용으로 제제화하기 위하여, 락토오스, 사카로오스, 솔비톨, 만니톨, 전분, 아밀로펙틴, 셀룰로오스 또는 젤라틴 등과 같은 결합제; 디칼슘 포스페이트 등과 같은 부형제; 옥수수 전분 또는 고구마 전분 등과 같은 붕해제; 스테아르산 마그네슘, 스테아르산 칼슘, 스테아릴 푸마르산 나트륨 또는 폴리에틸렌 글리콜 왁스 등과 같은 윤활유 등을 사용할 수 있으며, 감미제, 방향제, 시럽제 등도 사용할 수 있다. 나아가 캡슐제의 경우에는 상기 언급한 물질 외에도 지방유와 같은 액체 담체 등을추가로 사용할수 있다. 본 발명의 약학적 조성물을 이용한 비경구용 제제의 비제한적인 예로는, 주사액, 좌제, 호흡기 흡입용 분말, 스프레이용 에어로졸제, 연고, 도포용 파우더, 오일, 크림 등을 들 수 있다. 본 발명의 약학적 조성물을 비경구 투여용으로 제제화하기 위하여 , 멸균된 수용액 , 비수성용제 , 현탁제 , 유제 , 동결 건조 제제, 외용제 등을 사용할 수 있으며, 상기 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있으나 , 이에 제한되지 않는다. 본 발명은 상기 (1) 내지 (17) 중 어느 하나에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물을 개체에 투여하는 것을 포함하는 RIPK1 활성 관련 질환의 예방 또는 치료 방법을 제공한다. 본 발명에서 “투여” 는 적절한 방법으로 개체에게 소정의 물질을 도입하는 것을 의미한다. 본 발명에서 “개체” 는 RIPK1 활성 관련 질환이 발병하였거나 발병할 수 있는 인간을 포함한 쥐, 생쥐, 가축 등의 모든 동물을 의미하며, 구체적으로 인간을 포함하는 포유동물일 수 있으나, 이에 제한되는 것은 아니다. 본 발명의 RIPK1 활성 관련 질환의 예방 또는 치료 방법은 상기 (1) 내지 (17) 중 어느 하나에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물을 치료학적으로 유효한 양으로 투여하는 것일 수 있다. 본 발명에서 “치료학적으로 유효한 양” 이란 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며 , 이는 환자의 성별, 연령 , 체중, 건강상태, 질병의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로, 배출 비율, 치료 기간, 배합 또는 동시에 사용되는 약물을 포함한 요소 및 기타 의학분야에 잘 알려진 요소에 따라 당업자에 의해 결정될 수 있다 특정 환자에 대한 구체적인 치료학적으로 유효한 양은 달성하고자 하는 반응의 종류와 정도, 경우에 따라 다른 제제가 사용되는지의 여부를 비롯한 구체적 조성물, 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율 , 치료기간 , 구체적 조성물과 함께 사용되거나 동시 사용되는 약물을 비롯한다양한 인자와 의약분야에 잘 알려진 유사 인자에 따라 다르게 적용하는 것이 바람직하다. 본 발명은 RIPK1 활성 관련 질환의 예방 또는 치료를 위한 상기 (1) 내지 (17) 중 어느 하나에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물 또는 이를 포함하는 조성물의 용도를 제공한다. 본 발명은 RIPK1 활성 관련 질환의 예방 또는 치료용 약제의 제조를 위한, 상기 (1) 내지 (17) 중 어느 하나에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물, 또는 이를 포함하는 조성물의 용도를 제공한다. 약제의 제조를 위하여 상기 (1) 내지 (17) 중 어느 하나에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물에 약학적으로 허용 가능한보조제, 희석제, 담체 등을 혼합할 수 있으며 , 기타 활성제제와 함께 복합 제제로 제조되어 상승 작용을 가질 수도 있다. 본 발명의 화합물 , 약학적 조성물 , 치료 방법 및 용도에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다. [Table 2]
Figure imgf000040_0002
Figure imgf000041_0001
In the present invention, "pharmaceutically acceptable salt" means a salt commonly used in the pharmaceutical industry, and can be prepared by a conventional method known to those skilled in the art. In the present invention, pharmaceutically acceptable salts include, for example, inorganic ion salts prepared with calcium, potassium, sodium or magnesium; Hydrochloric Acid, Nitric Acid, Phosphoric Acid, Bromic Acid, inorganic acid salts prepared with iodic acid, perchloric acid, or sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid organic acid salts prepared from acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, and the like; sulfonic acid salts made of methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid, amino acid salts made of glycine, arginine, lysine, etc.; or amine salts made of trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but the types of salts meant in the present invention are not limited by these listed salts. In one embodiment of the present invention, the salt may be a hydrochloride salt. In the present invention, “stereoisomer” includes diastereomers, optical isomers, and position isomers, and optical isomers include enantiomers as well as mixtures and racemates of enantiomers. including all body These isomers can be separated by conventional techniques such as column chromatography or HPLC resolution. Alternatively, each stereoisomer of the compound according to any one of (1) to (17) can be stereospecifically synthesized using optically pure starting materials and/or reagents of known configuration. In the present invention, “tautomer (tautomer)” refers to a structural isomer that interconverts through a low energy barrier among the compounds according to any one of (1) to (17) above. A compound may have, for example, an imino, keto, or oxime group. When containing or an aromatic substituent is included, atoms constituting the compound may be in the form of tautomerization. Those skilled in the art will recognize that in certain instances structurally depicted compounds may be termed tautomers of the compounds of the present invention. It should be understood that references to named compounds or structurally depicted compounds are intended to encompass all tautomers of such compounds and any mixtures of tautomers thereof. In the present invention, "hydrate" means a compound according to any one of (1) to (17) above, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a tautomer thereof, etc., in which water is bound by non-covalent intermolecular forces, It may contain stoichiometric or non-stoichiometric amounts of water. For example, the hydrate may include water in an amount of about 0.25 to about 10 moles based on 1 mole of the active ingredient. In the present invention, "solvate" refers to a compound according to any one of (1) to (17) above, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a tautomer thereof, etc., in which a solvent other than water is bound by intermolecular force. As such, the solvent may be included in a stoichiometric or non-stoichiometric amount. Specifically, the solvate may include solvent molecules in an amount of about 0.25 to about 10 moles based on 1 mole of the active ingredient. In addition to salts, stereoisomers, tautomers, hydrates or solvates, the compounds according to any one of (1) to (17) in the present invention may exist in various forms or derivatives, and may have different crystalline or polycrystalline forms, and active metabolites. can include In the present invention, “prevention” refers to the compound according to any one of (1) to (17) above, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof. It means any action that suppresses or delays the onset of a disease by administration. In the present invention, “treatment” refers to a compound according to any one of (1) to (17) above, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof. It refers to all activities that improve or beneficially change the symptoms of suspected or affected individuals by administration. The compound according to any one of (1) to (17) of the present invention, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, prevents or prevents RIPK1 activity-related diseases It can be useful for treatment. The compound according to any one of (1) to (17) of the present invention, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, inhibits RIPK1 or inhibits the RIPK1 signaling pathway. can suppress The compound according to any one of (1) to (16), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof according to any one of the above (1) to (16) of the present invention is related to RIPK1 activity known in the art. It is possible to exhibit a preventive or therapeutic effect of a RIPK1 activity-related disease at a level similar to, substantially the same as, or superior to that of a drug for preventing or treating a disease. composition The present invention relates to a pharmaceutical preparation comprising the compound according to any one of (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof as an active ingredient. composition is provided. In addition, the present invention, the compound according to any one of (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, comprising as an active ingredient , It provides a pharmaceutical composition for the prevention or treatment of RIPK1 activity-related diseases. That is, a pharmaceutical composition comprising the compound according to any one of (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient. can be usefully used for the prevention or treatment of RIPK1 activity-related diseases. The RIPK1 activity-related diseases include inflammation, autoimmune disease, cancer, infection, central nervous system disease, metabolic disease, cardiovascular disease, respiratory disease, liver disease, kidney disease, eye disease, skin disease, lymphatic condition, psychological disorder, and graft versus It may include host disease, allodynia, wounds, scars, and the like. Inflammation refers to inflammation that occurs as a result of an inflammatory disorder, such as an autoinflammatory disease, inflammation that occurs as a symptom of a non-inflammatory disorder, inflammation that occurs as a result of infection, or inflammation that occurs as a result of infection or inflammation secondary to injury or autoimmunity. , sepsis, and systemic inflammatory response syndrome. Autoimmune diseases include acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), antisynthetase antibody syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune infections, Autoimmune oophoritis, autoimmune glandular dysfunction, autoimmune thyroiditis, celiac disease, Crohn's disease, inflammatory bowel disease including ulcerative colitis, ulcerative colitis, type 1 diabetes (T1D), Goodpas Cher's syndrome, Grave's disease, Galambare syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenia, reduced purpura, Kawasaki disease, lupus erythematosus including systemic lupus erythematosus (SLE), primary progressive multiple sclerosis : PPMS), multiple sclerosis (MS) including secondary progressive multiple sclerosis (SPMS) and relapsing remitting multiple sclerosis (RRMS), myasthenia gravis, ocular myoclonus syndrome (opsoclonus myoclonus syndrome: OMS), optic neuritis, Odd's thyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), spondyloarthritis, psoriatic arthritis, juvenile idiopathic arthritis or Still's disease, osteoarthritis , intractable gouty arthritis, Reiter's syndrome, Sjogren's syndrome, multiple sclerosis systemic connective tissue disorder, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, systemic alopecia, Behcet's disease, Chagas' disease, dysautonomia, uterus Endometriosis, hidradenitis suppur at iva: HS), interstitial cystitis, neuromuscular dystonia, psoriasis, sarcoidosis, scleroderma, congestive colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome , vitiligo or vulvar pain. Cancer, as parenchymal organ malignancies, includes lung cancer, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia including acute lymphocytic leukemia (ALL) and acute myeloid leukemia (acute mye 1 oid leukemia: AML), adrenal cancer , Anal cancer, basal squamous cell skin cancer, cholangiocarcinoma, bladder cancer, bone cancer, cerebrospinal tumor, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrium Cancer, esophageal cancer, Ewing's series tumor, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumor, gas trointestinal stromal tumor (GIST), gestational trophoblastic disease, glioma, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, hypopharyngeal cancer, liver cancer, lung carcinoid , lymphoma, including cutaneous T-cell lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal and paranasal cancer, nasopharyngeal cancer, neuroblastoma, Boho Hodgkin's lymphoma, non-small cell lung cancer, oral and oropharyngeal cancer, Osteosarcoma, ovarian cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thymus cancer, thyroid cancer including undifferentiated thyroid cancer, uterus sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, Wilms' tumor, and the like. Infections include viral infections (eg, influenza virus, human immunodeficiency virus (HIV), alphaviruses (eg, Chikungunya and Ross River virus), flaviviruses (eg, dengue virus and Zika virus) viruses), herpes viruses (e.g., Epstein Barr virus, cytomegalovirus, varicella-zoster virus, and KSHV), poxviruses (e.g., vaccinia virus (modified vaccinia virus Ankara) and myxoma virus) , adenovirus (eg, adenovirus 5), or papillomavirus),
Figure imgf000047_0001
Heliobacter pylori (、Hel icobacter pylori'), Bacillus anthracis (fec7//w ant hr ads'), Bordatel la pertussis, Burcoholderia Pseudomallei {Burkholder la pseudomallei) , Corynebacterium
Figure imgf000048_0001
diptheriae), Clostridium tetani>, Clostridium botulinum, Streptococcus
Figure imgf000048_0002
pyogenes), Listeria monocytogenes (Z/s*r/s monocytogenes), Hemophilus influenzae, Pasteurella multicida, Shigella dicenteriae (5 ways) / v/比 dysenteriae) , mycobacterium
Figure imgf000048_0003
lepree
Figure imgf000048_0004
leprae), Mycoplasma pneumoniae, Mycop 1 asma hominis, Neisseria meningi tidis, Neisseria gonorrhoeae, Rickett Rickettsia rickettsii, Legionera pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Propionibac Terium acnes (Propionibacteriiim acnes), Treponema pallidum, Chlamydia trachomatis (6方/ ⑦ gy(7北 trachomatis), Vibrio cholera
Figure imgf000048_0005
Salmonella Typhimurium (5% /WT*//Day Typhi Murium), Salmonella Lipi (Sahnonel la typhi), Borrelia Burgdorferi (及 zrre/7Day Burgdorferi) or Ercinia Pestis ( Jfers/刀/刀 pest is), fungal infection (eg, from Candida species or Aspergi 1 lus species), protozoan infection (eg, Plasmodium, Babesia, Giardia, Entah Ent amoeba, Leishmania or Trypanosoma (from Trypanosome), helminth infections (eg, from schistosomiasis, roundworm, tapeworm or trematodes), prion infections, and the like. Central nervous system diseases may include Parkinson's disease, Alzheimer's disease, dementia, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, cerebral aneurysm, traumatic brain injury and amyotrophic axial sclerosis, and the like. Metabolic diseases may include type 2 diabetes (T2D), atherosclerosis, obesity, gout, pseudogout, and the like. Cardiovascular disease includes hypertension, ischemia, reperfusion injury including ischemic reperfusion injury after MI, stroke including ischemic stroke, transient ischemic attack, myocardial infarction including recurrent myocardial infarction, congestive heart failure and ejection fraction heart failure. renal failure, embolism, aneurysms including abdominal aortic aneurysm, or pericarditis including Dressler syndrome. Respiratory diseases can include chronic obstructive pulmonary disorder (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, nanoparticle induced inflammation, cystic fibrosis, idiopathic pulmonary fibrosis, and the like. Liver diseases include non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), including advanced fibrosis stage F3 and F4, and alcoholic fatty liver disease ( It may include alcoholic fatty 1 iver disease (AFLD) and alcoholic steatohepatitis (ASH). Kidney disease may include chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, diabetic nephropathy, and the like. Ocular diseases can include ocular epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infection, diabetic retinopathy, optic nerve damage, dry eye, glaucoma, and the like. Skin disorders can include dermatitis, such as contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other cyst-causing skin disorders, acne vulgaris, and the like. Lymphatic conditions may include lymphangitis, Castleman's disease, and the like. In one embodiment, the disease associated with RIPK1 activity in the present invention is Crohn's disease, ulcerative colitis, ulcerative colitis, psoriasis, rheumatoid arthritis, spondyloarthritis, systemic onset juvenile idiopathic arthritis, psoriatic arthritis, osteoarthritis, ischemia-reperfusion of parenchymal organs injury, sepsis, systemic inflammatory response syndrome, multiple sclerosis, or parenchymal organ malignancies. The pharmaceutical composition of the present invention, in addition to the compound according to any one of (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, in addition to a pharmaceutical composition thereof It may include one or more types of generally acceptable carriers. Pharmaceutically acceptable carriers are commonly used in the art, specifically lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, It may be polyvinylpyrrolidine, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, minerals, or oil, but is not limited thereto. The pharmaceutical composition of the present invention, in addition to the above components, lubricant, wetting agent, sweetener, A flavoring agent, an emulsifying agent, a suspending agent, a preservative, a dispersing agent, a stabilizing agent, and the like may be further included. In addition, the pharmaceutical composition of the present invention can be formulated into oral formulations such as tablets, powders, granules, pills, capsules, suspensions, emulsions, solutions for internal use, emulsions, syrups, external preparations, and suppositories using pharmaceutically acceptable carriers and excipients. Alternatively, it may be formulated in the form of a sterile injectable solution to be prepared in unit dose form or introduced into a multi-dose container. The formulation may be prepared by a conventional method used for formulation in the art or a method disclosed in Remington's Pharmaceutical Science (19th ed., 1995), and may be formulated into various formulations according to each disease or component. Non-limiting examples of formulations for oral administration using the pharmaceutical composition of the present invention include tablets, troches, lozenges, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, and soft capsules, syrups or elixirs; and the like. In order to formulate the pharmaceutical composition of the present invention for oral administration, a binder such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; excipients such as dicalcium phosphate and the like; disintegrants such as corn starch or sweet potato starch; Lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol wax may be used, and sweeteners, aromatics, syrups, and the like may also be used. Furthermore, in the case of capsules, a liquid carrier such as fatty oil may be additionally used in addition to the above-mentioned materials. Non-limiting examples of parenteral preparations using the pharmaceutical composition of the present invention include injection solutions, suppositories, powders for respiratory inhalation, aerosols for sprays, ointments, powders for application, oils, creams, and the like. Parenteral administration of the pharmaceutical composition of the present invention In order to formulate for administration, sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, external preparations, etc. may be used, and the non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, Injectable esters such as ethyl oleate and the like may be used, but are not limited thereto. The present invention includes administering the compound according to any one of (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof to a subject. A method for preventing or treating a disease related to RIPK1 activity is provided. In the present invention, “administration” means introducing a predetermined substance into a subject by an appropriate method. In the present invention, "subject" refers to all animals such as rats, mice, livestock, etc., including humans who have or may develop RIPK1 activity-related diseases, and may specifically be mammals, including humans, but are not limited thereto no. The method for preventing or treating a disease related to RIPK1 activity of the present invention is a compound according to any one of (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate thereof. The solvate may be administered in a therapeutically effective amount. In the present invention, "therapeutically effective amount" means an amount that is sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and does not cause side effects, which is a patient's sex, age, weight, health condition, type of disease, severity, activity of drug, sensitivity to drug, method of administration, time of administration, A specific therapeutically effective amount for a particular patient can be determined by those skilled in the art depending on factors including route of administration, rate of excretion, duration of treatment, drugs used in combination or concomitantly, and other factors well known in the medical arts. and degree, if any, the specific composition including whether or not other agents are used, the patient's age, weight, general health condition, sex and diet, administration time, route of administration and excretion rate of the composition, duration of treatment, together with the specific composition It is preferable to apply differently according to various factors including drugs used or concurrently used and similar factors well known in the medical field. The present invention relates to a compound according to any one of (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a compound according to any one of (1) to (17) for the prevention or treatment of RIPK1 activity-related diseases. The use of the solvate or composition comprising it is provided. The present invention relates to the compound according to any one of (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof for the preparation of a drug for preventing or treating RIPK1 activity-related diseases. A hydrate of or a solvate thereof, or a composition comprising the same is provided. For the preparation of a drug, the compound according to any one of (1) to (17), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof is converted into a pharmaceutically acceptable compound according to any one of (1) to (17). Auxiliaries, diluents, carriers, etc. may be mixed, and may have a synergistic effect by being prepared as a combined preparation with other active agents. Matters mentioned in the compounds, pharmaceutical compositions, treatment methods and uses of the present invention are equally applied unless contradictory to each other.
【발명의 효과】 본 발명의 RIPK1 저해제로서의 화합물 , 이의 입체 이성질체 , 이의 호변 이성질체 , 이의 약학적으로 허용 가능한 염 , 이들의 수화물 또는 이들의 용매화물 ; 및 이를 유효성분으로 포함하는 약학적 조성물은 RIPK1 활성 관련 질환의 예방 또는 치료에 유용하게 사용될 수 있다. [Effect of the invention] The compound as a RIPK1 inhibitor of the present invention, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; And a pharmaceutical composition containing it as an active ingredient can be usefully used for the prevention or treatment of RIPK1 activity-related diseases.
【발명의 실시를 위한 형태】 이하, 실시 예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시 예는 오로지 본 발명을 예시하기 위한 것으로서 , 본 발명의 범위가 이들 실시 예에 의해 제한되는 것으로 해석되지는 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다. 화합물의 제조 본 발명의 화합물은 하기 기술된 방법을 통하여 제조될 수 있다. 달리 서술되지 않는 한, 출발 물질은 구매가능하거나 공지된 방법으로 제조될 수 있다. 본원에서 제공된 일체의 예 , 또는 예시적인 언어의 사용은 단지 본 발명을 더 잘 예시하고자 하는 것으로서 , 청구된 본 발명의 범주를 제한하는 것이 아니다. 이하, 실시 예 및 실험예에 기재된 약어들 및 그 의미는 다음과 같다.[Mode for Carrying out the Invention] Hereinafter, the present invention will be described in more detail through examples. These examples are only for exemplifying the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples. Preparation of Compounds The compounds of the present invention can be prepared through the methods described below. Unless otherwise stated, starting materials are commercially available or can be prepared by known methods. Any examples provided herein, or use of exemplary language, are merely intended to better illustrate the invention and do not limit the scope of the invention as claimed. Hereinafter, abbreviations and their meanings described in Examples and Experimental Examples are as follows.
[표 3]
Figure imgf000055_0001
실시예 1. （R）-l-벤질- N-（5 -메틸- 4 -옥소- 8-（피롤리딘- 1-일）- 2, 3, 4, 5 - 테트라하이드로피리도 [4,3~b] [1 ,4]싸이 °｝제핀一 3 —일 )~!!1~!,2,4~트리아졸一 3~ 카복사마이드의 제조
Figure imgf000056_0001
단계 1. 화합물 A1의 제조 [Table 3]
Figure imgf000055_0001
Example 1. (R) -l-benzyl- N- (5 -methyl- 4 -oxo- 8- (pyrrolidin- 1-yl) - 2, 3, 4, 5 - Tetrahydropyrido [4,3~b] [1,4]cy °｝zepine一 3 —yl)~!!1~!,2,4~triazole一 3~ Preparation of carboxamides
Figure imgf000056_0001
Step 1. Preparation of Compound A1
2, 4 -다이클로로- 5 -나이트로피리딘 (5.0 g, 26.0 mmol)을 아세토나이트릴 (130 mL)에 첨가하여 녹인 후, 탄산칼륨 (4.3 g, 31.2 mmol)과 N- Boc- L-시스테인 (6.3 g mL, 28.6 mmol)를 0°C에서 첨가하였다. 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물을 감압 농축하고 물에 희석시켰고, 1N HC1 수용액을 이용하여 혼합물의 농도를 pH 2- 3으로 맞춘 뒤, 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하여 황색 고체의 목적 화합물 A1 (9.5 g, 97%)을수득하였다. 단계 2. 목적 화합물 A2의 제조 화합물 A1 (9.5 g, 25.14 mmol)을 메탄올 (251 mL)에 첨가하여 녹인 후, 아연과 염화 암모늄을 첨가하였다. 혼합물은 75°C에서 30분 동안 교반하였다. 반응 종료 후, 반응 혼합물을 셀라이트를 이용하여 여과를 하였고, 감압 농축하여 보라색 고체의 목적 화합물 A2 (8.7 g, 99%)를수득하였다. 단계 3. 목적 화합물 A3의 제조 화합물 A2 (8.7 g, 25.14 mmol)를 테트라하이드로퓨란 (148 mL)에 첨가하여 녹인 후,
Figure imgf000057_0001
아이소프로필에틸아민 (8.76 mL, 50.3 mmol)과 T3PAfter dissolving 2,4-dichloro-5-nitropyridine (5.0 g, 26.0 mmol) in acetonitrile (130 mL), potassium carbonate (4.3 g, 31.2 mmol) and N- Boc- L-cysteine (6.3 g mL, 28.6 mmol) was added at 0 °C. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with water, and the concentration of the mixture was adjusted to pH 2-3 using 1N HCl aqueous solution, and the organic layer was extracted using ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain the target compound A1 (9.5 g, 97%) as a yellow solid. Step 2. Preparation of target compound A2 After dissolving compound A1 (9.5 g, 25.14 mmol) in methanol (251 mL), zinc and ammonium chloride were added. The mixture was stirred at 75 °C for 30 min. After completion of the reaction, the reaction mixture was filtered using celite and concentrated under reduced pressure to obtain the target compound A2 (8.7 g, 99%) as a purple solid. Step 3. Preparation of target compound A3 After dissolving compound A2 (8.7 g, 25.14 mmol) in tetrahydrofuran (148 mL),
Figure imgf000057_0001
Isopropylethylamine (8.76 mL, 50.3 mmol) and T 3 P
(50% 다이에틸아세테이트 용액; 29.9 mL, 50.3 mmol)을 0°C에서 첨가하였다. 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：2)로 정제하여 노란색 고체의 목적 화합물 A3 (4.7 g, 57%)를 수득하였다. 단계 4. 목적 화합물 A4의 제조 화합물 A3 (4.7 g, 14.25 mmol)을 다이메틸포름아마이드 (71 mL)에 첨가하여 녹인 후, 탄산칼륨 (2.17 g, 15.68 mmol)과 메틸요오드 (0.98 mL, 15.68 mmol)을 첨가하였다. 혼합물은 상온에서 1시간 동안 교반하였다. 반응 종결 후, 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고, 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하여 노란색 고체의 목적 화합물 A4 (4.8 g, 98%)를 수득하였다. 단계 5. 목적 화합물 A5의 제조 화합물 A4 (1 g, 2.91 mmol)와 탄산칼륨 (1.61 g, 11.63 mmol)를 1,4- 다이옥세인 (5.8 mL)에 희석하고, 피롤리딘 (0.96 mL, 11.63 mmol)을 첨가하였다. 혼합물은 환류되는 온도하에 24시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고, 에틸아세테이트로 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：2)로 정제하여 흰색 고체의 목적 화합물 A5 (1.07 g, 97%)를수득하였다. 단계 6. 목적 화합물 A6의 제조과정 화합물 A5 (450 mg, 1.19 mmol)를 다이클로로메테인 (8 mL)에 첨가하여 녹인 후, 염산 (4川 1,4 -다이옥세인 용액; 2.98 mL)을 첨가하였다. 혼합물은 상온에서 16시간 동안교반하였다. 반응 종결 후, 반응혼합물을 감압농축 하여 흰색 고체의 목적 화합물 A6 (400 mg, 96%)를수득하였다. 단계 7. 목적 화합물 A7의 제조 화합물 A6 (400 mg, 1.14 mmo 1 ) , EDC (210mg, 2.37 mmo 1 ) , HOAt (232 mg, 2.37 mmol), 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 (347 mg, 1.71 mmol)을 다이클로로메테인 (23 mL)에 희석하고, 트리에틸아민 (0.48 mL, 3.42 mmol)을 0°C에서 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 탄산수소나트륨 수용액을 넣어 반응을 종결한 후, 물과 염화나트륨 수용액을 이용하여 세척하고 , 다이클로로메테인을 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=5：l)로 정제하여 실시예 1에 따른 흰색 고체의 목적 화합물 A7 (376 mg, 71%)을수득하였다. 실시예 2내지 49 실시예 1의 단계 4의 피롤리딘에 대응하는 화합물로서 하기 표 4의 반응물 1을, 실시예 1의 단계 7의 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산에 대응하는 화합물로서 하기 표 4의 반응물 2를 이용한 것을 제외하고는 실시예(50% diethylacetate solution; 29.9 mL, 50.3 mmol) was added at 0 °C. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:2) to obtain the target compound A3 (4.7 g, 57%) as a yellow solid. Step 4. Preparation of target compound A4 After dissolving compound A3 (4.7 g, 14.25 mmol) in dimethylformamide (71 mL), potassium carbonate (2.17 g, 15.68 mmol) and methyl iodine (0.98 mL, 15.68 mmol) ) was added. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain the target compound A4 (4.8 g, 98%) as a yellow solid. Step 5. Preparation of target compound A5 Compound A4 (1 g, 2.91 mmol) and potassium carbonate (1.61 g, 11.63 mmol) were diluted in 1,4-dioxane (5.8 mL), and pyrrolidine (0.96 mL, 11.63 mmol) was added. The mixture was stirred for 24 hours at reflux temperature. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:2) The desired compound A5 (1.07 g, 97%) was obtained as a white solid. Step 6. Preparation of target compound A6 After dissolving compound A5 (450 mg, 1.19 mmol) in dichloromethane (8 mL), hydrochloric acid (4 River 1,4-dioxane solution; 2.98 mL) was added. did The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound A6 (400 mg, 96%) as a white solid. Step 7. Preparation of target compound A7 Compound A6 (400 mg, 1.14 mmo 1 ), EDC (210 mg, 2.37 mmo 1 ), HOAt (232 mg, 2.37 mmol), 1-benzyl-1woo 1,2,4-tria The sol-3-carboxylic acid (347 mg, 1.71 mmol) was diluted in dichloromethane (23 mL) and triethylamine (0.48 mL, 3.42 mmol) was added at 0 °C. The reaction was stirred at room temperature for 16 hours. After the reaction was terminated by adding an aqueous sodium bicarbonate solution, the mixture was washed with water and an aqueous sodium chloride solution, and the organic layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=5:l) to obtain the target compound A7 (376 mg, 71%) as a white solid according to Example 1. Examples 2 to 49 Reactant 1 in Table 4 below was used as a compound corresponding to pyrrolidine in Step 4 of Example 1, 1-benzyl-1,2,4-triazole- Examples except for using reactant 2 in Table 4 as a compound corresponding to 3-carboxylic acid
1의 화합물 A7을 제조하는 방법과 실질적으로 동일한 방법으로 실시예 2 내지 49에 따른 화합물들을 제조하였다. 각 실시 예에서 반응물 1 및 반응물 2 각각은 하기 표 4와 같다. Example 2 to Example 2 by substantially the same method as the method for preparing Compound A7 of 1 Compounds according to 49 were prepared. In each example, each of reactant 1 and reactant 2 is shown in Table 4 below.
[표 4]
Figure imgf000059_0001
Figure imgf000060_0001
실시 예 1 내지 49에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR 분석 결과는 하기 표 5에 나타낸다. [Table 4]
Figure imgf000059_0001
Figure imgf000060_0001
The structure and compound name of each of the compounds obtained according to Examples 1 to 49, and NMR analysis results are shown in Table 5 below.
[표 5]
Figure imgf000060_0002
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0002
실시예 50. (R)- 1-벤질- N- (5 -메틸- 4 -옥소- 8- (2 -옥소아제티딘- 1-일)-[Table 5]
Figure imgf000060_0002
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0002
Example 50. (R)-1-Benzyl-N-(5-methyl-4-oxo-8-(2-oxoazetidin-1-yl)-
2, 3, 4, 5 ■테트라하이드로피리도 [4,3- b] [1,4]싸이아제핀- 3 -일)- 1H- 1,2, 4 -트리아졸-2, 3, 4, 5 tetrahydropyrido [4,3-b] [1,4]thiazepin- 3 -yl)- 1H- 1,2,4 -triazole-
3 -카복사마이드의 제조
Figure imgf000071_0001
3-Manufacture of carboxamides
Figure imgf000071_0001
B3 단계 1. 목적 화합물 B1의 제조 화합물 A4 (400 mg, 1 . 16 mmo 1 ) , Cui (90 mg, 0.47 mmo 1 ) , 탄산칼륨 (482 mg, 3.49 mmo 1 ) , 아제티디논 (99 mg, 1.40 mmol )을 톨루엔 (5.8 mL)에 희석하고 , DMEDA (0.06 mL , 0.58 mmol )를 첨가하였다. 혼합물은 환류되는 조건하에 16시간 동안 교반하였다. 반응 종료 후 , 셀라이트를 이용하여 여과를 하였고 , 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：l)로 정제하여 흰색 고체의 목적 화합물 B1 (126 mg, 29%)을 수득하였다. 단계 2. 목적 화합물 B2의 제조 화합물 B1 (126 mg, 0.38 mmol )을 다이클로로메테인 (1.7 mL)에 첨가하여 녹여주고 , 트리플루오로아세트산 (0.51 mL , 6.66 mmol )을 상온에서 첨가하였다. 반응물은 상온에서 2시간 동안 교반하였다. 반응 종료 후, 반응 혼합물을 감압 농축하여 오렌지 고체의 목적 화합물 B2 (93.0 mg, 98%)를수득하였다. 단계 3. 목적 화합물 B3의 제조 화합물 B2 (93 mg, 0.33 mmo 1 ) , EDC (122 mg, 1.00 mmo 1 ) , HOAt (131 mg, 1.00 mmol), 및 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 (101 mg, 0.50 mmol)을 다이클로로메테인 (6.7 mL)에 희석하고, 트리에틸아민 (0.14 mL, 1.00 mmol)을 0°C에서 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 탄산수소나트륨 수용액을 넣어 반응을 종결한 후, 물과 염화나트륨 수용액을 이용하여 세척하고 , 다이클로로메테인을 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 실시예 50에 따른 흰색 고체의 목적 화합물 B3 (22 mg, 14%)를수득하였다. 실시예 51. (R)-l-벤질- N- (5 -메틸- 4 -옥소- 8- (2 -옥소피롤리딘- 1-일 )- 2, 3, 4, 5 ■테트라하이드로피리도 [4,3- b] [1,4]싸이아제핀- 3 -일)- 1H- 1,2, 4 -트리아졸- 3 -카복사마이드의 제조 실시예 50의 단계 1에서 아제티디논 대신 피롤리딘- 2 -온을 이용한 것을 제외하고는 실시예 50의 화합물 B3을 제조하는 방법과 실질적으로 동일한 방법으로 실시예 51에 따른화합물을 제조하였다. 실시예 52. (R)- 1-(2 -플루오로벤질)- N- (5 -메틸- 4 -옥소- 8- (2 - 옥소아제티딘- 1-일 )-2 , 3 , 4, 5 -테트라하이드로피리도 [4, 3- b] [ 1 , 4]싸이아제핀- 3 - 일）- 1H- 1 , 2 , 4 -트리아졸- 3 -카복사마이드의 제조 실시 예 50의 단계 3에서 1-벤질- 1우 1 , 2 , 4 -트리아졸 -3 -카르복실산 대신Step B3 1. Preparation of target compound B1 Compound A4 (400 mg, 1.16 mmo 1 ), Cui (90 mg, 0.47 mmo 1 ), potassium carbonate (482 mg, 3.49 mmo 1 ), azetidinone (99 mg, 1.40 mmol ) was diluted in toluene (5.8 mL) and DMEDA (0.06 mL , 0.58 mmol ) was added. The mixture was stirred for 16 hours under reflux conditions. After completion of the reaction, it was filtered using celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:l) to obtain the target compound B1 (126 mg, 29%) as a white solid. Step 2. Preparation of target compound B2 Compound B1 (126 mg, 0.38 mmol) was added and dissolved in dichloromethane (1.7 mL), and trifluoroacetic acid (0.51 mL, 6.66 mmol) was added at room temperature. The reaction was stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound B2 (93.0 mg, 98%) as an orange solid. Step 3. Preparation of target compound B3 Compound B2 (93 mg, 0.33 mmo 1 ), EDC (122 mg, 1.00 mmo 1 ), HOAt (131 mg, 1.00 mmol), and 1-benzyl- 1,2,4 -Triazole-3-carboxylic acid (101 mg, 0.50 mmol) was diluted in dichloromethane (6.7 mL) and triethylamine (0.14 mL, 1.00 mmol) was added at 0°C. The reaction was stirred at room temperature for 16 hours. After the reaction was terminated by adding an aqueous sodium bicarbonate solution, the mixture was washed with water and an aqueous sodium chloride solution, and the organic layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM: Me0H = 20: l) to obtain the target compound B3 (22 mg, 14%) as a white solid according to Example 50. Example 51. (R) -l-Benzyl- N- (5 -methyl- 4 -oxo- 8- (2 -oxopyrrolidin- 1-yl) -2, 3, 4, 5 tetrahydropyrido Preparation of [4,3-b] [1,4]thiazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide Example 50 in step 1 instead of azetidinone A compound according to Example 51 was prepared in substantially the same manner as in Example 50 for preparing Compound B3, except that pyrrolidin-2-one was used. Example 52. (R)-1-(2-fluorobenzyl)-N-(5-methyl-4-oxo-8-(2-oxoazetidin-1-yl)-2,3,4, 5 -Tetrahydropyrido [4, 3- b] [ 1 , 4] thiazepine - 3 - 1) - 1H- 1, 2, 4 -triazole- 3 -carboxamide In step 3 of Example 50, 1-benzyl- 1 is used instead of 1, 2, 4 -triazole-3-carboxylic acid
1-（2 -플루오로벤질）- 1H- 1 , 2 , 4 -트리아졸 -3 -카르복실산을 이용한 것을 제외하고는 실시 예 50의 화합물 B3을 제조하는 방법과 실질적으로 동일한 방법으로 실시 예 52에 따른 화합물을 제조하였다. 실시예 53. （R）- 2 -벤질- N-（5 -메틸- 4 -옥소- 8-（2 -옥소아제티딘- 1-일）-1-(2-fluorobenzyl)-1H- 1,2,4-triazole-3-carboxylic acid was prepared in Example 50 in substantially the same manner as in Compound B3, except that carboxylic acid was used. A compound according to 52 was prepared. Example 53. (R)-2-benzyl-N-(5-methyl-4-oxo-8-(2-oxoazetidin-1-yl)-
2 , 3 , 4 , 5 ■테트라하이드로피리도 [ 4 , 3- b ] [ 1 , 4 ]싸이아제핀- 3 -일） - 2H-테트라졸- 5- 카복사마이드의 제조 실시 예 50의 단계 3에서 1-벤질- 1우 1 , 2 , 4 -트리아졸 -3 -카르복실산 대신2, 3, 4, 5 Tetrahydropyrido [4, 3-b] [1, 4] thiazepin-3-yl) - Preparation of 2H-tetrazole-5-carboxamide Steps of Example 50 Instead of 3 to 1-benzyl- 1 , 2 , 4 -triazole -3 -carboxylic acid
2 -벤질- 2우테트라졸- 5 -카르복실산을 이용한 것을 제외하고는 실시 예 50의 화합물 B3을 제조하는 방법과 실질적으로 동일한 방법으로 실시 예 52에 따른 화합물을 제조하였다. 실시 예 50 내지 53에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR 분석 결과는 하기 표 6에 나타낸다. A compound according to Example 52 was prepared in substantially the same manner as in Example 50 for preparing Compound B3, except that 2-benzyl-2utetrazole-5-carboxylic acid was used. The structure and compound name of each of the compounds obtained according to Examples 50 to 53, and NMR analysis results are shown in Table 6 below.
[표 6]
Figure imgf000073_0001
Figure imgf000074_0001
실시예 54. （R）- 1-벤질- N-（l-메틸- 2 -옥소- 8-（피롤리딘- 1-일）- 1,2, 3,4- 테트라하이드로피리도 [3,4- b] [1,4]싸이아제핀- 3 -일）- 1H- 1,2, 4 -트리아졸 -3- 카복사마이드의 제조 [Table 6]
Figure imgf000073_0001
Figure imgf000074_0001
Example 54. (R)-1-benzyl-N-(l-methyl-2-oxo-8-(pyrrolidin-1-yl)-1,2,3,4-tetrahydropyrido [3, Preparation of 4-b] [1,4]thiazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide
Figure imgf000075_0001
단계 1. 목적 화합물 C1의 제조 질소분위기 하에서 4 -아미노- 2 -클로로- 5 -아이오도피리딘 (1.0 g, 3.93 mmo 1 ) , Pd(dba)2 (56.4 mg, 0.10 mmo 1 ) , 잔트포스 (Xantphos , 113.6 mg, 1.96 mmo 1 ) ,
Figure imgf000075_0001
Step 1. Preparation of target compound C1 Under a nitrogen atmosphere, 4-amino-2-chloro-5-iodopyridine (1.0 g, 3.93 mmo 1 ), Pd(dba) 2 (56.4 mg, 0.10 mmo 1 ), Zantphos ( Xantphos , 113.6 mg, 1.96 mmo 1 ) ,
>Boc- L-시스테인 (870 mg, 3.93 mmol)을 톨루엔 (23 mL)에 희석하고, <形- 다이아이소프로필에틸아민 (1.37 mL, 7.86 mmol)을 첨가하였다. 반응물은 100°C에서 1시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 셀라이트를 이용하여 여과를 하였고, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：MeOH=l：2)로 정제하여 보라색 고체의 목적 화합물 C1 (1.39 g, 98%)을수득하였다. 단계 2. 목적 화합물 C2의 제조 화합물 C1 (1.39 g, 4.00 mmol)을 테트라하이드로퓨란 (24 mL)에 첨가하여 녹여주고,
Figure imgf000075_0002
아이소프로필에틸아민 (1.5 mL, 7.99 mmol), T3P (in>Boc-L-cysteine (870 mg, 3.93 mmol) was diluted in toluene (23 mL) and <form- diisopropylethylamine (1.37 mL, 7.86 mmol) was added. The reaction was stirred at 100 °C for 1 hour. After completion of the reaction, the reaction mixture was filtered using celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM:MeOH=l:2) to obtain the target compound C1 (1.39 g, 98%) as a purple solid. Step 2. Preparation of target compound C2 Compound C1 (1.39 g, 4.00 mmol) was added to tetrahydrofuran (24 mL) to dissolve it,
Figure imgf000075_0002
Isopropylethylamine (1.5 mL, 7.99 mmol), T 3 P (in
50% EtOAc, 4.8 mL)를 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종결 후, 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고, 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피50% EtOAc, 4.8 mL) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer is magnesium sulfate After drying, it was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography.
