WO2022007461A1 - 一种免疫调节剂 - Google Patents
一种免疫调节剂 Download PDFInfo
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- WO2022007461A1 WO2022007461A1 PCT/CN2021/087548 CN2021087548W WO2022007461A1 WO 2022007461 A1 WO2022007461 A1 WO 2022007461A1 CN 2021087548 W CN2021087548 W CN 2021087548W WO 2022007461 A1 WO2022007461 A1 WO 2022007461A1
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- Prior art keywords
- alkylene
- alkyl
- membered
- ring
- cycloalkyl
- Prior art date
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- 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
- C07D403/02—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 two hetero rings
- C07D403/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- 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
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to an immunomodulator and its use in preparing medicine.
- IL-17 Interleukin-17 is a pro-inflammatory cytokine that plays a role in the induction of other inflammatory cytokines, chemokines and adhesion factors.
- the IL-17 family consists of cytokines involved in acute and chronic inflammatory responses, including IL-17A (CTLA-8), IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F .
- IL-17A is expressed by TH17 cells and is involved in the pathogenesis of inflammatory and autoimmune diseases.
- Human IL-17A is a glycoprotein with a molecular weight of approximately 17,000 Daltons.
- IL-17A transmits signals into cells through the IL-17 receptor complex (IL-17RA and IL-17RC) (Wright, et al. Journal of immunology, 2008, 181:2799-2805).
- the main function of IL-17A is through the upregulation of pro-inflammatory and neutrophil-migrating cytokines and chemokines including IL-6, G-CSF, TNF- ⁇ , IL-1, CXCL1, CCL2, CXCL2 Coordinate local tissue inflammation, and matrix metalloproteinases to allow activated T cells to penetrate the extracellular matrix.
- IL-17A plays an important role in severe asthma and chronic obstructive pulmonary disease (COPD), and those patients are often unresponsive or poorly responsive to currently available drugs (Al-Ramli et al. J Allergy Clin Immunol, 2009, 123:1185-1187). Upregulation of IL-17A levels is implicated in many diseases, including rheumatoid arthritis (RA), bone erosion, intraperitoneal abscess, inflammatory bowel disease, allograft rejection, psoriasis, atherosclerosis, asthma, and multiple Sclerosis (Gaffen, SL et al. Arthritis Research & Therapy, 2004, 6:240-247).
- IL-17A-mediated autoimmune inflammatory diseases Treatment of animals with IL-17A neutralizing antibodies reduces disease incidence and severity in autoimmune encephalomyelitis ( Komiyama Y et al. J. Immunol., 2006, 177:566-573). Clinical trials of IL-17A antibodies have shown promising results in IL-7A mediated inflammatory diseases including asthma, psoriasis, rheumatoid arthritis, ankylosing spondylitis and multiple sclerosis.
- the IL-17A antibody (Cosentyx/secukinumab by Novartis) was approved by the FDA in January 2015 for the treatment of psoriasis.
- the present invention provides a compound of formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
- R 1 is selected from -C 0-2 alkylene-(3-10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl), -C 0-2 alkylene Base-(5-10-membered aromatic ring), -C 0-2 alkylene-(5-10-membered aromatic heterocycle), -C 0-2 alkylene-C(O)R 11 , -C 0- 2 alkylene-C(O)NR 11 R 12 , -C 0-2 alkylene-C(O)OR 11 , -C 0-2 alkylene-S(O)R 11 , -C 0- 2 alkylene-S(O)NR 11 R 12 , -C 0-2 alkylene-S(O)OR 11 , -C 0-2 alkylene-S(O) 2 R 11 , -C 0 ⁇ 2 alkylene-S(O) 2 NR 11 R 12 , -C
- R 11 and R 12 are independently selected from hydrogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, -C 0-2 alkylene-(3-10-membered cycloalkyl), -C 0 ⁇ 2 alkylene-(3-10-membered heterocycloalkyl), -C 0-2 alkylene-(5-10-membered aromatic ring), -C 0-2 alkylene-(5-10-membered aromatic ring) heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic, aromatic heterocycle may be further substituted by one, two or three independent R 1a ;
- R 2 and R 3 are independently selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl);
- Ring A is selected from 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered aromatic heterocycle, 5-12-membered spirocycle, 5-12-membered spiroheterocycle, and 5-12-membered bridged ring , 5-12-membered bridged heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle can be further replaced by one, two or three independent R A1 replace;
- Ring B is selected from 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered aromatic heterocycle, 5-12-membered spirocycle, 5-12-membered spiroheterocycle, 5-12-membered bridged ring , 5-12-membered bridged heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle can be further replaced by one, two or three independent R B1 replace;