(EtOAc：Hexane=l：2)로 정제하여 흰색 고체의 목적 화합물 C2 (570 mg, 43%)를 수득하였다. 단계 3. 목적 화합물 C3의 제조 화합물 C2 (570 mg, 1.73 mmol)> 다이메틸포름아마이드 (8.6 mL)에 첨가하여 녹여주고, 탄산칼륨 (263 mg, 1.90 mmol), 메틸요오드 (0.12 mL, 1.90 mmol)을 첨가하였다. 반응물은 상온에서 2시간 동안 교반하였다. 반응 종결 후, 물과 염화나트륨 수용액을 이용하여 세척하고, 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하여 노란색 고체의 목적 화합물 C3 (470 mg, 79%)를수득하였다. 단계 4. 목적 화합물 C4의 제조 화합물 C3 (103 mg, 0.30 mmol), Pd(0Ac)2 (13.5 mg, 0.06 mmol), BI NAP (75 mg, 0.12 mmol), 탄산세슘 (293 mg, 0.90 mmol)을 톨루엔 (1.3 mL)에 희석하고, 피롤리딘 (0.04 mL, 0.45 mmol)을 첨가하였다. 반응물은 85°C에서 16시간 동안 교반하였다. 반응 종결 후, 반응 혼합물은 셀라이트를 이용하여 여과를 하였고, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：4)로 정제하여 흰색 고체의 목적 화합물 C4 (116 mg, 98%)를 수득하였다. 단계 5. 목적 화합물 C5의 제조 화합물 C4 (116 mg, 0.31 mmol)를 다이클로로메테인 (2 mL)에 첨가하여 녹여주고, 염산 (4> 1,4 -다이옥세인 용액; 0.77 mL, 3.07 mmol)을 첨가하였다. 반응물은 상온에서 2시간 동안 교반하였다. 반응 종결 후, 반응 혼합물을 감압 농축하여 흰색 고체의 목적 화합물 C5 (51 mg, 47%)를수득하였다. 단계 6. 목적 화합물 C6의 제조 화합물 C5 (51 mg, 0.14 mmol), EDC (35.0 mg, 0.29 mmol), HOAt (39.0 mg, 0.29 mmo 1 ) , 1-벤질 -L¥~l, 2, 4 -트리아졸 -3 -카르복실산 (44 mg, 0.22 mmol)을 다이클로로메테인 (2.9 mL)에 희석하고, 트리에틸아민 (0.06 mL, 0.43 mmol)을 0°C에서 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 탄산수소나트륨 수용액을 넣어 반응을 종결한 후, 물과 염화나트륨 수용액을 이용하여 세척하고 , 다이클로로메테인을 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=5：l)로 실시예 54에 따른 흰색 고체의 목적 화합물 C6 (22 mg, 33%)을수득하였다. 실시예 55 내지 74. 실시예 54의 단계 4의 피롤리딘에 대응하는 화합물로서 하기 표 7의 반응물 1을, 실시예 54의 단계 6의 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산에 대응하는 화합물로서 하기 표 7의 반응물 2를 이용한 것을 제외하고는 , 실시예 54의 화합물 C6을 제조하는 방법과 실질적으로 동일한 방법으로 실시예 55 내지 74에 따른화합물들을 제조하였다. (EtOAc:Hexane=l:2) to obtain the target compound C2 (570 mg, 43%) as a white solid. Step 3. Preparation of target compound C3 Compound C2 (570 mg, 1.73 mmol) > added to dimethylformamide (8.6 mL) to dissolve, potassium carbonate (263 mg, 1.90 mmol), methyl iodine (0.12 mL, 1.90 mmol) ) was added. The reaction was stirred for 2 hours at room temperature. After completion of the reaction, the mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain the target compound C3 (470 mg, 79%) as a yellow solid. Step 4. Preparation of target compound C4 Compound C3 (103 mg, 0.30 mmol), Pd(0Ac) 2 (13.5 mg, 0.06 mmol), BI NAP (75 mg, 0.12 mmol), cesium carbonate (293 mg, 0.90 mmol) was diluted in toluene (1.3 mL) and pyrrolidine (0.04 mL, 0.45 mmol) was added. The reaction was stirred at 85 °C for 16 hours. After completion of the reaction, the reaction mixture was filtered using celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:4) to obtain the target compound C4 (116 mg, 98%) as a white solid. Step 5. Preparation of target compound C5 Compound C4 (116 mg, 0.31 mmol) was added to and dissolved in dichloromethane (2 mL), and hydrochloric acid (4> 1,4-dioxane solution; 0.77 mL, 3.07 mmol) was added. The reaction was stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture is reduced under reduced pressure. Concentration gave the desired compound C5 (51 mg, 47%) as a white solid. Step 6. Preparation of target compound C6 Compound C5 (51 mg, 0.14 mmol), EDC (35.0 mg, 0.29 mmol), HOAt (39.0 mg, 0.29 mmol 1 ) , 1-benzyl-L¥~l, 2, 4 - Triazole-3-carboxylic acid (44 mg, 0.22 mmol) was diluted in dichloromethane (2.9 mL) and triethylamine (0.06 mL, 0.43 mmol) was added at 0 °C. The reaction was stirred at room temperature for 16 hours. After the reaction was terminated by adding an aqueous sodium bicarbonate solution, the mixture was washed with water and an aqueous sodium chloride solution, and the organic layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was subjected to silica gel column chromatography (EtOAc: Hexane = 5: l) to obtain the target compound C6 (22 mg, 33%) as a white solid according to Example 54. Examples 55 to 74. Reactant 1 in Table 7 below was used as a compound corresponding to pyrrolidine in Step 4 of Example 54, and 1-benzyl-1,2,4-triazole in Step 6 of Example 54. Compounds according to Examples 55 to 74 were prepared in substantially the same manner as the method for preparing compound C6 of Example 54, except that reactant 2 of Table 7 was used as a compound corresponding to -3-carboxylic acid. did
[표 7]
Figure imgf000077_0001
[Table 7]
Figure imgf000077_0001
Figure imgf000078_0001
실시 예 54 내지 74에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR 분석 결과는 하기 표 8에 나타낸다.
Figure imgf000078_0001
The structure and compound name of each of the compounds obtained according to Examples 54 to 74, and NMR analysis results are shown in Table 8 below.
[표 8]
Figure imgf000078_0002
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
실시예 75. (R)-l-벤질- N- (8 -아이소뷰틸아미도- 1-메틸- 2 -옥소- 1,2, 3, 4 - 테트라하이드로피리도 [3 ,4- b] [1 ,4]싸이아제핀- 3 -일 )-1오-1,2,4-트리아졸- 3- 카복사마이드의 제조
Figure imgf000083_0001
단계 1. 목적 화합물 DI의 제조 질소 분위기 하에서 화합물 C3 (50 mg, 0.15 mmo 1 ) , Pd2(dba)s (1.3 mg , 0 .002 mmo 1 ) , 잔트포스 (1.7 mg, 0 .003 mmo 1 ) , 탄산세슘 (61.0 mg, 0 . 19 mmo 1 ) , 및 아이소뷰틸아마이드 (14.0 mg, 0.16 mmol )를 1.4 -다이옥세인 (0.73 mL)에 희석시켰다. 반응물은 환류되는 조건하에 16시간 동안 교반하였다. 반응 종료 후 , 반응 혼합물은 셀라이트로 여과를 하였고 , 감압 농축하였다. 반응 농축물은 컬럼 크로마토그래피 (EtOAc：Hexane=l：2)로 정제하여 흰색 고체의 목적 화합물 D1 (38.0 mg, 66%)을 수득하였다. 단계 2. 목적 화합물 D2의 제조 화합물 D1 (38.0 mg, 0.01 mmol )을 다이클로로메테인 (0.48 mL)에 첨가하여 녹인 후 , 트리플루오로아세트산 (0.08 mL , 0.1 mmol )을 상온에서 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 물을 첨가하여 반응을 종결한 후 , 탄산칼륨 수용액으로 염기화를 하였고 , 다이클로로메테인을 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후 , 감압 농축하여 갈색 고체의 목적 화합물 D2 (28.3 mg, 98%)를 수득하였다. 단계 3. 목적 화합물 D3의 제조 화합물 D2 (28.3 mg, 0.10 nmol), EDC (23.5 mg, 0.20 mmol), HOAt (26.0 mg, 0.20 mmol), 및 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 (29.3 mg, 0.15 mmol)을 다이클로로메테인 (1.9 mL)에 희석하고, 트리에틸아민 (0.04 mL, 0.30 mmol)을 0°C에서 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 탄산수소나트륨 수용액을 넣어 반응을 종결한 후, 물과 염화나트륨 수용액을 이용하여 세척하고 , 다이클로로메테인을 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=5：l)로 정제하여 실시예 75에 따른 흰색 고체의 목적 화합물 D3 (16 mg, 35%)을수득하였다. 실시예 76및 77. 실시예 75의 단계 3의 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 대신 하기 표 9의 반응물을 이용한 것을 제외하고는, 실시예 75의 화합물 D3을 제조하는 방법과 실질적으로 동일한 방법으로 실시예 76 및 77에 따른 화합물들을 제조하였다. [Table 8]
Figure imgf000078_0002
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Example 75. (R) -l-Benzyl- N- (8 -isobutylamido- 1-methyl- 2 -oxo- 1,2, 3, 4 - Preparation of tetrahydropyrido [3,4-b] [1,4]thiazepin-3-yl)-1o-1,2,4-triazole-3-carboxamide
Figure imgf000083_0001
Step 1. Preparation of target compound DI Compound C3 (50 mg, 0.15 mmo 1 ), Pd2(dba)s (1.3 mg, 0.002 mmo 1 ), Zantphos (1.7 mg, 0.003 mmo 1 ) under nitrogen atmosphere , cesium carbonate (61.0 mg, 0.19 mmo 1 ), and isobutylamide (14.0 mg, 0.16 mmol ) were diluted in 1.4-dioxane (0.73 mL). The reaction was stirred for 16 hours under reflux conditions. After completion of the reaction, the reaction mixture was filtered through celite and concentrated under reduced pressure. The reaction concentrate was purified by column chromatography (EtOAc:Hexane=l:2) to obtain the target compound D1 (38.0 mg, 66%) as a white solid. Step 2. Preparation of target compound D2 After dissolving compound D1 (38.0 mg, 0.01 mmol) in dichloromethane (0.48 mL), trifluoroacetic acid (0.08 mL, 0.1 mmol) was added at room temperature. The reaction was stirred at room temperature for 16 hours. After the reaction was terminated by adding water, basification was performed with an aqueous solution of potassium carbonate, and the organic layer was extracted using dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain the target compound D2 (28.3 mg, 98%) as a brown solid. Step 3. Preparation of target compound D3 Compound D2 (28.3 mg, 0.10 nmol), EDC (23.5 mg, 0.20 mmol), HOAt (26.0 mg, 0.20 mmol), and 1-benzyl-1woo 1,2,4-tria The sol-3-carboxylic acid (29.3 mg, 0.15 mmol) was diluted in dichloromethane (1.9 mL) and triethylamine (0.04 mL, 0.30 mmol) was added at 0 °C. The reaction was stirred at room temperature for 16 hours. After the reaction was terminated by adding an aqueous sodium bicarbonate solution, the mixture was washed with water and an aqueous sodium chloride solution, and the organic layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc: Hexane = 5: l) to obtain the target compound D3 (16 mg, 35%) as a white solid according to Example 75. Examples 76 and 77. Example 75, except that the reactants in Table 9 below were used instead of the 1-benzyl-lwoo 1,2,4-triazole-3-carboxylic acid in Step 3 of Example 75. Compounds according to Examples 76 and 77 were prepared in substantially the same manner as the method for preparing compound D3.
[표 9]
Figure imgf000084_0001
실시예 78및 79. 실시예 75의 단계 1의 아이소뷰틸아마이드 대신 하기 표 10의 반응물 1을, 실시예 75의 단계 3의 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 대신 하기 표 10의 반응물 2를 이용한 것을 제외하고는, 실시예 75의 화합물 D3을 제조하는 방법과 실질적으로 동일한 방법으로 실시예 78 및 79에 따른 화합물들을 제조하였다. [Table 9]
Figure imgf000084_0001
Examples 78 and 79. The reactants in Table 10 below instead of isobutylamide in step 1 of Example 75. Compound D3 of Example 75, except that 1 was used as reactant 2 in Table 10 instead of 1,2,4-triazole-3-carboxylic acid in Step 3 of Example 75. The compounds according to Examples 78 and 79 were prepared in substantially the same manner as the method for preparing
[표 1이
Figure imgf000085_0001
실시예 75 내지 79에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR분석 결과는 하기 표 11에 나타낸다. [Table 1]
Figure imgf000085_0001
The structure and compound name of each of the compounds obtained according to Examples 75 to 79, and NMR analysis results are shown in Table 11 below.
[표 11]
Figure imgf000085_0002
Figure imgf000086_0001
실시예 80. （R）- 1-벤질- N-（5 -메틸- 6 -옥소- 2-（피롤리딘- 1-일）- 5, 6,7,8- 테트라하이드로피리미도 [4,5- b] [1,4]싸이아제핀- 7 -일）- 1H- 1,2, 4 -트리아졸 -3- 카복사마이드의 제조 [Table 11]
Figure imgf000085_0002
Figure imgf000086_0001
Example 80. (R)-1-benzyl-N-(5-methyl-6-oxo-2-(pyrrolidin-1-yl)-5,6,7,8-tetrahydropyrimido [4, Preparation of 5-b] [1,4]thiazepine-7-yl)-1H-1,2,4-triazole-3-carboxamide
Figure imgf000087_0001
단계 1. 목적 화합물 E1의 제조
Figure imgf000087_0001
Step 1. Preparation of target compound E1
2, 4 -다이클로로- 5 -나이트로피리미딘 (604.0 mg, 3.12 mmol)을 아세토나이트릴에 첨가하여 녹인 후, 탄산칼륨 (474.0 mg, 3.43 mmol)과 N- Boc-After dissolving 2,4-dichloro-5-nitropyrimidine (604.0 mg, 3.12 mmol) in acetonitrile, potassium carbonate (474.0 mg, 3.43 mmol) and N- Boc-
L-시스테인 메틸 에스테르 (733.0 mg, 3.12 mmol)를 첨가하였다. 반응물은 상온에서 3시간 동안 교반하였다. 반응 종료 후, 물과 염화나트륨 수용액을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다 . 유기층은 황산마그네슘으로 건조한 후, 감압 농축하여 노란색 고체의 목적 화합물 E1 (1.22 g, 99%)을 수득하였다. 단계 2. 목적 화합물 E2의 제조 화합물 E1 (1.22 g, 3.12 mmol)을 아세트산 (38.0 mL)에 첨가하여 녹인 후, 철 (1.74 g, 31.2 mmol)을 첨가하였다. 반응물은 60°C에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물을 셀라이트를 이용하여 여과를 하였다. 반응 혼합물은 물로 세척하고, 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하여 노란색 고체의 목적 화합물 E2 (1.25 g, 99%)를 수득하였다. 단계 3. 목적 화합물 E3의 제조 화합물 E2 (1.25 g, 3.12 mmol)를 다이클로로메테인 (31.0 mL)에 첨가하여 녹인 후, AlMes (2.0 M in toluene, 2.8 mL)을 0°C에서 첨가하여 15분 동안 교반하였다. 반응물은 상온에서 1시간 동안 교반한 뒤, 45°C에서 3시간 동안 교반하였다. 염화 암모늄 수용액으로 반응을 종결한 뒤, 염화나트륨 수용액으로 세척하고 , 유기층을 다이클로로메테인을 이용하여 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：2)로 정제하여 흰색 고체의 목적 화합물 E3 (120 mg, 12%)을수득하였다. 단계 4. 목적 화합물 E4의 제조 화합물 E3 (120 mg, 0.36 mmol)을 다이메틸포름아마이드에 첨가하여 녹인 후, 탄산칼륨 (55 mg, 0.40 mmol)과 메틸요오드 (0.03 mL, 0.40 mmol)를 첨가하였다. 반응물은 상온에서 1시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 물과 염화나트륨 수용액으로 세척하고, 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축 하여 흰색 고체의 목적 화합물 E4 (125 g, 98%)를수득하였다. 단계 5. 목적 화합물 E5의 제조 화합물 E4 (72 mg, 0.21 mmo 1 ) , Pd2(dba)s (12.0 mg, 0.013 mmo 1 ) , 엑스포스 (Xphos, 9.0 mg, 0.019 mmol), 및 탄산칼륨 (87.0 mg, 0.63 mmol)을 삼차 뷰틸 알코올 (2.5 mL)에 희석하고, 피롤리딘 (0.02 mL, 0.25 mmol)을 첨가하였다. 반응물은 100°C에서 5분 동안 교반하였다. 반응 종료 후, 반응 혼합물은 셀라이트를 이용하여 여과를 하였고, 감압 농축하였다. 반응 농축물은 실리카켈 컬럼 크로마토그래피 (EtOAc：Hexane=l：2)로 정제하여 노란색 고체의 목적 화합물L-cysteine methyl ester (733.0 mg, 3.12 mmol) was added. The reaction was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was washed with water and an aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain the target compound E1 (1.22 g, 99%) as a yellow solid. Step 2. Preparation of target compound E2 Compound E1 (1.22 g, 3.12 mmol) was dissolved in acetic acid (38.0 mL), and then iron (1.74 g, 31.2 mmol) was added. The reaction was stirred at 60 °C for 16 hours. After completion of the reaction, the reaction mixture was filtered using celite. The reaction mixture was washed with water, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain the target compound E2 (1.25 g, 99%) as a yellow solid. Step 3. Preparation of target compound E3 Compound E2 (1.25 g, 3.12 mmol) was added to and dissolved in dichloromethane (31.0 mL), then AlMes (2.0 M in toluene, 2.8 mL) was added at 0°C and stirred for 15 Stir for a minute. The reaction was stirred at room temperature for 1 hour and then at 45 °C for 3 hours. After the reaction was terminated with aqueous ammonium chloride solution, the mixture was washed with aqueous sodium chloride solution, and the organic layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:2) to obtain the target compound E3 (120 mg, 12%) as a white solid. Step 4. Preparation of target compound E4 After dissolving compound E3 (120 mg, 0.36 mmol) in dimethylformamide, potassium carbonate (55 mg, 0.40 mmol) and methyl iodine (0.03 mL, 0.40 mmol) were added. . The reaction was stirred for 1 hour at room temperature. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted using ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain the target compound E4 (125 g, 98%) as a white solid. Step 5. Preparation of target compound E5 Compound E4 (72 mg, 0.21 mmo 1 ), Pd2(dba)s (12.0 mg, 0.013 mmo 1 ), Xphos (9.0 mg, 0.019 mmol), and potassium carbonate (87.0 mg) , 0.63 mmol) was diluted in tertiary butyl alcohol (2.5 mL) and pyrrolidine (0.02 mL, 0.25 mmol) was added. The reaction was stirred at 100 °C for 5 min. After completion of the reaction, the reaction mixture was filtered using celite and concentrated under reduced pressure. The reaction concentrate is silica gel Purify by column chromatography (EtOAc：Hexane=l：2) to obtain the target compound as a yellow solid
E5 (36 mg, 45%)를수득하였다. 단계 6. 목적 화합물 E6의 제조 화합물 E5 (36.0 mg, 0.01 mmol)를 다이클로로메테인 (0.48 mL)에 첨가하여 녹인 후, 트리플루오로아세트산 (0.15 mL, 0.20 mmol)을 상온에서 첨가하였다. 반응물은 1시간 동안 상온에서 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하여 노란색 고체의 목적 화합물 E6 (26.5 mg, 98%)을 수득하였다. 단계 7. 목적 화합물 E7의 제조 화합물 E6 (26.5 mg, 0.10 mmo 1 ) , EDC (23 mg, 0.20 mmo 1 ) , HOAt (26 mg, 0.20 mmol), 및 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 (23.2 mg, 0.12 mmol)을 다이클로로메테인 (1.9 mL)에 희석하고, 트리에틸아민 (0.04 mL, 0.30 mmol)을 0°C에서 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 탄산수소나트륨 수용액을 넣어 반응을 종결한 후, 물과 염화나트륨 수용액을 이용하여 세척하고 , 다이클로로메테인을 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=5：l)로 정제하여 실시예 80에 따른 갈색 고체의 목적 화합물 E7 (1.3 mg, 3%)을수득하였다. iH NMR (400 MHz, Chloroform—沙) 5 8.01 (s, 1H), 7.67 (s, 1H), 7.41— 7.33 (m, 6H), 5.65 (s, 2H), 4.51 (t, J = 4.6 Hz, IH), 3.83 (dd, J = 4.2, 14.2 Hz, IH), 3.54 (m, J = 5.6, 14.0 Hz, IH), 3.49 (m, 4H), 3.29 (s, 3H), 1.94 (m, 4H) : LRMS (electrospray) m/z (M+H)+465. 실시예 81. (R)-l-벤질- N- (7 -플루오로- 5 -메틸- 4 -옥소- 8-(피롤리딘- 1- 일)- 2, 3, 4, 5 -테트라하이드로벤조 [b] [1,4]싸이아제핀- 3 -일)- 1H- 1,2, 4 -트리아졸 -3- 카복사마이드의 제조
Figure imgf000090_0001
단계 1. 목적 화합물 F1의 제조 E5 (36 mg, 45%) was obtained. Step 6. Preparation of target compound E6 After dissolving compound E5 (36.0 mg, 0.01 mmol) in dichloromethane (0.48 mL), trifluoroacetic acid (0.15 mL, 0.20 mmol) was added at room temperature. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound E6 (26.5 mg, 98%) as a yellow solid. Step 7. Preparation of target compound E7 Compound E6 (26.5 mg, 0.10 mmo 1 ), EDC (23 mg, 0.20 mmo 1 ), HOAt (26 mg, 0.20 mmol), and 1-benzyl- 1,2,4 -Triazole-3-carboxylic acid (23.2 mg, 0.12 mmol) was diluted in dichloromethane (1.9 mL) and triethylamine (0.04 mL, 0.30 mmol) was added at 0°C. The reaction was stirred at room temperature for 16 hours. After the reaction was terminated by adding an aqueous sodium bicarbonate solution, the mixture was washed with water and an aqueous sodium chloride solution, and the organic layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc: Hexane = 5: l) to obtain the target compound E7 (1.3 mg, 3%) as a brown solid according to Example 80. iH NMR (400 MHz, Chloroform—沙) 5 8.01 (s, 1H), 7.67 (s, 1H), 7.41— 7.33 (m, 6H), 5.65 (s, 2H), 4.51 (t, J = 4.6 Hz, IH), 3.83 (dd, J = 4.2, 14.2 Hz, IH), 3.54 (m, J = 5.6, 14.0 Hz, IH), 3.49 (m, 4H), 3.29 (s, 3H), 1.94 (m, 4H) ) : LRMS (electrospray) m/z (M+H) + 465. Example 81. (R)-l-Benzyl-N-(7-fluoro-5-methyl-4-oxo-8-(pyrrolidin-1-yl)-2,3,4,5-tetrahydro Preparation of benzo [b] [1,4]thiazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide
Figure imgf000090_0001
Step 1. Preparation of target compound F1
4 -브로모- 2, 5 -다이플루오로나이트로벤젠 (1.5 g, 6.30 mmol)을 에탄올4-bromo-2,5-difluoronitrobenzene (1.5 g, 6.30 mmol) in ethanol
(13.3 mL) 그리고 물 (12 mL)에 첨가하여 녹인 후, >Boc- L-시스테인 (1.39 g, 6.30 mmol)과 탄산수소나트륨 (1.59 g, 18.91 mmol)을 첨가하였다. 반응물은 환류되는 조건하에서 16시간 동안 교반하였다. 반응 종료 후, 감압 농축하여 물에 희석시키고, IN HC1 수용액을 이용하여 혼합물의 농도를 pH 2〜 3으로 맞춘 후, 다이클로로메테인을 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한후, 감압 농축하여 노란색 고체의 목적 화합물 F1 (2.6 g, 95%)을수득하였다. 단계 2. 목적 화합물 F2의 제조 화합물 F1 (2.6 g, 5.96 mmol)을 메탄올 (251 mL)에 첨가하여 녹인 후, 아연 (4.0 g, 59.6 mmol)과 염화 암모늄 (640 mg, 11.92 mmol)을 첨가하였다. 반응물은 75°C에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 셀라이트를 이용하여 여과를 하였고, 감압농축하여 회색 고체의 목적 화합물 F2 (1.9 g, 79%)를수득하였다. 단계 3. 목적 화합물 F3의 제조 화합물 F2 (1.9 g, 4.39 mmol), EDC (1.3 g, 10.99 mmol), 및 HOAt (1.5 g, 10.99 mmol)를 다이클로로메테인 (88.0 mL)에 희석하고, 트리에틸아민 (2.1 mL, 15.38 mmol)을 0°C에서 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 탄산수소나트륨 수용액으로 반응을 종결한 후, 물과 염화나트륨 수용액을 이용하여 세척하고, 다이클로로메테인을 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：2)로 정제하여 흰색 고체의 목적 화합물 F3 (1.4 g, 83%)를수득하였다. 단계 4. 목적 화합물 F4의 제조 화합물 F3 (1.4 g, 3.65 mmol)을 다이메틸포름아마이드 (21.5 mL)에 첨가하여 녹인 후, 탄산세슘 (1.4 g, 4.38 mmol)과 메틸요오드 (0.27 mL, 4.38 mmol)를 첨가하였다. 반응물은 상온에서 3시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고, 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하여 흰색 고체의 목적 화합물 F4 (758 mg, 51%)를수득하였다. 단계 5. 목적 화합물 F5의 제조 화합물 F4 (300 mg, 0.74 mmol), Pd(0Ac)2 (33 mg, 0.15 mmol), BI NAP (184 mg, 0.30 mmo 1 ) , 및 탄산세슘 (482 mg, 1.48 mmol)을 톨루엔 (3 mL)에 희석하고, 피롤리딘 (0.12 mL, 1.48 mmol)을 첨가하였다. 반응물은 85°C에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 셀라이트를 이용하여 여과를 하였고, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：2)로 정제하여 흰색 고체의 목적 화합물 F5 (175 mg, 60%) 를 수득하였다. 단계 6. 목적 화합물 F6의 제조 화합물 F5 (175 mg, 0.44 mmol)를 다이클로로메테인 (1 mL)에 첨가하여 녹인 후, 염산 (4> 1,4 -다이옥세인 용액; 0.55 mL, 2.21 mmol)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 감압 농축하여 흰색 고체의 목적 화합물 F6 (146 mg, 100%)를수득하였다. 단계 7. 목적 화합물 F7의 제조 화합물 F6 (175 mg, 0.53 mmol), EDC (129 mg, 1.05 mmol), HOAt (144 mg, 1.05 mmol), 및 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 (118 mg, 0.58 mmol)을 다이클로로메테인 (10 mL)에 희석하고, 트리에틸아민 (0.22 mL, 1.58 mmol)을 0°C에서 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 탄산수소나트륨 수용액으로 반응을 종결한 뒤, 물과 염화나트륨 수용액을 이용하여 세척하고 , 다이클로로메테인을 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=5：l)로 정제하여 실시예 81에 따른 흰색 고체의 목적 화합물 F7 (160 mg, 63%)을수득하였다. 실시예 82 내지 107. 실시 예 81의 단계 5의 피롤리딘에 대응하는 화합물로서 표 12의 반응물 1을 , 실시 예 81의 단계 7의 1-벤질- 1우 1 , 2 , 4 -트리아졸 -3 -카르복실산에 대응하는 화합물로서 표 12의 반응물 2를 이용한 것을 제외하고는 실시 예 81의 화합물 F7을 제조하는 방법과 실질적으로 동일한 방법으로 실시 예 82 내지 107에 따른 화합물들을 제조하였다. (13.3 mL) and dissolved in water (12 mL), >Boc-L-cysteine (1.39 g, 6.30 mmol) and sodium bicarbonate (1.59 g, 18.91 mmol) were added. The reaction was stirred for 16 hours under reflux conditions. After completion of the reaction, the mixture was concentrated under reduced pressure, diluted in water, and the concentration of the mixture was adjusted to pH 2-3 using IN HC1 aqueous solution, and the organic layer was extracted using dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain the target compound F1 (2.6 g, 95%) as a yellow solid. Step 2. Preparation of target compound F2 After dissolving compound F1 (2.6 g, 5.96 mmol) in methanol (251 mL), Zinc (4.0 g, 59.6 mmol) and ammonium chloride (640 mg, 11.92 mmol) were added. The reaction was stirred at 75 °C for 16 hours. After completion of the reaction, the reaction mixture was filtered using celite and concentrated under reduced pressure to obtain the target compound F2 (1.9 g, 79%) as a gray solid. Step 3. Preparation of target compound F3 Dilute compound F2 (1.9 g, 4.39 mmol), EDC (1.3 g, 10.99 mmol), and HOAt (1.5 g, 10.99 mmol) in dichloromethane (88.0 mL), Ethylamine (2.1 mL, 15.38 mmol) was added at 0 °C. The reaction was stirred at room temperature for 16 hours. After the reaction was terminated with an aqueous sodium bicarbonate solution, the mixture was washed with water and an aqueous sodium chloride solution, and the organic layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:2) to obtain the target compound F3 (1.4 g, 83%) as a white solid. Step 4. Preparation of target compound F4 After dissolving compound F3 (1.4 g, 3.65 mmol) in dimethylformamide (21.5 mL), cesium carbonate (1.4 g, 4.38 mmol) and methyl iodine (0.27 mL, 4.38 mmol) ) was added. The reaction was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain the target compound F4 (758 mg, 51%) as a white solid. Step 5. Preparation of target compound F5 Compound F4 (300 mg, 0.74 mmol), Pd(0Ac) 2 (33 mg, 0.15 mmol), BI NAP (184 mg, 0.30 mmo 1 ), and cesium carbonate (482 mg, 1.48 mmol) were diluted in toluene (3 mL), and pyrrolidine (0.12 mL, 1.48 mmol) was added. The reaction was stirred at 85 °C for 16 hours. After completion of the reaction, the reaction mixture was filtered using celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:2) to obtain the target compound F5 (175 mg, 60%) as a white solid. Step 6. Preparation of target compound F6 After dissolving compound F5 (175 mg, 0.44 mmol) in dichloromethane (1 mL), hydrochloric acid (4> 1,4-dioxane solution; 0.55 mL, 2.21 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the product was concentrated under reduced pressure to obtain the target compound F6 (146 mg, 100%) as a white solid. Step 7. Preparation of target compound F7 Compound F6 (175 mg, 0.53 mmol), EDC (129 mg, 1.05 mmol), HOAt (144 mg, 1.05 mmol), and 1-benzyl-1woo 1,2,4-tria The sol-3-carboxylic acid (118 mg, 0.58 mmol) was diluted in dichloromethane (10 mL) and triethylamine (0.22 mL, 1.58 mmol) was added at 0 °C. The reaction was stirred at room temperature for 16 hours. After the reaction was terminated with an aqueous sodium bicarbonate solution, the mixture was washed with water and an aqueous sodium chloride solution, and the organic layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc: Hexane = 5: l) to obtain the target compound F7 (160 mg, 63%) as a white solid according to Example 81. Examples 82 to 107. Reagent 1 in Table 12 was used as a compound corresponding to pyrrolidine in Step 5 of Example 81, 1-benzyl-1 in Example 81, Step 7, 1,2,4-Triazole- Compounds according to Examples 82 to 107 were prepared in substantially the same manner as the method for preparing compound F7 of Example 81, except that reactant 2 of Table 12 was used as a compound corresponding to 3-carboxylic acid.
[표 12]
Figure imgf000093_0001
실시예 81 내지 107에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭, 그리고 NMR분석 결과는 하기 표 13에 나타낸다. [Table 12]
Figure imgf000093_0001
The structures and compound names of each of the compounds obtained in Examples 81 to 107, and NMR analysis results are shown in Table 13 below.
[표 13]
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0002
실시예 108. (R)-l-벤질- N- (8 -클로로- 5 -메틸- 4 -옥소- 7-(피롤리딘- 1-일)-[Table 13]
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0002
Example 108. (R) -l-Benzyl- N- (8 -chloro- 5 -methyl- 4 -oxo- 7- (pyrrolidin- 1-yl) -
2,3,4, 5 -테트라하이드로벤조 [b] [ 1 , 4]싸이아제핀- 3 -일 )- 1H- 1 , 2 , 4 -트리아졸- 3 - 카복사마이드의 제조
Figure imgf000100_0001
단계 1. 목적 화합물 G1의 제조 실시 예 81의 단계 1에서 4 -브로모- 2, 5 -다이플루오로나이트로벤젠 대신Preparation of 2,3,4,5-tetrahydrobenzo [b] [1,4]thiazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide
Figure imgf000100_0001
Step 1. Preparation of target compound G1 In step 1 of Example 81, instead of 4-bromo-2,5-difluoronitrobenzene
1-브로모- 2 -클로로- 4 -플루오로- 5 -나이트로벤젠을 출발물질로 한 것을 제외하고는 실시예 81의 단계 1 내지 단계 4에 따른 화합물 F4의 제조과정과 실질적으로 동일한 방법으로 목적 화합물이을 합성하였다. 단계 2. 목적 화합물 G2의 제조 화합물 G1 (630 mg, 1.49 mmol)을 톨루엔 (11 mL)에 첨가하여 녹인 후, Pd(0Ac)2 (34 mg, 0.15 mmol), 잔트포스 (172 mg, 0.30 mmol), 탄산칼륨 (413 mg, 2.99 mmol) 그리고 피롤리딘 (0.18 mL, 2.24 mmol)을 첨가하였다. 혼합물은 80°C에서 16시간 동안 교반하였다. 반응 종료 후, 셀라이트를 이용하여 여과를 하였고, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：hexane=l：3)로 정제하여 흰색 고체의 목적 화합물 G2 (170 mg, 28%)를 수득하였다. 단계 3 및 단계 4. 목적 화합물 G3 및 G4의 제조 화합물 F5 대신 화합물 G2를 이용한 것을 제외하고는 실시예 81의 단계 6에서 화합물 F6을 제조한 것과 실질적으로 동일한 공정으로 목적 화합물 G3을 수득하였다. 이어서, 화합물 F6 대신 화합물 G3을 이용한 것을 제외하고는 실시예 81의 단계 7에서 화합물 F7을 제조한 것과 실질적으로 동일한 공정으로, 실시예 108에 따른 흰색 고체의 목적 화합물 G4를수득하였다. iH NMR (400 MHz, Chloroform-d) 5 8.11 (d, J= 7.6 Hz, 1H), 8.00 (s, 1H), 7.52 (s, IH), 7.40-7.36 (m, 3H), 7.30-7.27 (m, 2H), 6.63 (s, IH), 5.38 (s, 2H), 4.87-4.81 (m, IH), 3.86-3.82 (m, IH), 3.56-3.51 (m, 2H), 3.42-3.41 (m, 2H), 3.39 (s, 3H), 2.84 (t, J = 11.2 Hz, IH), 2.01-1.92 (m, 4H)； LRMS (electrospray) m/z (M+H)+ 497. 실시예 109. (R)- 1-벤질- N- (7 -브로모- 5 ■메틸- 4 -옥소- 8-(피롤리딘- 1-일)-Except starting with 1-bromo- 2 -chloro- 4 -fluoro- 5 -nitrobenzene The target compound was synthesized in substantially the same manner as in the preparation process of compound F4 according to steps 1 to 4 of Example 81. Step 2. Preparation of target compound G2 After adding and dissolving compound G1 (630 mg, 1.49 mmol) in toluene (11 mL), Pd(0Ac) 2 (34 mg, 0.15 mmol), Zantphos (172 mg, 0.30 mmol) ), potassium carbonate (413 mg, 2.99 mmol) and pyrrolidine (0.18 mL, 2.24 mmol) were added. The mixture was stirred at 80 °C for 16 hours. After completion of the reaction, the mixture was filtered using celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:hexane=l:3) to obtain the target compound G2 (170 mg, 28%) as a white solid. Step 3 and Step 4. Preparation of target compounds G3 and G4 Target compound G3 was obtained by substantially the same process as in preparing compound F6 in step 6 of Example 81, except that compound G2 was used instead of compound F5. Then, the target compound G4 as a white solid according to Example 108 was obtained by substantially the same process as in Example 81 for preparing compound F7 in step 7 of Example 81, except that compound G3 was used instead of compound F6. iH NMR (400 MHz, Chloroform-d) 5 8.11 (d, J= 7.6 Hz, 1H), 8.00 (s, 1H), 7.52 (s, IH), 7.40-7.36 (m, 3H), 7.30-7.27 ( m, 2H), 6.63 (s, IH), 5.38 (s, 2H), 4.87-4.81 (m, IH), 3.86-3.82 (m, IH), 3.56-3.51 (m, 2H), 3.42-3.41 ( m, 2H), 3.39 (s, 3H), 2.84 (t, J = 11.2 Hz, IH), 2.01-1.92 (m, 4H); LRMS (electrospray) m/z (M+H) + 497. Example 109. (R)-1-benzyl-N-(7-bromo-5 methyl-4-oxo-8-(pyrrolidin-1-yl)-
2,3,4, 5 -테트라하이드로벤조 [b] [ 1 , 4]싸이아제핀- 3 -일 )- 1H- 1 , 2 , 4 -트리아졸- 3- 카복사마이드의 제조
Figure imgf000102_0001
단계 1. 목적 화합물 Hl의 제조 Preparation of 2,3,4,5-tetrahydrobenzo [b] [1,4]thiazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide
Figure imgf000102_0001
Step 1. Preparation of target compound H1
1-브로모- 2, 4 -다이플루오로- 5 -나이트로벤젠 (3.0 g, 12.61 mmol)을 다이메틸설폭사이드 (12.6 mL)에 첨가하여 녹인 후, 탄산칼륨 (2.6 g, 18.91 mmol)과 피롤리딘 (1.0 mL, 12.61 mmol)을 첨가하였다. 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (Et0Ac：hexane=l：10)로 정제하여 노란색 고체의 목적 화합물 H1 (1.27 g, 35%)을수득하였다. 단계 2내지 단계 7. 목적 화합물 H2내지 H7의 제조 실시예 81의 단계 1에서 4 -브로모- 2, 5 -다이플루오로나이트로벤젠 대신 화합물 H1을 이용한 것을 제외하고는 실시예 81의 단계 1 내지 단계 4에서 설명한 것과 실질적으로 동일한 공정을 통해 각 단계에서 목적 화합물 H2, H3, H4 및 H5를 얻었다. 실시예 81의 단계 6에서 화합물 F5 대신 화합물 H5를 이용하고, 단계 7에서 화합물 F6 대신 화합물 H5를 이용한 것을 제외하고는 실시예 81의 단계 6 및 7에서 화합물 F6 및 화합물 F7의 제조와 실질적으로 동일한 방법으로 목적 화합물 H6 및 실시예 109에 따른 흰색 고체의 목적 화합물 H7을 얻었다. iH NMR (400 MHz, Chloroform-d) 5 8.16 (d, J= 6.8 Hz, 1H), 8.00 (s, 1H), 7.39-7.38 (m, 4H), 7.29 (m, 2H), 7.12 (s, IH), 5.38 (s, 2H), 4.88-4.82 (m, IH), 3.92-3.88 (m, IH), 3.51-3.40 (m, 4H), 3.37 (s, 3H), 3.38 (s, 3H),After dissolving 1-bromo-2,4-difluoro-5-nitrobenzene (3.0 g, 12.61 mmol) in dimethyl sulfoxide (12.6 mL), potassium carbonate (2.6 g, 18.91 mmol) and Pyrrolidine (1.0 mL, 12.61 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (Et0Ac:hexane=l:10) to obtain the target compound H1 (1.27 g, 35%) as a yellow solid. Steps 2 to 7. Preparation of Target Compounds H2 to H7 Step 1 of Example 81, except that Compound H1 was used instead of 4-bromo-2,5-difluoronitrobenzene in Step 1 of Example 81. in step 4 Target compounds H2, H3, H4 and H5 were obtained at each step through substantially the same process as described above. Substantially the same as the preparation of compounds F6 and F7 in steps 6 and 7 of Example 81, except that compound H5 was used instead of compound F5 in step 6 of Example 81, and compound H5 was used instead of compound F6 in step 7. In this way, target compound H6 and target compound H7 as white solids according to Example 109 were obtained. iH NMR (400 MHz, Chloroform-d) 5 8.16 (d, J= 6.8 Hz, 1H), 8.00 (s, 1H), 7.39-7.38 (m, 4H), 7.29 (m, 2H), 7.12 (s, IH), 5.38 (s, 2H), 4.88-4.82 (m, IH), 3.92-3.88 (m, IH), 3.51-3.40 (m, 4H), 3.37 (s, 3H), 3.38 (s, 3H) ,
2.89 (t, J= 11.0 Hz, IH), 1.99 (m, 4H)； LRMS (electrospray) m/z (M+H)+ 541. 실시예 110. (R)-l-벤질- N- (7 -시아노- 5 -메틸- 4 -옥소- 8-(피롤리딘- 1-일)-2.89 (t, J= 11.0 Hz, IH), 1.99 (m, 4H); LRMS (electrospray) m/z (M+H) + 541. Example 110. (R)-l-benzyl-N- (7 -Cyano-5-methyl-4-oxo-8-(pyrrolidin-1-yl)-
2,3,4, 5 -테트라하이드로벤조 [b] [ 1 , 4]싸이아제핀- 3 -일 )- 1H- 1 , 2 , 4 -트리아졸- 3 - 카복사마이드의 제조
Figure imgf000103_0001
단계 1. 목적 화합물 II의 제조 질소분위기 하에서 화합물 H5 (280 mg, 0.61 mmol )를 다이메틸포름아마이드 (1.9 mL)에 첨가하여 녹인 후, 시안화구리 (137 mg, 1.53 mmo 1 ) , L-프롤린 (106 mg, 0.92 mmol)을 첨가하였다. 혼합물은 120°C에서 48시간 동안 교반하였다. 반응 종료 후, 상온으로 온도를 낮추었다. 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：hexane=l：5) 로 정제하여 흰색 고체의 목적 화합물 II (103 mg, 42%)을 수득하였다. 단계 2 및 단계 3. 목적 화합물 12 및 13의 제조 실시예 81의 단계 6에서 화합물 F5 대신 화합물 II을 이용하여 목적 화합물 12를 얻고, 실시예 81의 단계 7에서 화합물 F6 대신 화합물 12를 이용하여 실시예 110에 따른 흰색 고체의 목적 화합물 13을 수득하였다. iH NMR (400 MHz, Chloroform—沙) 5 8.16 (d, J= 7.2 Hz, 1H), 8.01 (s, 1H), 7.39-7.38 (m, 3H), 7.31-7.29 (m, 3H), 6.96 (s, IH), 5.38 (s, 2H), 4.87- 4.81 (m, IH), 3.89-3.84 (m, IH), 3.68-3.64 (m, 4H), 3.36 (s, 3H), 2.90 (t, J = 11.2 Hz, IH), 2.07 (m, 4H)； LRMS (electrospray) m/z (M+H)+ 488. 실시예 111. (R)- 2 -벤질- N- (7 -시아노- 5 -메틸- 4 -옥소- 8-(피롤리딘- 1-일)- 2, 3, 4, 5 -테트라하이드로벤조 [b] [1,4]싸이아제핀- 3 -일)- 2H-테트라졸- 5- 카복사마이드의 제조 실시예 110의 단계 3에서 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 대신 2 -벤질- 2우테트라졸- 5 -카르복실산을 이용한 것을 제외하고는 실시예 110의 단계 3과 실질적으로 동일한 공정을 통해 , 실시예 111에 따른 흰색 고체의 목적 화합물을 수득하였다. iH NMR (400 MHz, Chloroform—沙) 5 8.13 (d, J = 7.6 Hz, 1H), 7.39-Preparation of 2,3,4,5-tetrahydrobenzo [b] [1,4]thiazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide
Figure imgf000103_0001
Step 1. Preparation of target compound II Compound H5 (280 mg, 0.61 mmol) was added and dissolved in dimethylformamide (1.9 mL) under a nitrogen atmosphere, and copper cyanide (137 mg, 1.53 mmo 1 ) and L-proline (106 mg, 0.92 mmol) were added. The mixture was stirred at 120 °C for 48 hours. After completion of the reaction, the temperature was lowered to room temperature. The reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:hexane=l:5) to obtain the target Compound II (103 mg, 42%) as a white solid. Step 2 and Step 3. Preparation of target compounds 12 and 13 Compound II was used instead of compound F5 in step 6 of Example 81 to obtain target compound 12, and compound 12 was used instead of compound F6 in step 7 of Example 81. The desired compound 13 as a white solid according to Example 110 was obtained. iH NMR (400 MHz, Chloroform—沙) 5 8.16 (d, J= 7.2 Hz, 1H), 8.01 (s, 1H), 7.39-7.38 (m, 3H), 7.31-7.29 (m, 3H), 6.96 ( s, IH), 5.38 (s, 2H), 4.87-4.81 (m, IH), 3.89-3.84 (m, IH), 3.68-3.64 (m, 4H), 3.36 (s, 3H), 2.90 (t, J = 11.2 Hz, IH), 2.07 (m, 4H); LRMS (electrospray) m/z (M+H) + 488. Example 111. (R)-2-Benzyl-N-(7-Cyano- 5 -methyl- 4 -oxo- 8- (pyrrolidin- 1-yl)- 2, 3, 4, 5 -tetrahydrobenzo [b] [1,4] thiazepin- 3 -yl)- 2H- Preparation of tetrazole-5-carboxamide In step 3 of Example 110, 2-benzyl-2utetrazole-5-carboxyl-1-benzyl-1woo 1,2,4-triazole-3-carboxylic acid was replaced with The target compound as a white solid according to Example 111 was obtained through substantially the same process as in Step 3 of Example 110, except for using boxylic acid. iH NMR (400 MHz, Chloroform—沙) 5 8.13 (d, J = 7.6 Hz, 1H), 7.39-
7.32 (m, 5H), 7.31 (s, IH), 6.95 (s, IH), 5.80 s, 2H), 4.85-4.80 (m, 1H),7.32 (m, 5H), 7.31 (s, IH), 6.95 (s, IH), 5.80 s, 2H), 4.85-4.80 (m, 1H),
3.87-3.83 (m, IH), 3.68-3.62 (m, 4H), 3.35 (s, 3H), 2.90 (t, 7 = 11.0 Hz,3.87-3.83 (m, IH), 3.68-3.62 (m, 4H), 3.35 (s, 3H), 2.90 (t, 7 = 11.0 Hz,
1H) , 2.07-2.04 (m, 4H) : LRMS (electrospray) m/z (M+H)+ 489. 실시예 112. (R)- 1-벤질- N- (8 -시아노- 5 -메틸- 4 -옥소- 7-(피롤리딘- 1-일)-1H), 2.07-2.04 (m, 4H): LRMS (electrospray) m/z (M+H)+ 489. Example 112. (R)-1-benzyl-N-(8-cyano-5-methyl -4-oxo-7-(pyrrolidin-1-yl)-
2,3,4, 5 ■테트라하이드로벤조 [b] [ 1 , 4]싸이아제핀- 3 -일 )- 1H- 1 , 2 , 4 -트리아졸- 3 - 카복사마이드의 제조
Figure imgf000105_0001
질소분위기 하에서 화합물 G2 (100 mg, 0.248 mmol)를 1,4 -다이옥서]인2,3,4,5 Tetrahydrobenzo [b] [1,4]Thiazepin-3-yl)-1H-1,2,4-Triazole-3-Carboxamide Preparation
Figure imgf000105_0001
Compound G2 (100 mg, 0.248 mmol) under a nitrogen atmosphere was 1,4-dioxer]
(0.25 mL)과 물 (0.25 mL)에 첨가하여 녹인 후, Pd(0Ac)2 (1.8 mg, 0.008 mmol), 잔트포스 (7.6 mg, 0.016 mmol), 탄산칼륨 (17.2 mg, 0.12 mmol), 및 K4[Fe(CN)4]3 수화물 (5.2 mg, 0.12 mmol)를 첨가하였다. 반응물은 120°C에서 16시간 동안 교반하였다. 반응 종료 후, 상온으로 온도를 낮춘 후 다이에틸에테르를 첨가하였다. 유기층을 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：hexane=l：2) 로 정제하여 흰색 고체의 목적 화합물 J1 (46 mg, 46%)를수득하였다. 단계 2 및 단계 3. 목적 화합물 J2 및 J3의 제조 목적 화합물 J2~J3는 F6〜 F7의 제조과정과 동일한 방법으로 합성하였다. 실시예 81의 단계 6에서 화합물 F5 대신 화합물 J1을 이용하고, 단계 7에서 화합물 F6 대신 화합물 J2를 이용한 것을 제외하고는 실시예 81의 단계 6 및 7에서 설명한 것과 실질적으로 동일한 공정을 통해 각 단계에서 목적 화합물 J2 및 실시예 112에 따른 흰색 고체의 목적 화합물 J3을 얻었다. iH NMR (400 MHz, Chloroform-d) 5 8.06 (d, J= 7.6 Hz, 1H), 8.00 (s, 1H), 7.72 (s, IH), 7.37 (s, 3H), 7.26 (s, 2H), 6.46 (s, IH), 5.37 (s, 2H), 4.83 (q, J = 8.9 Hz, IH), 3.64-3.63 (m, 4H), 3.41 (s, 3H), 2.81 (t, J = 11.0 Hz, IH), 2.05-2.04 (m, 4H)； LRMS (electrospray) m/z (M+H)+ 488. 실시예 113. (R)- 1-벤질- N- (5 -메틸- 4 -옥소- 7-(피롤리딘- 1-일)- 2, 3,4,5- 테트라하이드로벤조 [b][ 1,4]싸이아제핀- 3 -일)- 1H- 1,2, 4 -트리아졸 -3- 카복사마이드의 제조
Figure imgf000106_0001
단계 1. 목적 화합물 K1의 제조과정 실시예 81의 단계 4에서 화합물 F3 대신 4 -브로모- 1-플루오로- 2- 나이트로벤젠을 줄발물질로 한 것을 제외하고는 화합물 F4의 제조과정과 실질적으로 동일한 방법으로 목적 화합물 K1을 합성하였다. 단계 2 내지 단계 4. 목적 화합물 K2, K3 및 K4의 제조과정 화합물 F4 대신 화합물 K1를 이용하여 실시 예 81의 단계 5 , 6 및 7 각각에서 화합물 F5, F6 및 F7을 제조한 것과 실질적으로 동일한 방법으로 목적 화합물 K2 , K3 및 실시 예 113에 따른 목적 화합물 K4를 얻었다. 실시 예 114 내지 162. 실시 예 113의 단계 1에서 피롤리딘에 대응하는 화합물로서 하기 표 14의 반응물 1을 , 단계 3에서 1-벤질 - L¥~l , 2 , 4 -트리아졸 - 3 -카르복실산에 대응하는 화합물로 하기 표 14의 반응물 2를 이용한 것을 제외하고는 실시 예 113의 화합물 K4를 제조한 것과 실질적으로 동일한 방법으로 실시 예 114 내지 162에 따른 화합물들을 제조하였다. (0.25 mL) and water (0.25 mL) were added to dissolve, Pd(0Ac) 2 (1.8 mg, 0.008 mmol), Xantphos (7.6 mg, 0.016 mmol), potassium carbonate (17.2 mg, 0.12 mmol), and K 4 [Fe(CN) 4 ] 3 hydrate (5.2 mg, 0.12 mmol) was added. The reaction was stirred at 120 °C for 16 hours. After completion of the reaction, the temperature was lowered to room temperature, and then diethyl ether was added. After drying the organic layer with magnesium sulfate, it was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:hexane=l:2) to obtain the target compound J1 (46 mg, 46%) as a white solid. Step 2 and Step 3. Preparation of target compounds J2 and J3 Target compounds J2 to J3 were synthesized in the same manner as in the preparation process of F6 to F7. In each step through substantially the same process as described in Steps 6 and 7 of Example 81, except that Compound J1 was used instead of Compound F5 in Step 6 of Example 81, and Compound J2 was used instead of Compound F6 in Step 7. Target compound J2 and target compound J3 as white solids according to Example 112 were obtained. iH NMR (400 MHz, Chloroform-d) 5 8.06 (d, J= 7.6 Hz, 1H), 8.00 (s, 1H), 7.72 (s, IH), 7.37 (s, 3H), 7.26 (s, 2H) , 6.46 (s, IH), 5.37 (s, 2H), 4.83 (q, J = 8.9 Hz, IH), 3.64–3.63 (m, 4H), 3.41 (s, 3H), 2.81 (t, J = 11.0 Hz, IH), 2.05-2.04 (m, 4H); LRMS (electrospray) m/z (M+H) + 488. Example 113. (R)-1-Benzyl-N-(5-methyl-4- Oxo- 7- (pyrrolidin- 1-yl) - 2, 3,4,5- tetrahydrobenzo [b] [ 1,4] thiazepin- 3 -yl) - 1H- 1,2, 4 - Preparation of triazole-3-carboxamide
Figure imgf000106_0001
Step 1. Process for preparing target compound K1 Except for using 4-bromo-1-fluoro-2-nitrobenzene as a starting material instead of compound F3 in step 4 of Example 81, the process for preparing compound F4 and The target compound K1 was synthesized in substantially the same manner. Steps 2 to 4. Process for preparing target compounds K2, K3, and K4 Using compound K1 instead of compound F4, substantially the same method as preparing compounds F5, F6, and F7 in steps 5, 6, and 7 of Example 81, respectively. As a result, target compounds K2, K3 and target compound K4 according to Example 113 were obtained. Examples 114 to 162. In Example 113, reactant 1 in Table 14 was used as a compound corresponding to pyrrolidine in step 1, and in step 3, 1-benzyl-L¥~l, 2,4-triazole-3- Compounds according to Examples 114 to 162 were prepared in substantially the same manner as the compound K4 of Example 113, except that reactant 2 of Table 14 was used as a compound corresponding to carboxylic acid.