- Ring C is selected from 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 5-12-membered spirocycle, 5-12-membered spiroheterocycle , 5-12-membered bridged ring, 5-12-membered bridged heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle can be further replaced by a , two, three or four independent R C1 substitutions;
- R C2 and R C3 are independently selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-OR C4 , -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0-2 alkylene-(3-10 membered heterocycloalkyl); wherein alkyl, alkylene, cycloalkyl can be further substituted by one, two or three independent R C4 ;
- the two R C1 When two R C1 are connected to the same atom, the two R C1 can be connected to form 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl;
- L is selected from O, S, CR D1 R D1 , NR L , NR L C(O), NR L S(O), NR L S(O) 2 , C(O)NR L , C(O), S (O)NR L , S(O) 2 NR L or none;
- R L is selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl);
- D ring is selected from 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 5-12-membered spirocycle, 5-12-membered spiroheterocycle , 5-12-membered bridged ring, 5-12-membered bridged heterocycle or none; wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle can be further replaced by one, two or three independent R D1 ;
- R D2 and R D3 are independently selected from hydrogen, C 1-6 alkyl, -C 0-2 alkylene-OR D4 , -C 0-2 alkylene-(3-10 membered cycloalkyl), - C 0-2 alkylene-(3-10-membered heterocycloalkyl), -C 0-2 alkylene-(5-10-membered aromatic ring), -C 0-2 alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further substituted by one, two or three R D4 ;
- C ring is selected from benzene ring
- L is selected from none
- D ring is not selected from 5-6 membered aromatic heterocycle.
- R 1 is selected from -C(O)R 11 ;
- R 11 is selected from 5-6 membered aromatic heterocycle; wherein the aromatic heterocycle may be further replaced by one, two or three independent R 1a- substituted;
- R 1b is selected from hydrogen, C 1-6 alkyl, and halogen-substituted C 1-6 alkyl.
- R 1 is selected from -C(O)R 11 ;
- R 11 is selected from Wherein, the ring selected by R 11 can be further substituted by one, two or three independent R 1a ; each R 1a is independently selected from hydrogen, halogen, cyano, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, 3-6 membered cycloalkyl, -C 0-2 alkylene-OR 1b ;
- R 1b is selected from hydrogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl .
- R 1 is selected from -C(O)R 11 ;
- R 11 is selected from
- R 1 is selected from
- ring A is selected from 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 8-membered cycloalkyl, 5-membered aromatic heterocycle, 5-membered cycloalkyl, ⁇ 12-membered spiro ring, 5-12-membered bridged ring, Among them, cycloalkyl, aromatic heterocycle, spirocycle, bridged ring, May be further substituted with one, two or three independent R A1s .
- ring A is selected from
- ring B is selected from 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 8-membered cycloalkyl, 5-membered aromatic heterocycle, 5-membered cycloalkyl, ⁇ 12-membered spiro ring, 5-12-membered bridged ring, Among them, cycloalkyl, aromatic heterocycle, spirocycle, bridged ring, may be further substituted with one, two or three independent R B1 .
- ring B is selected from
- ring A is selected from and ring B is selected from Alternatively, the A ring is selected from and ring B is selected from Alternatively, the A ring is selected from and ring B is selected from Alternatively, the A ring is selected from and ring B is selected from Alternatively, the A ring is selected from and ring B is selected from Alternatively, the A ring is selected from and ring B is selected from Alternatively, the A ring is selected from and ring B is selected from
- C ring is selected from 5-6 membered aromatic heterocycle; wherein 5-6 membered aromatic heterocycle can be further substituted by one, two or three independent R C1 ;
- the C ring is selected from
- Ring C is selected from Two of R C1 can be connected to form a 3-10-membered cycloalkyl group or a 3-10-membered heterocycloalkyl group.
- the C ring is selected from
- the C ring is selected from
- D ring is selected from 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, benzene ring, 5-6 membered aromatic heterocycle or none; wherein cycloalkyl, heterocycloalkyl, benzene ring, aromatic heterocycle may be further substituted with one, two or three independent R D1 .