[표 14]
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0002
제조예 : 실시예 125의 제조를위한반응물 2(화합물 P3)의 제조
Figure imgf000109_0001
단계 1. 목적 화합물 P1의 제조 메틸 4 -나이트로 -1오피라졸- 3 -카복시레이트 (2 g, 11.69 mmol)를 메탄올 (32 mL)에 첨가하여 녹인 후, Pd/C (208 mg, 0.002 mmol)를 첨가하였다. 수소 분위기 하에 반응물은 상온에서 20시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 셀라이트를 이용하여 여과를 하였고, 감압 농축하여 보라색 고체의 목적 화합물 P1 (1.6 g, 98%)을수득하였다. 단계 2. 목적 화합물 P2의 제조 팔콘 튜브에 화합물 P1 (100 g, 0.71 mmol)과 HF (피리딘 용액; 1.3 mL)을 첨가한 후, 아질산나트륨 (73.3 mg, 1.06 mmol)을 0°C에서 첨가하였다. 반응물은 0°C에서 1시간 동안 교반하고, 상온으로 온도를 올려주었다. 그리고, 반응물은 70°C에서 1시간 동안 교반하였다. 반응 혼합물은 얼음물을 이용하여 반응을 종결한 후, 탄산수소나트륨 수용액을 이용하여 세척하였고, 다이클로로메테인을 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후 , 감압 농축하여 갈색 고체의 목적 화합물 P2 (56 g, 55%)를 수득하였다. 단계 3. 목적 화합물 P3의 제조 질소 분위기 하에 화합물 P2 (150 mg, 1.04 mmol )> 다이메틸포름아마이드 (4.3 mL)에 첨가하고 녹인 후 , 탄산세슘 (678 mg, 2.08 mmol )과 벤질 브로마이드 (0.14 mL , 1.14 mmol )를 첨가하였다. 반응물은 상온에서 24시간 동안 교반하였다. 반응 혼합물은 물을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후 , 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：5)로 정제하여 노란색 고체의 목적 화합물 P3 (77 mg, 30%)을 수득하였다. 단계 4. 목적 화합물 P4의 제조 화합물 P3 (77 mg, 0.32 mmol )을 테트라하이드로퓨란 (3.6 mL)과 메탄올 (1.8 mL)에 첨가하여 녹인 후 , 수산화 리튬 (134 mg, 3.2 mmol )을 첨가하였다. 반응물은 상온에서 2시간 동안 교반하였다. 반응 종료 후 , 반응 혼합물은 감압 농축하였다. 반응 농축물은 물로 희석하고 , 1川 HC1 수용액을 이용하여 혼합물의 농도를 pH 2- 3으로 맞춰 고체 생성물을 침전시켰다. 침전된 고체 생성물은 여과하여 노란색 고체의 목적 화합물 P4 (67 mg, 93%)를 수득하였다. 제조예 2： 실시예 126의 제조를 위한 반응물 2(화합물 P8)의 제조
Figure imgf000111_0001
단계 1. 목적 화합물 P5의 제조 화합물 P2 대신 메틸 4 -나이트로 -1H-피라졸- 3 -카복실레이트를 이용한 것을 제외하고는 제조예 1의 단계 3에서 화합물 P3을 제조하는 것과 실질적으로 동일한 공정을 통해 목적 화합물 P5를수득하였다. 단계 2. 목적 화합물 P6의 제조 화합물 P5 (700 mg, 2.67 mmol)를 메탄올 (16 mL)과 물 (5 mL)에 첨가하여 녹인 후, 철 (447.4 mg, 8.01 mmol)과 염화 암모늄 (143 mL, 2.67 mmol)를 첨가하였다. 반응물은 80°C에서 5시간 동안 교반하였다. 반응 종료 후, 셀라이트를 이용하여 여과를 하였고, 감압농축하여 갈색 고체의 목적 화합물 P6 (600 mg, 97%)을수득하였다. 단계 3. 목적 화합물 P7의 제조 질소 분위기 하에 P6 (600 mg, 2.59 mmol)를 테트라하이드로퓨란 (9.0 mL)에 첨가하여 녹인 후, 트리에틸아민 (0.72 mL, 5.18 mmol)과 다이-*北-뷰틸 다이카보네이트 (565 mg, 2.59 mmol)를 0°C에서 첨가하였다. 반응물은 상온에서 24시간 동안 교반하였다. 반응 종료후, 반응혼합물은 물을 이용하여 세척하고, 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：3)로 정제하여 흰색 고체의 목적 화합물 P7 (419 mg, 49%)을 수득하였다. 단계 4. 목적 화합물 P8의 제조 화합물 P3 대신에 화합물 P7을 이용한 것을 제외하고는 제조예 1의 단계 4에서 화합물 P4를 제조하는 것과실질적으로 동일한공정으로 목적 화합물 P8을 합성하였다. iH NMR (400 MHz, DMSO-d) 5 7.77-7.72 (m, 4H), 7.62-7.58 (m, 2H), 7.54-7.53 (m, 4H), 4.51 (d, J = 8.8 Hz, 2H), 1.48 (s, 9H). 실시예 113 내지 162에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭, 그리고 NMR분석 결과는 하기 표 15에 나타낸다. [Table 14]
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0002
Preparation Example: Preparation of Reactant 2 (Compound P3) for the preparation of Example 125
Figure imgf000109_0001
Step 1. Preparation of target compound P1 After dissolving methyl 4-nitro-1opyrazole-3-carboxylate (2 g, 11.69 mmol) in methanol (32 mL), Pd/C (208 mg, 0.002 mmol) ) was added. The reactants were stirred at room temperature for 20 hours under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered using celite and concentrated under reduced pressure to obtain the target compound P1 (1.6 g, 98%) as a purple solid. Step 2. Preparation of target compound P2 After adding compound P1 (100 g, 0.71 mmol) and HF (pyridine solution; 1.3 mL) to a falcon tube, sodium nitrite (73.3 mg, 1.06 mmol) was added at 0°C. . The reaction was stirred at 0 °C for 1 hour, and the temperature was raised to room temperature. Then, the reaction was stirred at 70 °C for 1 hour. The reaction mixture was washed with an aqueous sodium bicarbonate solution after terminating the reaction with ice water, The organic layer was extracted using dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain the target compound P2 (56 g, 55%) as a brown solid. Step 3. Preparation of target compound P3 Under a nitrogen atmosphere, compound P2 (150 mg, 1.04 mmol) > dimethylformamide (4.3 mL) was added and dissolved, and cesium carbonate (678 mg, 2.08 mmol) and benzyl bromide (0.14 mL) were added. , 1.14 mmol) was added. The reaction was stirred at room temperature for 24 hours. The reaction mixture was washed with water, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:5) to obtain the target compound P3 (77 mg, 30%) as a yellow solid. Step 4. Preparation of target compound P4 After dissolving compound P3 (77 mg, 0.32 mmol) in tetrahydrofuran (3.6 mL) and methanol (1.8 mL), lithium hydroxide (134 mg, 3.2 mmol) was added. The reaction was stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was diluted with water, and the concentration of the mixture was adjusted to pH 2-3 using 1 River HCl aqueous solution to precipitate a solid product. The precipitated solid product was filtered to obtain the target compound P4 (67 mg, 93%) as a yellow solid. Preparation Example 2: Preparation of reactant 2 (compound P8) for the preparation of Example 126
Figure imgf000111_0001
Step 1. Preparation of target compound P5 Substantially the same process as for preparing compound P3 in step 3 of Preparation Example 1, except that methyl 4-nitro-1H-pyrazole-3-carboxylate was used instead of compound P2. Through this, the target compound P5 was obtained. Step 2. Preparation of target compound P6 After dissolving compound P5 (700 mg, 2.67 mmol) in methanol (16 mL) and water (5 mL), iron (447.4 mg, 8.01 mmol) and ammonium chloride (143 mL, 2.67 mmol) was added. The reaction was stirred at 80 °C for 5 hours. After completion of the reaction, the mixture was filtered using celite and concentrated under reduced pressure to obtain the target compound P6 (600 mg, 97%) as a brown solid. Step 3. Preparation of target compound P7 After dissolving P6 (600 mg, 2.59 mmol) in tetrahydrofuran (9.0 mL) under a nitrogen atmosphere, triethylamine (0.72 mL, 5.18 mmol) and di-*buk-butyl Dicarbonate (565 mg, 2.59 mmol) was added at 0 °C. The reaction was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was washed with water, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography. (EtOAc:Hexane=l:3) to obtain the target compound P7 (419 mg, 49%) as a white solid. Step 4. Preparation of target compound P8 Target compound P8 was synthesized by substantially the same process as in preparing compound P4 in step 4 of Preparation Example 1, except that compound P7 was used instead of compound P3. iH NMR (400 MHz, DMSO-d) 5 7.77-7.72 (m, 4H), 7.62-7.58 (m, 2H), 7.54-7.53 (m, 4H), 4.51 (d, J = 8.8 Hz, 2H), 1.48 (s, 9H). The structure and compound name of each of the compounds obtained according to Examples 113 to 162, and NMR analysis results are shown in Table 15 below.
[표 15]
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
실시예 163. (R)-l-벤질- N- (8- ((3 -클로로프로필)아미노) -7 -플루오로- 5- 메틸- 4 -옥소- 2, 3, 4, 5 -테트라하이드로벤조 [b] [1,4]싸이아제핀- 3 -일)- 1H- 1,2,4- 트리아졸 -3 -카복사마이드의 제조
Figure imgf000125_0001
단계 1. 목적 화합물 LI의 제조 피롤리딘 대신 아제티딘을 이용한 것을 제외하고는 실시예 81의 단계 5에서 화합물 F5를 제조하는 것과 실질적으로 동일한 공정을 통해 목적 화합물 L1을 합성하였다. 단계 2. 목적 화합물 L2의 제조 화합물 L1 (135 mg, 0.35 mmol)을 다이클로로메테인 (2.4 mL)에 첨가하여 녹인 후, 염산 (4> 1,4 -다이옥세인 용액; 0.89 mL, 3.50 mmol)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종결 후, 반응 혼합물을 감압 농축하여 흰색 고체의 목적 화합물 L2 (148 mg, 98%)를 수득하였다. 수득한 화합물 L2는추가 정제과정 없이 다음 반응을 진행하였다. 단계 3. 목적 화합물 L3의 제조과정 화합물 F6 대신 화합물 L2를 이용한 것을 제외하고는 실시예 81의 단계 7에서 화합물 F7을 제조하는 것과 실질적으로 동일한 공정으로 실시예 163에 따른 목적 화합물 L3를 합성하였다. iH NMR (400 MHz, Chloroform-d) 5 8.17 (d, J= 6.8 Hz, 1H), 8.02 (s, 1H), 7.39 (m, 3H), 7.28 (m, 2H), 6.97-6.92 (m, 2H), 5.39 (s, 2H), 4.91-4.85 (m, 1H), 4.12 (m, 1H), 3.75-3.70 (m, 1H), 3.73 (t, J = 6.2 Hz, 2H), 3.48-[Table 15]
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Example 163. (R)-l-Benzyl-N-(8-((3-chloropropyl)amino)-7-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydro Preparation of benzo [b] [1,4] thiazepin- 3 -yl) - 1H- 1,2,4- triazole -3 -carboxamide
Figure imgf000125_0001
Step 1. Preparation of target compound LI Target compound L1 was synthesized through substantially the same process as in preparing compound F5 in step 5 of Example 81, except that azetidine was used instead of pyrrolidine. Step 2. Preparation of target compound L2 After dissolving compound L1 (135 mg, 0.35 mmol) in dichloromethane (2.4 mL), hydrochloric acid (4> 1,4-dioxane solution; 0.89 mL, 3.50 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound L2 (148 mg, 98%) as a white solid. The obtained compound L2 was subjected to the next reaction without additional purification. Step 3. Preparation of target compound L3 Target compound L3 according to Example 163 was synthesized by substantially the same process as in preparing compound F7 in step 7 of Example 81, except that compound L2 was used instead of compound F6. iH NMR (400 MHz, Chloroform-d) 5 8.17 (d, J= 6.8 Hz, 1H), 8.02 (s, 1H), 7.39 (m, 3H), 7.28 (m, 2H), 6.97-6.92 (m, 2H), 5.39 (s, 2H), 4.91-4.85 (m, 1H), 4.12 (m, 1H), 3.75–3.70 (m, 1H), 3.73 (t, J = 6.2 Hz, 2H), 3.48–
3.43 (m, 2H), 3.36 (s, 3H), 2.90 (t, J= 11.0 Hz, 1H), 2.20-2.15 (m, 2H), ； LRMS (electrospray) m/z (M+H)+ 503. 실시예 164. (R)- 1-(2- (1-메틸- 1H-피라졸- 4 -일 )벤질 )- N- (5 -메틸- 4 -옥소- 7-(피롤리딘- 1-일)- 2, 3, 4, 5 -테트라하이드로벤조 [b][ 1,4]싸이아제핀- 3 -일)- 1H-3.43 (m, 2H), 3.36 (s, 3H), 2.90 (t, J= 11.0 Hz, 1H), 2.20-2.15 (m, 2H), ; LRMS (electrospray) m/z (M+H) + 503 Example 164. (R)-1-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)-N-(5-methyl-4-oxo-7-(pyrrolidin-1 -yl)- 2, 3, 4, 5 -tetrahydrobenzo[b][1,4]thiazepin- 3 -yl)- 1H-
1,2, 4 -트리아졸 -3 -카복사마이드의 제조
Figure imgf000126_0001
단계 1. 목적 화합물 Ml의 제조 실시예 113의 단계 4에서 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 대신 1-(2 -브로모벤질)- 1우 1,2, 4 -트리아졸 -3 -카르복실산을 이용한 것을 제외하고는 화합물 K4를 제조한 과정과 실질적으로 동일한 방법으로 목적 화합물 Ml을 합성하였다. 단계 2. 목적 화합물 M2의 제조 화합물 Ml (23 mg, 0.04 mmol)을 에탄올 (0.09 mL)과 톨루엔 (0.09 mL)에 첨가하여 녹인 후, Pd(PPh3)4 (2.5 mg, 0.002 mmol), 탄산칼륨 (7.7 mg, 0.056 mmol)과 1-메틸- 1月“피라졸- 4 -보론산 (6.5 mg, 0.06 mmol)을 첨가하였다. 혼합물은 80°C에서 16시간 동안 교반하였다. 반응 종료 후 감압 농축하였다. 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고, 에틸아세테이트로 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 실시예 164에 따른 흰색 고체의 목적 화합물 M2 (3 mg, 13%)를수득하였다. iH NMR (400 MHz, Chloroform-d) 5 8.11 (d, J= 7.6 Hz, 1H), 7.77 (s, 1H), 7.49 (s, IH), 7.43-7.25 (m, 6H), 6.42 (d, J = 8.0 Hz, IH), 6.37 (s, IH), 5.42 (s, 2H), 4.86-4.80 (m, IH), 3.95 (s, 3H), 3.84 (dd, J = 7.0, 11.0 Hz, IH), 3.42 (s, 3H), 3.30 (m, 4H) , 2.80 (t, J= 11.2 Hz, IH), 2.05 (m, 4H)；Preparation of 1,2,4-triazole-3-carboxamide
Figure imgf000126_0001
Step 1. Preparation of target compound Ml In step 4 of Example 113, 1-benzyl-1,2,4-triazole-3-carboxylic acid was replaced with 1-(2-bromobenzyl)-1, The target compound Ml was synthesized in substantially the same manner as in the preparation of compound K4, except that 2,4-triazole-3-carboxylic acid was used. Step 2. Preparation of target compound M2 After dissolving compound Ml (23 mg, 0.04 mmol) in ethanol (0.09 mL) and toluene (0.09 mL), Pd(PPh 3 ) 4 (2.5 mg, 0.002 mmol), carbonic acid Potassium (7.7 mg, 0.056 mmol) and 1-methyl-Jan “pyrazole-4-boronic acid (6.5 mg, 0.06 mmol) were added. The mixture was stirred at 80 °C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM:Me0H=20:1) to obtain the target compound M2 (3 mg, 13%) as a white solid according to Example 164. iH NMR (400 MHz, Chloroform-d) 5 8.11 (d, J= 7.6 Hz, 1H), 7.77 (s, 1H), 7.49 (s, IH), 7.43-7.25 (m, 6H), 6.42 (d, J = 8.0 Hz, IH), 6.37 (s, IH), 5.42 (s, 2H), 4.86–4.80 (m, IH), 3.95 (s, 3H), 3.84 (dd, J = 7.0, 11.0 Hz, IH) ), 3.42 (s, 3H), 3.30 (m, 4H), 2.80 (t, J = 11.2 Hz, IH), 2.05 (m, 4H);
LRMS (electrospray) m/z (M+H)+ 543. 실시예 165. (R)- 4 -아미노- 1-벤질- N- (5 -메틸- 4 -옥소- 7-(피롤리딘- 1-일)-LRMS (electrospray) m/z (M+H) + 543. Example 165. (R)-4-Amino-1-benzyl-N-(5-methyl-4-oxo-7-(pyrrolidine-1 -Day)-
2,3,4, 5 ■테트라하이드로벤조 [b] [ 1 , 4]싸이아제핀- 3 -일 )- 1H-피라졸- 3- 카복사마이드의 제조
Figure imgf000127_0001
단계 1. 목적 화합물 N1의 제조 실시예 113의 단계 4에서 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 대신 1-벤질- 4- (tert-뷰톡시카르복실아미노)- 1오피라졸- 3 -카르복실산을 이용한 것을 제외하고는 화합물 K4의 제조와 실질적으로 동일한 방법으로 목적 화합물 N1을 합성하였다. 단계 2. 목적 화합물 N2의 제조 화합물 N1 (32.0 mg, 0.06 mmol)을 다이클로로메테인 (0.29 mL)에 첨가하여 녹인 후, 트리플루오로아세트산 (0.29 mL)를 상온에서 첨가하였다 혼합물은 상온에서 1시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 탄산수소나트륨 수용액과 염화나트륨 수용액을 이용하여 세적하고 , 다이클로로메테인으로 유기층을 추출한 후 , 황산마그네슘으로 건조하고 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 실시예 165에 따른 흰색 고체의 목적 화합물 N2 (7.7 mg, 29%)을 수득하였다. iH NMR (400 MHz, Chloroform—沙) 5 7.73(d, J= 7.6 Hz, 1H), 7.44(d, J = 8.0 Hz, IH), 7.37-7.35(m, 3H), 7.24- 7.22(m, 2H), 8.87(s, IH), 6.44- 6.41(m, 2H), 5.19(s, 2H), 4.86(q, J = 8.5 Hz, IH), 4.09(br, 1.5H), 3.78(q, J = 8.8 Hz, IH), 3.47(s, 3H), 3.32(s, 4H), 2.88(t, J = 11.2 Hz, IH), 2.06(s, 4H)；2,3,4,5 Tetrahydrobenzo [b] [1,4]thiazepin-3-yl)-1H-pyrazole-3-carboxamide preparation
Figure imgf000127_0001
Step 1. Preparation of target compound N1 In step 4 of Example 113, 1-benzyl- 1woo 1,2,4-triazole-3-carboxylic acid was replaced with 1-benzyl-4- (tert-butoxycarboxylamino) Target compound N1 was synthesized in substantially the same manner as in the preparation of compound K4, except that )-1opyrazole-3-carboxylic acid was used. Step 2. Preparation of target compound N2 After dissolving compound N1 (32.0 mg, 0.06 mmol) in dichloromethane (0.29 mL), trifluoroacetic acid (0.29 mL) was added at room temperature. Stir for an hour. After completion of the reaction, the reaction mixture is After washing with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, the organic layer was extracted with dichloromethane, dried over magnesium sulfate, and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM:Me0H=20:1) to obtain the target compound N2 (7.7 mg, 29%) according to Example 165 as a white solid. iH NMR (400 MHz, Chloroform—沙) 5 7.73 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.0 Hz, IH), 7.37-7.35 (m, 3H), 7.24- 7.22 (m, 2H), 8.87(s, IH), 6.44- 6.41(m, 2H), 5.19(s, 2H), 4.86(q, J = 8.5 Hz, IH), 4.09(br, 1.5H), 3.78(q, J = 8.8 Hz, IH), 3.47 (s, 3H), 3.32 (s, 4H), 2.88 (t, J = 11.2 Hz, IH), 2.06 (s, 4H);
LRMS (electrospray) m/z (M+H)+ 477.
Figure imgf000128_0001
단계 1. 목적 화합물 01의 제조 실시예 81의 단계 5에서 피롤리딘 대신 몰포린을 이용하고, 단계 7에서LRMS (electrospray) m/z (M+H) + 477.
Figure imgf000128_0001
Step 1. Preparation of target compound 01 In step 5 of Example 81, morpholine was used instead of pyrrolidine, and in step 7
1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 대신 2 -플루오로- 5 -페녹시벤조산을 이용한 것을 제외하고는 실시예 81의 화합물 F7의 제조과정과 동일한 방법으로 목적 화합물 01을 합성하였다. 단계 2. 목적 화합물 02 및 03의 제조 화합물 01 (75 mg, 0.14 mmol)을 다이클로로메테인 (1 mL)에 첨가하여 녹인 후, /sCPBA (87 mg, 0.50 mmol)를 0°C에서 첨가하였다. 혼합물은 상온에서 16시간 동안 교반하였다. 반응 완료 후, 반응 혼합물을 티오황산나트륨 수용액을 이용하여 반응 종결한 뒤, 탄산수소나트륨 수용액을 이용하여 세척하고 다이클로로메테인으로 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피In the same manner as in the preparation of compound F7 of Example 81, except that 2-fluoro-5-phenoxybenzoic acid was used instead of 1-benzyl-1,2,4-triazole-3-carboxylic acid. The target compound 01 was synthesized. Step 2. Preparation of target compounds 02 and 03 Compound 01 (75 mg, 0.14 mmol) was dissolved in dichloromethane (1 mL), and then /sCPBA (87 mg, 0.50 mmol) was added at 0°C. . The mixture was incubated for 16 hours at room temperature. while stirring. After completion of the reaction, the reaction mixture was terminated with an aqueous solution of sodium thiosulfate, washed with an aqueous solution of sodium bicarbonate, and the organic layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography.
(DCM：Me0H=20：l) 로 정제하여 실시예 166에 따른 흰색 고체의 목적 화합물 02(DCM: Me0H = 20: l) to obtain the target compound 02 as a white solid according to Example 166
(45.4 mg, 58%)와 실시예 167에 따른 흰색 고체의 목적 화합물 03 (14.8 mg,(45.4 mg, 58%) and the desired compound 03 as a white solid according to Example 167 (14.8 mg,
19%)을 수득하였다. 실시예 166 및 167에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR분석 결과는 하기 표 16에 나타낸다. 19%) was obtained. The structure and compound name of each of the compounds obtained according to Examples 166 and 167, and the results of NMR analysis are shown in Table 16 below.
[표 16]
Figure imgf000129_0001
Figure imgf000130_0002
[Table 16]
Figure imgf000129_0001
Figure imgf000130_0002
1,2, 4 -트리아졸 -3 —카복사마이드의 제조 실시예 166 및 167을 제조하는 단계 2에서 화합물 01 대신 실시예 83의 (R)- 1-벤질- N- (7 -플루오로- 5 -메틸- 8 -모폴리노- 4 -옥소- 2 ,3, 4, 5 -
Figure imgf000130_0001
아졸- 3- 카복사마이드를 이용한 것을 제외하고는 화합물 02를 제조한 것과 실질적으로 동일한 제조 방법으로실시예 168에 따른흰색 고체의 화합물을수득하였다. iH NMR (400 MHz, Chloroform—沙) 5 9.61 (d, J= 8.8 Hz, 1H), 8.16 (d, J = 7.2 Hz, IH), 8.02 (s, IH) , 7.38-7.37 (m, 3H), 7.29-7.25 (m, 3H), 5.37 (s, 2H), 5.03-4.96 (m, IH), 4.71-4.73 (m, 2H), 4.35-4.20 (m, 3H), 3.95 (t, J= 12.4 Hz, 2H), 3.59 (t, J= 12.2 Hz, 2H), 3.47 (s, 3H), 3.26 (d, J= 11.2 Hz, IH), 3.15 (d, J = 10.4 Hz, IH)； LRMS (electrospray) m/z (M+H)+ 529. 실시예 169및 170. 실시예 166 및 167을 제조하는 단계 2에서 화합물 01 대신 실시예 84의 (R)- 2 -플루오로- N- (7 -플루오로- 5 -메틸- 4 -옥소- 8-(피롤리딘- 1-일 )-2, 3, 4, 5 - 테트라하이드로벤조 [b] [ 1 , 4]싸이아제핀- 3 -일 )-5 -페녹시벤즈아마이드를 이용한 것을 제외하고는 실시예 166 및 167의 화합물 01 및 02를 제조하는 것과 실질적으로 동일한 방법으로실시예 169 및 170의 화합물들을수득하였다. 실시 예 169 및 170에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR 분석 결과는 하기 표 17에 나타낸다. 1,2,4-Triazole-3—Preparation of carboxamide In step 2 of preparing Examples 166 and 167, (R)-1-benzyl-N-(7-fluoro- of Example 83 instead of Compound 01 5 -methyl- 8 -morpholino- 4 -oxo- 2,3, 4, 5 -
Figure imgf000130_0001
A white solid compound according to Example 168 was obtained in substantially the same manner as in Compound 02, except that azole-3-carboxamide was used. iH NMR (400 MHz, Chloroform—沙) 5 9.61 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 7.2 Hz, IH), 8.02 (s, IH) , 7.38-7.37 (m, 3H) , 7.29-7.25 (m, 3H), 5.37 (s, 2H), 5.03-4.96 (m, IH), 4.71-4.73 (m, 2H), 4.35-4.20 (m, 3H), 3.95 (t, J= 12.4 Hz, 2H), 3.59 (t, J= 12.2 Hz, 2H), 3.47 (s, 3H), 3.26 (d, J= 11.2 Hz, IH), 3.15 (d, J = 10.4 Hz, IH)； LRMS (electrospray) m/z (M+H) + 529. Examples 169 and 170. In step 2 of preparing Examples 166 and 167, (R)-2-fluoro-N- of Example 84 instead of Compound 01 7 -Fluoro- 5 -methyl- 4 -oxo- 8-(pyrrolidin- 1-yl)-2, 3, 4, 5 - tetrahydrobenzo [b] [ 1 , 4] thiazepine- 3 - The compounds of Examples 169 and 170 were obtained in substantially the same manner as the preparation of Compounds 01 and 02 of Examples 166 and 167, except that 1)-5-phenoxybenzamide was used. The structure and compound name of each of the compounds obtained according to Examples 169 and 170, and NMR analysis results are shown in Table 17 below.
[표 17]
Figure imgf000131_0001
실시예 171. (R)- 1-벤질- N- (5 -메틸- 7- (4 -메틸피페라진 -1-일 )- 1, 1- 다이옥시도- 4 -옥소- 2, 3, 4, 5 -테트라하이드로벤조 [b] [1,4]싸이아제핀- 3 -일)- 1H-[Table 17]
Figure imgf000131_0001
Example 171. (R)-1-Benzyl-N-(5-methyl-7-(4-methylpiperazin-1-yl)-1,1-dioxido-4-oxo-2,3,4, 5-tetrahydrobenzo [b] [1,4]thiazepin- 3 -yl)- 1H-
1,2, 4 -트리아졸 -3 -카복사마이드의 제조 실시 예 166 및 167을 제조하는 단계 2에서 화합물 01 대신 실시 예 124의Preparation of 1,2,4-triazole-3-carboxamide Examples 166 and 167 were prepared in step 2 of Example 124 instead of Compound 01.
(R)- 1-벤질- N- (5 -메틸- 7- (4 -메틸피페라진- 1-일 )-4 -옥소- 2 ,3 , 4, 5 - 테트라하이드로벤조 [b] [ 1 , 4]싸이아제핀- 3 -일 , 2 , 4 -트리아졸- 3 -카복사마이드 를 이용한 것을 제외하고는 화합물 02를 제조한 것과 실질적으로 동일한 제조 방법으로 실시예 1기에 따른 아이보리색 고체의 화합물을수득하였다. iH NMR (400 MHz, Chloroform—沙) 5 8.33 (d, J= 6.8 Hz, 1H), 8.04 (s, 1H), 7.48 (d, J = 7.2 Hz, IH), 7.40 (m, 3H), 7.28 (m, 2H), 6.86, d, J = 9.2 Hz, IH), 6.82 (s, IH), 5.40 (s, 2H), 5.04-5.01 (m, IH), 4.14-4.09 (m, 3H), 3.89-3.81 (m, IH), 3.69-3.66 (m, 2H), 3.47 (s, 3H), 3.24 (dd, J= 14.4, 10.8 Hz, IH), 2.77-2.75 (m, 2H), 2.28-2.27 (m, 2H)； LRMS (electrospray) m/z (M+H)+ 524. 실시예 173. (R)- 1-벤질- N- (7 -플루오로- 5 -메틸- 1,1 ■다이옥시도- 4 -옥소- 8-(피롤리딘- 1-일)- 2, 3, 4, 5 -테트라하이드로벤조 [b] [1,4]싸이아제핀- 3 -일)- 1H- 1,2, 4 -트리아졸 -3 -카복사마이드의 제조 실시예 166 및 167를 제조하는 단계 2에서 화합물 01 대신 실시예 81의 화합물 F7을 이용한 것을 제외하고는 실시예 166 및 167의 화합물 02 및 03를 제조하는 것과 실질적으로 동일한 방법으로 실시예 173에 따른 베이지색 고체의 화합물을 수득하였다. 피 NMR (400 MHz, Chloroform-沙) 5 9.47 (d, J = 8.4 Hz, IH), 8.17 (d, J = 6.8 Hz, IH), 8.03 (s, IH) , 7.39-7.37 (m, 3H), 7.29-7.23 (m, 3H), 5.38 (s, 2H), 5.04-4.97 (m, IH), 4.23 (dd, J = 13.2, 7.2 Hz, IH), 4.13-4.05 (m, 2H), 3.84-3.79 (m, 2H), 3.59 (t, J = 12.0 Hz, IH), 3.47 (s, 3H), 2.80-2.78(R)- 1-benzyl- N- (5 -methyl- 7- (4 -methylpiperazin- 1-yl)-4 -oxo- 2,3, 4, 5 - Carried out by substantially the same method as for preparing Compound 02, except that tetrahydrobenzo[b][1,4]thiazepin-3-yl,2,4-triazole-3-carboxamide was used. An ivory-colored solid compound according to Example 1 was obtained. iH NMR (400 MHz, Chloroform—沙) 5 8.33 (d, J= 6.8 Hz, 1H), 8.04 (s, 1H), 7.48 (d, J = 7.2 Hz, IH), 7.40 (m, 3H), 7.28 (m, 2H), 6.86, d, J = 9.2 Hz, IH), 6.82 (s, IH), 5.40 (s, 2H), 5.04–5.01 (m, IH), 4.14–4.09 (m, 3H), 3.89-3.81 (m, IH), 3.69-3.66 (m, 2H), 3.47 (s, 3H), 3.24 (dd, J= 14.4, 10.8 Hz, IH), 2.77-2.75 (m, 2H), 2.28- 2.27 (m, 2H)； LRMS (electrospray) m/z (M+H) + 524. Example 173. (R)-1-benzyl-N-(7-fluoro-5-methyl-1,1 ■ Dioxido- 4 -oxo- 8- (pyrrolidin- 1-yl) - 2, 3, 4, 5 -tetrahydrobenzo [b] [1,4] thiazepin- 3 -yl) - 1H- 1 ,2,4-triazole-3-carboxamide Preparation of Examples 166 and 167 In step 2 of preparing Compound 01, Compound F7 of Example 81 was used, except for using Compound 02 of Examples 166 and 167 and A beige solid compound according to Example 173 was obtained in substantially the same manner as for preparing 03. Blood NMR (400 MHz, Chloroform-沙) 5 9.47 (d, J = 8.4 Hz, IH), 8.17 (d, J = 6.8 Hz, IH), 8.03 (s, IH) , 7.39-7.37 (m, 3H) , 7.29–7.23 (m, 3H), 5.38 (s, 2H), 5.04–4.97 (m, IH), 4.23 (dd, J = 13.2, 7.2 Hz, IH), 4.13–4.05 (m, 2H), 3.84 -3.79 (m, 2H), 3.59 (t, J = 12.0 Hz, IH), 3.47 (s, 3H), 2.80-2.78
(m, 2H), 2.90-2.80 (m, 2H)； LRMS (electrospray) m/z (M+H)+ 513. 실시예 172 및 174. 실시 예 166 및 167를 제조하는 단계 2에서 화합물 01 대신 실시 예 122의 (R)- 1-벤질- N- (5 -메틸- 4 -옥소- 7-(피페리딘- 1-일 )-2 , 3 , 4 , 5 -
Figure imgf000133_0001
아졸- 3- 카복사마이드를 이용한 것을 제외하고는 실시 예 166 및 167의 화합물 02 및 03를 제조하는 것과 실질적으로 동일한 방법으로 실시 예 172에 따른 베이지색 고체의 화합물과 , 실시 예 174에 따른 흰색 고체의 화합물을 각각 수득하였다. 실시 예 172 및 174에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR 분석 결과는 하기 표 18에 나타낸다. (m, 2H), 2.90-2.80 (m, 2H); LRMS (electrospray) m/z (M+H) + 513. Examples 172 and 174. In step 2 of preparing Examples 166 and 167, (R)-1-benzyl-N-(5-methyl-4-oxo-7-(piperidine- 1-day)-2, 3, 4, 5 -
Figure imgf000133_0001
The beige solid compound according to Example 172 and the white solid compound according to Example 174 were prepared in substantially the same manner as in preparing Compounds 02 and 03 of Examples 166 and 167, except that azole-3-carboxamide was used. Solid compounds were obtained respectively. The structure and compound name of each of the compounds obtained according to Examples 172 and 174, and NMR analysis results are shown in Table 18 below.
[표 18]
Figure imgf000133_0002
실시예 175. (R)- 1-벤질- N- (8- ((2 -하이드록시에틸)아미노) -5 -메틸- 4- 옥소- 2, 3, 4, 5 ■테트라하이드로피리도 [4,3- b] [1,4]싸이아제핀- 3 -일)- 1H- 1,2, 4 - 트리아졸- 3 -카복사마이드의 제조
Figure imgf000134_0001
단계 1. 목적 화합물 Q1의 제조 화합물 A4 (200 mg, 0.58 mmol)를 다이클로로메테인 (5 mL)에 첨가하여 녹인 후, 염산 (4川 1,4 -다이옥세인 용액; 0.73 mL)을 첨가하였다. 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종결 후, 반응 혼합물을 감압 농축하여 흰색 고체의 목적 화합물 목적 화합물 Q1 (163 mg, 100%)를 수득하였다. 수득한 화합물 Q1은추가 정제과정 없이 다음 반응을 진행하였다. 단계 2. 목적 화합물 Q2의 제조 화합물 Q1 (163 mg, 0.58 mmol), 트리틸클로라이드 (195 mg, 0.70 mmol)를 다이클로로메테인 (5 mL)에 첨가하여 녹인 후, 트리에틸아민 (0.41 mL, 2.91 mmol)을 첨가하였다. 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 흰색 고체의 목적 화합물 Q2 (160 mg, 58%)를 수득하였다. 단계 3. 목적 화합물 Q3의 제조 화합물 Q2 (100 mg, 0.21 mmol)를 에탄올아민 (5 mL)에 첨가하여 녹인 후, 100°C에서 24시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고 , 에틸아세테이트로 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l) 로 정제하여 흰색 거품 형태의 목적 화합물 Q3 (105 mg, 100%)를수득하였다. 단계 4. 목적 화합물 Q4의 제조과정 화합물 Q3 (152 mg, 0.30 mmol)를 다이클로로메테인 (5 mL)에 첨가하여 녹인 후, 염산 (4川 1,4 -다이옥세인 용액; 0.38 mL)을 첨가하였다. 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종결 후, 반응 혼합물을 감압 농축하여 흰색 고체의 목적 화합물 목적 화합물 Q4 (102 mg, 100%)를 수득하였다. 수득한 화합물 Q4는추가 정제과정 없이 다음 반응을 진행하였다. 단계 5. 목적 화합물 Q5의 제조 화합물 Q4 (102 mg, 0.30 mmol)와 EDC (74 mg, 0.60 mmo 1 ) , HOAt (82 mg, 0.60 mmol), 및 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 (73 mg, 0.36 mmol)을 다이클로로메테인 (5mL)에 희석하고, 트리에틸아민 (0.17 mL, 1.20 mmol)을 첨가하였다. 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종결 후, 반응 혼합물을 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l) 로 정제하여 실시예 175에 따른 흰색 고체의 목적 화합물 Q5 (57 mg, 42%)를 수득하였다. 실시예 176 내지 190. 실시 예 175의 단계 3에서 에탄올아민에 대응하는 화합물로서 하기 표 19의 반응물 1을 , 단계 5의 1-벤질- 1우 1 , 2 , 4 -트리아졸 -3 -카르복실산에 대응하는 화합물로서 하기 표 19의 반응물 2를 이용한 것을 제외하고는 실시 예 175의 화합물 Q5를 제조한 것과 실질적으로 동일한 방법으로 실시 예 176 내지 190에 따른 화합물들을 제조하였다. [Table 18]
Figure imgf000133_0002
Example 175. (R)-1-Benzyl-N-(8-((2-hydroxyethyl)amino)-5-methyl-4-oxo-2, 3, 4, 5 Tetrahydropyrido [4 Preparation of ,3-b] [1,4]thiazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide
Figure imgf000134_0001
Step 1. Preparation of target compound Q1 After dissolving compound A4 (200 mg, 0.58 mmol) in dichloromethane (5 mL), hydrochloric acid (4 River 1,4-dioxane solution; 0.73 mL) was added. . The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Q1 (163 mg, 100%) as a white solid. The obtained compound Q1 was subjected to the next reaction without further purification. Step 2. Preparation of target compound Q2 After dissolving compound Q1 (163 mg, 0.58 mmol) and tritylchloride (195 mg, 0.70 mmol) in dichloromethane (5 mL), triethylamine (0.41 mL, 2.91 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography. Purification by (DCM:Me0H=20:1) gave the desired compound Q2 (160 mg, 58%) as a white solid. Step 3. Preparation of target compound Q3 After dissolving compound Q2 (100 mg, 0.21 mmol) in ethanolamine (5 mL), the mixture was stirred at 100°C for 24 hours. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM:Me0H=20:1) to obtain the target compound Q3 (105 mg, 100%) in the form of a white foam. Step 4. Preparation of target compound Q4 After dissolving compound Q3 (152 mg, 0.30 mmol) in dichloromethane (5 mL), hydrochloric acid (4 River 1,4-dioxane solution; 0.38 mL) was added. did The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound Q4 (102 mg, 100%) as a white solid. The obtained compound Q4 was subjected to the next reaction without further purification. Step 5. Preparation of target compound Q5 Compound Q4 (102 mg, 0.30 mmol) and EDC (74 mg, 0.60 mmo 1 ), HOAt (82 mg, 0.60 mmol), and 1-benzyl-1woo 1,2,4- Triazole-3-carboxylic acid (73 mg, 0.36 mmol) was diluted in dichloromethane (5 mL) and triethylamine (0.17 mL, 1.20 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM: Me0H = 20: l) to obtain the target compound Q5 as a white solid according to Example 175. (57 mg, 42%). Examples 176 to 190. Reactant 1 in Table 19 below was used as a compound corresponding to ethanolamine in step 3 of Example 175, and 1-benzyl-1-1,2,4-triazole-3-carboxyl in step 5 Compounds according to Examples 176 to 190 were prepared in substantially the same manner as the compound Q5 of Example 175, except that reactant 2 in Table 19 was used as a compound corresponding to the acid.
［표 19］
Figure imgf000136_0001
실시 예 175 내지 190에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR 분석 결과는 하기 표 20에 나타낸다. [Table 19]
Figure imgf000136_0001
The structure and compound name of each of the compounds obtained according to Examples 175 to 190, and NMR analysis results are shown in Table 20 below.
［표 2이
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
실시예 191. （R）- 1-벤질- N-（5 -메틸- 8-（메틸（테트라하이드로 -2H-파이란-[Table 2 is
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Example 191. (R)-1-benzyl-N-(5-methyl-8-(methyl(tetrahydro-2H-pyran-
4 -일）아미노）- 4 -옥소- 2 ,3 ,4,5 -테트라하이드로피리도［4,3- b］［1 ,4］싸이아제핀- 3- 일）- 1H- 1 , 2 , 4 -트리아졸- 3 -카복사마이드의 제조
Figure imgf000141_0001
4 -yl）amino）- 4 -oxo- 2 ,3 ,4,5 -tetrahydropyrido[4,3- b][1 ,4]thiazepin- 3-yl)- 1H- 1 , 2 , Preparation of 4-triazole-3-carboxamide
Figure imgf000141_0001
R4 단계 1. 목적 화합물 R1의 제조 실시 예 1의 단계 5에서 피롤리딘 대신 테트라하이드로 -2오피란- 4 -아민을 이용한 것을 제외하고는 화합물 A5를 제조하는 것과 실질적으로 동일한 방법으로 목적 화합물 R1을 합성하였다. 단계 2. 목적 화합물 R2의 제조 화합물 R1 (100 mg, 0.25 mmol )을 다이메틸포름아마이드 (5 mL)에 첨가하여 녹인 후 , 탄산세슘 (160 mg, 0.49 mmol )와 메틸요오드 (0.24 mL , 0.37 mmol )> 첨가한 후 , 상온에서 16시간 동안 교반하였다. 반응 종결 후 , 물과 염화암모늄 수용액을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후 , 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 목적 화합물 목적 화합물 R2 (64 mg, 62%)를 수득하였다. 단계 3. 목적 화합물 R3의 제조 화합물 R2 (64 mg, 0.15 mmol )를 다이클로로메테인 (5 mL)에 희석하고 염산 (4> 1 , 4 -다이옥세인 용액 ; 0.19 mL)을 첨가한다. 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종결 후 , 반응 혼합물을 감압 농축하여 노란색 고체의 목적 화합물 R3 (54 mg, 100%)을 수득하였다. 수득된 화합물 R3는 추가 정제과정 없이 다음 반응을 진행하였다. 단계 4. 목적 화합물 R4의 제조 화합물 R3 (54 mg, 0.15 mmo 1 ) , EDC (37 mg, 0.30 mmo 1 ) , HOAT (41 mg, 0.30 mmol), 및 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 (37 mg, 0.18 mmol)를 다이클로로메테인 (5 mL)에 희석한후, 트리에틸아민 (0.08 mL, 0.60 mmol)을 첨가하였다. 반응 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l) 로 정제하여 실시예 191에 따른 흰색 고체의 목적 화합물 R4 (32 mg, 42%)를 수득하였다. iH NMR (400 MHz, DMSO— d6) 5 8.83 (s, 1H), 8.41 (d, J= 8.0 Hz, 1H), 8.26 (s, IH), 7.40-7.28 (m, 5H), 6.89 (s, IH), 5.48 (s, 2H), 4.75-4.60 (m, 2H), 3.94-3.91 (m, 2H), 3.50-3.41 (m, 4H), 3.29-3.25 (m, 7H), 2.96 (s, 3H)； LRMS (electrospray) m/z (M+H)+ 508. 실시예 194. (S)- 2 -벤질- N- (7 -플루오로- 1-메틸- 2 -옥소- 8-(피롤리딘- 1- 일)- 2 , 3 , 4 , 5 -테트라하이드로- 1H-벤조 [b ]아제핀- 3 -일 )- 2H-테트라졸- 5- 카복사마이드의 제조 R4 Step 1. Preparation of target compound R1 Object compound R1 in substantially the same manner as in preparing compound A5, except that tetrahydro-2opyran-4-amine was used instead of pyrrolidine in step 5 of Example 1. was synthesized. Step 2. Preparation of target compound R2 After dissolving compound R1 (100 mg, 0.25 mmol) in dimethylformamide (5 mL), cesium carbonate (160 mg, 0.49 mmol) and methyl iodine (0.24 mL, 0.37 mmol) )> After addition, the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was washed with water and aqueous ammonium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM:Me0H=20:1) to obtain the target compound R2 (64 mg, 62%). Step 3. Preparation of target compound R3 Dilute compound R2 (64 mg, 0.15 mmol) in dichloromethane (5 mL) and add hydrochloric acid (4> 1,4-dioxane solution; 0.19 mL). The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound R3 (54 mg, 100%) as a yellow solid. The obtained compound R3 is further purified The following reaction proceeded without Step 4. Preparation of target compound R4 Compound R3 (54 mg, 0.15 mmo 1 ), EDC (37 mg, 0.30 mmo 1 ), HOAT (41 mg, 0.30 mmol), and 1-benzyl- 1,2,4 After diluting -triazole-3-carboxylic acid (37 mg, 0.18 mmol) in dichloromethane (5 mL), triethylamine (0.08 mL, 0.60 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM:Me0H=20:1) to obtain the desired compound R4 (32 mg, 42%) as a white solid according to Example 191. iH NMR (400 MHz, DMSO—d6) 5 8.83 (s, 1H), 8.41 (d, J= 8.0 Hz, 1H), 8.26 (s, IH), 7.40-7.28 (m, 5H), 6.89 (s, IH), 5.48 (s, 2H), 4.75-4.60 (m, 2H), 3.94-3.91 (m, 2H), 3.50-3.41 (m, 4H), 3.29-3.25 (m, 7H), 2.96 (s, 3H)； LRMS (electrospray) m/z (M+H) + 508. Example 194. (S)-2-Benzyl-N-(7-fluoro-1-methyl-2-oxo-8-(p Preparation of Rolidin-1-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-2H-tetrazole-5-carboxamide
Figure imgf000143_0001
Figure imgf000143_0001
T8 T9 단계 1. 목적 화합물 T1의 제조 T8 T9 Step 1. Preparation of target compound T1
7 -브로모- 6 -플루오로- 3, 4 -다이하이드로나프탈렌- 1(2아)-온 (3 g, 12.3 mmol), 및 아자이드화나트륨 (3.21 g, 49.4 mmol)을 톨루엔 (20 mL)에 0°C에서 희석한 후, 황산 (3.3 mL)을 적가하였다. 반응물은 0°C에서 30분 동안교반한후, 상온에서 6시간 동안 교반하였다. 반응 종결 후, 탄산수소나트륨 수용액을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다 . 유기층은 황산마그네슘으로 건조한 후, 감압 농축하여 노란색 고체의 목적 화합물 T1 (3.19 g, 100%)을 수득하였다. 수득한 화합물 T1은 추가 정제과정 없이 다음 반응을 진행하였다. 단계 2. 목적 화합물 T2의 제조 화합물 T1 (3.19 g, 12.3 mmol), 및 테트라메틸에틸렌다이아민 (8.35 mL, 55.6 mmoL)을 다이클로로메테인 (50 mL)에 첨가하여 녹인 후, 0°C에서 TMSI (7.92 mL)를 20분동안 적가한다. 혼합물을 0°C에서 1시간 동안 교반한 후, 아이오딘 (7.22 g, 28.4 mmol )을 0°C에서 첨가하여 1시간 동안 교반하였다. 5% 티오황산나트륨 수용액을 넣어 반응 종결 후 , 15분 동안 교반하였다. 반응물은 물과 염화암모늄 수용액을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후 , 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 목적 화합물 T2 (2.6 g, 55%)를 수득하였다. 단계 3. 목적 화합물 T3의 제조 화합물 T2 (2.6 g, 6.77 mmol )를 다이메틸포름아마이드 (25 mL)에 첨가하여 녹인 후 , 아자이드화나트륨 (530 mg, 8.13 mmol )을 첨가하여 상온에서 1시간 동안 교반하였다. 반응 종결 후 , 물과 염화암모늄 수용액을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다 . 유기층은 황산마그네슘으로 건조한 후 , 감압 농축하였다. 여기에 테트라하이드로퓨란 (25 mL)을 첨가하여 농축된 반응물을 녹인 후 , 물 (1 mL)과 트리페닐포스핀 수지 (2.5 g, 7.45 mmol , 3 mmo 1 / g loading)를 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응물을 여과하여 수지를 없앤 후 , 테트라하이드로퓨란을 이용하여 씻어내고 필터된 화합물을 감압 농축하였다. 고체 화합물을 다이클로로메테인/다이에틸에테르 (1/10)에 녹인 후 , 여과하고 건조하여 흰색 고체의 목적 화합물 T3 (841 mg, 45.4%)을 수득하였다. 단계 4. 목적 화합물 T4의 제조 화합물 T3 (841 mg, 3.08 mmol )을 아이소프로판올 (10 mL)에 첨가하여 녹인 후 , L-피로글루탐산 (402 mg, 3.11 mmol )을 첨가하였다. 반응물은 70°C에서 30분 동안 교반한 후 , 아이소프로판올 (14 mL)와 2 -하이드록시- 5 - 나이트로벤잘데하이드 (16 mg, 0.092 mmol)를 순서대로 첨가하여 70°C에서 3일 동안 교반하였다. 반응물을 상온으로 식혀준 후, 고체를 여과하고 헥세인과 아이소프로판올로 씻어주었다. 고체를 건조하여 피로글루타메이트 염으로 수득 하였다 . 고체는 암모니아수를 이용하여 염기화하여 다이클로로메테인을 이용하여 추출하였다. 유기층을 감압 농축하여 다이에틸에테르로 씻어 준 후, 건조하여 목적 화합물 T4 (306 mg, 36%)를 수득하였다. 단계 5. 목적 화합물 T5의 제조 화합물 T4 (306 mg, 1.12 mmol)와 (Boc)20 ( 293 mg, 1.34 mmol)를 다이클로로메테인 (10 mL)에 첨가하여 녹여준 후, 트리에틸아민 (0.24 mL, 1.68 mmol)을 첨가한다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종결 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l) 로 정제하여 목적 화합물 T5 (361 mg, 96%)를 수득하였다. 단계 6. 목적 화합물 T6의 제조 화합물 T5 (391 mg, 1.08 mmol)를 다이메틸포름아마이드 (5 mL)에 첨가하여 녹여준 후, 탄산칼륨 (180 mg, 1.29 mmol)과 메틸요오드 (0.067 mL, 1.08 mmol)을 넣어준 후, 상온에서 16시간 동안 교반하였다. 반응 종결 후, 물과 염화나트륨 수용액을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 목적 화합물 T6 (402 mg, 97%)을 수득하였다. 단계 7. 목적 화합물 T7의 제조 화합물 T6 (201 mg, 0.52 mmol), Pd(0Ac)2 (12.0 mg, 0.052 mmol), BI NAP (65 mg, 0.11 mmol), 및 탄산세슘 (677 mg, 2.08 mmol)을 톨루엔 (5 mL)에 희석시킨 후, 피롤리딘 (0.047 mL, 0.57 mmol)을 첨가하였다. 반응물은 90°C에서 16시간 동안 교반하였다. 반응 종결 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：MeOH =20：1)로 정제하여 노란색 고체의 목적 화합물 T7 (196 mg, 100%)을수득하였다. 단계 8. 목적 화합물 T8의 제조 화합물 T7 (196 mg, 0.52 mmol)을 다이클로로메테인 (5 mL)에 첨가하여 녹여준 후, 염산 (4> 1,4 -다이옥세인 용액; 0.65 mL)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종결 후, 감압 농축하여 흰색 고체의 목적 화합물 T8 (163 mg, 100%)을 수득하였다. 수득한 화합물 T8은 추가 정제과정 없이 다음 반응을 진행하였다. 단계 9. 목적 화합물 T9의 제조 화합물 T8 (163 mg, 0.52 mmol), EDC (127 mg, 1.04 mmol), HOAt (142 mg, 1.04 mmol), 및 2 -벤질- 2우 1,2, 3, 4 -테트라졸- 5 -카르복실산 (117 mg, 0.57 mmol)을 다이클로로메테인 (5 mL)에 희석한 후, 트리에틸아민 (0.29 mL, 2.08 mmol)을 첨가하였다. 반응물은 상온에서 16시간동안 교반하였다. 반응 종결 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l) 로 정제하여 실시예 194에 따른 흰색 고체의 목적 화합물 T9 (21 mg, 8.7%)를 수득하였다. 실시예 192, 193, 195 및 196 실시예 194의 단계 7에서 피롤리딘에 대응하는 화합물로서 하기 표 21의 반응물 1을 이용한 것을 제외하고는 , 실시 예 194의 화합물 T9를 제조하는 것과 실질적으로 동일한 방법으로 실시예 192 , 195 및 196에 따른 화합물을 제조하였다. 실시 예 194의 단계 4에서 L-피로글루탐산 대신 D-피로글루탐산을 이용하고 단계 7에서 피롤리딘 대신 하기 표 21의 반응물 1을 이용한 것을 제외하고는 실시예 194의 화합물 T9를 제조하는 것과 실질적으로 동일한 방법으로 실시 예 193에 따른 화합물을 제조하였다. 7-Bromo-6-fluoro-3,4-dihydronaphthalen-1(2a)-one (3 g, 12.3 mmol), and sodium azide (3.21 g, 49.4 mmol) were added to toluene (20 mL). ) at 0 °C, sulfuric acid (3.3 mL) was added dropwise. The reaction was stirred at 0 °C for 30 minutes and then stirred at room temperature for 6 hours. After completion of the reaction, it was washed with an aqueous solution of sodium bicarbonate, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain the target compound T1 (3.19 g, 100%) as a yellow solid. The obtained compound T1 was subjected to the next reaction without additional purification. Step 2. Preparation of target compound T2 After dissolving compound T1 (3.19 g, 12.3 mmol) and tetramethylethylenediamine (8.35 mL, 55.6 mmoL) in dichloromethane (50 mL), at 0°C TMSI (7.92 mL) is added dropwise over 20 minutes. After the mixture was stirred at 0 °C for 1 h, iodine (7.22 g, 28.4 mmol) was added at 0 °C and stirred for 1 hour. After completion of the reaction by adding a 5% aqueous solution of sodium thiosulfate, the mixture was stirred for 15 minutes. The reactant was washed with water and aqueous ammonium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM:Me0H=20:1) to obtain the target compound T2 (2.6 g, 55%). Step 3. Preparation of target compound T3 After dissolving compound T2 (2.6 g, 6.77 mmol) in dimethylformamide (25 mL), sodium azide (530 mg, 8.13 mmol) was added and stirred at room temperature for 1 hour. while stirring. After completion of the reaction, the mixture was washed with water and aqueous ammonium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. After dissolving the concentrated reactant by adding tetrahydrofuran (25 mL) thereto, water (1 mL) and triphenylphosphine resin (2.5 g, 7.45 mmol , 3 mmo 1 / g loading) were added. The reaction was stirred at room temperature for 16 hours. After filtering the reaction product to remove the resin, it was washed with tetrahydrofuran and the filtered compound was concentrated under reduced pressure. The solid compound was dissolved in dichloromethane/diethylether (1/10), filtered and dried to obtain the target compound T3 (841 mg, 45.4%) as a white solid. Step 4. Preparation of target compound T4 After dissolving compound T3 (841 mg, 3.08 mmol) in isopropanol (10 mL), L-pyroglutamic acid (402 mg, 3.11 mmol) was added. The reaction was stirred at 70 °C for 30 min, then dissolved in isopropanol (14 mL) and 2-hydroxy-5- Nitrobenzaldehyde (16 mg, 0.092 mmol) was added sequentially and stirred at 70 °C for 3 days. After cooling the reactant to room temperature, the solid was filtered and washed with hexane and isopropanol. The solid was dried to obtain the pyroglutamate salt. The solid was basified using aqueous ammonia and extracted using dichloromethane. The organic layer was concentrated under reduced pressure, washed with diethyl ether, and dried to obtain the target compound T4 (306 mg, 36%). Step 5. Preparation of target compound T5 After dissolving compound T4 (306 mg, 1.12 mmol) and (Boc)20 (293 mg, 1.34 mmol) in dichloromethane (10 mL), triethylamine (0.24 mL, 1.68 mmol) is added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM:Me0H=20:1) to give the target compound T5 (361 mg, 96%). Step 6. Preparation of target compound T6 After dissolving compound T5 (391 mg, 1.08 mmol) in dimethylformamide (5 mL), potassium carbonate (180 mg, 1.29 mmol) and methyl iodine (0.067 mL, 1.08 mL) mmol) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM:Me0H=20:1) to obtain the target compound T6 (402 mg, 97%). Step 7. Preparation of target compound T7 Compound T6 (201 mg, 0.52 mmol), Pd(0Ac) 2 (12.0 mg, 0.052 mmol), BI NAP (65 mg, 0.11 mmol), and cesium carbonate (677 mg, 2.08 mmol) were diluted in toluene (5 mL), then pyrrolidine (0.047 mL, 0.57 mmol) was added. The reaction was stirred at 90 °C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM:MeOH =20:1) to obtain the target compound T7 (196 mg, 100%) as a yellow solid. Step 8. Preparation of target compound T8 After dissolving compound T7 (196 mg, 0.52 mmol) in dichloromethane (5 mL), hydrochloric acid (4> 1,4-dioxane solution; 0.65 mL) was added. did The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the product was concentrated under reduced pressure to obtain the target compound T8 (163 mg, 100%) as a white solid. The obtained compound T8 was subjected to the next reaction without additional purification. Step 9. Preparation of target compound T9 Compound T8 (163 mg, 0.52 mmol), EDC (127 mg, 1.04 mmol), HOAt (142 mg, 1.04 mmol), and 2-benzyl-2woo 1,2, 3, 4 -Tetrazole- 5-carboxylic acid (117 mg, 0.57 mmol) was diluted in dichloromethane (5 mL), then triethylamine (0.29 mL, 2.08 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM:Me0H=20:1) to obtain the target compound T9 (21 mg, 8.7%) as a white solid according to Example 194. Examples 192, 193, 195 and 196 As the compound corresponding to pyrrolidine in step 7 of Example 194, Table 21 Compounds according to Examples 192, 195 and 196 were prepared in substantially the same manner as in Example 194 to prepare compound T9, except that reactant 1 was used. It is substantially the same as preparing compound T9 of Example 194, except that D-pyroglutamic acid was used instead of L-pyroglutamic acid in step 4 of Example 194 and reactant 1 of Table 21 was used instead of pyrrolidine in step 7. A compound according to Example 193 was prepared in the same manner.
[표 21]
Figure imgf000147_0001
실시 예 192 내지 196에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR 분석 결과는 하기 표 22에 나타낸다. [Table 21]
Figure imgf000147_0001
The structure and compound name of each of the compounds obtained according to Examples 192 to 196, and NMR analysis results are shown in Table 22 below.
[표 22]
Figure imgf000147_0002
Figure imgf000148_0001
실시예 197. 1-벤질- N-((S)- 8 -플루오로- 7- ((S)- 3 -메톡시피롤리딘- L-일)- -메틸- 2 -옥소- 2, 3, 4, 5 -테트라하이드로- 1H-벤조 [b]아제핀- 3 -일)- 1H- 1,2, 4 - 트리아졸- 3 -카복사마이드의 제조
Figure imgf000149_0001
실시예 194의 단계 1에서 7 -브로모- 6 -플루오로- 3 , 4 - 다이하이드로나프탈렌- 1(2아)-온 대신 6 -브로모- 7 -플루오로- 3 , 4 - 다이하이드로나프탈렌- 1(2才)-온을 출발물질로 하고, 단계 7에서 피롤리딘 대신[Table 22]
Figure imgf000147_0002
Figure imgf000148_0001
Example 197. 1-Benzyl-N-((S)-8-fluoro-7-((S)-3-methoxypyrrolidin-L-yl)-methyl-2-oxo-2, 3, 4, 5 -tetrahydro- 1H-benzo [b] azepin- 3 -yl)- 1H- 1,2, 4 - Preparation of triazole-3-carboxamides
Figure imgf000149_0001
7-Bromo-6-fluoro-3,4-dihydronaphthalen-1(2a)-one in step 1 of Example 194 is replaced with 6-bromo-7-fluoro-3,4-dihydronaphthalene - 1(2才)-one as starting material, instead of pyrrolidine in step 7
(S)-메톡시피롤리딘을 이용하며, 단계 9에서 2 -벤질- 2우 1,2, 3, 4 -테트라졸- 5- 카르복실산 대신 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산을 이용한 것을 제외하고는, 실시예 194의 화합물 T9의 제조과정과 동일한 방법으로 실시예 197에 따른 흰색 고체의 화합물 U4를 합성하였다. 中 NMR (400 MHz, DMS0-d6) 5 8.81 (s, 1H), 8.20-8.19 (m, 1H), 7.39—(S)-methoxypyrrolidine is used, and in step 9 2-benzyl- 2 right 1,2, 3, 4 -tetrazole- 5- 1-benzyl- 1 right instead of carboxylic acid 1,2, 4 - Compound U4 as a white solid according to Example 197 was synthesized in the same manner as in the preparation process of Compound T9 of Example 194, except that triazole-3-carboxylic acid was used. Medium NMR (400 MHz, DMS0-d 6 ) 5 8.81 (s, 1H), 8.20-8.19 (m, 1H), 7.39—
7.20 (m, 5H), 7.21 (d, J = 14.8 Hz, 0.5 H), 7.06 (d, J = 14.0 Hz, 0.5 H), 6.69 (t, 7= 8 Hz, 1H), 5.47 (s, 2H), 4.38-4.31 (m, 1H), 4.03 (s, 1H), 3.55 (m, 1H), 3.44-3.39 (m, 1H), 3.33 (s, 4H), 3.28-3.23 (m, 7H), 2.64-2.54 (m.7.20 (m, 5H), 7.21 (d, J = 14.8 Hz, 0.5 H), 7.06 (d, J = 14.0 Hz, 0.5 H), 6.69 (t, 7= 8 Hz, 1H), 5.47 (s, 2H) ), 4.38-4.31 (m, 1H), 4.03 (s, 1H), 3.55 (m, 1H), 3.44-3.39 (m, 1H), 3.33 (s, 4H), 3.28-3.23 (m, 7H), 2.64-2.54 (m.
2H), 2.35-2.31 (m, 1H), 2.10-2.00 (m, 3H)； LRMS (electrospray) m/z (M+H)+ 2H), 2.35-2.31 (m, 1H), 2.10-2.00 (m, 3H); LRMS (electrospray) m/z (M+H) +
493. 실시예 198. 2 -벤질- N-((S)- 8 -플루오로- 7-( (S)- 3 -메톡시피롤리딘- L-일)-493. Example 198. 2-Benzyl-N-((S)-8-fluoro-7-((S)-3-methoxypyrrolidin- L-yl)-
1-메틸- 2 -옥소- 2 , 3 , 4, 5 -테트라하이드로- 1H-벤조 [b]아제핀- 3 -일 )- 2H-테트라졸- 5- 카복사마이드의 제조 실시예 194의 단계 1에서 7 -브로모- 6 -플루오로- 3 , 4 - 다이하이드로나프탈렌- 1（2아）-온 대신 6 -브로모- 7 -플루오로- 3 , 4- 다이하이드로나프탈렌- 1（2才）-온을 출발물질로 하고, 단계 7에서 피롤리딘 대신1-methyl- 2 -oxo- 2, 3, 4, 5 -tetrahydro- 1H-benzo [b] azepin- 3 -yl)- 2H-tetrazole- 5- Preparation of carboxamide In step 1 of Example 194, 7-bromo-6-fluoro-3,4-dihydronaphthalen-1(2a)-one is replaced with 6-bromo-7-fluoro-3, 4-dihydronaphthalen-1(2才)-one as a starting material, instead of pyrrolidine in step 7
（S）-메톡시피롤리딘을 이용한 것을 제외하고는, 실시예 194의 화합물 T9를 제조한 것과 실질적으로 동일한 제조 방법으로 실시예 198에 따른 흰색 고체의 화합물을 합성하였다. iH NMR (400 MHz, DMS0-d6) 5 8.86-8.81 (m, 1H), 7.39 (s, 5H), 7.23A white solid compound according to Example 198 was synthesized in substantially the same manner as in Example 194 to prepare compound T9, except that (S)-methoxypyrrolidine was used. iH NMR (400 MHz, DMS0-d 6 ) 5 8.86-8.81 (m, 1H), 7.39 (s, 5H), 7.23
(d, J = 15.2 Hz, 0.5 H), 7.05 (d, J = 14 Hz, 0.5 H) , 7.72-6.59 (m, 1H), 6.02 s, 2H), 4.41-4.39 (m, 1H), 4.03 (s, 1H), 3.57-3.55 (m, 1H), 3.43-3.39 (m,(d, J = 15.2 Hz, 0.5 H), 7.05 (d, J = 14 Hz, 0.5 H), 7.72-6.59 (m, 1H), 6.02 s, 2H), 4.41-4.39 (m, 1H), 4.03 (s, 1H), 3.57-3.55 (m, 1H), 3.43-3.39 (m,
1H), 3.33 (m, 3H), 3.28-3.23 (m, 6H), 2.61-2.56 (m, 2H), 2.30-2.23 (m, 2H),1H), 3.33 (m, 3H), 3.28-3.23 (m, 6H), 2.61-2.56 (m, 2H), 2.30-2.23 (m, 2H),
2.00 (s , 2H) : LRMS (electrospray) m/z (M+H)+ 494. 실시예 199. （S）-l-벤질- N-（l-메틸- 2 -옥소- 8-（피롤리딘- 1-일）- 2, 3, 4, 5 - 테트라하이드로- 1H-벤조 [b]아제핀- 3 -일）- 1H- 1 , 2 , 4 -트리아졸- 3 -카복사마이드의
Figure imgf000150_0001
실시예 194의 단계 1에서 7 -브로모- 6 -플루오로- 3 , 4 - 다이하이드로나프탈렌- 1（2아）-온 대신 7 -브로모- 3, 4 -다이하이드로나프탈렌- 1（2이- 온을 이용하고, 단계 7에서 2 -벤질- 2우 1,2, 3, 4 -테트라졸- 5 -카르복실산 대신 1- 벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산을 이용한 것을 제외하고는 실시예 194의 화합물 T9를 제조하는 것과 실질적으로 동일한 방법으로 화합물 VI, V2, V3 및 실시예 199에 따른화합물 V4를 순차적으로 합성하였다. 실시예 200내지 202. 실시예 199의 화합물 V2를 제조하는 단계에서 피롤리딘에 대응하는 화합물로서 하기 표 23의 반응물 1을, 화합물 V4를 제조하는 단계에서 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산에 대응하는 화합물로서 하기 표 23의 반응물 2를 이용한 것을 제외하고는 실시예 199의 화합물 V4를 제조하는 것과 실질적으로 동일한 방법으로실시예 200 내지 202에 따른 화합물들을 제조하였다. 2.00 (s, 2H): LRMS (electrospray) m/z (M+H) + 494. Example 199. (S) -l-benzyl-N-(l-methyl-2-oxo-8-(pyrroly) of din-1-yl)-2, 3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide
Figure imgf000150_0001
In step 1 of Example 194, 7-bromo-6-fluoro-3,4- Instead of dihydronaphthalene-1(2a)-one, 7-bromo-3,4-dihydronaphthalene-1(using di-one, 2-benzyl-2 in step 7 1,2,3, Substantially the same as for preparing compound T9 of Example 194, except that 1-benzyl-1woo 1,2,4-triazole-3-carboxylic acid was used instead of 4-tetrazole-5-carboxylic acid. Compounds VI, V2, V3 and Compound V4 according to Example 199 were sequentially synthesized by the method. Examples 200 to 202. In the step of preparing compound V2 of Example 199, reactant 1 in Table 23 was used as a compound corresponding to pyrrolidine, and in the step of preparing compound V4, 1-benzyl-1, 1,2, Compounds according to Examples 200 to 202 in substantially the same manner as in Example 199, except that reactant 2 in Table 23 was used as a compound corresponding to 4-triazole-3-carboxylic acid. were manufactured.
[표 23]
Figure imgf000151_0001
실시예 199 내지 202에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR분석 결과는 하기 표 24에 나타낸다. [Table 23]
Figure imgf000151_0001
The structure and compound name of each of the compounds obtained according to Examples 199 to 202, and the results of NMR analysis are shown in Table 24 below.
[표 24]
Figure imgf000151_0002
Figure imgf000152_0001
실시예 203. (S)-l-벤질- N- (7 -플루오로- 5 -메틸- 4 -옥소- 8-(피롤리딘- 1- 일)- 2, 3, 4, 5 -테트라하이드로벤조 [b] [1,4]옥사제핀- 3 -일)- 1H- 1,2, 4 -트리아졸 -3 - 카복사마이드의 제조
Figure imgf000153_0001
단계 1. 목적 화합물 XI의 제조 [Table 24]
Figure imgf000151_0002
Figure imgf000152_0001
Example 203. (S)-l-Benzyl-N-(7-fluoro-5-methyl-4-oxo-8-(pyrrolidin-1-yl)-2,3,4,5-tetrahydro Benzo [b] [1,4]oxazepin- 3 -yl)- 1H- 1,2, 4 -triazole -3 - Preparation of carboxamides
Figure imgf000153_0001
Step 1. Preparation of target compound XI
4 -브로모- 2 , 5 -다이플루오로아닐린 (5 g, 24.0 mmol ) , HATU (11 g, 28.8 mmo 1 ) , 및 AHBoc- 0- *八-뷰틸- L-세린 (6.6 g, 25.2 mmol )를 다이메틸설폭사이드 (70 mL)에 첨가하고 다이아이소프로필에틸아민 (8.4 mL , 48.1 mmol )을 첨가하였다. 반응 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후 , 에틸아세테이트로 추출하고 염화나트륨 수용액으로 씻어준 뒤 , 황산나트륨으로 건조하고 감압 농축하였다. 농축액은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：4)로 정제하여 흰색 고체의 목적 화합물 XI (7.04 g, 70%)을 수득하였다. 단계 2. 목적 화합물 X2의 제조 화합물 XI (7.04 g, 15.6 mmol )을 다이메틸포름아마이드 (100 mL)에 녹인 후, 탄산세슘 (6.1 g, 18.7 mmol)과 메틸요오드 (0.981 mL, 15.8 mmol)을 첨가한 뒤, 반응 혼합물을 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 에틸아세테이트로 추출하고 염화 암모늄 수용액과 염화나트륨 수용액으로 씻어준 뒤 , 황산나트륨으로 건조하고 여과하였다. 여과액은 감압농축 하였다. 농축액은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：4)로 정제하여 목적 화합물 X2 (4.72 g, 65%)를수득하였다. 단계 3. 목적 화합물 X3의 제조 화합물 X2 (4.72 g, 10.1 mmol)를 다이클로로메테인 (75 mL)에 첨가한 뒤, 염산 1,4 -다이옥세인 용액; 12.7 mL)을 첨가하였다. 반응 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 감압 농축을 통해 용매를 제거하여 연노란색 고체의 목적 화합물 X3 (3.51 g, 100%)을 얻었다. 수득한 화합물 X3은추가 정제과정 없이 다음 반응을 진행하였다. 단계 4. 목적 화합물 X4의 제조 화합물 X3 (3.51 g, 10.1 mmol), 트리틸클로라이드 (3.12 g, 11.2 mmol)> 클로로포름 (60 mL)에 첨가한 뒤 트리에틸아민 (4.25 mL, 30.4 mmol)을 첨가하였다. 반응 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 감압 농축을 통해 용매를 제거하였다. 농축액을 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 목적 화합물 X4 (4.2 g, 75%)를수득하였다. 단계 5. 목적 화합물 X5의 제조 화합물 X4 (4.19 g, 7.60 mmol)를 다이메틸설폭사이드 (65 mL)에 첨가한 뒤 , 탄산세슘 (4.97 g, 15.2 mmol)을 첨가하였다. 반응혼합액은 50°C에서 16시간 동안 교반하였다. 반응 종료 후, 용액을 상온으로 식힌 뒤, 에틸아세테이트로 추출하고 물과 염화나트륨 수용액으로 씻어준 뒤, 황산나트륨으로 건조하고 여과하였다. 감압 농축하여 용매를 제거하였다. 농축액은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 목적 화합물 X5 (3.28 g, 81%)를 수득하였다. 단계 6. 목적 화합물 X6의 제조 화합물 X5 (300 mg, 0.56 mmo 1 ) , Pd(0Ac)2 (12 mg, 0.056 mmo 1 ) , BI NAP (70 mg, 0.112 mmo 1 ) , 및 탄산세슘 (364 mg, 1.12 mmol)를 톨루엔 (2 mL)에 첨가한 뒤 피롤리딘 (0.07 mL, 0.85 mmol)을 첨가하였다. 반응 혼합물을 90°C에서 16시간 동안 교반하였다. 반응 종료 후, 감압 농축하여 용매를 제거하였다. 농축액은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：4)로 정제하여 흰색 고체의 목적 화합물 X6 (250 mg, 86%)을수득하였다. 단계 7. 목적 화합물 X7의 제조 화합물 X6 (250 mg, 0.48 mmol)을 다이클로로메테인 (2 mL)에 첨가한 뒤 , 염산 1,4 -다이옥세인 용액; 0.6 mL)을 첨가하였다. 반응 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료후, 감압 농축을 통해 용매를 제거하여 흰색 고체의 목적 화합물 X7 (146 mg, 96%)을 수득하였다. 수득한 화합물 X7은 추가 정제과정 없이 다음 반응을 진행하였다. 단계 8. 목적 화합물 X8의 제조 화합물 X7 (90 mg, 0.28 mmol), HATU (130 mg, 0.342 mmol), 및 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 (58 mg, 0.28 mmol)을 다이메틸설폭사이드 (1 mL)에 첨가한 뒤 , 다이아이소프로필에틸아민 (0.1 mL, 0.57 mmol)을 첨가하였다. 반응 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 에틸아세테이트로 추출하고 염화나트륨 수용액으로 씻어준 뒤 , 황산나트륨으로 건조하고 감압 농축하였다. 농축액은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l) 로 정제하여 실시 예 203에 따른 흰색 고체의 목적 화합물 X8 (50 g, 40%)을 수득하였다. 실시예 204 내지 214. 실시 예 203의 단계 6의 피롤리딘에 대응하는 화합물로서 하기 표 25의 반응물 1을 , 실시 예 203의 단계 8의 1-벤질- 1우 1 , 2 , 4 -트리아졸 -3 -카르복실산에 대응하는 화합물로서 하기 표 25의 반응물 2를 이용한 것을 제외하고는 , 실시 예 203의 화합물 X8을 제조하는 방법과 실질적으로 동일한 방법으로 실시 예 204 내지 214에 따른 화합물들을 제조하였다. 4-Bromo-2,5-difluoroaniline (5 g, 24.0 mmol), HATU (11 g, 28.8 mmol), and AHBoc-0-*8-butyl-L-serine (6.6 g, 25.2 mmol) ) was added to dimethylsulfoxide (70 mL) and diisopropylethylamine (8.4 mL, 48.1 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, washed with aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:4) to obtain the target compound XI (7.04 g, 70%) as a white solid. Step 2. Preparation of target compound X2 Compound XI (7.04 g, 15.6 mmol) was dissolved in dimethylformamide (100 mL). Then, cesium carbonate (6.1 g, 18.7 mmol) and methyl iodine (0.981 mL, 15.8 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, washed with aqueous ammonium chloride solution and aqueous sodium chloride solution, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:4) to obtain the target compound X2 (4.72 g, 65%). Step 3. Preparation of target compound X3 Compound X2 (4.72 g, 10.1 mmol) was added to dichloromethane (75 mL), followed by 1,4-dioxane hydrochloric acid solution; 12.7 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure to obtain the target compound X3 (3.51 g, 100%) as a pale yellow solid. The obtained compound X3 was subjected to the next reaction without additional purification. Step 4. Preparation of target compound X4 Compound X3 (3.51 g, 10.1 mmol) and tritylchloride (3.12 g, 11.2 mmol) were added to chloroform (60 mL), followed by triethylamine (4.25 mL, 30.4 mmol). did The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM: Me0H = 20: l) to obtain the target compound X4 (4.2 g, 75%). Step 5. Preparation of target compound X5 Compound X4 (4.19 g, 7.60 mmol) was added to dimethylsulfoxide (65 mL) followed by cesium carbonate (4.97 g, 15.2 mmol). The reaction mixture was stirred at 50 °C for 16 hours. After completion of the reaction, the solution was cooled to room temperature and then washed with ethyl acetate. After extraction and washing with water and aqueous sodium chloride solution, dried over sodium sulfate and filtered. The solvent was removed by concentration under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:Me0H=20:1) to obtain the target compound X5 (3.28 g, 81%). Step 6. Preparation of target compound X6 Compound X5 (300 mg, 0.56 mmo 1 ), Pd(0Ac) 2 (12 mg, 0.056 mmo 1 ), BI NAP (70 mg, 0.112 mmo 1 ), and cesium carbonate (364 mg , 1.12 mmol) was added to toluene (2 mL) followed by pyrrolidine (0.07 mL, 0.85 mmol). The reaction mixture was stirred at 90 °C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent. The concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:4) to obtain the target compound X6 (250 mg, 86%) as a white solid. Step 7. Preparation of target compound X7 Compound X6 (250 mg, 0.48 mmol) was added to dichloromethane (2 mL), followed by 1,4-dioxane hydrochloric acid solution; 0.6 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure to obtain the target compound X7 (146 mg, 96%) as a white solid. The obtained compound X7 was subjected to the next reaction without additional purification. Step 8. Preparation of target compound X8 Compound X7 (90 mg, 0.28 mmol), HATU (130 mg, 0.342 mmol), and 1-benzyl-1woo 1,2,4-triazole-3-carboxylic acid (58 mg, 0.28 mmol) in dimethylsulfoxide (1 mL), followed by diisopropylethylamine (0.1 mL, 0.57 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction is complete, After extraction with ethyl acetate, washing with aqueous sodium chloride solution, drying over sodium sulfate and concentration under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:Me0H=20:1) to obtain the target compound X8 (50 g, 40%) as a white solid according to Example 203. Examples 204 to 214. Reactant 1 in Table 25 below was used as a compound corresponding to pyrrolidine in Step 6 of Example 203, 1-benzyl-1, 2, 4-triazole in Step 8 of Example 203. Compounds according to Examples 204 to 214 were prepared in substantially the same manner as the method for preparing compound X8 of Example 203, except that reactant 2 of Table 25 was used as a compound corresponding to -3-carboxylic acid. did
[표 25]
Figure imgf000156_0001
실시 예 203 내지 214에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR 분석 결과는 하기 표 26에 나타낸다 . [Table 25]
Figure imgf000156_0001
The structures and compound names of each of the compounds obtained according to Examples 203 to 214, and NMR analysis results are shown in Table 26 below.