- the D ring is selected from
- the D ring is selected from
- C ring is selected from benzene ring; wherein the benzene ring can be further substituted by one, two or three independent R C1 ; each R C1 is independently selected from hydrogen, C 1-6 alkyl, halogen-substituted C 1-6 Alkyl, halogen, cyano;
- L is selected from none
- D ring is selected from 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered aromatic ring, 7-10-membered aromatic heterocycle, 5-12-membered spirocycle, 5-12-membered spiroheterocycle , 5-12-membered bridged ring, 5-12-membered bridged heterocycle or none; wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle can be further Substituted with one, two or three independent R D1.
- R 1 is selected from -C(O)R 11 , -C(O)NR 11 R 12 , -C(O)OR 11 , -S(O)R 11 , -S(O)NR 11 R 12 , -S (O)OR 11 , -S(O) 2 R 11 , -S(O) 2 NR 11 R 12 , -S(O) 2 OR 11 , -P(O)R 11 R 12 , -P(O) (OR 11 )R 12 , -P(O)(OR 11 )(OR 12 );
- R 11 and R 12 are independently selected from hydrogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, -C 0-2 alkylene-(3-10-membered cycloalkyl), -C 0 ⁇ 2 alkylene-(3-10-membered heterocycloalkyl), -C 0-2 alkylene-(5-10-membered aromatic ring), -C 0-2 alkylene-(5-10-membered aromatic ring) heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic, aromatic heterocycle may be further substituted by one, two or three independent R 1a ;
- R 2 and R 3 are independently selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl);
- Ring A is selected from 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 5-12-membered spirocycle, 5-12-membered spiroheterocycle , 5-12-membered bridged ring, 5-12-membered bridged heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle can be further replaced by a , two or three independent R A1 substitutions;
- Ring B is selected from 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 5-12-membered spirocycle, 5-12-membered spiroheterocycle , 5-12-membered bridged ring, 5-12-membered bridged heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle can be further replaced by a , two or three independent R B1 substitutions;
- C ring is selected from 5-6 membered aromatic heterocycle; wherein the aromatic heterocycle can be further substituted by one, two, three or four independent R C1 ;
- R C2 and R C3 are independently selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-OR C4 , -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0-2 alkylene-(3-10 membered heterocycloalkyl); wherein alkyl, alkylene, cycloalkyl can be further substituted by one, two or three independent R C4 ;
- D ring is selected from 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 5-12-membered spirocycle, 5-12-membered spiroheterocycle , 5-12-membered bridged ring, 5-12-membered bridged heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle can be further replaced by a , two or three independent R D1 substitutions;
- R D2 and R D3 are independently selected from hydrogen, C 1-6 alkyl, -C 0-2 alkylene-OR D4 , -C 0-2 alkylene-(3-10 membered cycloalkyl), - C 0-2 alkylene-(3-10-membered heterocycloalkyl), -C 0-2 alkylene-(5-10-membered aromatic ring), -C 0-2 alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further substituted by one, two or three R D4 ;
- R 1 is selected from -C(O)R 11 ;
- R 11 is selected from Wherein, the ring selected by R 11 can be further substituted by one, two or three independent R 1a ; each R 1a is independently selected from hydrogen, halogen, cyano, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, 3-6 membered cycloalkyl, -C 0-2 alkylene-OR 1b ;
- R 1b is selected from hydrogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl .
- R 2 and R 3 are independently selected from hydrogen, -C 1-6 alkyl
- Ring A is selected from
- Ring B is selected from
- Ring C is selected from
- D ring is selected from
- R 1 is selected from -C(O)R 11 , -C(O)NR 11 R 12 , -C(O)OR 11 , -S(O)R 11 , -S(O)NR 11 R 12 , -S (O)OR 11 , -S(O) 2 R 11 , -S(O) 2 NR 11 R 12 , -S(O) 2 OR 11 , -P(O)R 11 R 12 , -P(O) (OR 11 )R 12 , -P(O)(OR 11 )(OR 12 );
- R 11 and R 12 are independently selected from hydrogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, -C 0-2 alkylene-(3-10-membered cycloalkyl), -C 0 ⁇ 2 alkylene-(3-10-membered heterocycloalkyl), -C 0-2 alkylene-(5-10-membered aromatic ring), -C 0-2 alkylene-(5-10-membered aromatic ring) heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic, aromatic heterocycle may be further substituted by one, two or three independent R 1a ;
- R 2 and R 3 are independently selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl);
- Ring A is selected from 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 5-12-membered spirocycle, 5-12-membered spiroheterocycle , 5-12-membered bridged ring, 5-12-membered bridged heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle can be further replaced by a , two or three independent R A1 substitutions;
- Ring B is selected from 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 5-12-membered spirocycle, 5-12-membered spiroheterocycle , 5-12-membered bridged ring, 5-12-membered bridged heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle can be further replaced by a , two or three independent R B1 substitutions;
- C ring is selected from 6-membered aromatic ring and 5-6 membered aromatic heterocycle; wherein the aromatic ring and aromatic heterocycle can be further substituted by one, two, three or four independent R C1 ;
- R C2 and R C3 are independently selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-OR C4 , -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0-2 alkylene-(3-10 membered heterocycloalkyl); wherein alkyl, alkylene, cycloalkyl can be further substituted by one, two or three independent R C4 ;
- Ring D is selected from 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered aromatic ring, 5-12-membered spirocyclic ring, 5-12-membered spiroheterocyclic ring, 5-12-membered bridged ring, 5-12-membered bridged heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle can be further separated by one, two or three independent R D1 substituted;
- R D2 and R D3 are independently selected from hydrogen, C 1-6 alkyl, -C 0-2 alkylene-OR D4 , -C 0-2 alkylene-(3-10 membered cycloalkyl), - C 0-2 alkylene-(3-10-membered heterocycloalkyl), -C 0-2 alkylene-(5-10-membered aromatic ring), -C 0-2 alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further substituted by one, two or three R D4 ;
- R 1 is selected from -C(O)R 11 ;
- R 11 is selected from Wherein, the ring selected by R 11 can be further substituted by one, two or three independent R 1a ; each R 1a is independently selected from hydrogen, halogen, cyano, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, 3-6 membered cycloalkyl, -C 0-2 alkylene-OR 1b ;
- R 1b is selected from hydrogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl .
- R 2 and R 3 are independently selected from hydrogen, -C 1-6 alkyl
- Ring A is selected from
- Ring B is selected from
- Ring C is selected from
- D ring is selected from
- R 1 is selected from -C(O)R 11 ;
- R 11 is selected from Wherein, the ring selected by R 11 can be further substituted by one, two or three independent R 1a ; each R 1a is independently selected from hydrogen, halogen, cyano, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, 3-6 membered cycloalkyl, -C 0-2 alkylene-OR 1b ;
- R 1b is selected from hydrogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl .
- R 2 and R 3 are independently selected from hydrogen, -C 1-6 alkyl
- Ring A is selected from
- Ring B is selected from
- Ring C is selected from
- D ring is selected from
- R D2 and R D3 are independently selected from hydrogen, C 1-6 alkyl, -C 0-2 alkylene-OR D4 , -C 0-2 alkylene-(3-10 membered cycloalkyl), - C 0-2 alkylene-(3-10-membered heterocycloalkyl), -C 0-2 alkylene-(5-10-membered aromatic ring), -C 0-2 alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further substituted by one, two or three R D4 ;
- D ring is selected from
- R 1 is selected from -C(O)R 11 ;
- R 11 is selected from Wherein, the ring selected by R 11 can be further substituted by one, two or three independent R 1a ; each R 1a is independently selected from hydrogen, halogen, cyano, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, 3-6 membered cycloalkyl, -C 0-2 alkylene-OR 1b ;
- R 1b is selected from hydrogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl .
- R 2 and R 3 are independently selected from hydrogen, -C 1-6 alkyl
- Ring A is selected from
- Ring B is selected from
- Ring C is selected from
- R C1 is selected from -C 0-4 alkylene-C(O)NR C2 R C3 ;
- R C2 and R C3 are independently selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-OR C4 , -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0-2 alkylene-(3-10 membered heterocycloalkyl); wherein alkyl, alkylene, cycloalkyl can be further substituted by one, two or three independent R C4 ;
- R 1 is selected from -C(O)R 11 ;
- R 11 is selected from Wherein, the ring selected by R 11 can be further substituted by one, two or three independent R 1a ; each R 1a is independently selected from hydrogen, halogen, cyano, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, 3-6 membered cycloalkyl, -C 0-2 alkylene-OR 1b ;
- R 1b is selected from hydrogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl .
- R 2 and R 3 are independently selected from hydrogen, -C 1-6 alkyl
- Ring A is selected from
- Ring B is selected from
- Ring C is selected from Two of R C1 can be connected to form a 3-10-membered cycloalkyl group or a 3-10-membered heterocycloalkyl group.
- Ring C is selected from
- the present invention also provides the use of the aforementioned compound, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of IL-17A-mediated diseases.
- the IL-17A-mediated disease is one or more of diseases related to inflammation, autoimmune disease, infectious disease, cancer, and precancerous syndrome.
- the present invention also provides a pharmaceutical composition, which is prepared from the aforementioned compound, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, and pharmaceutically acceptable auxiliary materials. preparation.
- the present invention also provides the aforementioned compounds, or their stereoisomers, or their pharmaceutically acceptable salts, or their solvates, or their prodrugs, or their metabolites, in the preparation of the treatment of IL-17A-mediated Use in medicine for disease.
- IL-17A-mediated diseases as defined in the present invention are diseases in which IL-17A plays an important role in the pathogenesis of the disease.
- the main function of IL-17A is to coordinate local tissue inflammation, thus playing a role in various diseases.
- IL-17A-mediated diseases include one or more of inflammation, autoimmune diseases, infectious diseases, cancer, and precancerous syndrome-related diseases. .
- Cancer refers to any of a variety of diseases characterized by uncontrolled abnormal cell proliferation, the ability of affected cells to spread locally or through the bloodstream and lymphatic system to other sites Body (ie metastasis) and any of a number of characteristic structural and/or molecular characteristics.
- Cancer cell refers to cells that undergo early, intermediate or late stages of tumor progression through multiple steps. Cancers include sarcoma, breast, lung, brain, bone, liver, kidney, colon and prostate.
- the compound of formula I is used to treat a cancer selected from colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma.
- the cancer is selected from the group consisting of melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer.
- the cancer being treated is metastatic cancer.
- autoimmune diseases are caused by the body's immune response to substances and tissues that are normally present in the body.
- autoimmune diseases include myocarditis, lupus nephritis, primary biliary cirrhosis, psoriasis, type 1 diabetes, Grave's disease, celiac disease, Crohn's disease, autoimmune neutropenia, juvenile Arthritis, rheumatoid arthritis, fibromyalgia, Guillain-Barre syndrome, multiple sclerosis and autoimmune retinopathy.
- Some embodiments of the present invention relate to the treatment of autoimmune diseases such as psoriasis or multiple sclerosis.
- Inflammatory diseases include a variety of disorders characterized by histopathological inflammation.
- inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, Airway inflammation and interstitial cystitis caused by house dust mites.
- Some embodiments of the present invention relate to the treatment of the inflammatory disease asthma.
- the immune system is often involved in inflammatory disorders, manifested in allergic reactions and some myopathies, and many immune system disorders lead to abnormal inflammation.
- IL-17A-mediated diseases also include autoimmune inflammatory diseases.
- the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
- substitution means that the hydrogen atom in the molecule is replaced by other different atoms or groups; or the lone pair of electrons of the atoms in the molecule is replaced by other atoms or groups, for example, the lone pair of electrons on the S atom can be replaced by O atomic substitution
- C a-b alkyl denotes any alkyl group containing "a" to "b” carbon atoms.
- C 1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms.
- Alkyl refers to a saturated hydrocarbon chain having the specified number of member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) base) and hexyl. Alkyl groups can also be part of other groups such as -O(C 1-6 alkyl).
- Alkylene refers to a divalent saturated aliphatic hydrocarbon group having the specified number of member atoms.
- C a - b alkylene refers to an alkylene group having a to b carbon atoms.
- Alkylene groups include branched and straight chain hydrocarbyl groups.
- the term "propylene” can be exemplified by the following structures:
- the term "dimethylbutylene” can be exemplified, for example, by any of the following structures:
- the -C 0 -2 alkylene group may be a C 0 alkylene group, a C 1 alkylene group (for example, -CH 2 -), a C 2 alkylene group (for example, -CH 2 CH 2 -, etc.) ;
- C 0 alkylene means that the group here does not exist and is connected in the form of a chemical bond, such as A 0 alkylene-B refers to AB, that is, the A group and the B group are directly connected through a chemical bond.