[표 26]
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
실시예 215. （S）-l-벤질- N-（8 -플루오로- 5 -메틸- 4 -옥소- 7-（피롤리딘- 1- 일）- 2 , 3 , 4 , 5 -테트라하이드로벤조 [b] [ 1 , 4]옥사제핀- 3 -일）- 1H- 1 , 2 , 4 -트리아졸- 3- 카복사마이드의 제조
Figure imgf000160_0001
실시 예 203의 단계 1에서 4 -브로모- 2 , 5 -다이플루오로아닐린 대신 5 - 브로모- 2 , 4 -다이플루오로아닐린을 이용한 것을 제외하고는 실시 예 203의 단계 1 내지 단계 5를 거쳐 화합물 Y1을 제조하고 , 실시 예 203의 단계 6에서 화합물 X5 대신 화합물 Y1을 이용하여 실시 예 203의 단계 6 , 단계 7 및 단계 8 과 실질적으로 동일한 방법으로 화합물 Y2, Y3 및 실시 예 215에 따른 목적 화합물 Y4를 순차적으로 합성하였다. 실시예 216 내지 228. 실시 예 215에서 화합물 Y2를 제조하는 단계에서 피롤리딘에 대응하는 화합물로서 하기 표 27의 반응물 1을 , 실시 예 215에서 화합물 Y4를 제조하는 단계에서 1-벤질 - L¥~l , 2 , 4 -트리아졸 - 3 -카르복실산에 대응하는 화합물로서 하기 표 27의 반응물 2를 이용한 것을 제외하고는 , 실시 예 215의 화합물 Y4> 제조하는 방법과 실질적으로 동일한 방법으로 실시 예 216 내지 228에 따른 화합물들을 제조하였다. [Table 26]
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Example 215. (S)-l-Benzyl-N-(8-fluoro-5-methyl-4-oxo-7-(pyrrolidin-1-yl)-2,3,4,5-tetrahydro Preparation of benzo [b] [1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide
Figure imgf000160_0001
Steps 1 to 5 of Example 203 were followed except that 5-bromo-2,4-difluoroaniline was used instead of 4-bromo-2,5-difluoroaniline in Step 1 of Example 203. to prepare compound Y1, and in step 6 of Example 203, using compound Y1 instead of compound X5, in substantially the same manner as in step 6, step 7 and step 8 of Example 203, according to compounds Y2, Y3 and Example 215 The target compound Y4 was sequentially synthesized. Examples 216 to 228. In the step of preparing compound Y2 in Example 215, reactant 1 in Table 27 was used as a compound corresponding to pyrrolidine, and in the step of preparing compound Y4 in Example 215, 1-benzyl-L¥ Carried out in substantially the same manner as in Example 215 for preparing compound Y4>, except that reactant 2 in Table 27 was used as a compound corresponding to ~l,2,4-triazole-3-carboxylic acid. Compounds according to Examples 216-228 were prepared.
[표 27]
Figure imgf000160_0002
[Table 27]
Figure imgf000160_0002
Figure imgf000161_0001
실시 예 215 내지 228에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR 분석 결과는 하기 표 28에 나타낸다 .
Figure imgf000161_0001
The structure and compound name of each of the compounds obtained according to Examples 215 to 228, and NMR analysis results are shown in Table 28 below.
[표 28]
Figure imgf000161_0002
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
실시예 229. (S)- 1-벤질- N- (8- (3, 3 -다이플루오로피롤리딘- 1-일)- 7- 플루오로- 5 -메틸- 4 -옥소- 2, 3, 4, 5 -테트라하이드로벤조 [b] [1,4]옥사제핀- 3 -일)- 1H- 1,2, 4 -트리아졸 -3 -카복사마이드의 제조
Figure imgf000165_0001
실시 예 203의 단계 6에서 피롤리딘 대신 3 , 3 -다이플루오로피롤리딘을 이용한 것을 제외하고는 실시 예 203의 화합물 X8을 제조한 것과 실질적으로 동일한 방법으로 화합물 Z1, 72, Z3 및 실시 예 229에 따른 목적 화합물 Z4를 순차적으로 합성하였다. 실시예 230 내지 232. 실시 예 229에서 화합물 12를 제조하는 단계에서 3 , 3 - 다이플루오로피롤리딘에 대응하는 화합물로서 하기 표 29의 반응물 1을 , 실시 예 229에서 화합물 Z4를 제조하는 단계에서 1-벤질- 1우 1 , 2 , 4 -트리아졸 -3- 카르복실산에 대응하는 화합물로서 하기 표 29의 반응물 2를 이용한 것을 제외하고는 , 실시 예 229의 화합물 Z4를 제조하는 방법과 실질적으로 동일한 방법으로 실시 예 230 내지 232에 따른 화합물들을 제조하였다. [Table 28]
Figure imgf000161_0002
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Example 229. (S)-1-Benzyl-N-(8-(3,3-difluoropyrrolidin-1-yl)-7-fluoro-5-methyl-4-oxo-2,3 Preparation of , 4,5-tetrahydrobenzo [b] [1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide
Figure imgf000165_0001
Compounds Z1, 72, Z3 and Example 203 were prepared in substantially the same manner as in Example 203, except that 3,3-difluoropyrrolidine was used instead of pyrrolidine in Step 6 of Example 203. The target compound Z4 according to Example 229 was sequentially synthesized. Examples 230 to 232. In the step of preparing compound 12 in Example 229, reactant 1 in Table 29 was used as a compound corresponding to 3,3-difluoropyrrolidine, preparing compound Z4 in Example 229. Method for preparing compound Z4 of Example 229, except that reactant 2 of Table 29 was used as a compound corresponding to 1-benzyl-1woo 1,2,4-triazole-3-carboxylic acid in Compounds according to Examples 230 to 232 were prepared in substantially the same manner.
[표 29]
Figure imgf000165_0002
실시 예 229 내지 232에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR 분석 결과는 하기 표 30에 나타낸다 . [Table 29]
Figure imgf000165_0002
The structure and compound name of each of the compounds obtained according to Examples 229 to 232, and NMR analysis results are shown in Table 30 below.
[표 3이
Figure imgf000166_0001
Figure imgf000167_0002
실시예 233. (R)- 1-벤질- N- (8- ((2 ■메톡시에틸)아미노) -5 -메틸- 4 -옥소-[Table 3
Figure imgf000166_0001
Figure imgf000167_0002
Example 233. (R)-1-Benzyl-N-(8-((2 Methoxyethyl)amino)-5-methyl-4-oxo-
2, 3, 4, 5 -테트라하이드로피리도 [4,3- b] [1,4]싸이아제핀- 3 -일)- 1H- 1,2, 4 -트리아졸-2, 3, 4, 5 -tetrahydropyrido [4,3- b] [1,4] thiazepin- 3 -yl) - 1H- 1,2, 4 -triazole-
3 -카복사마이드의 제조
Figure imgf000167_0001
화합물 AA1 (50 mg, 0.12 mmol)을 피리딘 (0.09 mL)에 첨가한 뒤 2- 메톡시에틸아민 (0.01 mL, 0.13 mmol)을 첨가하였다. 반응 혼합물은 100°C에서3-Manufacture of carboxamides
Figure imgf000167_0001
Compound AA1 (50 mg, 0.12 mmol) was added to pyridine (0.09 mL) followed by 2-methoxyethylamine (0.01 mL, 0.13 mmol). The reaction mixture at 100 °C
16시간 동안 교반하였다. 반응 종료 후 반응 혼합물은 감압 농축하였다. 농축액은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=5：l)로 정제하여 실시예Stir for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc: Hexane = 5: l), and
233에 따른주황색 고체의 목적 화합물 AA2 (4.6 mg, 8%)를 얻었다. 실시예 234내지 238. 실시예 233에서 화합물 AA1을 제조하는 단계에서 1-벤질- 1우 1,2,4- 트리아졸 -3 -카르복실산에 대응하는 화합물로서 하기 표 31의 반응물 1을, 메톡시에틸아민에 대응하는 화합물로서 하기 표 31의 반응물 2를 이용한 것을 제외하고는, 실시예 233의 화합물 AA2를 제조하는 방법과 실질적으로 동일한 방법으로 실시예 234내지 238에 따른화합물들을 제조하였다. 233 to obtain the desired compound AA2 as an orange solid (4.6 mg, 8%). Examples 234 to 238. In the step of preparing compound AA1 in Example 233, reactant 1 in Table 31 below was used as a compound corresponding to 1-benzyl-1woo 1,2,4-triazole-3-carboxylic acid, Compounds according to Examples 234 to 238 were prepared in substantially the same manner as the method for preparing compound AA2 of Example 233, except that reactant 2 in Table 31 was used as a compound corresponding to methoxyethylamine.
[표 31]
Figure imgf000167_0003
Figure imgf000168_0001
실시 예 233 내지 238에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR 분석 결과는 하기 표 32에 나타낸다 . [Table 31]
Figure imgf000167_0003
Figure imgf000168_0001
The structure and compound name of each of the compounds obtained according to Examples 233 to 238, and NMR analysis results are shown in Table 32 below.
[표 32]
Figure imgf000168_0002
Figure imgf000169_0001
실시예 239. 메틸 （R）- 3-（（3-（1-벤질- 1H- 1,2, 4 -트리아졸 -3- 카르복사미도）- 5 -메틸- 4 -옥소- 2, 3, 4, 5 -테트라하이드로피리도［4,3- b］［1,4］싸이아제핀- 8 -일）아미노）프로파노에이트의 제조
Figure imgf000170_0001
단계 1. 목적 화합물 AB1의 제조 화합물 Bl (268 mg, 0.71 mmol)을 다이클로로메테인 (2 mL)에 녹인 후 염산 1,4 -다이옥세인 용액; 0.9 mL)을 첨가하였다. 반응 혼합물은 상온에서 6 시간 동안 교반하였다. 반응 종료 후 감압 농축을 통해 용매를 제거한 후, 여기에 메탄올 (1 mL)을 첨가한 뒤 상온에서 16시간동안 교반하였다. 반응 종료 후, 감압 농축을 통해 용매를 제거하여 흰색 고체의 목적 화합물 AB1 (246 mg, 99%)를 수득하였다. 수득한 화합물 AB1은 추가 정제과정 없이 다음 반응을 진행하였다. 단계 2. 목적 화합물 AB2의 제조 화합물 AB1 (246 mg, 0.71 mmol)을 다이클로로메테인 (14 mL)에 녹인 후, EDC (173 mg, 1.42 mmol), HOAt (191 mg, 1.42 mmol), 1-벤질- 1우 1,2, 4 -트리아졸- 3 -카르복실산 (159 mg, 0.78 mmol) 그리고 트리에틸아민 (0.3 mL, 2.16 mmol)을 0°C에서 첨가하였다. 반응 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료후 반응 용액은 다이클로로메테인으로추출하고, 탄산수소나트륨 수용액, 물 그리고 염화나트륨 수용액으로 씻어준 뒤, 황산마그네슘으로 건조하고 감압 농축하였다. 농축액은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 실시예 239에 따른 흰색 고체의 목적 화합물 AB2 (80 mg, 23%)를 수득하였다. iH NMR (400 MHz, Chloroform-d) 5 8.17 (d, J= 7.6 Hz, IH), 8.01 (s, 2H), 7.40-7.36 (m, 3H), 7.29-7.27 (m, 2H), 6.66 (s, IH), 5.38 (s, 2H)m 5.12(t, J = 6.4 Hz, IH), 4.93-4.87 (m, IH), 3.85-3.81 (m, IH), 3.73 (s, 3H), 3.71- 3.64 (m, 2H), 3.38 (s, 3H), 2.71-2.67 (m, 2H). 실시예 240. (R)- 3- ((3-(1-벤질- IH- 1,2, 4 -트리아졸 -3 -카르복사마이드)-[Table 32]
Figure imgf000168_0002
Figure imgf000169_0001
Example 239. Methyl (R)-3-((3-(1-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3, Preparation of 4,5-tetrahydropyrido[4,3-b][1,4]thiazepin-8-yl)amino)propanoate
Figure imgf000170_0001
Step 1. Preparation of target compound AB1 After dissolving compound Bl (268 mg, 0.71 mmol) in dichloromethane (2 mL), 1,4-dioxane hydrochloric acid solution; 0.9 mL) was added. The reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, the solvent was removed through concentration under reduced pressure, and methanol (1 mL) was added thereto, followed by stirring at room temperature for 16 hours. After completion of the reaction, the solvent was removed through concentration under reduced pressure to obtain the target compound AB1 (246 mg, 99%) as a white solid. The obtained compound AB1 was subjected to the next reaction without further purification. Step 2. Preparation of target compound AB2 After dissolving compound AB1 (246 mg, 0.71 mmol) in dichloromethane (14 mL), EDC (173 mg, 1.42 mmol), HOAt (191 mg, 1.42 mmol), 1- Benzyl-1woo 1,2,4-triazole-3-carboxylic acid (159 mg, 0.78 mmol) and triethylamine (0.3 mL, 2.16 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was extracted with dichloromethane, washed with aqueous sodium bicarbonate solution, water, and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM: Me0H = 20: l). Purification gave the desired compound AB2 (80 mg, 23%) as a white solid according to Example 239. iH NMR (400 MHz, Chloroform-d) 5 8.17 (d, J= 7.6 Hz, IH), 8.01 (s, 2H), 7.40-7.36 (m, 3H), 7.29-7.27 (m, 2H), 6.66 ( s, IH), 5.38 (s, 2H)m 5.12(t, J = 6.4 Hz, IH), 4.93-4.87 (m, IH), 3.85-3.81 (m, IH), 3.73 (s, 3H), 3.71 - 3.64 (m, 2H), 3.38 (s, 3H), 2.71-2.67 (m, 2H). Example 240. (R)-3-((3-(1-benzyl-IH-1,2,4-triazole-3-carboxamide)-
5 -메틸- 4 -옥소- 2 , 3 , 4 , 5 -테트라하이드로피리도 [4 , 3- b] [ 1 , 4]싸이아제핀- 8- 일)아미노)프로피온산의 제조
Figure imgf000171_0001
화합물 AB2 (50 mg, 0.1 mmol)를 메탄올 (0.2 mL)에 녹인 후 2N 수산화나트륨 수용액 (0.2 ml, 0.5 mmol)을 첨가하였다. 반응 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후 반응 용액을 감압 농축하였다. 반응 혼합물을 물로 희석하였다. 수용액 층은 1川염산 수용액을 이용하여 pH 2- 3으로 맞춘 뒤 다이클로로메테인으로추출하고 황산마그네슘으로 건조하고 여과하였다 . 감압 농축을 통해 용매를 제거하여 실시예 240에 따른 베이지색 고체의 목적 화합물 AB3 (3 mg, 6%)을수득하였다. iH NMR (400 MHz, DMSO— d6) 5 8.83 (s, 1H), 8.46 (d, J= 7.6 Hz, 1H), 8.17 (s, IH), 7.39-7.28 (m, 5H), 6.96 (s, IH), 5.48 (s, 2H), 4.67-4.62 (m, 1H), 3.51-3.45 (m, 3H), 3.29-3.27 (m, 1H), 3.24 (s, 3H), 2.56-2.53 (m, 2H). 실시예 241. 메틸 (R)- 3- ((3- (5 -벤질- 1H- 1,2, 4 -트리아졸 -3- 카르복사미도)- 5 -메틸- 4 -옥소- 2 , 3 , 4 , 5 -테트라하이드로피리도 [4 , 3- b] [1,4]싸이아제핀- 8 -일)아미노)프로파노에이트의 제조 실시예 239의 단계 2에서 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 대신 5 -벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산을 이용한 것을 제외하고는 실시예 239에서 화합물 AB2를 제조하는 것과 실질적으로 동일한 방법으로 실시예 241에 따른 흰색 고체의 화합물을 합성하였다. iH NMR (400 MHz, Chloroform-d) 5 8.20 (d, J= 8.0 Hz, 1H), 8.01 (s, 1H), 7.34-7.29 (m, 5H), 6.66 (s, IH), 5.21 (s, IH), 4.85-4.84 (m, IH), 4.16 (s, 2H), 3.79-3.75 (m, IH), 3.73 (s, 3H), 3.67 (t, J = 5.8 Hz, 2H), 3.38 (s, 3H), 2.93 (t, J = 11.2 Hz, IH), 2.68 (t, J = 5.8 Hz, 2H). 실시예 242. (R)- 5 -벤질- N-(l-메틸- 2 -옥소- 8- (3,3,3- 트리플루오로프로판아세트아미도)- 1,2, 3, 4 -테트라하이드로피리도 [3,4- b] [ 1 , 4]싸이아제핀- 3 -일 )- 1H- 1 , 2 , 4 -트리아졸- 3 -카복사마이드의 제조 Preparation of 5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]thiazepin-8-yl)amino)propionic acid
Figure imgf000171_0001
After dissolving compound AB2 (50 mg, 0.1 mmol) in methanol (0.2 mL), 2N aqueous sodium hydroxide solution (0.2 ml, 0.5 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The reaction mixture was diluted with water. The aqueous layer was adjusted to pH 2-3 using an aqueous solution of 1 River hydrochloric acid, extracted with dichloromethane, dried over magnesium sulfate, and filtered. The solvent was removed through concentration under reduced pressure to obtain the target compound AB3 (3 mg, 6%) as a beige solid according to Example 240. iH NMR (400 MHz, DMSO—d6) 5 8.83 (s, 1H), 8.46 (d, J= 7.6 Hz, 1H), 8.17 (s, IH), 7.39-7.28 (m, 5H), 6.96 (s, IH), 5.48 (s, 2H), 4.67-4.62 (m, 1H), 3.51–3.45 (m, 3H), 3.29–3.27 (m, 1H), 3.24 (s, 3H), 2.56–2.53 (m, 2H). Example 241. Methyl (R)-3-((3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3, Preparation of 4,5-tetrahydropyrido[4,3-b][1,4]thiazepin-8-yl)amino)propanoate 1-benzyl-1 in step 2 of Example 239, It is substantially the same as preparing compound AB2 in Example 239, except that 5-benzyl-1woo 1,2,4-triazole-3-carboxylic acid was used instead of 2,4-triazole-3-carboxylic acid. A white solid compound according to Example 241 was synthesized in the same manner. iH NMR (400 MHz, Chloroform-d) 5 8.20 (d, J= 8.0 Hz, 1H), 8.01 (s, 1H), 7.34-7.29 (m, 5H), 6.66 (s, IH), 5.21 (s, IH), 4.85-4.84 (m, IH), 4.16 (s, 2H), 3.79-3.75 (m, IH), 3.73 (s, 3H), 3.67 (t, J = 5.8 Hz, 2H), 3.38 (s , 3H), 2.93 (t, J = 11.2 Hz, IH), 2.68 (t, J = 5.8 Hz, 2H). Example 242. (R)-5-Benzyl-N-(l-methyl-2-oxo-8-(3,3,3-trifluoropropaneacetamido)-1,2,3,4-tetra Preparation of hydropyrido [3,4-b] [1,4]thiazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide
Figure imgf000173_0001
Figure imgf000173_0001
AQ11 단계 1. 목적 화합물人이의 제조 AQ11 Step 1. Preparation of target compound 人I
4 -아미노- 2 -플루오로피리딘 (15.0 g, 116.6 mmol )을 아세트산 (448 mL)에 녹인 후 칼륨 아세테이트 (22.8 g, 233.2 mmol ) 와 아이오딘화염소 (20.8 g, 128.3 mmol )를 첨가하였다. 반응 혼합물은 70°C에서 16시간 동안 교반하였다. 반응 종료 후 반응 혼합물은 에틸아세테이트로 추출하고 물과 염화나트륨 수용액으로 씻어준 뒤 , 황산마그네슘으로 건조하고 감압 농축하였다. 농축액은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：3)로 정제하여 갈색 고체의 목적 화합물 AQ1 (7.1 g, 25%)을 수득하였다. 단계 2. 목적 화합물 AQ2의 제조 화합물 AQ1 (7.1 g, 30 mmol )을 톨루엔 (200 mL)에 녹인 후 Pd(dba)2 (431 mg, 0.75 mmo 1 ) , 잔트포스 (867 mg, 1.5 mmo 1 ) , AHBoc- L-시스테인 (7261 mg, 33 mmol ) 그리고 다이아이소프로필에틸아민 (10.3 mL , 60 mmol )을 질소 분위기 하에 넣어주었다. 반응 혼합물은 100°C에서 2 시간 동안 교반하였다. 반응 종료 후 셀라이트를 이용하여 여과를 하고 , 감압 농축하였다. 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=l：10)로 정제하여 베이지색 오일의 목적 화합물 AQ2 (9.8 g, 98%)를 수득하였다. 단계 3. 목적 화합물 AQ3의 제조 화합물 AQ2 (10.46 g, 31.56 mmol )를 다이클로로메테인 (310 mL)에 녹인 뒤 다이아이소프로필에틸아민 (11 mL , 63.12 mmol )과 T3P (50% 에틸아세테이트 용액 ; 27.6 mL； 63.12 mmol )을 첨가하였다. 반응 혼합물은 상온에서 1시간 동안 교반하였다. 반응 종료 후 반응 혼합물은 에틸아세테이트로 추출하고 물과 염화나트륨 수용액으로 씻어준 뒤 , 황산마그네슘으로 건조하고 감압 농축하였다. 농축액은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：2)로 정제하여 노란색 고체의 목적 화합물 AQ3 (1.2 g, 12%)을 수득하였다. 단계 4. 목적 화합물 AQ4의 제조 화합물 AQ3 (1212 mg, 3.87 mmol )을 다이메틸포름아마이드 (30 mL)에 녹인 후 , 탄산칼륨 (1069 mg, 7.74 mmol )과 메틸요오드 (0.24 mL , 3.87 mmol )를 첨가하였다. 반응 혼합물은 상온에서 1시간 동안 교반하였다. 반응 종료 후 반응 혼합물은 에틸아세테이트로 추출하고 물과 염화나트륨 수용액으로 씻어준 뒤 , 황산마그네슘으로 건조하고 여과하였다. 감압 농축을 통해 용매를 제거하여 노란색 고체의 목적 화합물 AQ4 (800 mg, 63%)를 수득하였다. 단계 5. 목적 화합물 AQ5의 제조 화합물 AQ4 (800 mg, 2.44 mmol )을 다이클로로메테인 (2 mL)에 녹인 후 염산 (4> 1 , 4 -다이옥세인 용액 ; 3 mL)을 첨가하였다. 반응 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후 감압 농축을 통해 용매를 제거하여 갈색 고체의 목적 화합물 AQ5 (733 mg, 99%)를 수득하였다. 수득한 화합물 AQ5는 추가 정제과정 없이 다음 반응을 진행하였다. 단계 6. 목적 화합물 AQ6의 제조 화합물 AQ5 (733 mg, 2.44 mmol ) , 및 트리틸클로라이드 (816 mg, 2.928 mmol )를 다이클로로메테인 (3 mL)에 녹인 후 트리에틸아민 (1.7 mL , 12.2 mmol )을 첨가하였다. 반응 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후 감압 농축을 통해 용매를 제거하였다. 농축액은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 갈색 고체의 목적 화합물 AQ6 (438 mg, 38%)을 수득하였다. 단계 7. 목적 화합물 AQ7의 제조 화합물 AQ6 (438 mg, 0.94 mmol )을 4 -메톡시벤질아민 (2 mL)에 첨가한 후 60°C에서 16시간 동안 교반하였다. 반응 종료 후 반응 혼합물은 에틸아세테이트로 추출하고 물과 염화나트륨 수용액으로 씻어준 뒤 , 황산마그네슘으로 건조하고 여과하였다 . 농축액은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：3)로 정제하여 흰색 고체의 목적 화합물 AQ7 (493 mg, 89%)을 수득하였다. 단계 8. 목적 화합물 AQ8의 제조 화합물 AQ7 (493 mg, 0.84 mmol)을 다이클로로메테인 (2 mL)에 녹인 후 염산 (4> 1,4 -다이옥세인 용액; 1.1 mL)을 첨가하였다. 반응 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후 감압 농축을 통해 용매를 제거하여 흰색 고체의 목적 화합물 AQ8 (319 mg, 99%)를수득하였다. 수득된 화합물 AQ8은 추가 정제과정 없이 다음 반응을 진행하였다. 단계 9. 목적 화합물 AQ9의 제조 화합물 AQ8 (319 mg, 0.84 mmol), 및 5 -벤질- 1우 1,2, 4 -트리아졸 -3- 카르복실산 (257 mg, 1.26 mmol)을 다이클로로메테인 (2 mL)에 녹인 후 다이아이소프로필에틸아민 (0.3 mL, 1.68 mmol)과 T3P (50% 에틸아세테이트 용액 ; 1 mL, 1.68 mmol)을 0°C에서 첨가하였다. 반응 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후 반응 혼합물은 에틸아세테이트로 추출하고 물과 염화나트륨 수용액으로 씻어준 뒤, 황산나트륨으로 건조하고 감압 농축하였다. 농축액은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 베이지색 고체의 목적 화합물 AQ9 (430 mg, 96%)을수득하였다. 단계 10. 목적 화합물 AQ10의 제조 화합물 AQ9 (500 mg, 0.94 mmol)를 트리플루오로아세트산 (2 mL)에 첨가한 뒤 80°C에서 5시간 동안 교반하였다. 반응 종료 후 반응 용액을 에틸아세테이트로 주줄하고 탄산수소나트륨 수용액, 물 그리고 염화나트륨 수용액으로 씻어준 뒤, 황산나트륨으로 건조하고 감압 농축하였다. 농축액은 실리카겔 컬럼 크로마토그래피 (Et0Ac：Hexane=l：10)로 정제하여 흰색 고체의 목적 화합물 AQ10 (200 mg, 50%)을수득하였다. 단계 11. 목적 화합물 AQ11의 제조 화합물 AQ10 (20 mg, 0.049 mmol), 및 3, 3, 3 - 트리플루오로프로피오닐클로라이드 (5.5 uL, 0.053 mmol)을 다이클로로메테인 (2 mL)에 첨가한 뒤, 트리에틸아민 (13.0 uL, 0.098 mmol)을 첨가하였다. 반응 혼합물은 상온에서 2시간 동안 교반하였다. 반응 종료 후 감압 농축을 통해 용매를 제거하였다. 농축액은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 실시예 242에 따른 흰색 고체의 목적 화합물 AQ11 (5 mg, 20 %)을 수득하였다. 실시예 243내지 246. 실시예 242의 단계 11에서 3, 3, 3 -트리플루오로프로피오닐클로라이드와 대응하는 화합물로서 하기 표 33의 반응물 1을 이용하는 것을 제외하고는, 실시예 242의 화합물 AQ11를 제조하는 방법과 실질적으로 동일한 방법으로 실시예 243 내지 246에 따른화합물들을제조하였다. 4-Amino-2-fluoropyridine (15.0 g, 116.6 mmol) was dissolved in acetic acid (448 mL), then potassium acetate (22.8 g, 233.2 mmol) and chlorine iodide (20.8 g, 128.3 mmol) were added. The reaction mixture was stirred at 70 °C for 16 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and water and sodium chloride After washing with aqueous solution, dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:3) to obtain the target compound AQ1 (7.1 g, 25%) as a brown solid. Step 2. Preparation of target compound AQ2 After dissolving compound AQ1 (7.1 g, 30 mmol) in toluene (200 mL), Pd(dba) 2 (431 mg, 0.75 mmo 1 ) and Zantphos (867 mg, 1.5 mmo 1 ) , AHBoc-L-cysteine (7261 mg, 33 mmol) and diisopropylethylamine (10.3 mL, 60 mmol) were added under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 2 h. After completion of the reaction, the mixture was filtered using celite and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:Me0H=l:10) to give the target compound AQ2 (9.8 g, 98%) as a beige oil. Step 3. Preparation of target compound AQ3 After dissolving compound AQ2 (10.46 g, 31.56 mmol) in dichloromethane (310 mL), diisopropylethylamine (11 mL, 63.12 mmol) and T 3 P (50% ethyl acetate) solution; 27.6 mL; 63.12 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, washed with water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:2) to obtain the target compound AQ3 (1.2 g, 12%) as a yellow solid. Step 4. Preparation of target compound AQ4 After dissolving compound AQ3 (1212 mg, 3.87 mmol) in dimethylformamide (30 mL), potassium carbonate (1069 mg, 7.74 mmol) and methyl iodine (0.24 mL, 3.87 mmol) were added. added. The reaction mixture was stirred for 1 hour at room temperature. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, washed with water and aqueous sodium chloride solution, dried over magnesium sulfate, and filtered. The solvent was removed through concentration under reduced pressure to obtain the target compound AQ4 (800 mg, 63%) as a yellow solid. Step 5. Preparation of target compound AQ5 After dissolving compound AQ4 (800 mg, 2.44 mmol) in dichloromethane (2 mL), hydrochloric acid (4> 1,4-dioxane solution; 3 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed through concentration under reduced pressure to obtain the target compound AQ5 (733 mg, 99%) as a brown solid. The obtained compound AQ5 was subjected to the next reaction without further purification. Step 6. Preparation of target compound AQ6 After dissolving compound AQ5 (733 mg, 2.44 mmol) and tritylchloride (816 mg, 2.928 mmol) in dichloromethane (3 mL), triethylamine (1.7 mL, 12.2 mmol) ) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:Me0H=20:1) to obtain the target compound AQ6 (438 mg, 38%) as a brown solid. Step 7. Preparation of target compound AQ7 After adding compound AQ6 (438 mg, 0.94 mmol) to 4-methoxybenzylamine (2 mL), the mixture was stirred at 60°C for 16 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, washed with water and aqueous sodium chloride solution, dried over magnesium sulfate, and filtered. The concentrate was purified by silica gel column chromatography. (EtOAc:Hexane=l:3) to obtain the target compound AQ7 (493 mg, 89%) as a white solid. Step 8. Preparation of target compound AQ8 After dissolving compound AQ7 (493 mg, 0.84 mmol) in dichloromethane (2 mL), hydrochloric acid (4> 1,4-dioxane solution; 1.1 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure to obtain the target compound AQ8 (319 mg, 99%) as a white solid. The obtained compound AQ8 was subjected to the following reaction without further purification. Step 9. Preparation of target compound AQ9 Compound AQ8 (319 mg, 0.84 mmol) and 5-benzyl-1woo 1,2,4-triazole-3-carboxylic acid (257 mg, 1.26 mmol) were dissolved in dichloromethane. After dissolving in phosphorus (2 mL), diisopropylethylamine (0.3 mL, 1.68 mmol) and T 3 P (50% ethyl acetate solution; 1 mL, 1.68 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, washed with water and aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM: Me0H = 20: l) to obtain the target compound AQ9 (430 mg, 96%) as a beige solid. Step 10. Preparation of target compound AQ10 Compound AQ9 (500 mg, 0.94 mmol) was added to trifluoroacetic acid (2 mL) and stirred at 80°C for 5 hours. After completion of the reaction, the reaction solution was poured with ethyl acetate, washed with aqueous sodium bicarbonate solution, water, and aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. Concentrate is Purification was performed by silica gel column chromatography (Et0Ac:Hexane=l:10) to obtain the target compound AQ10 (200 mg, 50%) as a white solid. Step 11. Preparation of target compound AQ11 Compound AQ10 (20 mg, 0.049 mmol) and 3,3,3-trifluoropropionylchloride (5.5 uL, 0.053 mmol) were added to dichloromethane (2 mL). Then, triethylamine (13.0 uL, 0.098 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:Me0H=20:1) to obtain the target compound AQ11 (5 mg, 20%) according to Example 242 as a white solid. Examples 243 to 246. Compound AQ11 of Example 242 was prepared, except that reactant 1 in Table 33 was used as a compound corresponding to 3,3,3-trifluoropropionyl chloride in step 11 of Example 242. Compounds according to Examples 243 to 246 were prepared in substantially the same manner as the preparation method.
[표 33]
Figure imgf000177_0001
실시예 242 내지 246에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR분석 결과는 하기 표 34에 나타낸다. [Table 33]
Figure imgf000177_0001
Structures and compound names of each of the compounds obtained according to Examples 242 to 246, And the NMR analysis results are shown in Table 34 below.
[표 34]
Figure imgf000178_0001
Figure imgf000179_0002
실시예 247. (R)-l-벤질- N- (7 -플루오로- 5 -메틸- 4 -옥소- 8-(2- 옥소아제티딘- 1-일)- 2, 3, 4, 5 -테트라하이드로벤조 [b] [1,4]싸이아제핀- 3 -일)- 1H-[Table 34]
Figure imgf000178_0001
Figure imgf000179_0002
Example 247. (R)-l-Benzyl-N-(7-fluoro-5-methyl-4-oxo-8-(2-oxoazetidin-1-yl)-2, 3, 4, 5 -Tetrahydrobenzo [b] [1,4]thiazepin- 3 -yl)- 1H-
1,2, 4 -트리아졸 -3 -카복사마이드의 제조
Figure imgf000179_0001
Preparation of 1,2,4-triazole-3-carboxamide
Figure imgf000179_0001
AC3 단계 1. 목적 화합물 AC1의 제조 화합물 F4 (300 mg, 0.74 mmol )를 톨루엔 (3.7 mL)에 첨가한 뒤 , 아이오딘화구리 (28 mg, 0.15 mmo 1 ) , 탄산칼륨 (205 mg, 1.48 mmol ) , 아제티디논AC3 Step 1. Preparation of target compound AC1 After adding compound F4 (300 mg, 0.74 mmol) to toluene (3.7 mL), copper iodide (28 mg, 0.15 mmol 1 ), potassium carbonate (205 mg, 1.48 mmol) ) , azetidinone
(79 mg, 1 . 11 mmol ) 그리고 DMEDA (0.02 mL , 0.22 mmol )> 첨가하였다. 반응 혼합물은 16시간 동안 환류하였다. 반응 종료 후 반응 혼합물은 셀라이트를 이용하여 여과하였고, 감압 농축하였다. 농축액은실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：2)로 정제하여 흰색 고체의 목적 화합물 AC1 (130 mg, 44%)을 수득하였다. 단계 2. 목적 화합물 AC2의 제조 화합물 AC1 (149 mg, 0.38 mmol)를 다이클로로메테인 (1.9 mL)에 첨가한 뒤 트리플루오로아세트산 (0.04 mL, 0.57 mmol)을 상온에서 첨가하였다. 반응 혼합물은 상온에서 30 분 동안 교반하였다. 반응 종료 후 반응 용액을 다이클로로메테인으로 추출하고 탄산수소나트륨 수용액과 염화나트륨 수용액으로 씻어준 뒤, 황산마그네슘으로 건조하고 여과하였다. 감압 농축을 통해 용매를 제거하여 노란색 고체의 목적 화합물 AC2 (41 mg, 37%)를 수득하였다. 수득된 화합물 AC2는추가 정제과정 없이 다음 반응을 진행하였다. 단계 3. 목적 화합물 AC3의 제조 화합물 AC2 (41 mg, 0.14 mmol)를 다이클로로메테인 (2.8 mL)에 첨가한 뒤, EDC (34 mg, 0.28 mmol), HOAt (34 mg, 0.28 mmol), 1-벤질- 1우 1,2,4- 트리아졸 -3 -카르복실산 (42 mg, 0.21 mmol) 그리고 트리에틸아민 (0.06 mL, 0.42 mmol)을 0°C에서 첨가하였다. 반응 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후 반응 용액을 다이클로로메테인으로 추출하고 탄산수소나트륨 수용액, 물 그리고 염화나트륨 수용액으로 씻어준 뒤, 황산마그네슘으로 건조하고 감압 농축하였다. 농축액은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=5：l)로 정제하여 실시예 247에 따른 흰색 고체의 목적 화합물 AC3(79 mg, 1.11 mmol) and DMEDA (0.02 mL, 0.22 mmol)> were added. The reaction mixture was refluxed for 16 hours. After completion of the reaction, the reaction mixture is celite It was filtered using and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:2) to obtain the target compound AC1 (130 mg, 44%) as a white solid. Step 2. Preparation of target compound AC2 After adding compound AC1 (149 mg, 0.38 mmol) to dichloromethane (1.9 mL), trifluoroacetic acid (0.04 mL, 0.57 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was extracted with dichloromethane, washed with aqueous sodium bicarbonate solution and aqueous sodium chloride solution, dried over magnesium sulfate, and filtered. The solvent was removed through concentration under reduced pressure to obtain the target compound AC2 (41 mg, 37%) as a yellow solid. The obtained compound AC2 was subjected to the following reaction without further purification. Step 3. Preparation of target compound AC3 Compound AC2 (41 mg, 0.14 mmol) was added to dichloromethane (2.8 mL), followed by EDC (34 mg, 0.28 mmol), HOAt (34 mg, 0.28 mmol), 1 -Benzyl- 1,2,4-triazole-3-carboxylic acid (42 mg, 0.21 mmol) and triethylamine (0.06 mL, 0.42 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was extracted with dichloromethane, washed with aqueous sodium bicarbonate solution, water, and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc: Hexane = 5: l) to obtain the target compound AC3 as a white solid according to Example 247.
(30 mg, 45%)을수득하였다. 실시예 248 내지 252. 실시 예 247의 단계 1에서 아제티디논과 대응하는 화합물로서 하기 표 35의 반응물 1을 , 단계 3에서 1-벤질- 1우 1 , 2 , 4 -트리아졸 -3 -카르복실산과 대응하는 화합물로서 하기 표 35의 반응물 2를 이용한 것을 제외하고는 실시예 247의 화합물 AC3을 제조하는 방법과 실질적으로 동일한 방법으로 실시 예 248 내지 252에 따른 화합물들을 제조하였다. (30 mg, 45%). Examples 248 to 252. Reactant 1 in Table 35 below was used as a compound corresponding to azetidinone in step 1 of Example 247, and 1-benzyl-1-1,2,4-triazole-3-carboxyl in step 3 Compounds according to Examples 248 to 252 were prepared in substantially the same manner as the method for preparing compound AC3 of Example 247, except that reactant 2 in Table 35 was used as a compound corresponding to the acid.
[표 35]
Figure imgf000181_0001
실시 예 247 내지 252에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR 분석 결과는 하기 표 36에 나타낸다. [Table 35]
Figure imgf000181_0001
The structure and compound name of each of the compounds obtained according to Examples 247 to 252, and NMR analysis results are shown in Table 36 below.
[표 36]
Figure imgf000181_0002
Figure imgf000182_0001
Figure imgf000183_0002
실시예 253. (R)-l-벤질- N- (5 -메틸- 4 -옥소- 8-(피롤리딘- 1-일)- 2, 3, 4, 5 - 테트라하이드로벤조 [b] [ 1,4]싸이아제핀- 3 -일)- 1H- 1,2, 4 -트리아졸 -3 - 카복사마이드의 제조
Figure imgf000183_0001
[Table 36]
Figure imgf000181_0002
Figure imgf000182_0001
Figure imgf000183_0002
Example 253. (R) -l-Benzyl- N- (5 -methyl- 4 -oxo- 8- (pyrrolidin- 1-yl) - 2, 3, 4, 5 - tetrahydrobenzo [b] [ Preparation of 1,4]thiazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide
Figure imgf000183_0001
AE7 단계 1. 목적 화합물 AE1의 제조 AE7 Step 1. Preparation of target compound AE1
5 -브로모- 2 -플루오로나이트로벤젠 (3.7 mL, 33.58 mmol )을 에탄올 (71 mL)과 물 (59 mL)에 첨가한 뒤 AHk)c-L- cysteine (7.43 g, 33.58 mmol )과 탄산수소나트륨 (8.46 g, 100.74 mmol )을 첨가하였다. 반응 혼합물은 16시간 동안 환류하였다. 반응 종료 후 반응 용액은 감압농축 하였다. 반응 혼합물은 물로 희석한 후 에테르로 씻어주었다. 수용액 층을 1川염산 수용액을 이용하여 pH 2 - 3으로 맞춘 뒤 , 다이클로로메테인으로 추출하고 , 황산마그네슘으로 건조 후 여과하였다. 감압 농축을 통해 용매를 제거하여 노란색 고체의 목적 화합물 AE1 (13.4 g, 95%)을 수득하였다. 단계 2. 목적 화합물 AE2의 제조 화합물 AE1 (13.4 g, 31.8 mmol )을 메탄올에 첨가한 후 MeOH (318 mL) , 아연 (20.8 g, 318 mmol )과 염화암모늄 (3.4 g, 63.6 mmol )을 첨가하였다. 반응 혼합물은 75°C에서 16시간 동안 교반하였다. 반응 종료 후 반응 혼합물은 셀라이트를 이용하여 여과하였다. 농축액을 감압 농축하여 베이지색의 목적 화합물 AE2 (12.4 g, 99%)를 수득하였다. 단계 3. 목적 화합물 AE3의 제조 화합물 AE2 (12.4 g, 31.8 mmol ) , EDC (7.8 g, 63.6 mmol ) , 및 HOAt (8.7 g, 63.6 mmol )를 다이클로로메테인 (636 mL)에 첨가한 후 트리에틸아민 (8.9 mL , 63.6 mmol )을 0°C에서 첨가하였다. 반응 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후 반응 용액을 다이클로로메테인으로 추출하고 탄산수소나트륨 수용액 , 물 그리고 염화나트륨 수용액으로 씻어준 뒤 , 황산마그네슘으로 건조하고 감압 농축하였다. 농축액은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：2)로 정제하여 흰색 고체의 목적 화합물 AE35-Bromo-2-fluoronitrobenzene (3.7 mL, 33.58 mmol) in ethanol (71 mL) and water (59 mL), followed by the addition of AHk)cL-cysteine (7.43 g, 33.58 mmol) and sodium bicarbonate (8.46 g, 100.74 mmol). The reaction mixture was refluxed for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The reaction mixture was diluted with water and washed with ether. The aqueous layer was adjusted to pH 2-3 using an aqueous solution of 1 River hydrochloric acid, extracted with dichloromethane, dried with magnesium sulfate, and filtered. The solvent was removed through concentration under reduced pressure to obtain the target compound AE1 (13.4 g, 95%) as a yellow solid. Step 2. Preparation of target compound AE2 Compound AE1 (13.4 g, 31.8 mmol) was added to methanol, followed by MeOH (318 mL), zinc (20.8 g, 318 mmol) and ammonium chloride (3.4 g, 63.6 mmol). . The reaction mixture was stirred at 75 °C for 16 hours. After completion of the reaction, the reaction mixture was filtered using Celite. The concentrate was concentrated under reduced pressure to obtain a beige target compound AE2 (12.4 g, 99%). Step 3. Preparation of target compound AE3 Compound AE2 (12.4 g, 31.8 mmol), EDC (7.8 g, 63.6 mmol), and HOAt (8.7 g, 63.6 mmol) were added to dichloromethane (636 mL) and then trichloromethane (636 mL) was added. Ethylamine (8.9 mL , 63.6 mmol ) was added at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was extracted with dichloromethane, washed with aqueous sodium bicarbonate solution, water, and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:2) to obtain the target compound AE3 as a white solid.
(3.8 g, 32 %)을 수득하였다. 단계 4. 목적 화합물 AE4의 제조 화합물 AE3 (3.8 g, 10.11 mmol )를 다이메틸포름아마이드 (60 mL)에 녹인 후 , 탄산세슘 (4.9 g, 15.17 mmol )과 메틸요오드 (0.76 mL , 12.13 mmol )을 첨가하였다. 반응 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후 반응 혼합물은 에틸아세테이트로 추출하고 물과 염화나트륨 수용액으로 씻어준 뒤 , 황산마그네슘으로 건조하고 여과하였다. 감압 농축을 통해 용매를 제거하여 흰색 고체의 목적 화합물 AE4 (2.4 g, 60%)를 수득하였다. 단계 5. 목적 화합물 AE5의 제조 화합물 AE4 (300 mg, 0.78 mmol )를 톨루엔 (3.2 mL)에 첨가한 뒤 , Pd(0Ac)2 (18 mg, 0.08 mmo 1 ) , BI NAP (97 mg, 0.16 mmo 1 ) , 탄산세슘 (504 mg, 1.55 mmol ) 그리고 피롤리딘 (0.01 mL , 1.16 mmol )을 첨가하였다. 반응 혼합물은 70°C에서 16시간 동안 교반하였다. 반응 종료 후 반응 혼합물은 셀라이트를 이용하여 여과한 뒤 , 감압 농축하였다. 농축액은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：2)로 정제하여 흰색 고체의 목적 화합물 AE5 (262 mg, 90%)을 수득하였다. 단계 6. 목적 화합물 AE6의 제조 화합물 AE5 (262 mg, 0.69 mmol )를 다이클로로메테인 (4.6 mL)에 첨가한 뒤 염산 (4> 1 , 4 -다이옥세인 용액 ; 0.87 mL , 3.47 mmol )을 첨가하였다. 반응 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후 감압 농축을 통해 용매를 제거하여 흰색 고체의 목적 화합물 AE6 (67 mg, 31 %)을 수득하였다. 수득한 화합물 AE6은 추가 정제과정 없이 다음 반응을 진행하였다. 단계 7. 목적 화합물 AE7의 제조 화합물 AE6 (67 mg, 0.21 mmol)을 다이클로로메테인 (3.8 mL)에 첨가한 뒤 EDC (46 mg, 0.38 mmol), HOAt (51 mg, 0.38 mmol), 1-벤질- 1우 1,2, 4 -트리아졸- 3 -카르복실산 (38 mg, 0.19 mmol) 그리고 트리에틸아민 (0.09 mL, 0.62 mmol)을 0°C에서 첨가하였다. 반응 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후 반응 용액을 다이클로로메테인으로추출하고 탄산수소나트륨 수용액, 물 그리고 염화나트륨 수용액으로 씻어준 뒤, 황산마그네슘으로 건조하고 감압 농축하였다. 농축액은 실리카겔 컬럼 크로마토그래피 (DCM：MeOH=5：l)로 정제하여 실시예 253에 따른 흰색 고체의 목적 화합물 AE7 (66 mg, 69%)을수득하였다. iH NMR (400 MHz, Chloroform—沙) 5 8.18 (d, J= 7.2 Hz, 1H), 7.99 (s, 1H), 7.38-7.35 (m, 3H), 7.29-7.26 (m, 2H), 7.07 (d, J = 8.4 Hz, IH), 6.79 (s, IH), 6.54 (d, J = 8.4 Hz, IH) , 5.36 (s, 2H) , 4.89-4.82 (m, IH), 3.93- 3.88 (m, IH), 3.35 (s, 3H), 3.34-3.29 (m, 4H), 2.86 (t, J = 11.0 Hz, IH), 2.06-2.03 (m, 4H) : LRMS (electrospray) m/z (M+H)+ 463. 실시예 254. (R)- 1-벤질- N- (5 -메틸- 8 -모폴리노- 4 -옥소- 2, 3,4,5- 테트라하이드로벤조 [b] [ 1 , 4]싸이아제핀- 3 -일 )- 1H-이미다졸- 4 -카복사마이드의 제조 실시예 253의 단계 5에서 피롤리딘 대신 몰포린을 이용한 것을 제외하고는 실시예 253에 따른 화합물 AE7을 제조하는 것과 실질적으로 동일한 방법으로 실시예 254에 따른 흰색 고체의 화합물을수득하였다. iH NMR (400 MHz, DMS0-d6) 5 7.992 (d, 7= 8 Hz, IH), 7.91 (s, IH),(3.8 g, 32%). Step 4. Preparation of target compound AE4 After dissolving compound AE3 (3.8 g, 10.11 mmol) in dimethylformamide (60 mL), cesium carbonate (4.9 g, 15.17 mmol) and methyl iodine (0.76 mL, 12.13 mmol) were added. added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, washed with water and aqueous sodium chloride solution, dried over magnesium sulfate, and filtered. The solvent was removed through concentration under reduced pressure to obtain the target compound AE4 (2.4 g, 60%) as a white solid. Step 5. Preparation of target compound AE5 After adding compound AE4 (300 mg, 0.78 mmol) to toluene (3.2 mL), Pd(0Ac)2 (18 mg, 0.08 mmo 1 ) and BI NAP (97 mg, 0.16 mmo 1), cesium carbonate (504 mg, 1.55 mmol) and pyrrolidine (0.01 mL, 1.16 mmol) were added. The reaction mixture was stirred at 70 °C for 16 hours. After completion of the reaction, the reaction mixture was filtered using celite and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:2) to obtain the target compound AE5 (262 mg, 90%) as a white solid. Step 6. Preparation of target compound AE6 After adding compound AE5 (262 mg, 0.69 mmol) to dichloromethane (4.6 mL), hydrochloric acid (4> 1,4-dioxane solution; 0.87 mL, 3.47 mmol) was added. did The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure to obtain the target compound AE6 (67 mg, 31%) as a white solid. The obtained compound AE6 was subjected to the following reaction without further purification. Step 7. Preparation of target compound AE7 Compound AE6 (67 mg, 0.21 mmol) was added to dichloromethane (3.8 mL) followed by EDC (46 mg, 0.38 mmol), HOAt (51 mg, 0.38 mmol), 1-benzyl-1woo 1,2, 4-Triazole- 3-carboxylic acid (38 mg, 0.19 mmol) and triethylamine (0.09 mL, 0.62 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was extracted with dichloromethane, washed with aqueous sodium bicarbonate solution, water, and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH=5:l) to obtain the target compound AE7 (66 mg, 69%) as a white solid according to Example 253. iH NMR (400 MHz, Chloroform—沙) 5 8.18 (d, J= 7.2 Hz, 1H), 7.99 (s, 1H), 7.38-7.35 (m, 3H), 7.29-7.26 (m, 2H), 7.07 ( d, J = 8.4 Hz, IH), 6.79 (s, IH), 6.54 (d, J = 8.4 Hz, IH), 5.36 (s, 2H), 4.89-4.82 (m, IH), 3.93-3.88 (m , IH), 3.35 (s, 3H), 3.34-3.29 (m, 4H), 2.86 (t, J = 11.0 Hz, IH), 2.06-2.03 (m, 4H): LRMS (electrospray) m/z (M +H) + 463. Example 254. (R)- 1-Benzyl- N- (5 -methyl- 8 -morpholino- 4 -oxo- 2, 3,4,5- tetrahydrobenzo [b] [ Preparation of 1,4]thiazepin-3-yl)-1H-imidazole-4-carboxamide The compound according to Example 253 except that morpholine was used instead of pyrrolidine in step 5 of Example 253. A white solid compound according to Example 254 was obtained in substantially the same manner as for preparing AE7. iH NMR (400 MHz, DMS0-d 6 ) 5 7.992 (d, 7= 8 Hz, IH), 7.91 (s, IH),
7.75 (s, IH), 7.46 (d, J = 8.4 Hz, IH), 7.38-7.28 (m, 6H), 7.08 (s, IH), 6.88 (dd, J = 6.4 Hz, 2 Hz, IH), 5.22 (s, 2H), 4.55-4.48 (m, IH), 3.83 (s,7.75 (s, IH), 7.46 (d, J = 8.4 Hz, IH), 7.38-7.28 (m, 6H), 7.08 (s, IH), 6.88 (dd, J = 6.4 Hz, 2 Hz, IH), 5.22 (s, 2H), 4.55–4.48 (m, IH), 3.83 (s,
4H), 3.30 (s, 3H), 3.22 (s, 4H)； LRMS (electrospray) m/z (M+H)+ 478. 실시예 255. (R)-l-벤질- N- (7 -메톡시- 5 -메틸- 4 -옥소- 8-(피롤리딘- 1-일)-4H), 3.30 (s, 3H), 3.22 (s, 4H); LRMS (electrospray) m/z (M+H) + 478. Example 255. (R)-l-benzyl-N-(7-methyl Toxy- 5 -methyl- 4 -oxo- 8- (pyrrolidin- 1-yl)-
2,3,4, 5 -테트라하이드로벤조 [b] [ 1 , 4]싸이아제핀- 3 -일 )- 1H- 1 , 2 , 4 -트리아졸- 3- 카복사마이드의 제조
Figure imgf000187_0001
실시예 253의 단계 1에서 5 -브로모- 2 -플루오로나이트로벤젠 대신 1- 브로모- 5 -플루오로- 2 -메톡시- 4 -나이트로벤젠을 이용한 것을 제외하고는 실시예 253의 화합물 AE7을 제조한 것과실질적으로 동일한제조 방법으로실시예 255에 따른 화합물 AF7을 합성하였다. iH NMR (400 MHz, Chloroform—沙) 5 8.15 (d, J= 7.6 Hz, 1H), 7.97 (s, 1H), 7.40-7.33 (m, 3H), 7.29-7.24 (m, 2H), 6.89 (s, IH), 6.66 (s, IH), 5.36 (s, 2H), 4.88-4.82 (m, IH), 3.93-3.88 (m, IH), 3.83 (s, 3H), 3.42-3.30 (m, 7H), 2.86 (t, J = 11.0 Hz, IH), 2.00-1.94 (m, 4H)； LRMS (electrospray) m/zPreparation of 2,3,4,5-tetrahydrobenzo [b] [1,4]thiazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide
Figure imgf000187_0001
Except for using 1-bromo-5-fluoro-2-methoxy-4-nitrobenzene instead of 5-bromo-2-fluoronitrobenzene in step 1 of Example 253. Compound AF7 according to Example 255 was synthesized in substantially the same manner as for preparing compound AE7. iH NMR (400 MHz, Chloroform—沙) 5 8.15 (d, J= 7.6 Hz, 1H), 7.97 (s, 1H), 7.40-7.33 (m, 3H), 7.29-7.24 (m, 2H), 6.89 ( s, IH), 6.66 (s, IH), 5.36 (s, 2H), 4.88-4.82 (m, IH), 3.93-3.88 (m, IH), 3.83 (s, 3H), 3.42-3.30 (m, 7H), 2.86 (t, J = 11.0 Hz, IH), 2.00-1.94 (m, 4H); LRMS (electrospray) m/z
(M+H)+ 493. 실시예 256. (R)- 1-벤질- N- (4 -옥소- 8-(피롤리딘- 1-일)- 2, 3,4,5- 테트라하이드로피리도 [4,3- b] [1 ,4]싸이아제핀- 3 -일 )-1오-1,2,4-트리아졸- 3 -
Figure imgf000188_0001
(M+H)+ 493. Example 256. (R)-1-benzyl-N-(4-oxo-8-(pyrrolidin-1-yl)-2,3,4,5-tetrahydropyrido[4,3-b] [1,4]thiazepine- 3 -yl)-1OH-1,2,4-triazole- 3 -
Figure imgf000188_0001
AG5 단계 1. 목적 화합물 AG1의 제조 화합물 A3 (1 g, 3.03 mmol)을 다이클로로메테인 (10 mL)에 첨가하고 녹인 후, 염산 (4川 1,4 -다이옥세인 용액; 3.80 mL)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하여 흰색 고체의 목적 화합물 AG1 (807 mg, 100%)을수득하였다. 단계 2. 목적 화합물 AG2의 제조 화합물 AG1 (807 mg, 3.03 mmol)과 트리틸클로라이드 (1.02 g, 3.64 mmol)를 다이클로로메테인 (10 mL)에 첨가하고 녹인 후, 트리에틸아민 (2.12 mL,AG5 Step 1. Preparation of target compound AG1 Compound A3 (1 g, 3.03 mmol) was added to and dissolved in dichloromethane (10 mL), and then hydrochloric acid (4 River 1,4-dioxane solution; 3.80 mL) was added. did The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound AG1 (807 mg, 100%) as a white solid. Step 2. Preparation of target compound AG2 Compound AG1 (807 mg, 3.03 mmol) and tritylchloride (1.02 g, 3.64 mmol) were added to and dissolved in dichloromethane (10 mL), and triethylamine (2.12 mL,
15.2 mmol)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 목적 화합물 AG2 (1.43 g, 77%)를 수득하였다. 단계 3. 목적 화합물 AG3의 제조 화합물 AG2 (100 mg, 0.21 mmol)를 피롤리딘 (1 mL)에 첨가하고, 90°C에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：l)로 정제하여 흰색 고체의 목적 화합물 AG3 (97 mg, 90.6%)>수득하였다. 단계 4. 목적 화합물 AG4의 제조 화합물 AG3 (97 mg, 0.19 mmol)를 다이클로로메테인 (5 mL)에 첨가하여 녹인 후, 염산 (4川 1,4 -다이옥세인 용액; 0.24 mL)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 농축물은 감압 농축하여 흰색 고체의 목적 화합물 AG4 (57 mg, 100%)를수득하였다. 단계 5. 목적 화합물 AG5의 제조 화합물 AG4 (57 mg, 0.19 mmo 1 ) , EDC (47 mg, 0.38 mmo 1 ) , HOAt (53 mg, 0.38 mmol), 및 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 (47 mg, 0.23 mmol)을 다이클로로메테인 (5mL)에 희석하고, 트리에틸아민 (0.11 mL, 0.76 mmol)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 실시예 256에 따른 흰색 고체의 목적 화합물 AG5 (17 mg, 20%)를수득하였다. iH NMR (400 MHz, DMSO— d6) 5 9.94 (s, 1H), 8.84 (s, 1H), 8.38 (d, J = 7.2 Hz, IH), 7.89 (s, IH), 7.39-7.29 (m, 5H), 6.64 (s, IH), 5.48 (s, 2H), 4.62-4.55 (m, 1H), 3.56-3.52 (m, 1H), 3.39-3.39 (m, 4H), 3.31 (t, 7 = 12 Hz, 15.2 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was placed on a silica gel column Purification by chromatography (DCM:Me0H=20:1) gave the target compound AG2 (1.43 g, 77%). Step 3. Preparation of target compound AG3 Compound AG2 (100 mg, 0.21 mmol) was added to pyrrolidine (1 mL) and stirred at 90°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:l) to obtain the target compound AG3 (97 mg, 90.6%)> as a white solid. Step 4. Preparation of target compound AG4 After dissolving compound AG3 (97 mg, 0.19 mmol) in dichloromethane (5 mL), hydrochloric acid (4 River 1,4-dioxane solution; 0.24 mL) was added. . The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction concentrate was concentrated under reduced pressure to obtain the target compound AG4 (57 mg, 100%) as a white solid. Step 5. Preparation of target compound AG5 Compound AG4 (57 mg, 0.19 mmo 1 ), EDC (47 mg, 0.38 mmo 1 ), HOAt (53 mg, 0.38 mmol), and 1-benzyl- 1,2,4 -Triazole-3-carboxylic acid (47 mg, 0.23 mmol) was diluted in dichloromethane (5 mL) and triethylamine (0.11 mL, 0.76 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM:Me0H=20:1) to obtain the target compound AG5 (17 mg, 20%) according to Example 256 as a white solid. iH NMR (400 MHz, DMSO—d6) 5 9.94 (s, 1H), 8.84 (s, 1H), 8.38 (d, J = 7.2 Hz, IH), 7.89 (s, IH), 7.39-7.29 (m, 5H), 6.64 (s, IH), 5.48 (s, 2H), 4.62-4.55 (m, 1H), 3.56-3.52 (m, 1H), 3.39-3.39 (m, 4H), 3.31 (t, 7 = 12 Hz,
1H), 1.93 (t, 7= 6 Hz, 4H)； LRMS (electrospray) m/z (M+H)+ 450. 실시예 257. (R)- 1-벤질- N- (8-(사이클로펜틸 (메틸)아미노) -5-메틸- 4- 옥소- 2, 3, 4, 5 -테트라하이드로피리도 [4,3- b] [1,4]싸이아제핀- 3 -일)- 1H- 1,2,4- 트리아졸- 3 -카복사마이드의 제조
Figure imgf000190_0001
단계 1. 목적 화합물 AH1의 제조 화합물 Q2 (100 mg, 0.21 mmol)를 사이클로펜틸아민 (1 mL)에 첨가하여 녹인 후, 100°C에서 16시간 동안교반하였다. 반응 종료후, 반응혼합물은 감압 농축하여 미황색 고체의 목적 화합물 AH1 (70 mg, 100 %)을수득하였다. 단계 2. 목적 화합물 AH2의 제조 화합물 AH1 (70 mg, 0.21 mmol)을 다이클로로메테인 (5 mL)에 첨가하여 녹인 후, 염산 (4> 1,4 -다이옥세인 용액; 250 uL, 0.0011 mmol)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하여 미황색 고체의 목적 화합물 AH2 (67 mg, 100%)를수득하였다. 단계 3. 목적 화합물 AH3의 제조 화합물 AH2 (67 mg, 0.21 mmo 1 ) , EDC (51 mg, 0.41 mmo 1 ) , HOAt (56 mg, 0.41 mmol), 및 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 (51 mg, 0.25 mmol)을 다이클로로메테인 (5 mL)에 희석하고, 트리에틸아민 (0.12 mL, 0.82 mmol)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압하여 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 흰색 고체의 목적 화합물 AH3 (41 mg, 42%)를 수득하였다. 단계 4. 목적 화합물 AH4의 제조 화합물 AH4 (46 mg, 0.093 mmol)에 포름산 (45 甘 L, 1.17 mmol) 및 포름알데히드 수용액 (5 mL)를 첨가하고, 환류되는 조건하에 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 탄산수소나트륨 수용액으로 염기화 시켜주고, 물과 염화나트륨 수용액을 이용하여 세척하였다. 유기층은 에틸아세티이트를 이용하여 추출하였다. 유기층은 황산 나트륨으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (Et0Ac：Hexane=l：10에서 EtOAc)로 정제하여 실시예 257에 따른 흰색 고체의 목적 화합물 AH4 (27 mg, 57%)를수득하였다. 실시예 258내지 260. 실시예 257의 단계 1에서 사이클로펜틸아민에 대응하는 화합물로서 하기 표 37의 반응물 1을, 단계 3에서 1-벤질- 1H- 1,2, 4 -트리아졸 -3 -카르복실산에 대응하는 화합물로서 하기 표 37의 반응물 2를 이용한 것을 제외하고는, 실시예 257의 화합물 AH4를 제조하는 방법과 실질적으로 동일한 방법으로 실시예 258 내지 260에 따른화합물들을 제조하였다. [표 37]
Figure imgf000192_0001
실시 예 257 내지 260에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR 분석 결과는 하기 표 38에 나타낸다 . 1H), 1.93 (t, 7=6 Hz, 4H); LRMS (electrospray) m/z (M+H) + 450. Example 257. (R)-1-Benzyl-N-(8-(cyclopentyl) (methyl) amino) -5-methyl- 4- oxo- 2, 3, 4, 5 -tetrahydropyrido [4,3- b] [1,4] thiazepin- 3 -yl)- 1H- 1 Preparation of ,2,4-triazole-3-carboxamide
Figure imgf000190_0001
Step 1. Preparation of target compound AH1 Compound Q2 (100 mg, 0.21 mmol) was dissolved in cyclopentylamine (1 mL) and stirred at 100°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound AH1 (70 mg, 100%) as a pale yellow solid. Step 2. Preparation of target compound AH2 After dissolving compound AH1 (70 mg, 0.21 mmol) in dichloromethane (5 mL), hydrochloric acid (4> 1,4-dioxane solution; 250 uL, 0.0011 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound AH2 (67 mg, 100%) as a pale yellow solid. Step 3. Preparation of target compound AH3 Compound AH2 (67 mg, 0.21 mmo 1 ) , EDC (51 mg, 0.41 mmo 1 ) , HOAt (56 mg, 0.41 mmol), and 1-benzyl-1woo 1,2,4-triazole-3-carboxylic acid (51 mg, 0.25 mmol) were diluted in dichloromethane (5 mL) and triethylamine (0.12 mL, 0.82 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM:Me0H=20:1) to obtain the target compound AH3 (41 mg, 42%) as a white solid. Step 4. Preparation of target compound AH4 To compound AH4 (46 mg, 0.093 mmol) were added formic acid (45 甘 L, 1.17 mmol) and formaldehyde aqueous solution (5 mL), and the mixture was stirred under reflux conditions for 16 hours. After completion of the reaction, the reaction mixture was basified with an aqueous solution of sodium bicarbonate and washed with water and an aqueous solution of sodium chloride. The organic layer was extracted using ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:10 in EtOAc) to obtain the target compound AH4 (27 mg, 57%) according to Example 257 as a white solid. Examples 258 to 260. Reactant 1 in Table 37 below was used as a compound corresponding to cyclopentylamine in step 1 of Example 257, and 1-benzyl-1H- 1,2,4-triazole-3-carboxylate in step 3. Compounds according to Examples 258 to 260 were prepared in substantially the same manner as the method for preparing compound AH4 of Example 257, except that reactant 2 in Table 37 was used as a compound corresponding to the boxylic acid. [Table 37]
Figure imgf000192_0001
The structure and compound name of each of the compounds obtained according to Examples 257 to 260, and NMR analysis results are shown in Table 38 below.
[표 38]
Figure imgf000192_0002
Figure imgf000193_0002
실시예 261. （R）- 5 -벤질- N-（l-메틸- 2 -옥소- 8-（（4,4,4- 트리플루오로뷰틸）아미노）- 1,2, 3, 4 -테트라하이드로피리도［3,4- b］［1,4］싸이아제핀- 3 -일）- 1H- 1,2, 4 -트리아졸 -3 —카복사마이드의 제조
Figure imgf000193_0001
[Table 38]
Figure imgf000192_0002
Figure imgf000193_0002
Example 261. (R)-5-Benzyl-N-(l-methyl-2-oxo-8-((4,4,4-trifluorobutyl)amino)-1,2,3,4-tetra Hydropyrido [3,4- b] [1,4] thiazepine- 3 -yl) - 1H- 1,2, 4 -triazole -3 - Preparation of carboxamides
Figure imgf000193_0001
AI2 AI3 단계 1. 목적 화합물 All의 제조 화합물 S2 （100 mg, 0.21 mmol）에 4, 4, 4 -트리플루오로뷰탄- 1-아민 （1 mL）을 첨가하고 , 100°C에서 24시간 동안 교반하였다. 반응 종료 후 , 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산 나트륨으로 건조한 후 , 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 （DCM：Me0H=20：l）로 정제하여 흰색 포말의 목적 화합물 AU (81 mg, 66%)을수득하였다. 단계 2. 목적 화합물 AI2의 제조 화합물 All (81 mg, 0.14 mmol)을 다이클로로메테인 (5 mL)에 첨가하여 녹인 후, 염산 (4川 1,4 -다이옥세인 용액; 0.17 mL)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하여 흰색 고체의 목적 화합물 AI2 (51 mg, 100%)를수득하였다. 단계 3. 목적 화합물 AI3의 제조 화합물 AI2 (51 mg, 0.14 mmo 1 ) , EDC (38 mg, 0.31 mmo 1 ) , HOAt (42 mg, 0.31 mmol), 및 5 -벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 (38 mg, 0.18 mmol)을 다이클로로메테인 (5 mL)에 희석하고, 트리에틸아민 (0.086 mL, 0.62 mmol)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 실시예 261에 따른 흰색 고체의 목적 화합물 AI3 (31 mg, 39%)를수득하였다. iH NMR (400 MHz, DMSO— d6) 5 8.74 (s, 1H), 8.15 (s, 1H), 7.34-7.25 (m, 5H), 6.83 (s, IH) , 4.57 (m, IH), 4.11 (s, 2H), 3.44-3.38 (m, 3H), 3.31- 3.25 (m, 4H), 2.39-2.35 (m, 2H), 1.79 (m, 2H)； LRMS (electrospray) m/z (M+H)+ 520. 실시예 262. (S)- 1-벤질- N- (5 -메틸- 4 -옥소- 8-(피롤리딘- 1-일)- 2, 3,4,5- 테트라하이드로피리도 [4 , 3- b] [ 1 , 4]옥사제핀- 3 -일 )- 1H- 1 , 2 , 4 -트리아졸- 3- 카복사마이드의 제조
Figure imgf000195_0001
단계 1. 목적 화합물 AK1의 제조 AI2 AI3 Step 1. Preparation of target compound All To compound S2 (100 mg, 0.21 mmol) was added 4,4,4-trifluorobutan-1-amine (1 mL), and stirred at 100°C for 24 hours. did After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM: Me0H = 20: l). Purification gave the target compound AU (81 mg, 66%) as a white foam. Step 2. Preparation of target compound AI2 Compound All (81 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), and then hydrochloric acid (4 River 1,4-dioxane solution; 0.17 mL) was added. . The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound AI2 (51 mg, 100%) as a white solid. Step 3. Preparation of target compound AI3 Compound AI2 (51 mg, 0.14 mmo 1 ), EDC (38 mg, 0.31 mmo 1 ), HOAt (42 mg, 0.31 mmol), and 5-benzyl- 1,2,4 -Triazole-3-carboxylic acid (38 mg, 0.18 mmol) was diluted in dichloromethane (5 mL) and triethylamine (0.086 mL, 0.62 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM: Me0H = 20: l) to obtain the target compound AI3 (31 mg, 39%) according to Example 261 as a white solid. iH NMR (400 MHz, DMSO—d6) 5 8.74 (s, 1H), 8.15 (s, 1H), 7.34-7.25 (m, 5H), 6.83 (s, IH) , 4.57 (m, IH), 4.11 ( s, 2H), 3.44-3.38 (m, 3H), 3.31-3.25 (m, 4H), 2.39-2.35 (m, 2H), 1.79 (m, 2H); LRMS (electrospray) m/z (M+H) ) + 520. Example 262. (S)-1-Benzyl-N-(5-methyl-4-oxo-8-(pyrrolidin-1-yl)-2,3,4,5-tetrahydropyryl Preparation of [4,3-b] [1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide
Figure imgf000195_0001
Step 1. Preparation of target compound AK1
2, 4 -다이클로로- 5 -나이트로피리딘 (10 g, 51.8 mmol)과 18 -크라운- 6 (2.2 g, 8.3 mmol)을 ＞메틸피롤리돈 (41 mL)에 첨가하여 녹인 후, 플루오린화 칼륨 (9.0 g, 155.4 mmol)을 첨가하였다. 반응물은 110°C에서 3시간동안 교반하였다. 반응 종료 후, 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고, 다이에틸에테르와 헥세인을 이용하여 유기층을 추출하였다 . 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (Et0Ac：Hexane=l：20)로 정제하여 노란색 고체의 목적 화합물 AK1After dissolving 2,4-dichloro-5-nitropyridine (10 g, 51.8 mmol) and 18-crown-6 (2.2 g, 8.3 mmol) in >methylpyrrolidone (41 mL), fluorination Potassium (9.0 g, 155.4 mmol) was added. The reaction was stirred at 110 °C for 3 hours. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with diethyl ether and hexane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (Et0Ac:Hexane=l:20) to obtain the target compound AK1 as a yellow solid.
(8.3 g, 98%)을수득하였다. 단계 2. 목적 화합물 AK2의 제조 화합물 AK1 (8.3 g, 51.8 mmol)을 메탄올 (259 mL)에 첨가하여 녹인 후, Pd/C (1.3 g, 12.4 mmol)을 첨가하였다. 수소 분위기 하에 반응물은 40 프사이 (psi.)의 압력으로 상온에서 2시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 셀라이트를 이용하여 여과를 하였고, 감압 농축하여 갈색 고체의 목적 화합물 AK2 (6.7 g, 99%)를수득하였다. 단계 3. 목적 화합물 AK3의 제조 화합물 AK2 (6.7 g, 51.8 mmol), EDC (9.5 g, 77.7 mmol), HOAt (10.6 g, 77.7 mmo 1 ) , 및 AHBoc- 0- *八-뷰틸- L-세린 (AHBoc- 0-*八- butyl- L- serine, 16.2 g, 62.2 mmol)을 다이클로로메테인 (259 mL)에 희석하고, 트리에틸아민 (14.4 mL, 103.6 mmol)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 혼합물은 탄산수소나트륨 수용액으로 반응을 종결한 후, 물과 염화나트륨 수용액을 이용하여 세척하고, 다이클로로메테인을 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：2)로 정제하여 흰색 고체의 목적 화합물 AK3 (12.2 g, 60%)을수득하였다. 단계 4. 목적 화합물 AK4의 제조 화합물 AK3 (12.2 g, 32.7 mmol)을 다이메틸포름아마이드 (252 mL)에 첨가하여 녹인 후, 탄산칼륨 (12.7 g, 39.2 mmol)과 메틸요오드 (2.26 mL, 36.0 mmol)을 첨가하였다. 반응물은 상온에서 3시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고, 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하여 노란색 고체의 목적 화합물 AK4 (12.6 g, 98%)를 수득하였다. 단계 5. 목적 화합물 AK5의 제조 화합물 AK4 (12.7 g, 32.7 mmol )를 다이클로로메테인 (164 mL)에 첨가하여 녹인 후 , 염산 (4> 1 , 4 -다이옥세인 용액 ; 61 mL)을 첨가하였다. 반응물은 상온에서 3일 동안 교반하였다. 반응 종료 후 , 반응 혼합물은 감압 농축하여 흰색 고체의 목적 화합물 AK5 (9 g, 98%)를 수득하였다. 단계 6. 목적 화합물 AK6의 제조 화합물 AK5 (5 g, 21.6 mmol )와 트리틸클로라이드 (6.6 g, 23.8 mmol )를 클로로포름 (216 mL)에 첨가하여 녹인 후 , 트리에틸아민 (6.6 mL , 47.6 mmol )을 0°C에서 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 혼합물은 탄산수소나트륨 수용액으로 반응을 종결한 후 , 다이클로로메테인을 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후 , 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：2)로 정제하여 흰색 고체의 목적 화합물 AK6 (1.8 g, 17%)을 수득하였다. 단계 7. 목적 화합물 AK7의 제조 화합물 AK6 (1.8 g, 3.7 mmol )을 다이메틸설폭사이드 (18.6 mL)에 첨가하여 녹인 후 , 탄산 세슘 (1.8 g, 5.6 mmol )을 첨가하였다. 반응물은 70°C에서 16시간 동안 교반하였다. 반응 종료 후 , 반응 혼합물은 물을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다 . 유기층은 황산마그네슘으로 건조한 후 , 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：5)로 정제하여 흰색 고체의 목적 화합물 AK7(8.3 g, 98%) was obtained. Step 2. Preparation of target compound AK2 Compound AK1 (8.3 g, 51.8 mmol) was dissolved in methanol (259 mL), and then Pd/C (1.3 g, 12.4 mmol) was added. The reactants were stirred for 2 hours at room temperature under a hydrogen atmosphere at a pressure of 40 psi. After completion of the reaction, the reaction mixture was filtered using celite and concentrated under reduced pressure to obtain the target compound AK2 (6.7 g, 99%) as a brown solid. Step 3. Preparation of target compound AK3 Compound AK2 (6.7 g, 51.8 mmol), EDC (9.5 g, 77.7 mmol), HOAt (10.6 g, 77.7 mmo 1 ), and AHBoc-0-*8-butyl-L-serine (AHBoc-0-*8-butyl-L-serine, 16.2 g, 62.2 mmol) was diluted in dichloromethane (259 mL), and triethylamine (14.4 mL, 103.6 mmol) was added. The reaction was stirred at room temperature for 16 hours. After the reaction mixture was terminated with an aqueous solution of sodium hydrogen carbonate, the mixture was washed with water and an aqueous solution of sodium chloride, and the organic layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:2) to obtain the target compound AK3 (12.2 g, 60%) as a white solid. Step 4. Preparation of target compound AK4 After dissolving compound AK3 (12.2 g, 32.7 mmol) in dimethylformamide (252 mL), potassium carbonate (12.7 g, 39.2 mmol) and methyl iodine (2.26 mL, 36.0 mmol) ) was added. The reaction was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. After drying the organic layer with magnesium sulfate, reduced pressure Concentration gave the desired compound AK4 (12.6 g, 98%) as a yellow solid. Step 5. Preparation of target compound AK5 Compound AK4 (12.7 g, 32.7 mmol) was dissolved in dichloromethane (164 mL), and then hydrochloric acid (4> 1,4-dioxane solution; 61 mL) was added. . The reaction was stirred at room temperature for 3 days. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound AK5 (9 g, 98%) as a white solid. Step 6. Preparation of target compound AK6 Compound AK5 (5 g, 21.6 mmol) and tritylchloride (6.6 g, 23.8 mmol) were added and dissolved in chloroform (216 mL), and triethylamine (6.6 mL, 47.6 mmol) was added at 0 °C. The reaction was stirred at room temperature for 16 hours. After the reaction mixture was terminated with an aqueous solution of sodium hydrogen carbonate, the organic layer was extracted using dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:2) to obtain the target compound AK6 (1.8 g, 17%) as a white solid. Step 7. Preparation of target compound AK7 Compound AK6 (1.8 g, 3.7 mmol) was added to and dissolved in dimethyl sulfoxide (18.6 mL), and then cesium carbonate (1.8 g, 5.6 mmol) was added. The reaction was stirred at 70 °C for 16 hours. After completion of the reaction, the reaction mixture was washed with water, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:5) to obtain the target compound AK7 as a white solid.
(1.3 g, 76%)을 수득하였다. 단계 8. 목적 화합물 AK8의 제조 화합물 AK7 (1.3 g, 2.8 mmol)과 탄산칼륨 (1.5 g, 11.3 mmol)을 1,4 - 다이옥세인 (5.6 mL)에 첨가하여 희석하고, 피롤리딘 (0.92 mL, 11.3 mmol)을 첨가하였다. 반응물은 환류되는 조건하에 16시간동안 교반하였다. 반응 종료후, 반응 혼합물은 물을 이용하여 세척하고, 에틸아세테이트를 이용하여 유기증을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：2)로 정제하여 흰색 고체의 목적 화합물 AK8 (1.3 g, 91%)을수득하였다. 단계 9. 목적 화합물 AK9의 제조 화합물 AK8 (1.3 g, 2.6 mmol)을 다이클로로메테인 (12.8 mL)에 첨가하여 녹인 후, 염산 (4川 1,4 -다이옥세인 용액; 6.4 mL)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하여 흰색 고체의 목적 화합물 AK9 (900 mg, 98%)를수득하였다. 단계 10. 목적 화합물 AK10의 제조 화합물 AK9 (400 mg, 1.34 mmol), EDC (409 mg, 3.35 mmol), HOAt (456 mg, 3.35 mmol), 및 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 (544 mg, 2.68 mmol)을 다이클로로메테인 (6.7 mL)에 희석하고, 트리에틸아민 (0.56 mL, 4.02 mmol)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 혼합물은 탄산수소나트륨 수용액으로 반응을 종결한 후, 물과 염화나트륨 수용액을 이용하여 세척하고 , 다이클로로메테인을 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=5：l)로 정제하여 실시예 262에 따른 흰색 고체의 목적 화합물 AK10 (410 mg, 68%)를 수득하였다. 실시예 263 내지 271. 실시 예 262의 단계 8에서 피롤리딘에 대응하는 화합물로서 하기 표 39의 반응물 1을 , 단계 10에서 1-벤질- 1H- 1 , 2 , 4 -트리아졸 - 3 -카르복실산에 대응하는 화합물로서 하기 표 39의 반응물 2를 이용한 것을 제외하고는 , 실시 예 262의 화합물 AK10을 제조하는 방법과 실질적으로 동일한 방법으로 실시 예 263 내지 2기에 따른 화합물들을 제조하였다. (1.3 g, 76%). Step 8. Preparation of target compound AK8 Compound AK7 (1.3 g, 2.8 mmol) and potassium carbonate (1.5 g, 11.3 mmol) were added to 1,4-dioxane (5.6 mL) to dilute, pyrrolidine (0.92 mL) , 11.3 mmol) was added. The reaction was stirred for 16 hours under reflux conditions. After completion of the reaction, the reaction mixture was washed with water, and the organic vapor was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:2) to obtain the target compound AK8 (1.3 g, 91%) as a white solid. Step 9. Preparation of target compound AK9 Compound AK8 (1.3 g, 2.6 mmol) was dissolved in dichloromethane (12.8 mL), and then hydrochloric acid (4 River 1,4-dioxane solution; 6.4 mL) was added. . The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound AK9 (900 mg, 98%) as a white solid. Step 10. Preparation of target compound AK10 Compound AK9 (400 mg, 1.34 mmol), EDC (409 mg, 3.35 mmol), HOAt (456 mg, 3.35 mmol), and 1-benzyl-1woo 1,2,4-tria The sol-3-carboxylic acid (544 mg, 2.68 mmol) was diluted in dichloromethane (6.7 mL) and triethylamine (0.56 mL, 4.02 mmol) was added. The reaction was stirred at room temperature for 16 hours. After the reaction mixture was terminated with an aqueous solution of sodium hydrogen carbonate, the mixture was washed with water and an aqueous solution of sodium chloride, and the organic layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc: Hexane = 5: l) to Example 262. The target compound AK10 (410 mg, 68%) was obtained as a white solid. Examples 263 to 271. Reactant 1 in Table 39 below was used as a compound corresponding to pyrrolidine in step 8 of Example 262, and 1-benzyl-1H-1,2,4-triazole-3-carboxylate in step 10. Compounds according to Examples 263 to 2 were prepared in substantially the same manner as the method for preparing compound AK10 of Example 262, except that reactant 2 in Table 39 was used as a compound corresponding to the boxylic acid.
[표 39]
Figure imgf000199_0001
실시 예 262 내지 2기에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR 분석 결과는 하기 표 40에 나타낸다. [Table 39]
Figure imgf000199_0001
The structure and compound name of each of the compounds obtained according to Examples 262 to 2, and NMR analysis results are shown in Table 40 below.
[표 4이
Figure imgf000199_0002
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0002
실시예 272. (S)- 1-벤질- N- (8-(다이메틸아미노)- 5 -메틸- 4 -옥소- 2, 3,4,5- 테트라하이드로피리도 [4 , 3- b] [ 1 , 4]옥사제핀- 3 -일 )- 1H- 1 , 2 , 4 -트리아졸- 3 - 카복사마이드의 제조
Figure imgf000202_0001
단계 1. 목적 화합물 AL1의 제조 화합물 AK7 (40 mg, 0.09 mmol )을 다이메틸포름아마이드 (0.3 mL)에 첨가하여 녹인 후 , 수산화나트륨 (7.0 mg, 0.18 mmol )을 첨가하였다. 반응물은 130°C에서 16시간 동안 교반하였다. 반응 종료 후 , 반응 혼합물은 물을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다 . 유기층은 황산마그네슘으로 건조한 후 , 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：2)로 정제하여 흰색 고체의 목적 화합물 AL1 (53 mg, 98 %)을 수득하였다. 단계 2. 목적 화합물 AL2의 제조 화합물 AL1 (53 mg, 0.11 mmol)을 다이클로로메테인 (0.56 mL)에 첨가하여 녹인 후, 염산 (4> 1,4 -다이옥세인 용액; 0.28 mL)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하여 흰색 고체의 목적 화합물 AL2 (27 mg, 98%)를수득하였다. 단계 3. 목적 화합물 AL3의 제조 화합물 AL2 (14 mg, 0.05 mmo 1 ) , EDC (11 mg, 0.09 mmo 1 ) , HOAt (12 mg, 0.09 mmol), 및 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 (14 mg, 0.07 mmol)을 다이클로로메테인 (0.9 mL)에 희석하고, 트리에틸아민 (0.02 mL, 0.14 mmol)을 0°C에서 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 혼합물은 탄산수소나트륨 수용액으로 반응을 종결한 후, 물과 염화나트륨 수용액을 이용하여 세척하고 , 다이클로로메테인을 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=5：l)로 정제하여 흰색 고체의 목적 화합물 AL3 (6 mg, 31%)을수득하였다. iH NMR (400 MHz, Chloroform-d) 5 8.10-8.07 (m, 2H), 8.03 (s, 1H), 7.39 (m, 3H), 7.31 (m, 2H), 6.29 (s, IH), 5.40 (s, 2H), 5.18-5.12 (m, IH), 4.74 (t, J = 8.2 Hz, IH), 4.27 (t, J =10.2 Hz, IH), 3.42 (s, 3H), 3.12 (s, 6H) : LRMS (electrospray) m/z (M+H)+ 422. 실시예 273. (S)- 5 -벤질- N- (8-(다이메틸아미노)- 5 -메틸- 4 -옥소- 2, 3,4,5- 테트라하이드로피리도 [4 , 3- b] [ 1 , 4]옥사제핀- 3 -일 )- 1H- 1 , 2 , 4 -트리아졸- 3- 카복사마이드의 제조 실시예 272의 단계 3에서 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 대신 5 -벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산을 이용한 것을 제외하고는실시예 272의 화합물 AL3를 제조하는 것과 실질적으로 동일한 방법으로 실시예 273에 따른 흰색 고체의 화합물을수득하였다. iH NMR (400 MHz, Chloroform-d) 5 8.12 (d, J= 6.8 Hz, 1H), 8.07 (s, 1H), 8.02 (s, IH), 7.31-7.28 (m, 5H), 6.28 (s, IH), 5.15-5.09 (m, IH), 4.66 (t, J = 8.2 Hz, IH), 4.28 (t, J =10.8 Hz, IH), 4.17 (s, 2H), 3.40 (s, 3H),[Table 4
Figure imgf000199_0002
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0002
Example 272. (S)-1-Benzyl-N-(8-(dimethylamino)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b] Preparation of [1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide
Figure imgf000202_0001
Step 1. Preparation of target compound AL1 Compound AK7 (40 mg, 0.09 mmol) was dissolved in dimethylformamide (0.3 mL), and then sodium hydroxide (7.0 mg, 0.18 mmol) was added. The reaction was stirred at 130 °C for 16 hours. After completion of the reaction, the reaction mixture was washed with water, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:2) to obtain the target compound AL1 (53 mg, 98%) as a white solid. Step 2. Preparation of target compound AL2 After compound AL1 (53 mg, 0.11 mmol) was added to and dissolved in dichloromethane (0.56 mL), hydrochloric acid (4> 1,4-dioxane solution; 0.28 mL) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound AL2 (27 mg, 98%) as a white solid. Step 3. Preparation of target compound AL3 Compound AL2 (14 mg, 0.05 mmo 1 ), EDC (11 mg, 0.09 mmo 1 ), HOAt (12 mg, 0.09 mmol), and 1-benzyl- 1,2,4 -Triazole-3-carboxylic acid (14 mg, 0.07 mmol) was diluted in dichloromethane (0.9 mL) and triethylamine (0.02 mL, 0.14 mmol) was added at 0°C. The reaction was stirred at room temperature for 16 hours. After the reaction mixture was terminated with an aqueous solution of sodium hydrogen carbonate, the mixture was washed with water and an aqueous solution of sodium chloride, and the organic layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc: Hexane = 5: l) to obtain the target compound AL3 (6 mg, 31%) as a white solid. iH NMR (400 MHz, Chloroform-d) 5 8.10-8.07 (m, 2H), 8.03 (s, 1H), 7.39 (m, 3H), 7.31 (m, 2H), 6.29 (s, IH), 5.40 ( s, 2H), 5.18-5.12 (m, IH), 4.74 (t, J = 8.2 Hz, IH), 4.27 (t, J =10.2 Hz, IH), 3.42 (s, 3H), 3.12 (s, 6H) ): LRMS (electrospray) m/z (M+H) + 422. Example 273. (S)-5-benzyl-N-(8-(dimethylamino)-5-methyl-4-oxo-2, Preparation of 3,4,5-tetrahydropyrido [4,3-b] [1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide In step 3 of Example 272, 5-benzyl-1-1,2,4-triazole-3-carboxylic acid was used instead of 1-benzyl-1-1,2,4-triazole-3-carboxylic acid. A white solid compound according to Example 273 was obtained in substantially the same manner as in Example 272, except for the preparation of compound AL3. iH NMR (400 MHz, Chloroform-d) 5 8.12 (d, J= 6.8 Hz, 1H), 8.07 (s, 1H), 8.02 (s, IH), 7.31-7.28 (m, 5H), 6.28 (s, IH), 5.15-5.09 (m, IH), 4.66 (t, J = 8.2 Hz, IH), 4.28 (t, J =10.8 Hz, IH), 4.17 (s, 2H), 3.40 (s, 3H),
3.11 (s , 6H) : LRMS (electrospray) m/z (M+H)+ 422. 실시예 274. (R)- N- (8 -아미노- 5 -메틸- 4 -옥소- 2, 3,4,5- 테트라하이드로피리도 [4,3- b] [1,4]싸이아제핀- 3 -일)- 5 -벤질- 1H- 1,2, 4 -트리아졸-3.11 (s, 6H): LRMS (electrospray) m/z (M+H) + 422. Example 274. (R)-N-(8-amino-5-methyl-4-oxo-2, 3,4 ,5- tetrahydropyrido [4,3- b] [1,4] thiazepin- 3 -yl) - 5 -benzyl- 1H- 1,2,4 -triazole-
3 -카복사마이드의 제조
Figure imgf000204_0001
단계 1. 목적 화합물 AM1의 제조 화합물 Q2 (500 mg, 1.03 mmol)를 7메톡시벤질아민 (3 mL)에 첨가하고, 100°C에서 16시간 동안 교반하였다. 반응 종료 후, 물을 이용하여 세척하고, 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조하고, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (Et0Ac：Hexane=l：10에서 EtOAc)로 정제하여 흰색 포말의 목적 화합물 AM1 (347 mg, 57 %)을수득하였다. 단계 2. 목적 화합물 AM2의 제조 화합물 AM1 (347 mg, 0.591 mmol)을 다이클로로메테인 (5 mL)에 첨가하여 녹인 후, 염산 (4> 1,4 -다이옥세인 용액; 740 uL, 0.296 mmol)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하여 미황색 고체의 목적 화합물 AM2 (225 mg, 91 %)를수득하였다. 단계 3. 목적 화합물 AM3의 제조 화합물 AM2 (225 mg, 0.591 mmol)와 5 -벤질- 1우 1,2, 4 -트리아졸 -3- 카르복실산 (133 mg, 0.65 mmol)을 다이클로로메테인 (5 mL)에 희석하고,
Figure imgf000205_0001
다이아이소프로필아민 (0.21 mL, 1.2 mmol)과 T3P (50% 에틸아세테이트 용액 ; 0.71 mL, 1.2 mmol)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 흰색 포말의 목적 화합물 AM3 (170 mg, 54%)을수득하였다. 단계 4. 목적 화합물 AM4의 제조 화합물 AM3 (20 mg, 0.038 mmol)를 트리플루오로아세트산 (1 mL)에 첨가하여 녹인 후, 환류되는 조건 하에 16시간 동안 교반하였다. 반응 혼합물은 탄산수소나트륨 수용액으로 반응을 종결한 후, 물과 염화나트륨 수용액을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다 . 유기층은 황산 나트륨으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l： 10 今 100% EtOAc)로 정제하여 실시예 274에 따른 흰색 고체의 목적 화합물 AM4 (14 mg, 87%)를수득하였다. iH NMR (400 MHz, DMSO— d6) 5 8.29 (m, 1H), 8.08 (s, 1H), 7.32-7.25 (m, 4H), 6.70 (s, IH) , 6.34 (s, 2H), 4.65-4.59 (m, IH), 4.13 (s, 2H), 3.47 (q, J= 4.4 Hz, 11.6 Hz, IH), 3.32 (s, IH), 3.23 (s, 3H)； LRMS (electrospray) m/z (M+H)+ 410. 실시예 275. (R)- 5 -벤질- N- (5 -메틸- 4 -옥소- 8- (3,3,3- 트리플루오로프로판아미도)- 2 , 3 , 4 , 5 -테트라하이드로피리도 [4 , 3- b] [ 1 , 4]싸이아제핀- 3 -일 )- 1H- 1 , 2 , 4 -트리아졸- 3 -카복사마이드의 제조
Figure imgf000206_0001
화합물 AM4 (7 mg, 0.017 mmol)와 3, 3, 3 -트리플루오로프로피오닐 클로라이드 (2.12 uL, 0.0342 mmol)> 다이클로로메테인 (2 mL)에 첨가하여 녹인 후, 트리에틸아민 (4.77 uL, 0.0342 mmoL)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (Et0Ac：hexane=l：10에서 EtOAc)로 정제하여 실시예 275에 따른 흰색 고체의 목적 화합물 AM5 (6 mg, 75%)를수득하였다. iH NMR (400 MHz, DMSO— d6) 5 11.20 (s, IH), 8.59 (s, IH), 8.48 (s, IH), 7.33-7.25 (s, 6H), 4.64-4.58 IH), 4.13 (s, 2H), 3.70-4.58 (m, 5H), 3.33 (s , 3H) : LRMS (electrospray) m/z (M+H)+520. 실시예 276. (R)- 5 -벤질- N- (8-(다이메틸아미노)- 5 -메틸- 4 -옥소- 2, 3,4,5- 테트라하이드로피리도 [4,3- b] [1 ,4]싸이아제핀- 3 -일 )-1오-1,2,4-트리아졸- 3- 카복사마이드의 제조
Figure imgf000207_0001
단계 1. 목적 화합물 AN1의 제조 화합물 AG2 (300 mg, 0.62 mmol)를 다이메틸아민 용액 (2M 메탄올용액;3-Manufacture of carboxamides
Figure imgf000204_0001
Step 1. Preparation of target compound AM1 Compound Q2 (500 mg, 1.03 mmol) was added to 7methoxybenzylamine (3 mL) and stirred at 100°C for 16 hours. After completion of the reaction, the mixture was washed with water, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography. (EtOAc:Hexane=l:EtOAc at 10) to obtain the target compound AM1 (347 mg, 57%) as a white foam. Step 2. Preparation of target compound AM2 After dissolving compound AM1 (347 mg, 0.591 mmol) in dichloromethane (5 mL), hydrochloric acid (4> 1,4-dioxane solution; 740 uL, 0.296 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound AM2 (225 mg, 91%) as a pale yellow solid. Step 3. Preparation of target compound AM3 Compound AM2 (225 mg, 0.591 mmol) and 5-benzyl-1woo 1,2,4-triazole-3-carboxylic acid (133 mg, 0.65 mmol) were mixed with dichloromethane. (5 mL),
Figure imgf000205_0001
Diisopropylamine (0.21 mL, 1.2 mmol) and T 3 P (50% ethyl acetate solution; 0.71 mL, 1.2 mmol) were added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM: Me0H = 20: l) to obtain the target compound AM3 (170 mg, 54%) as a white foam. Step 4. Preparation of target compound AM4 Compound AM3 (20 mg, 0.038 mmol) was added to trifluoroacetic acid (1 mL) to dissolve, and stirred under reflux conditions for 16 hours. After the reaction mixture was terminated with an aqueous solution of sodium hydrogen carbonate, the mixture was washed with water and an aqueous solution of sodium chloride, and the organic layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc: Hexane = l: 10 今 100% EtOAc) to Example 274. The target compound AM4 (14 mg, 87%) was obtained as a white solid. iH NMR (400 MHz, DMSO—d6) 5 8.29 (m, 1H), 8.08 (s, 1H), 7.32-7.25 (m, 4H), 6.70 (s, IH) , 6.34 (s, 2H), 4.65- 4.59 (m, IH), 4.13 (s, 2H), 3.47 (q, J= 4.4 Hz, 11.6 Hz, IH), 3.32 (s, IH), 3.23 (s, 3H); LRMS (electrospray) m/z (M+H) + 410. Example 275. (R)-5-Benzyl-N-(5-methyl-4-oxo-8-(3,3,3-trifluoropropanamido)-2, Preparation of 3,4,5-tetrahydropyrido[4,3-b][1,4]thiazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide
Figure imgf000206_0001
Compound AM4 (7 mg, 0.017 mmol) and 3,3,3-trifluoropropionyl chloride (2.12 uL, 0.0342 mmol)> were added to dichloromethane (2 mL) to dissolve, and triethylamine (4.77 uL , 0.0342 mmoL) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (Et0Ac: hexane = l: 10 to EtOAc) to obtain the target compound AM5 (6 mg, 75%) according to Example 275 as a white solid. iH NMR (400 MHz, DMSO—d6) 5 11.20 (s, IH), 8.59 (s, IH), 8.48 (s, IH), 7.33-7.25 (s, 6H), 4.64-4.58 IH), 4.13 (s , 2H), 3.70-4.58 (m, 5H), 3.33 (s, 3H): LRMS (electrospray) m/z (M+H) + 520. Example 276. (R)-5-Benzyl-N-(8-(dimethylamino)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b] Preparation of [1,4]thiazepin-3-yl)-1o-1,2,4-triazole-3-carboxamide
Figure imgf000207_0001
Step 1. Preparation of target compound AN1 Compound AG2 (300 mg, 0.62 mmol) was dissolved in a dimethylamine solution (2M methanol solution;
2 mL)에 첨가하고, 90°C에서 24시간 동안 교반하였다. 반응 혼합물은 물을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다 . 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：5)로 정제하여 노란색 오일의 목적 화합물 AN1 (157 mg, 51%)을수득하였다. 단계 2. 목적 화합물 AN2의 제조 화합물 AN1 (156 mg, 0.31 mmol)을 다이클로로메테인 (2 mL)에 첨가하여 녹인 후, 염산 (4川 1,4 -다이옥세인 용액; 0.4 mL)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하여 흰색 고체의 목적 화합물 AN2 (85 mg, 97%)를수득하였다. 단계 3. 목적 화합물 AN3의 제조 화합물 AN2 (85 mg, 0.3 mmol)와 5 -벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산2 mL) and stirred at 90 °C for 24 hours. The reaction mixture was washed with water, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:5) to obtain the target compound AN1 (157 mg, 51%) as a yellow oil. Step 2. Preparation of target compound AN2 After dissolving compound AN1 (156 mg, 0.31 mmol) in dichloromethane (2 mL), hydrochloric acid (4 River 1,4-dioxane solution; 0.4 mL) was added. . The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound AN2 (85 mg, 97%) as a white solid. Step 3. Preparation of target compound AN3 Compound AN2 (85 mg, 0.3 mmol) with 5-benzyl-1woo 1,2,4-triazole-3-carboxylic acid
(92 mg, 0.45 mmol)을 다이클로로메테인 (1.7 mL)에 희석하고,
Figure imgf000208_0001
다이아이소프로필아민 (0.12 mL, 0.6 mmol)과 T3P (50% 에틸아세테이트 용액 ;(92 mg, 0.45 mmol) was diluted in dichloromethane (1.7 mL),
Figure imgf000208_0001
Diisopropylamine (0.12 mL, 0.6 mmol) and T 3 P (50% ethyl acetate solution;
0.36 mL, 0.12 mmol)을 0°C에서 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고, 에틸아세테이트를 이용하여 유기층을 추출하였다 . 유기층은 황산 나트륨으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 실시예 267에 따른 옅은 황갈색 고체의 목적 화합물 AN3 (9 mg, 5%)를수득하였다. iH NMR (400 MHz, Chloroform-d) 5 8.21 (d, J= 8.8 Hz, 1H), 8.09 (s, 1H), 7.31-7.27 (m, 5H), 6.75 (s, IH), 4.90-4.86 (m, IH), 4.17 (s, 2H), 3.80- 3.76 (m, IH), 3.38 (s, 3H), 3.13 (s, 6H), 2.94 (t, 7 = 11 Hz, IH)； LRMS (electrospray) m/z (M+H)+ 438. 실시예 277. (R)- 5 -벤질- N- (8-(다이메틸아미노)- 1-메틸- 2 -옥소- 1,2, 3,4- 테트라하이드로피리도 [3 , 4- b] [ 1 , 4]싸이아제핀- 3 -일 )- 1H- 1 , 2 , 4 -트리아졸- 3 - 카복사마이드의 제조
Figure imgf000208_0002
단계 1. 목적 화합물人이의 제조 화합물 S2 (200 mg, 0.41 mmol)를 다이메틸아민 용액 (2M 메탄올 용액, 2 mL)에 첨가하고, 110°C에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 물을 이용하여 세척하고, 에틸아세테이트를 이용하여 유기증을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：5)로 정제하여 노란색 오일의 목적 화합물 A01 (100 mg, 49%)을수득하였다. 단계 2. 목적 화합물 A02의 제조 화합물 A01 (100 mg, 0.202 mmol)을 다이클로로메테인 (2 mL)에 첨가하여 녹인 후, 염산 (4川 1,4 -다이옥세인 용액; 0.25 mL)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하여 흰색 고체의 목적 화합물 A02 (36 mg, 62%)를수득하였다. 단계 3. 목적 화합물 A03의 제조 화합물 A02 (36 mg, 0.125 mmol)과 5 -벤질- 1우 1,2, 4 -트리아졸 -3- 카르복실산 (38 mg, 0.187 mmol)을 다이클로로메테인 (0.7 mL)에 희석하고,
Figure imgf000209_0001
다이아이소프로필아민 (0.045 mL, 0.25 mmol)과 T3P (50% 에틸아세테이트 용액 ; 0.15 mL, 0.25 mmol)을 0°C에서 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다 . 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 실시예 277에 따른 옅은 황갈색 고체의 목적 화합물 A03 (41 mg, 75%)를수득하였다. iH NMR (400 MHz, Chloroform-d) 5 8.32 (s, 1H), 8.07 (d, J = 5.2 Hz,0.36 mL, 0.12 mmol) was added at 0 °C. The reaction was stirred at room temperature for 16 hours. The reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM:Me0H=20:1) to obtain the desired compound AN3 (9 mg, 5%) according to Example 267 as a light tan solid. iH NMR (400 MHz, Chloroform-d) 5 8.21 (d, J= 8.8 Hz, 1H), 8.09 (s, 1H), 7.31-7.27 (m, 5H), 6.75 (s, IH), 4.90-4.86 ( m, IH), 4.17 (s, 2H), 3.80- 3.76 (m, IH), 3.38 (s, 3H), 3.13 (s, 6H), 2.94 (t, 7 = 11 Hz, IH); ) m/z (M+H) + 438. Example 277. (R)-5-Benzyl-N-(8-(dimethylamino)-1-methyl-2-oxo-1,2, 3,4 - Tetrahydropyrido [3, 4- b] [1, 4] thiazepin- 3 -yl) - 1H- 1, 2, 4 -triazole- 3 - Preparation of carboxamides
Figure imgf000208_0002
Step 1. Preparation of target compound 人 This compound S2 (200 mg, 0.41 mmol) was added to a dimethylamine solution (2M methanol solution, 2 mL), and stirred at 110°C for 16 hours. After completion of the reaction, the reaction mixture was washed with water, and the organic vapor was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:5) to obtain the target compound A01 (100 mg, 49%) as a yellow oil. Step 2. Preparation of target compound A02 After dissolving compound A01 (100 mg, 0.202 mmol) in dichloromethane (2 mL), hydrochloric acid (4 River 1,4-dioxane solution; 0.25 mL) was added. . The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound A02 (36 mg, 62%) as a white solid. Step 3. Preparation of target compound A03 Compound A02 (36 mg, 0.125 mmol) and 5-benzyl-1woo 1,2,4-triazole-3-carboxylic acid (38 mg, 0.187 mmol) were dissolved in dichloromethane. (0.7 mL),
Figure imgf000209_0001
Diisopropylamine (0.045 mL, 0.25 mmol) and T 3 P (50% ethyl acetate solution; 0.15 mL, 0.25 mmol) were added at 0°C. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM:Me0H=20:1) to obtain the desired compound A03 (41 mg, 75%) according to Example 277 as a light tan solid. iH NMR (400 MHz, Chloroform-d) 5 8.32 (s, 1H), 8.07 (d, J = 5.2 Hz,
1H), 7.34-7.26 (m, 5H), 6.30 (s, IH), 4.83-4.76 (m, IH), 4.15 (s, 2H), 3.72- 3.68 (m, IH), 3.42 (s, 3H), 3.13 (s, 6H), 2.84 (t, J = 11.2 Hz, IH)； LRMS (electrospray) m/z (M+H)+ 438. 실시예 278. (S)- 5 -벤질- N- (5 -메틸- 8-(피롤리딘- 1-일 )- 4 -싸이옥소- 2, 3, 4, 5 ■테트라하이드로피리도 [4,3- b] [1,4]싸이아제핀- 3 -일)- 1H- 1,2, 4 -트리아졸- 3 -카복사마이드의 제조
Figure imgf000210_0001
단계 1. 목적 화합물 API의 제조 화합물 A4 (500 mg, 1.45 mmol)를 톨루엔 (27 mL)에 첨가하여 녹인 후, 라웨슨 시약 (883 mg, 2.19 mmol)을 첨가하였다. 반응물은 110°C에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 물을 이용하여 세척하고, 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：5)로 정제하여 노란색 고체의 목적 화합물 API (110 mg, 21 %)을 수득하였다. 단계 2. 목적 화합물 AP2의 제조 화합물 API (110 mg, 0.31 mmol)과 탄산칼륨 (169 mg, 1.22 mmol)을 1,4- 다이옥세인 (0.6 mL)에 희석하고, 피롤리딘 (0.1 mL, 1.22 mmol)을 첨가하였다. 반응물은 환류되는 조건 하에 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 물을 이용하여 세척하고, 에틸아세테이트를 이용하여 유기증을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：5)로 정제하여 노란색 고체의 목적 화합물 AP2 (22 mg, 18%)를수득하였다. 단계 3. 목적 화합물 AP3의 제조 화합물 AP2 (22 mg, 0.06 mmol)를 다이클로로메테인 (0.4 mL)에 첨가하여 녹인 후, 염산 (4川 1,4 -다이옥세인 용액; 0.15 mL)을 첨가하였다. 반응물은 상온에서 16시간 동안교반하였다. 반응 종료후, 반응 혼합물은 감압 농축하여 , 흰색 고체의 목적 화합물 AP3 (21 mg, 98%)를수득하였다. 단계 4. 목적 화합물 AP4의 제조 화합물 AP3 (21 mg, 0.06 mmol)과 5 -벤질- 1우 1,2, 4 -트리아졸 -3- 카르복실산 (17 mg, 0.08 mmol) 을 다이클로로메테인 (0.33 mL)에 희석하고,
Figure imgf000211_0001
다이아이소프로필아민 (0.02 mL, 0.11 mmol)과 T3P (50% 에틸아세테이트 용액 ; 0.07 mL, 0.11 mmol)을 0°C에서 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다 . 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=5：l)로 정제하여 옅은 황갈색 고체의 목적 화합물1H), 7.34-7.26 (m, 5H), 6.30 (s, IH), 4.83-4.76 (m, IH), 4.15 (s, 2H), 3.72- 3.68 (m, IH), 3.42 (s, 3H) , 3.13 (s, 6H), 2.84 (t, J = 11.2 Hz, IH); LRMS (electrospray) m/z (M+H) + 438. Example 278. (S)-5-benzyl-N- ( 5-methyl-8-(pyrrolidin-1-yl)-4-thioxo-2, 3, 4, 5 tetrahydropyrido [4,3- b] [1,4] thiazepine- 3 Preparation of -yl)- 1H- 1,2, 4 -triazole- 3 -carboxamide
Figure imgf000210_0001
Step 1. Preparation of target compound API Compound A4 (500 mg, 1.45 mmol) was added to toluene (27 mL) to dissolve, Lawesson's reagent (883 mg, 2.19 mmol) was added. The reaction was stirred at 110 °C for 16 hours. After completion of the reaction, the reaction mixture was washed with water, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:5) to obtain the target compound API (110 mg, 21%) as a yellow solid. Step 2. Preparation of target compound AP2 Compound API (110 mg, 0.31 mmol) and potassium carbonate (169 mg, 1.22 mmol) were diluted in 1,4-dioxane (0.6 mL) and pyrrolidine (0.1 mL, 1.22 mmol) was added. The reaction was stirred for 16 hours under reflux conditions. After completion of the reaction, the reaction mixture was washed with water, and the organic vapor was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:5) to obtain the target compound AP2 (22 mg, 18%) as a yellow solid. Step 3. Preparation of target compound AP3 After dissolving compound AP2 (22 mg, 0.06 mmol) in dichloromethane (0.4 mL), hydrochloric acid (4 River 1,4-dioxane solution; 0.15 mL) was added. . The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound AP3 (21 mg, 98%) as a white solid. Step 4. Preparation of target compound AP4 Compound AP3 (21 mg, 0.06 mmol) and 5-benzyl-1woo 1,2,4-triazole-3-carboxylic acid (17 mg, 0.08 mmol) were mixed with dichloromethane. (0.33 mL),
Figure imgf000211_0001
Diisopropylamine (0.02 mL, 0.11 mmol) and T 3 P (50% ethyl acetate solution; 0.07 mL, 0.11 mmol) were added at 0°C. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc: Hexane = 5: l) to obtain the target compound as a light tan solid.
AP4 (13 mg, 48%)를수득하였다. iH NMR (400 MHz, Chloroform-d) 5 8.79 (d, J = 8.0 Hz, 1H), 8.01 (s,AP4 (13 mg, 48%) was obtained. iH NMR (400 MHz, Chloroform-d) 5 8.79 (d, J = 8.0 Hz, 1H), 8.01 (s,
1H), 7.24-7.20 (m, 5H), 6.58 (s, IH), 5.09-5.03 (m, IH), 4.15 (s, 2H), 3.79 (s, 3H), 3.74-3.70 (m, IH), 3.46 (m, 4H), 2.97 (t, J = 11.0 Hz, IH), 2.03 (m, 4H) : LRMS (electrospray) m/z (M+H)+ 480. 실시예 279. (R)- 5- (2 -플루오로벤질)- N- (5 -메틸- 8-1H), 7.24-7.20 (m, 5H), 6.58 (s, IH), 5.09-5.03 (m, IH), 4.15 (s, 2H), 3.79 (s, 3H), 3.74-3.70 (m, IH) , 3.46 (m, 4H), 2.97 (t, J = 11.0 Hz, IH), 2.03 (m, 4H): LRMS (electrospray) m/z (M+H) + 480. Example 279. (R)- 5- (2 -fluorobenzyl) -N- (5 -methyl- 8-
(메틸 (테트라하이드로- 2H-파이란- 4 -일 )아미노) -4 -옥소- 2 ,3,4,5- 테트라하이드로피리도 [4,3- b] [1 ,4]싸이아제핀- 3 -일 )-1오-1,2,4-트리아졸- 3- 카복사마이드의 제조
Figure imgf000212_0001
단계 1. 목적 화합물 AU1의 제조 화합물 A4 (300 mg, 0.87 mmol ) Pd(0Ac)2 (39 mg, 0.17 mmol), BI NAP(methyl (tetrahydro-2H-pyran-4-yl)amino)-4-oxo-2,3,4,5-tetrahydropyrido [4,3- b] [1,4] thiazepine-3 Preparation of -yl)-1oh-1,2,4-triazole-3-carboxamide
Figure imgf000212_0001
Step 1. Preparation of target compound AU1 Compound A4 (300 mg, 0.87 mmol) Pd(0Ac) 2 (39 mg, 0.17 mmol), BI NAP
(217 mg, 0.35 mmol), 및 탄산세슘 (847 mg, 2.62 mmol)을 톨루엔 (3.6 mL)에 희석하고, 4 -아미노테트라 하이드로파이란 (132 mg, 1.31 mmol)을 첨가하였다. 반응물은 85°C에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 셀라이트를 이용하여 여과를 하였고, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：2)로 정제하여 흰색 고체의 목적 화합물 AU1 (221 mg, 62%)를수득하였다. 단계 2. 목적 화합물 AU2의 제조 화합물 AU1 (221 mg, 0.54 mmol)을 다이클로로메테인 (2 mL)에 첨가하여 녹인 후, 염산 (4> 1,4 -다이옥세인 용액; 0.68 mL, 2.7 mmol)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하여 , 옅은 황갈색 고체의 목적 화합물 AU2 (206 mg, 99%)를수득하였다. 단계 3. 목적 화합물 AU3의 제조 화합물 AU2 (95 mg, 0.25 mmol)와 트리틸클로라이드 (76 mg, 0.28 mmol)를 다이클로로메테인 (2.5 mL)에 첨가하여 녹인 후, 트리에틸아민 (0.1 mL, 0.75 mmol)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 투명한오일의 목적 화합물 AU3 (68 mg, 50%)을수득하였다. 단계 4. 목적 화합물 AU4의 제조 화합물 AU3 (58 mg, 0.11 mmol)을 다이메틸포름아마이드 (2 mL)에 첨가하여 녹인 후, 수소화나트륨 (8 mg, 0.32 mmol)와 메틸요오드 (8 yL, 0.13 mmol)를 첨가하였다. 반응물은 상온에서 1시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고, 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하여 투명한오일의 목적 화합물 AU4 (60 mg, 99%)를수득하였다. 단계 5. 목적 화합물 AU5의 제조 화합물 AU4 (60 mg, 0.11 mmol)를 다이클로로메테인 (2 mL)에 첨가하여 녹인 후, 염산 (4> 1,4 -다이옥세인 용액; 0.13 mL, 0.53 mmol)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 감압 농축하여 갈색 고체의 목적 화합물 AU5 (42 mg, 99%)를수득하였다. 단계 6. 목적 화합물 AU6의 제조 화합물 AU5 (70 mg, 0.11 mmol)오｝ 5 - [(2 -플루오로페닐)메틸]- 4우 1,2,4- 트리아졸 -3 -카르복실산 (35 mg, 0.16 mmol)을 테트라하이드로퓨란 (2 mL)에 희석하고 <>다 이아이소프로필아민 (0.04 mL, 0.21 mmol)과 T3P (50% 에틸아세테에트 용액; 0.62 mL, 0.21 mmol)를 0°C에서 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고 , 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：Me0H=20：l)로 정제하여 흰색 고체의 목적 화합물 AU6 (25 mg, 45%)를수득하였다. 실시예 280및 281. 실시예 279의 단계 1에서 4 -아미노테트라 하이드로파이란과 대응하는 화합물로서 하기 표 41의 반응물 1을, 단계 6의 5 - [(2 -플루오로페닐)메틸]- 4우 1,2, 4 -트리아졸 -3 -카르복실산과 대응하는 화합물로서 하기 표 41의 반응물 2를 이용한 것을 제외하고는, 실시예 279의 화합물 AU6을 제조하는 것과 실질적으로 동일한 방법으로실시예 280 및 281에 따른화합물들을 제조하였다. [표 41]
Figure imgf000215_0001
실시 예 279 내지 281에 따라 얻은 화합물들 각각의 구조 및 화합물 명칭 , 그리고 NMR 분석 결과는 하기 표 42에 나타낸다 . (217 mg, 0.35 mmol), and cesium carbonate (847 mg, 2.62 mmol) were diluted in toluene (3.6 mL) and 4-aminotetra hydropyran (132 mg, 1.31 mmol) was added. The reaction was stirred at 85 °C for 16 hours. After completion of the reaction, the reaction mixture is It was filtered using Celite and concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:2) to obtain the target compound AU1 (221 mg, 62%) as a white solid. Step 2. Preparation of target compound AU2 After dissolving compound AU1 (221 mg, 0.54 mmol) in dichloromethane (2 mL), hydrochloric acid (4> 1,4-dioxane solution; 0.68 mL, 2.7 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound AU2 (206 mg, 99%) as a light tan solid. Step 3. Preparation of target compound AU3 After dissolving compound AU2 (95 mg, 0.25 mmol) and tritylchloride (76 mg, 0.28 mmol) in dichloromethane (2.5 mL), triethylamine (0.1 mL, 0.75 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM: Me0H = 20: l) to obtain the target compound AU3 (68 mg, 50%) as a clear oil. Step 4. Preparation of target compound AU4 After dissolving compound AU3 (58 mg, 0.11 mmol) in dimethylformamide (2 mL), sodium hydride (8 mg, 0.32 mmol) and methyl iodine (8 yL, 0.13 mmol) ) was added. The reaction was stirred for 1 hour at room temperature. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain the target compound AU4 (60 mg, 99%) as a clear oil. Step 5. Preparation of target compound AU5 Compound AU4 (60 mg, 0.11 mmol) was added to and dissolved in dichloromethane (2 mL), then hydrochloric acid (4> 1,4-dioxane solution; 0.13 mL, 0.53 mmol) was added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound AU5 (42 mg, 99%) as a brown solid. Step 6. Preparation of target compound AU6 Compound AU5 (70 mg, 0.11 mmol) O｝ 5 - [(2-fluorophenyl) methyl] - 4u 1,2,4-triazole-3-carboxylic acid (35 mg, 0.16 mmol) was diluted in tetrahydrofuran (2 mL) and <> diisopropylamine (0.04 mL, 0.21 mmol) and T 3 P (50% ethyl acetate solution; 0.62 mL, 0.21 mmol) It was added at 0 °C. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM: Me0H = 20: l) to obtain the target compound AU6 (25 mg, 45%) as a white solid. Examples 280 and 281. Reactant 1 in Table 41 below was used as a compound corresponding to 4-aminotetrahydropyran in step 1 of Example 279, and 5-[(2-fluorophenyl)methyl]-4 in step 6 Example 280 and Example 280 in substantially the same manner as the compound AU6 of Example 279, except that reactant 2 in Table 41 was used as a compound corresponding to 1,2,4-triazole-3-carboxylic acid. Compounds according to 281 were prepared. [Table 41]
Figure imgf000215_0001
The structure and compound name of each of the compounds obtained according to Examples 279 to 281, and the results of NMR analysis are shown in Table 42 below.
[표 42]
Figure imgf000215_0002
Figure imgf000216_0002
실시예 282. (R)-l-벤질- N- (7 -클로로- 5 -메틸- 4 -옥소- 8-(피롤리딘- 1-일)-[Table 42]
Figure imgf000215_0002
Figure imgf000216_0002
Example 282. (R) -l-Benzyl- N- (7 -chloro- 5 -methyl- 4 -oxo- 8- (pyrrolidin- 1-yl) -
2,3,4, 5 ■테트라하이드로벤조 [b] [ 1 , 4]싸이아제핀- 3 -일 )- 1H- 1 , 2 , 4 -트리아졸- 3 - 카복사마이드의 제조
Figure imgf000216_0001
단계 1. 목적 화합물 AV1의 제조 2,3,4,5 Tetrahydrobenzo [b] [1,4]Thiazepin-3-yl)-1H-1,2,4-Triazole-3-Carboxamide Preparation
Figure imgf000216_0001
Step 1. Preparation of target compound AV1
1-클로로- 2, 4 -다이플루오로- 5 -나이트로벤젠 (1.6 g, 8.27 mmol )과 탄산칼륨 (1.14 g, 8.27 mmol)을 다이메틸설폭사이드 (8 mL)에 희석하고, 피롤리딘 (0.68 mL, 8.27 mmol)을 첨가하였다. 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종료 후, 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고 , 에틸아세테이트로 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：8)로 정제하여 노란색 고체의 목적 화합물 AV1 (881 mg, 43%)을 수득하였다. 단계 2. 목적 화합물 AV2의 제조 화합물 AV1 (885 mg, 3.62 mmol)을 에탄올 (10 mL) , 및 물 (13 mL)에 첨가한 뒤, AHBoc- L-시스테인 (800 mg, 3.62 mmol)과 탄산수소나트륨 (910 mg, 10.9 mmoL)을 첨가한다. 반응 혼합액을 16시간 동안 환류한다. 반응 종결 후, 감압 농축하여 용매를 제거한 뒤, 물을 넣고 다이에틸에테르로 씻어준다. 1川 염산 수용액을 넣어 pH를 4로 맞춘 뒤, 다이클로로메테인으로 추출한다. 황산나트륨으로 건조한 뒤 감압 농축하여 노란색 고체의 목적 화합물 AV2 (1.24 g, 77%)을수득하였다. 단계 3. 목적 화합물 AV3의 제조 화합물 AV2 (1.24 g, 2.78 mmol)을 메탄올 (28 mL)에 첨가하여 녹인 후, 아연 (1.82 g, 27.81 mmol)과 염화암모늄 (297 mg, 5.56 mmol)을 첨가하였다. 혼합물은 75°C에서 3시간 동안 교반하였다. 반응 종료 후, 반응 혼합물을 셀라이트를 이용하여 여과를 하였고, 감압 농축하여 회색 고체의 목적 화합물 AV3 (1.28 g, 110%)를수득하였다. 단계 4. 목적 화합물 AV4의 제조 화합물 AV3 (1.19 g, 2.78 mmol), EDC (679 mg, 5.56 mmol), 및 HOAt (757 mg, 5.56 mmol)를 다이클로로메테인 (19 mL)에 희석하고, 트리에틸아민 (1.16 mL, 8.34 mmol)을 첨가하였다. 반응물은 상온에서 16시간동안 교반하였다. 탄산수소나트륨 수용액을 넣어 반응을 종결한 후, 물과 염화나트륨 수용액을 이용하여 세척하고 , 다이클로로메테인을 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (EtOAc：Hexane=l：5)로 정제하여 베이지색 고체의 목적 화합물 AV4 (420 mg, 38%)를수득하였다. 단계 5. 목적 화합물 AV5의 제조 화합물 AV4 (420 mg, 1.06 mmol)을 다이메틸포름아마이드 (4 mL)에 첨가하여 녹인 후, 탄산세슘 (516 mg, 1.58 mmol)과 메틸요오드 (0.08 mL, 1.27 mmol)을 첨가하였다. 혼합물은 상온에서 4시간 동안 교반하였다. 반응 종결 후, 반응 혼합물은 물과 염화나트륨 수용액을 이용하여 세척하고, 에틸아세테이트를 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하여 흰색 고체의 목적 화합물 AV5 (380 mg, 87%)를수득하였다. 단계 6. 목적 화합물 AV6의 제조 화합물 AV5 (380 mg, 0.92 mmol)를 다이클로로메테인 (6 mL)에 첨가하여 녹인 후, 염산 (4>1,4 -다이옥세인; 1.15 mL, 4.61 mmol)을 첨가하였다. 혼합물은 상온에서 16시간 동안 교반하였다. 반응 종결 후, 반응 혼합물을 감압 농축하여 흰색 고체의 목적 화합물 AV6 (302 mg, 94%)을수득하였다. 단계 7. 목적 화합물 AV7의 제조 화합물 AV6 (60 mg, 0.17 mmo 1 ) , EDC (42 mg, 0.34 mmo 1 ) , HOAt (47 mg, 0.34 mmol), 및 1-벤질- 1우 1,2, 4 -트리아졸 -3 -카르복실산 (39 mg, 0.19 mmol)을 다이클로로메테인 (3 mL)에 희석하고, 트리에틸아민 (0.07 mL, 0.52 mmol)을 첨가하였다. 반응물은 상온에서 16시간 동안 교반하였다. 탄산수소나트륨 수용액을 넣어 반응을 종결한후, 물과 염화나트륨수용액을 이용하여 세척하고, 다이클로로메테인을 이용하여 유기층을 추출하였다. 유기층은 황산마그네슘으로 건조한 후, 감압 농축하였다. 반응 농축물은 실리카겔 컬럼 크로마토그래피 (DCM：MeOH=3O：l)로 정제하여 실시예 282에 따른 흰색 고체의 목적 화합물 AV7 (59.1 mg, 70%)을수득하였다. iH NMR (400 MHz, Chloroform—沙) 5 8.16 (d, J= 6.8 Hz, 1H), 7.99 (s, 1H), 7.38-7.36 (m, 2H), 7.29-7.26 (m, 3H), 7.18 (s, IH), 7.08 (s, IH), 5.37 (s, 2H), 4.85-4.83 (m, IH), 3.91-3.87 (m, IH), 3.52-3.40 (m, 4H), 3.36 (s, 3H), 2.88 (t, J = 11.0 Hz, IH), 2.03-1.96 (m, 4H)； LRMS (electrospray) m/z (M+H)+ 498. 실험예 1： 세포사멸유도조건에서의 세포보호효과평가 본 발명의 화합물들이 TNF- a (Tumor Necrosis Factor- alpha)에 따른 세포사멸유도 조건에서 세포 보호 효과능을 나타내는지 세포 생존능 시험법 (Cell Viability Assay)을 통해 확인하였다. 세포 외부에서 인간 단핵구 세포 (U937, ATCC)와 마우스 섬유아세포 (L929, ATCC)의 세포사멸을 유도하고 본 발명의 화합물을 처리하였을 때 세포 보호효과가 있는지 여부를 확인하기 위해 하기와 같이 분석을 시행하였다. 인간 U937 세포주와 마우스 L929 세포주 각각을 10% 소 태아 혈청 (Fetal Bovine Serum, Hyc 1 one ) 및 1% 페니실린-스트렙토마이신 (Penicillin-1-Chloro-2,4-difluoro-5-nitrobenzene (1.6 g, 8.27 mmol) and potassium carbonate (1.14 g, 8.27 mmol) were diluted in dimethylsulfoxide (8 mL), pyrrolidine (0.68 mL, 8.27 mmol) was added. The mixture was incubated at room temperature for 16 hours. Stir. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:8) to obtain the target compound AV1 (881 mg, 43%) as a yellow solid. Step 2. Preparation of target compound AV2 Compound AV1 (885 mg, 3.62 mmol) was added to ethanol (10 mL) and water (13 mL), followed by AHBoc-L-cysteine (800 mg, 3.62 mmol) and hydrogen carbonate. Sodium (910 mg, 10.9 mmoL) is added. The reaction mixture is refluxed for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and then water was added and washed with diethyl ether. After adding 1 River hydrochloric acid solution to adjust the pH to 4, extract with dichloromethane. After drying with sodium sulfate and concentrating under reduced pressure, the target compound AV2 (1.24 g, 77%) was obtained as a yellow solid. Step 3. Preparation of target compound AV3 Compound AV2 (1.24 g, 2.78 mmol) was dissolved in methanol (28 mL), and then zinc (1.82 g, 27.81 mmol) and ammonium chloride (297 mg, 5.56 mmol) were added. . The mixture was stirred at 75 °C for 3 hours. After completion of the reaction, the reaction mixture was filtered using celite and concentrated under reduced pressure to obtain the target compound AV3 (1.28 g, 110%) as a gray solid. Step 4. Preparation of target compound AV4 Compound AV3 (1.19 g, 2.78 mmol), EDC (679 mg, 5.56 mmol), and HOAt (757 mg, 5.56 mmol) were diluted in dichloromethane (19 mL), ethylamine (1.16 mL, 8.34 mmol) was added. The reaction was stirred at room temperature for 16 hours. After the reaction was terminated by adding an aqueous sodium bicarbonate solution, the mixture was washed with water and an aqueous sodium chloride solution, and the organic layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (EtOAc:Hexane=l:5) to obtain the target compound AV4 (420 mg, 38%) as a beige solid. Step 5. Preparation of target compound AV5 After dissolving compound AV4 (420 mg, 1.06 mmol) in dimethylformamide (4 mL), cesium carbonate (516 mg, 1.58 mmol) and methyl iodine (0.08 mL, 1.27 mmol) ) was added. The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was washed with water and aqueous sodium chloride solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain the target compound AV5 (380 mg, 87%) as a white solid. Step 6. Preparation of target compound AV6 After dissolving compound AV5 (380 mg, 0.92 mmol) in dichloromethane (6 mL), hydrochloric acid (4>1,4-dioxane; 1.15 mL, 4.61 mmol) was added. added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the target compound AV6 (302 mg, 94%) as a white solid. Step 7. Preparation of target compound AV7 Compound AV6 (60 mg, 0.17 mmo 1 ), EDC (42 mg, 0.34 mmo 1 ), HOAt (47 mg, 0.34 mmol), and 1-benzyl- 1,2,4 -Triazole-3-carboxylic acid (39 mg, 0.19 mmol) was diluted in dichloromethane (3 mL), and triethylamine (0.07 mL, 0.52 mmol) was added. added. The reaction was stirred at room temperature for 16 hours. After the reaction was terminated by adding an aqueous sodium bicarbonate solution, the mixture was washed with water and an aqueous sodium chloride solution, and the organic layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The reaction concentrate was purified by silica gel column chromatography (DCM:MeOH=3O:l) to obtain the target compound AV7 (59.1 mg, 70%) according to Example 282 as a white solid. iH NMR (400 MHz, Chloroform—沙) 5 8.16 (d, J= 6.8 Hz, 1H), 7.99 (s, 1H), 7.38-7.36 (m, 2H), 7.29-7.26 (m, 3H), 7.18 ( s, IH), 7.08 (s, IH), 5.37 (s, 2H), 4.85-4.83 (m, IH), 3.91-3.87 (m, IH), 3.52-3.40 (m, 4H), 3.36 (s, 3H), 2.88 (t, J = 11.0 Hz, IH), 2.03-1.96 (m, 4H); LRMS (electrospray) m/z (M+H)+ 498. Experimental Example 1: Cells under apoptosis inducing conditions Evaluation of protective effect Whether the compounds of the present invention exhibit cell protective effects under apoptosis inducing conditions according to TNF-a (Tumor Necrosis Factor-alpha) was confirmed through a cell viability assay. In order to induce apoptosis of human monocytic cells (U937, ATCC) and mouse fibroblasts (L929, ATCC) outside the cell and to confirm whether there is a cell protective effect when treated with the compound of the present invention, the following analysis was performed. did The human U937 cell line and the mouse L929 cell line were each treated with 10% fetal bovine serum (Fetal Bovine Serum, Hyc 1 one) and 1% penicillin-streptomycin (Penicillin-
Streptomycin, Hyclone)을 포함한 RPMI 배지 (Hyclone)에서 배양하였다. 시험 수행 시에는 페놀레드 (Phenol- red)가 포함되어 있지 않은 RPMI 배지를 이용하였으며, 96웰 플레이트 (ViewPlate-96, white 96-well, PerkinElmer)에 U937 세포는 15, 000세포/웰, L929세포는 5, 000세포/웰의 농도로 각각 분주한 후, 5% C02 , 37 °C 조건에서 5 내지 6시간 동안 배양하였다. 그 후, 본원 실시예 화합물들 각각을, U937 세포에는 0.01 nM 내지 1 uM, L929 세포에는 O.lnM내지 10uM의 농도 범위에서 10배 농도구배를 주어 5% C02 , 37 °C 조건에서 1시간 동안 처리하였다. 이후 TNF-a (lOOng/mL, Sigma) 및 Q- VD- Oph (50uM, Selleckchem)를 추가한 뒤, 5% C02 , 37 °C 조건에서 19 내지 21시간 동안 배양하였다. 세포의 생존 정도를 확인하기 위하여, 상기 배양된 세포에 각각 Cel ITiter-Glo® Luminescent Cel 1 Viability Assay Kit (Promega)에서 제공되는 혼합물을 동량 첨가하고, 실온 (10 내지 25°C)에서 10분간 방치한 후, 발광도 (Luminescence)를 측정하였다 . 사용된 각각의 화합물과 TNF- a를 처리하지 않은 대조군 세포의 발광도를 기준으로 각화합물들의 처리 농도에 따른세포사멸유도 저해 정도를 산출하였으며, 이때 저해능이 50%인 농도를 IC5o 값으로 결정하였고 시그마플랏 (Sigmaplot, 버전 10.0) 시스탓 소프트웨어 (Systat software)를 이용하여 산출하였다. 그 결과를 하기 표 43에 나타낸다. It was cultured in RPMI medium (Hyclone) containing Streptomycin and Hyclone. During the test, RPMI medium without phenol red was used, and 15,000 cells/well of U937 cells and L929 cells were placed in a 96-well plate (ViewPlate-96, white 96-well, PerkinElmer). After dispensing at a concentration of 5,000 cells/well, respectively, 5% C02, and incubated for 5 to 6 hours at 37 °C conditions. After that, each of the compounds of the present invention was given a 10-fold concentration gradient in the concentration range of 0.01 nM to 1 uM for U937 cells and 0.lnM to 10 uM for L929 cells, 5% C0 2 , 1 hour at 37 °C. treated during. Then, after adding TNF-a (lOOng/mL, Sigma) and Q-VD-Oph (50uM, Selleckchem), they were incubated for 19 to 21 hours at 5% C0 2 and 37 °C. In order to confirm the degree of cell viability, an equal amount of the mixture provided in the Cel ITiter-Glo® Luminescent Cel 1 Viability Assay Kit (Promega) was added to the cultured cells, and left at room temperature (10 to 25 ° C) for 10 minutes. After that, the luminescence was measured. Based on the luminescence of each compound used and control cells not treated with TNF-a, the degree of apoptosis induction inhibition according to the treatment concentration of each compound was calculated. It was determined and calculated using Sigmaplot (Version 10.0) Systat software. The results are shown in Table 43 below.
<L929 (마우스 세포주)에서의 활성 (IC5o)> <Activity in L929 (mouse cell line) (IC 5 o)>
A： lOOnM미만 A: Less than lOOnM
B： lOOnM내지 500nM B: lOOnM to 500nM
C： 500nM초과 내지 luM C: greater than 500 nM to luM
D： luM초과 <U937 (인간 세포주)에서의 활성 ( IC5o)>D: Exceeding luM <Activity in U937 (human cell line) (IC5o)>
A： InM 미만 A: Less than InM
B： InM 내지 lOnM B: InM to lOnM
C： lOnM 초과 내지 lOOnM C: greater than lOnM to lOOnM
D： lOOnM 초과 내지 luM D: greater than lOOnM to luM
E： luM 초과 E: Exceeding luM
[표 43 ]
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
[Table 43]
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
* NT： not tested 상기 표 43에서 확인할 수 있는 바와 같이 본 발명의 실시 예 화합물들은 세포사멸유도 조건에서 우수한 세포보호 효과를 가지는 것을 확인하였다. 즉 , 본 발명의 화합물들은 세포사멸 저해 효과를 제공하며 이에 따라 RIPK1 활성 관련 질환의 치료에 유용하게 사용될 수 있다. 실험예 2： 생체 내 생물학적 분석 본 발명의 화합물들이 생체 내에서 TNF- a (Tumor Necrosis Factor- alpha）에 따른 치명적인 쇼크로부터의 보호 효과를 나타내는지 급성 마우스 모델 （ lethal shock mouse model）을 통해 확인하였다. 이 모델에서 , 카스파제 억제제 zVAD와 결합된 TNF의 주입은 저혈압, 간염 , 저체온 및 장 괴사를 특징으로 하는 전신 염증 반응을 유도한다. 효능은 체온 손실을 방지하는 RIPK1 억제제의 능력으로 측정할 수 있다. 그룹당 총 5마리의 C57BL/c 마우스에 10 mg/kg의 용량으로 부형제（DMSO , cremophor EL 및 DW의 혼합물） 또는 화합물들을 경구투여 하였고 , 15분 후 마우스 TNF- a （30 쓔/마우스） 및 z-VAD-fmk （0.4 mg/마우스）를 정맥내 투여하였다. 2시간 후 마우스의 체온 손실（체온 손실 = 정맥 투여 2시간 후 마우스 체온 - 경구투여 전 마우스 체온）은 직장 프로브로 측정하였다. * NT: not tested As can be seen in Table 43 above, it was confirmed that the Example compounds of the present invention have excellent cell protection effects under apoptosis inducing conditions. That is, the compounds of the present invention provide an apoptosis inhibitory effect, and thus can be usefully used for the treatment of RIPK1 activity-related diseases. Experimental Example 2: In vivo biological analysis The compounds of the present invention were tested in vivo by TNF-a (Tumor Necrosis Factor- alpha) was confirmed through an acute mouse model ( lethal shock mouse model). In this model, infusion of TNF combined with the caspase inhibitor zVAD induces a systemic inflammatory response characterized by hypotension, hepatitis, hypothermia and intestinal necrosis. Efficacy can be measured by the ability of RIPK1 inhibitors to prevent loss of body temperature. A total of 5 C57BL/c mice per group were orally administered with vehicle (a mixture of DMSO, cremophor EL and DW) or compounds at a dose of 10 mg/kg, and after 15 minutes, mouse TNF-a (30 doses/mouse) and z -VAD-fmk (0.4 mg/mouse) was administered intravenously. The body temperature loss of the mouse after 2 hours (body temperature loss = mouse body temperature 2 hours after intravenous administration - mouse body temperature before oral administration) was measured with a rectal probe.
[표 44]
Figure imgf000229_0001
[Table 44]
Figure imgf000229_0001
[표 45]
Figure imgf000229_0002
실험예 3： CYP（Cytrochrome P450）의 활성 저해 능력 평가 본 발명의 화합물들의 CYP（ Cytochrome P450）에 대한 활성 저해 능력을 평가하기 위하여, 사람에서 약물대사에 중요하게 관여하는 것으로 알려진, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 및 CYP3A4를 대상으로본 발명 실시예 화합물들의 약물대사효소에 대한 억제활성을 평가하였다. 구체적으로, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 및 CYP3A4의 억제 활성 분석은 Invitrogen(P2863, P3019, PV6141 , P2861 , P2864, P2972, P2858) kit를사용하였다. 상기 Invitrogen kit의 경우, 실시예 화합물은 최종실험농도의 2.5X가 되도록 Vivid CYP450 반응 버퍼 (reaction buffer) (IX)에 희석하여 준비하고, P450 BACULOSOMES 시료와 재생 시스템 (Regenerat ion system)(100X )을 Vivid CYP450 반응 버퍼 (1＞〈 )에 CYP450 종류에 맞는 농도로 희석하여 준비하였다. U-bottom 96 -웰 플레이트에, 최종실험농도의 2.5X로 준비된 실시예 화합물 40M와 희석한 P450 BACULOSOMES 시료 혼합물 50砂를 섞어준 후, 20분〜 30분간 전반응 (pre- incubation) 하였다. Vivid CYP450 Substrate와 NADP+(100＞〈 )를 CYP450과 Substrate 종류에 맞는 농도로 Vivid CYP450 반응 버퍼 (IX)에 희석하여 준비한 후, 전반응이 끝난 플레이트에 Substr at e-NADP+ mix 10M를 넣어주고 30분〜 1시간 동안 반응시켰다. 반응이 끝난후, 반응물을 흰색 플레이트 (white plate)에 옮겨 마이크로플레이트 리더 (microplate reader)에서 형광 파장을 읽었다 (1A2, 2B6, 2C9, 2C19, 2D6, 3A4 excitation 409 nm, emission 460 nm, 2C8 excitation 485 nm, emission 535 nm) . 실험결과는 (1-(시험물질 형광 값/ Vehicle 형광 값)) X 100%로 계산하여 하기 표 46에 나타낸다. [Table 45]
Figure imgf000229_0002
Experimental Example 3: Evaluation of activity inhibitory ability of CYP (Cytrochrome P450) In order to evaluate, the inhibitory activity of the compounds of the present invention on drug metabolizing enzymes was evaluated for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, which are known to be critically involved in drug metabolism in humans. Specifically, the inhibitory activities of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 were analyzed using Invitrogen (P2863, P3019, PV6141, P2861, P2864, P2972, P2858) kits. In the case of the Invitrogen kit, the example compounds were prepared by diluting in Vivid CYP450 reaction buffer (IX) to 2.5X of the final experimental concentration, and the P450 BACULOSOMES sample and the Regenerate ion system (100X) It was prepared by diluting the concentration suitable for the type of CYP450 in Vivid CYP450 reaction buffer (1><). In a U-bottom 96-well plate, after mixing 50 pieces of P450 BACULOSOMES sample mixture diluted with 40M of Example compound prepared at 2.5X the final experimental concentration, pre-incubation was performed for 20 to 30 minutes. After diluting Vivid CYP450 Substrate and NADP+ (100＞< ) in Vivid CYP450 Reaction Buffer (IX) at a concentration suitable for the type of CYP450 and Substrate, add Substr at e-NADP+ mix 10M to the plate after the pre-reaction and leave for 30 minutes Reacted for ~ 1 hour. After the reaction was completed, the reactant was transferred to a white plate and the fluorescence wavelength was read on a microplate reader (1A2, 2B6, 2C9, 2C19, 2D6, 3A4 excitation 409 nm, emission 460 nm, 2C8 excitation 485 nm, emission 535 nm). The experimental results are shown in Table 46 below, calculated as (1-(test substance fluorescence value/Vehicle fluorescence value)) X 100%.
[표 46]
Figure imgf000230_0001
Figure imgf000231_0001
실험예 4： 마우스 생체내 약물동태 평가 실시예 화합물을 BALB/c 마우스에 경구 투여 하였을 때의 약물동태학적 특징을 알아보기 위하여 다음과 같이 실시하였다. 실시예 화합물을 BALB/c 마우스에 10 mg/kg 용량으로 경구 투여하였다. 채혈은 안와 정맥에서 헤파린 나트륨 (sodium- heparin)으로 코팅된 모세관을 이용하여 정해진 시간 (투여 후 5분, 30분, 1시간, 3시간, 5시간, 8시간)에 혈액 200 uL을 채혈하였고, 채혈한 혈액은 1.7mL 튜브에 옮긴 뒤 , 6,000g, 4°C , 5분 원심분리하여 혈장을 분리하였다. 혈장 내 실시예 화합물은 단백침전법으로 전처리 하였고, 정량 분석은 LC-MS/MS system을 이용하여 분석하였다. 마우스 혈장 시료에서 얻어진 약물 농도-시간 곡선으로부터 PK Solution 프로그램을 이용하여, 비-구획 모델 (non- compartment analysis)방법으로, 최고 혈중 농도 도달시간 (Tmax) , 최고 혈중 농도 (Cmax) , 반감기 (tl/2) , 혈중 곡선하 면적 (AUCo- t)의 파라미터를산출하였다. 그 결과를 하기 표 47에 나타낸다. [Table 46]
Figure imgf000230_0001
Figure imgf000231_0001
Experimental Example 4: Evaluation of pharmacokinetics in vivo in mouse In order to examine the pharmacokinetic characteristics when the Example compound was orally administered to BALB/c mice, the following was performed. Example compounds were orally administered to BALB/c mice at a dose of 10 mg/kg. For blood collection, 200 uL of blood was collected from the orbital vein using a capillary tube coated with sodium-heparin at fixed times (5 minutes, 30 minutes, 1 hour, 3 hours, 5 hours, and 8 hours after administration). The collected blood was transferred to a 1.7mL tube, and plasma was separated by centrifugation at 6,000g, 4°C, and 5 minutes. Example compounds in plasma were pretreated by protein precipitation, and quantitative analysis was performed using an LC-MS/MS system. From the drug concentration-time curve obtained from mouse plasma samples, using the PK Solution program, non-compartment analysis method, time to reach peak blood concentration (Tmax), peak blood concentration (Cmax), half-life (tl /2) , and the parameter of area under the curve (AUCo-t) in blood was calculated. The results are shown in Table 47 below.
[표 47]
Figure imgf000231_0002
이상, 본 발명을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 , 이러한 구체적 기술은 단지 바람직한 실시 예일뿐이며 , 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 , 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다. [Table 47]
Figure imgf000231_0002
As described above, the present invention has been described in detail, and those skilled in the art It will be clear to the reader that these specific descriptions are merely preferred embodiments, and the scope of the present invention is not limited thereby. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims

【특허청구범위】 【Scope of Patent Claims】
【청구항 11 하기 화학식 I로 나타내는 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용가능한 염, 이들의 수화물 또는 이들의 용매화물:
Figure imgf000233_0001
화학식 I에서, [Claim 11] A compound represented by Formula I, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof:
Figure imgf000233_0001
In Formula I,
Z1은 CH 또는시이고, Z1 is CH or Si;
Z2 및 Z3은 각각독립적으로 N, CRi또는 0여이되 , Z2 및 Z3중 어느 하나는 반드시 CRi이고, Z 2 and Z3 are each independently N, CRi or 0, but any one of Z2 and Z3 is necessarily CRi,
Ri은 CRi의 으와 직접 결합하는 니을 포함하는 고리형 작용기, NR7R8, NH(CH2)e-C(=O)-R9 또는 NHS(=O)2_RIO이고, e는 0 내지 2의 정수이고, Ri is a cyclic functional group, NR 7 R 8 , NH(CH 2 ) e -C(=O)-R 9 or NHS(=O) 2 _RIO, including Ni directly bonded to , of CRi, and e is 0 to is an integer of 2,
R2는 H, 할로겐, CN 또는 - 0- (Cl- C5알킬)이고, R2 is H, halogen, CN or - 0- (Cl- C5 alkyl);
R3은 H또는 CH3이고, R3 is H or CH3;
Wi은 CH2, S, 0, 8(=0) 또는 S(=0)2이고, Wi is CH2, S, 0, 8(=0) or S(=0)2;
W2는 0또는으이고, W2 is 0 or
A는 아릴 또는 헤테로아릴이고, A is aryl or heteroaryl;
L은 CH2, CH(CHs), CD2 또는 0이고, 0 하 L is CH2, CH(CHs), CD 2 or 0; 0 ha
B는 아릴 , 헤테로아릴 또는 A 이고, B is aryl, heteroaryl or A;
R4는 H, 할로겐, NH2, Cl- C5알킬, NHC（=O）O-（Cl- C5알킬） 또는 0-（C1-R4 is H, halogen, NH2, Cl-C5alkyl, NHC(=O)O-(Cl-C5alkyl) or 0-(C1-
C5알킬）이고, C5 alkyl),
R5 및 R6은 각각 독립적으로 H, Cl- C5알킬, CN, 할로겐, -（Cl- C5알킬）- 0-R5 and R6 are each independently H, Cl- C5alkyl, CN, halogen, -(Cl-C5alkyl)- 0-
（Cl- C5알킬） 또는 헤테로아릴이고, 여기서 헤테로아릴의 적어도 1 이상의 보는 각각 독립적으로 Cl- C5알킬로치환될 수 있고, (Cl-C5alkyl) or heteroaryl, wherein at least one member of the heteroaryl may each independently be substituted with Cl-C5alkyl;
R7은 H또는 C1-C5알킬이고, R7 is H or C1-C5 alkyl;
R8은 H, Cl- C5알킬, 사이클로알킬 또는 헤테로사이클로알킬이고, 여기서 Cl- C5알킬의 적어도 1 이상의 보는 각각 독립적으로 CF3, 할로겐, N（C1- C5알킬） 2, 0-（Cl- C5알킬）, 0H, 헤테로사이클로알킬, 아릴 또는 헤테로아릴로 치환될 수 있으며, 상기 아릴 또는 헤테로아릴의 적어도 1 이상의 보는 각각 독립적으로 （Cl- C5알킬） 또는 - 0-（Cl- C5알킬）로치환될 수 있고, R8 is H, Cl-C5alkyl, cycloalkyl or heterocycloalkyl, wherein at least one group of Cl-C5alkyl is each independently CF 3 , halogen, N(C1-C5alkyl) 2, 0-(Cl-C5 alkyl), 0H, heterocycloalkyl, aryl or heteroaryl, and at least one group of the aryl or heteroaryl is each independently substituted with (Cl- C5 alkyl) or -0- (Cl- C5 alkyl) can be,
R9는 Cl- C5알킬, 0-（Cl- C5알킬）, OH, CF3또는 （C1-C5알킬）- CF3이고,R9 is Cl-C5alkyl, 0-(Cl-C5alkyl), OH, CF 3 or (C1-C5alkyl)-CF3;
Rio은 Cl- C5알킬 또는사이클로알킬이고, Rio is Cl-C5alkyl or cycloalkyl;
Zi 내지 Z3가 N을 포함하지 않고 Wi이 0일 때, R2는 할로겐, CN 또는 - 0- （Cl- C5알킬）이다. When Zi to Z3 do not contain N and Wi is 0, R2 is halogen, CN or -0- (Cl-C5alkyl).
【청구항이 제 1항에 있어서, 화학식 I에서, [The claim according to claim 1, in formula I,
Zi은 CH또는시이고, Z2 및 Z3은 각각독립적으로 N, CR1 또는 CR2이되 , Z2 및 Z3중 어느 하나는 반드시 CRi이고,
Figure imgf000235_0001
, e 고,Zi is CH or Si, Z 2 and Z3 are each independently N, CR1 or CR2, but any one of Z2 and Z3 is necessarily CRi,
Figure imgf000235_0001
, e high,
Z4는 CRcRd, 0, S 또는 NRe이고, Z4 is CRcRd, 0, S or NR e ;
Ra, Rb, Rc, Rd 및 Re는 각각독립적으로 H, Cl- C5알킬, 할로겐, CF3, CH2F, (Cl- C5알킬)- OH 또는 - 0- (Cl- C5알킬)이고, Ra, Rb, Rc, Rd and Re are each independently H, Cl- C5 alkyl, halogen, CF 3 , CH 2 F, (Cl- C5 alkyl)- OH or - 0- (Cl- C5 alkyl);
Z5 및 Z6은 각각 독립적으로 CH 또는 N이되, Z5 및 Z6 중 적어도 어느 하나는 시이고, n, m, a, b, c 및 거는 각각 독립적으로 0 내지 2의 정수이되, n과 m은 동시에 0일 수 없고, a와으는 동시에 0일 수 없으며 , e는 0 내지 2의 정수이고, Z 5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a, b, and c are each independently an integer from 0 to 2, but n and m are simultaneously cannot be 0, a and cannot be 0 at the same time, e is an integer from 0 to 2,
R2는 H, 할로겐, CN 또는 - 0- (Cl- C5알킬)이고, R2 is H, halogen, CN or - 0- (Cl- C5 alkyl);
R3은 H또는 CH3이고, R3 is H or CH3;
Wi은 CH2, S, 0, S(=0) 또는 S(=0)2이고, Wi is CH 2 , S, 0, S(=0) or S(=0)2;
W2는 0또는으이고, W2 is 0 or
A는 아릴 또는 헤테로아릴이고, A is aryl or heteroaryl;
L은 CH2, CH(CHs), CD2 또는 0이고, 0 하 L is CH2, CH(CHs), CD 2 or 0; 0 ha
B는 아릴 , 헤테로아릴 또는 A 이고, B is aryl, heteroaryl or A;
R4는 H, 할로겐, NH2, Cl- C5알킬, NHC（=O）O-（Cl- C5알킬） 또는 0-（C1-R4 is H, halogen, NH2, Cl-C5alkyl, NHC(=O)O-(Cl-C5alkyl) or 0-(C1-
C5알킬）이고, C5 alkyl),
R5 및 R6은 각각 독립적으로 H, Cl- C5알킬, CN, 할로겐, -（Cl- C5알킬）- 0-R5 and R6 are each independently H, Cl- C5alkyl, CN, halogen, -(Cl-C5alkyl)- 0-
（Cl- C5알킬） 또는 헤테로아릴이고, 여기서 헤테로아릴의 적어도 1 이상의 보는 각각 독립적으로 Cl- C5알킬로치환될 수 있고, (Cl-C5alkyl) or heteroaryl, wherein at least one member of the heteroaryl may each independently be substituted with Cl-C5alkyl;
R7은 H또는 C1-C5알킬이고, R7 is H or C1-C5 alkyl;
R8은 H, Cl- C5알킬, 사이클로알킬 또는 헤테로사이클로알킬이고, 여기서 Cl- C5알킬의 적어도 1 이상의 보는 각각 독립적으로 CF3, 할로겐, N（C1- C5알킬） 2, 0-（Cl- C5알킬）, 0H, 헤테로사이클로알킬, 아릴 또는 헤테로아릴로 치환될 수 있으며, 상기 아릴 또는 헤테로아릴의 적어도 1 이상의 보는 각각 독립적으로 （Cl- C5알킬） 또는 - 0-（Cl- C5알킬）로치환될 수 있고, R8 is H, Cl-C5alkyl, cycloalkyl or heterocycloalkyl, wherein at least one group of Cl-C5alkyl is each independently CF 3 , halogen, N(C1-C5alkyl) 2, 0-(Cl-C5 alkyl), 0H, heterocycloalkyl, aryl or heteroaryl, and at least one group of the aryl or heteroaryl is each independently substituted with (Cl- C5 alkyl) or -0- (Cl- C5 alkyl) can be,
R9는 Cl- C5알킬, 0-（Cl- C5알킬）, OH, CF3또는 （C1-C5알킬）- CF3이고,R9 is Cl-C5alkyl, 0-(Cl-C5alkyl), OH, CF 3 or (C1-C5alkyl)-CF3;
Rio은 Cl- C5알킬 또는사이클로알킬이고, Rio is Cl-C5alkyl or cycloalkyl;
Zi 내지 Z3가 N을 포함하지 않고 Wi이 0일 때, R2는 할로겐, CN 또는 - 0- （Cl- C5알킬）인, 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용가능한 염, 이들의 수화물 또는 이들의 용매화물. When Zi to Z3 do not contain N and Wi is 0, R2 is halogen, CN or -0- (Cl-C5alkyl), a compound, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, Hydrates thereof or solvates thereof.
【청구항 3] 제 1항에 있어서, 상기 화학식 I로 나타내는 화합물은 하기 화학식 II로 나타내는 것인, 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용가능한 염, 이들의 수화물 또는 이들의 용매화물: [Claim 3] The method of claim 1, The compound represented by Formula I is a compound represented by Formula II, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof:
<화학식 11>
Figure imgf000237_0001
상기 화학식 II의 Z2, Z3, Wi, W2, Rs, A, B, L, R4, R5 및 R6 각각은, 제 1항의 화학식 I에서 정의한 것과 동일하다. <Formula 11>
Figure imgf000237_0001
Each of Z 2 , Z 3 , Wi, W 2 , Rs, A, B, L, R 4 , R 5 and R 6 in Formula II is the same as defined in Formula I of claim 1.
【청구항 4] 제 1항에 있어서, 상기 화학식 I에서, [Claim 4] According to claim 1, in the formula I,
Zi은이이고, Zi is
Z2 및 Z3은 각각독립적으로 N, CR1또는 CR2이되 , Z2 및 Z3중 어느 하나는 반드시 CRi이고, Z2 and Z3 are each independently N, CR1 or CR2, but one of Z2 and Z3 is necessarily CRi,
Ri은
Figure imgf000237_0002
Ri is
Figure imgf000237_0002
236
Figure imgf000238_0001
NR7R8, 또는 NH(CH2)e-C(=O)-R9 이고,236
Figure imgf000238_0001
NR7R8, or NH(CH 2 ) e -C(=0)-R 9 ;
Z4는 CRcRd, 0, S 또는 NRe이고, Z4 is CRcRd, 0, S or NR e ;
Ra, Rb, Rc, Rd 및 Re는 각각독립적으로 H, Cl- C5알킬, 할로겐, CF3, CH2F, (Cl- C5알킬)- OH 또는 - 0- (Cl- C5알킬)이고, Ra, Rb, Rc, Rd and Re are each independently H, Cl- C5 alkyl, halogen, CF 3 , CH 2 F, (Cl- C5 alkyl)- OH or - 0- (Cl- C5 alkyl);
Z5 및 Z6은 각각 독립적으로 CH 또는 N이되, Z5 및 Z6 중 적어도 어느 하나는 시이고, n, m, a, b, c 및 거는 각각 독립적으로 0 내지 2의 정수이되, n과 m은 동시에 0일 수 없고, a와으는 동시에 0일 수 없으며 , e는 0 내지 2의 정수이고, Z 5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a, b, and c are each independently an integer from 0 to 2, but n and m are simultaneously cannot be 0, a and cannot be 0 at the same time, e is an integer from 0 to 2,
R2는 H, 할로겐, CN또는 - 0- (Cl- C5알킬)이고, R2 is H, halogen, CN or - 0- (Cl- C5 alkyl);
R3은 H또는 CH3이고, R3 is H or CH3;
Wi은 CH2, S, 0, 8(=0) 또는 S(=0)2이고, Wi is CH2, S, 0, 8(=0) or S(=0)2;
W2는 0또는으이고, W2 is 0 or
A는 페닐 또는 0 및 N 중에서 선택된 적어도 1 이상의 헤테로원자를 포함하는 5원 또는 6원의 헤테로아릴이고, A is phenyl or a 5-membered or 6-membered heteroaryl containing at least one heteroatom selected from 0 and N;
L은 CH2, CH(CHs), CD2 또는 0이고, L is CH2, CH(CHs), CD 2 or 0;
B는 페닐, 1 또는 2개의 시을 포함하는 6원의 헤테로아릴 또는
Figure imgf000238_0002
B is phenyl, a 6-membered heteroaryl containing 1 or 2 cy, or
Figure imgf000238_0002
R4는 H, 할로겐, NH2, Cl- C5알킬, NHC(=O)O- (Cl- C5알킬) 또는 0- (Cl- C5알킬）이고, R4 is H, halogen, NH 2 , Cl- C5 alkyl, NHC(=0)0- (Cl- C5 alkyl) or 0- (Cl- C5 alkyl),
R5 및 R6은 각각 독립적으로 H, Cl- C5알킬, CN, 할로겐, -（Cl- C5알킬）- o- （Cl- C5알킬） 또는 1 또는 2개의 N을 갖는 5원 또는 6원의 헤테로아릴이고, 여기서 헤테로아릴의 적어도 1 이상의 보는 각각 독립적으로 Cl- C5알킬로 치환될 수 있고, R5 and R6 are each independently H, Cl-C5alkyl, CN, halogen, -(Cl-C5alkyl)-o-(Cl-C5alkyl) or a 5-membered or 6-membered heteroaryl having 1 or 2 N atoms. , wherein at least one group of heteroaryl groups may each independently be substituted with Cl-C5alkyl;
R7은 H또는 C1-C5알킬이고, R7 is H or C1-C5 alkyl;
R8은 H, Cl- C5알킬, 탄소수 3 내지 6을 갖는 사이클로알킬 또는 0 및 N 중에서 선택된 적어도 1 이상의 헤테로원자를 포함하는 5원 또는 6원의 헤테로사이클로알킬이고, 여기서 Cl- C5알킬의 적어도 1 이상의 보는 각각 독립적으로 CF3, 할로겐, N（C1- C5알킬） 2, 0-（Cl- C5알킬）, 0H, 0 및 N 중에서 선택된 적어도 1 이상의 헤테로원자를 포함하는 5원 또는 6원의 헤테로사이클로알킬, 페닐 또는 0 및 N 중에서 선택된 적어도 1 이상의 헤테로원자를 포함하는 5원 또는 6원의 헤테로아릴로 치환될 수 있으며, 상기 페닐 또는 헤테로아릴의 적어도 1 이상의 보는 각각 독립적으로 （Cl- C5알킬） 또는 - 0-（Cl- C5알킬）로치환될 수 있고, R8 is H, Cl-C5alkyl, cycloalkyl having 3 to 6 carbon atoms, or 5- or 6-membered heterocycloalkyl containing at least one heteroatom selected from 0 and N, wherein at least one of Cl-C5alkyl Each of the above is independently CF 3 , halogen, N (C1- C5 alkyl) 2, 0- (Cl- C5 alkyl), 5-membered or 6-membered hetero including at least one heteroatom selected from 0H, 0 and N It may be substituted with cycloalkyl, phenyl, or 5-membered or 6-membered heteroaryl containing at least one heteroatom selected from 0 and N, and at least one group of the phenyl or heteroaryl is each independently (Cl-C5alkyl ) or - 0- (Cl- C5 alkyl),
R9는 Cl- C5알킬, 0-（Cl- C5알킬）, OH, CF3 또는 （C1-C5알킬）- CF3이고,R9 is Cl-C5alkyl, 0-(Cl-C5alkyl), OH, CF 3 or (C1-C5alkyl)-CF3;
Z2 및 Z3가 N을 포함하지 않고 Wi이 0일 때 , R2는 할로겐인, 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용가능한 염, 이들의 수화물 또는 이들의 용매화물. A compound, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, wherein when Z 2 and Z3 do not contain N and Wi is 0, R2 is halogen.
【청구항 5] 제 1항에 있어서, [Claim 5] The method of claim 1,
238 상기 화학식 I로 나타내는 화합물은 하기 화학식 Illa로 나타내는 것인, 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용가능한 염, 이들의 수화물 또는 이들의 용매화물;
Figure imgf000240_0001
238 The compound represented by Formula I is a compound represented by the following Formula Illa, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof;
Figure imgf000240_0001
Z4는 CRcRd 또는 0이고, Z4 is CRcRd or 0;
Ra, Rb, Rc 및 Rd는 각각 독립적으로 H, Cl- C5알킬, 할로겐, CH2F, （C1- C5알킬）- OH 또는 - 0-（Cl- C5알킬）이고, n, m 및 c는 각각 독립적으로 0 내지 2의 정수이되, n과 m은 동시에 0일 수 없고, R a , Rb, Rc and Rd are each independently H, Cl-C5alkyl, halogen, CH 2 F, (C1-C5alkyl)-OH or -0-(Cl-C5alkyl), n, m and c are each independently an integer from 0 to 2, but n and m cannot be 0 at the same time,
R3는 H또는 CH3이고, R3 is H or CH3;
A는 1 내지 4의 시을 포함하는 5원 또는 6원의 헤테로아릴이고, B는 페닐이고, A is a 5- or 6-membered heteroaryl containing 1 to 4 cy, B is phenyl;
L은 CH2또는 CD2이고, L is CH 2 or CD2;
R4는 H, 할로겐, Cl- C5알킬 또는 0-（Cl- C5알킬）이고, R4 is H, halogen, Cl-C5alkyl or 0-(Cl-C5alkyl);
Rs 및 R6은 각각독립적으로 H 또는 할로겐이다. Rs and R6 are each independently H or halogen.
【청구항 6] 제 1항에 있어서, 상기 화학식 I에서, [Claim 6] According to claim 1, in the formula I,
Zi은이이고, Zi is
Z2 및 Z3중 어느 하나는 CRi이고, 다른하나는 CR2이고,
Figure imgf000241_0001
One of Z2 and Z3 is CRi, the other is CR2,
Figure imgf000241_0001
Z4는 CRcRd, 0, S 또는 NRe이고, Z4 is CRcRd, 0, S or NR e ;
Ra, Rb, Rc, Rd 및 Re는 각각 독립적으로 H, Cl- C5알킬, 할로겐, CF3 또는 - 0-（Cl- C5알킬）이고, R a , Rb, Rc, Rd and Re are each independently H, Cl-C5alkyl, halogen, CF 3 or -0-(Cl-C5alkyl);
Z5 및 Z6은 각각 독립적으로 CH 또는 N이되, Z5 및 Z6 중 적어도 어느 하나는 시이고, n, m, a, b, c 및 거는 각각 독립적으로 0 내지 2의 정수이되, n과 m은 동시에 0일 수 없고, a와으는 동시에 0일 수 없으며 , Z 5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a, b, and c are each independently an integer from 0 to 2, but n and m are simultaneously cannot be 0, and a and cannot be 0 at the same time,
R2는 H, 할로겐, CN 또는 - 0-（Cl- C5알킬）이고, R3은 CH3이고, R2 is H, halogen, CN or -O-(Cl-C5alkyl); R3 is CH3;
W1은 CH2, S, 0, S(=0) 또는 S(=0)2이고, W1 is CH 2 , S, 0, S(=0) or S(=0)2;
W2는 0이고, W2 is 0;
A는 페닐 또는 N 또는 0를 1 내지 4개 포함하는 5원 또는 6원의 헤테로아릴이고, A is phenyl or a 5-membered or 6-membered heteroaryl containing 1 to 4 N or 0;
B는 페닐, 시을 1 또는 2개 포함하는 6원의 헤테로아릴 또는
Figure imgf000242_0001
B is phenyl, 6-membered heteroaryl containing 1 or 2 cyyls, or
Figure imgf000242_0001
L은 CH2, CH（CHs）, 또는 0이고, L is CH2, CH (CHs), or 0;
R4는 H, 할로겐, NH2, Cl- C5알킬 또는 NHC（=O）O-（Cl- C5알킬）이고, R4 is H, halogen, NH2, Cl-C5alkyl or NHC(=O)O-(Cl-C5alkyl);
R5 및 R6은 각각 독립적으로 H, Cl- C5알킬, CN, 할로겐, -（Cl- C5알킬）- 0- （Cl- C5알킬） 또는 적어도 1 이상의 N을 갖는 5원의 헤테로아릴이고, 여기서 상기 5원의 헤테로아릴의 적어도 1 이상의 보는 각각 독립적으로 Cl- C5알킬로 치환될 수 있고, R5 and R6 are each independently H, Cl-C5alkyl, CN, halogen, -(Cl-C5alkyl)-0-(Cl-C5alkyl) or a 5-membered heteroaryl having at least one N, wherein the above At least one group of 5-membered heteroaryl may each independently be substituted with Cl-C5alkyl;
Wi이 0일 때 R2는 할로겐, CN 또는 - 0-（Cl- C5알킬）인, 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용가능한 염, 이들의 수화물 또는 이들의 용매화물. When Wi is 0, R2 is halogen, CN or -0-(Cl-C5alkyl), a compound, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.
【청구항 7] 제 1항에 있어서, 상기 화학식 I로 나타내는 화합물은 하기 화학식 IV로 나타내는 것인, 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 [Claim 7] The compound according to claim 1, wherein the compound represented by Formula I is represented by the following Formula IV, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically thereof.
241 허용가능한 염, 이들의 수화물 또는 이들의 용매화물;
Figure imgf000243_0001
NHC(=O)-R9 또는241 acceptable salts, hydrates thereof, or solvates thereof;
Figure imgf000243_0001
NHC(=0)-R 9 or
NHS(=0)2- Rio이고, NHS(=0)2- Rio,
Z4는 CRcRd, 0 또는 NRe이고, Z4 is CRcRd, 0 or NRe;
Rc, Rd 및 Re는 각각 독립적으로 H, Cl- C5알킬, 할로겐, 또는 - 0-（Cl-R c , Rd and Re are each independently H, Cl- C5 alkyl, halogen, or - 0- (Cl-
C5알킬）이고, C5 alkyl),
Z5 및 Z6은 각각 독립적으로 CH 또는 N이되, Z5 및 Z6 중 적어도 어느 하나는 시이고, n, m, a 및 으는 각각 독립적으로 0 내지 2의 정수이되, n과 m은 동시에 0일 수 없고, a와으는 동시에 0일 수 없으며 , Z 5 and Z6 are each independently CH or N, but at least one of Z5 and Z6 is Si, n, m, a and are each independently an integer from 0 to 2, but n and m can be 0 at the same time no, a and cannot be 0 at the same time,
R7은 H또는 C1-C5알킬이고, R7 is H or C1-C5 alkyl;
R8은 H, Cl- C5알킬, （Cl- C5알킬）- CF3 또는 0를 포함하는 5원 또는 6원의 헤테로사이클로알킬이고, R8 is H, Cl- C5 alkyl, (Cl- C5 alkyl) - CF3 or 5-membered or 6-membered heterocycloalkyl including 0;
242 R9는 Cl- C5알킬, CF3 또는 （Cl- C5알킬）- CF3이고, 242 R9 is Cl-C5alkyl, CF 3 or (Cl-C5alkyl)-CF3;
Rio은 Cl- C5알킬 또는 C3-C6사이클로알킬이고, Rio is Cl- C5 alkyl or C3-C6 cycloalkyl;
R3은 CH3이고, R3 is CH3;
Wi은으이고 Wi is
W2는 0이고, W2 is 0;
A는 N을 2 내지 4개 포함하는 5원 또는 6원의 헤테로아릴이고, A is a 5- or 6-membered heteroaryl containing 2 to 4 N,
R4는보이고, R4 is visible,
L은 CH2이고, L is CH2;
B는 페닐이고, B is phenyl;
Rs 및 R6은 각각독립적으로 H 또는 할로겐이다. Rs and R6 are each independently H or halogen.
【청구항 8] 하기 표에 나타내는 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용가능한 염, 이들의 수화물 또는 이들의 용매화물;
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
[Claim 8] A compound shown in the table below, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof;
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000255_0001
【청구항이 제 1항 내지 제 8항 중 어느 한 항에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용가능한 염, 이들의 수화물 또는 이들의 용매화물을 포함하는, 약학적 조성물. [Claim 8] A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.
【청구항 10】 제 9항에 있어서, 상기 약학적 조성물은 RIPK1 활성 관련 질환의 치료 또는 예방을 위한 것인, 약학적 조성물. 【청구항 11】 제 10항에 있어서, 상기 RIPK1 활성 관련 질환은 염증, 자가면역 질환, 암, 감염, 중추신경계 질환, 대사 질환, 심혈관 질환, 호흡기 질환, 간 질환, 신장 질환, 안구 질환, 피부 질환, 림프 병태, 심리 장애, 이식편대숙주 질환, 이질통, 창상 및 반흔 중 선택된 1 이상의 질환을 포함하는, 약학적 조성물. [Claim 10] The pharmaceutical composition according to claim 9, which is for the treatment or prevention of RIPK1 activity related diseases. [Claim 11] The method of claim 10, wherein the disease related to RIPK1 activity is inflammation, autoimmune disease, cancer, infection, central nervous system disease, metabolic disease, cardiovascular disease, respiratory disease, liver disease, kidney disease, eye disease, skin disease , Lymphatic conditions, psychological disorders, graft-versus-host disease, allodynia, a pharmaceutical composition comprising at least one disease selected from wounds and scars.
【청구항 1이 제 10항에 있어서, 상기 RIPK1 활성 관련 질환은 크론병, 궤양성 대장염, 궤양성 결장염, 건선, 류마티스 관절염, 척추관절염, 전신 발병 소아 특발성 관절염, 건선성 관절염, 골관절염, 실질 기관의 허혈 재관류 손상, 패혈증, 전신 염증 반응 증후군, 다발성 경화증, 및 실질 기관 악성종양으로부터 선택된 1 이상의 질환을 포함하는, 약학적 조성물. [Claim 1 according to claim 10, wherein the disease associated with RIPK1 activity is Crohn's disease, ulcerative colitis, ulcerative colitis, psoriasis, rheumatoid arthritis, spondyloarthritis, systemic-onset juvenile idiopathic arthritis, psoriatic arthritis, osteoarthritis, parenchymal organ A pharmaceutical composition comprising at least one disease selected from ischemia reperfusion injury, sepsis, systemic inflammatory response syndrome, multiple sclerosis, and parenchymal organ malignancies.
【청구항 13】 제 1항 내지 제 8항 중 어느 한 항에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용가능한 염, 이들의 수화물 또는 이들의 용매화물을 투여하는 것을 포함하는, [Claim 13] Including administering the compound according to any one of claims 1 to 8, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof,
255 RIPK1 활성 관련 질환의 예방또는치료를 위한 방법 . 255 Methods for preventing or treating diseases related to RIPK1 activity.
【청구항 14】 【Claim 14】
RIPK1 활성 관련 질환의 예방 또는 치료를 위한 제 1항 내지 제 8항 중 어느 한 항에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용가능한 염, 이들의 수화물 또는 이들의 용매화물의 용도. A compound according to any one of claims 1 to 8, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof for the prevention or treatment of RIPK1 activity-related diseases Usage.
【청구항 15】 【Claim 15】
RIPK1 활성 관련 질환의 예방 또는 치료용 약제의 제조를 위한, 제 1항 내지 제 8항 중 어느 한 항에 따른 화합물, 이의 입체 이성질체, 이의 호변 이성질체, 이의 약학적으로 허용가능한 염, 이들의 수화물 또는 이들의 용매화물의 용도. The compound according to any one of claims 1 to 8, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate thereof, for the preparation of a drug for preventing or treating RIPK1 activity-related diseases Uses of their solvates.
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