- cycloalkyl and “cycloalkane” refer to saturated or partially saturated cyclic rings having carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including condensed and bridged). group.
- the terms “cycloalkyl”, “cycloalkane” include cycloalkenyl groups such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.
- cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like. Two such bicycloalkyl polycyclic structures are exemplified and named below: dicyclohexyl and Dicyclohexyl.
- the terms "cycloalkyl” and “cycloalkane” also include the case of a partially saturated cyclic group formed by condensing an aromatic ring with a non-aromatic ring, and its attachment point may be located at a non-aromatic carbon atom or an aromatic carbon atom. Including 1,2,3,4-tetralin-5-yl, 5,6,7,8-tetralin-5-yl.
- Unsaturation described in the present invention refers to groups or molecules containing carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, etc.; the unsaturated carbocyclic bonds of the present invention
- the group includes or does not include an aromatic ring group, and the unsaturated heterocyclic group includes and does not include a heteroaryl group, which can be freely selected by those skilled in the art.
- (Ca-Cb)alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.
- Alkynyl means a straight-chain monovalent hydrocarbon group or a branched-chain monovalent hydrocarbon group containing at least one triple bond.
- alkynyl is also intended to include those hydrocarbyl groups having one triple bond and one double bond.
- (C2-C6)alkynyl is intended to include ethynyl, propynyl, and the like.
- Halogen is fluorine, chlorine, bromine or iodine.
- Haloalkyl means that the hydrogen atoms in the alkyl group may be replaced by one or more halogen atoms.
- a halogen-substituted C 1-4 alkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are substituted by one or more halogen atoms; also examples include monofluoromethyl, difluoromethyl, and trifluoromethyl.
- Heterocycloalkyl refers to a saturated ring or a non-aromatic partially saturated ring containing at least one heteroatom and having a single ring or multiple rings (fused, bridged) Ring; wherein heteroatom refers to nitrogen atom, oxygen atom, sulfur atom and the like.
- heteroatom refers to nitrogen atom, oxygen atom, sulfur atom and the like.
- Typically represents a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of multiple ring atoms containing 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
- Bicyclic means consisting of two rings that share two ring atoms, i.e.
- the bridge separating the two rings is a single bond or a chain of one or two ring atoms.
- monocyclic saturated heterocycloalkyl are oxetanyl, azetidine, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidine base, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, Thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl.
- bicyclic saturated heterocycloalkyl groups are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-Aza-bicyclo[3.3.1]nonyl.
- partially unsaturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl.
- heterocycloalkyl also includes the case where an aromatic ring containing at least one heteroatom is fused to a partially saturated cyclic group formed by a non-aromatic ring, and the point of attachment may be at a non-aromatic carbon atom, an aromatic carbon atom or heteroatoms, examples include
- Aromatic ring group and aromatic ring refer to an aromatic hydrocarbon group having a plurality of carbon atoms.
- Aryl groups are typically monocyclic, bicyclic or tricyclic aryl groups having multiple carbon atoms.
- aryl refers to an aromatic substituent which may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.
- Stepoisomer includes enantiomers and diastereomers
- the oxygen atom in "-C(O)R", “-S(O) 2 R”, etc. described in the present invention is connected with a carbon atom or a sulfur atom by a double bond, and the R group is connected with a carbon atom or a sulfur atom Connect with a single key.
- the "deuterated compound” of the present invention means that one or more hydrogen atoms in a molecule or group are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.
- pharmaceutically acceptable means that a carrier, vehicle, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form, and is physiologically Compatible with receptors.
- salts and “pharmaceutically acceptable salts” refer to the above-mentioned compounds or their stereoisomers, acid and/or base salts with inorganic and/or organic acids and bases, and also zwitterionic salts (internal). salts), also including quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above-mentioned compound, or a stereoisomer thereof, with a certain amount of acid or base as appropriate (for example, an equivalent amount).
- salts may be precipitated in solution and collected by filtration, recovered after evaporation of the solvent, or obtained by lyophilization after reaction in an aqueous medium.
- the salts described in the present invention can be hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate of the compound salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
- one or more compounds of the present invention may be used in combination with each other.
- the compounds of the present invention may be used in combination with any other active agent for the preparation of medicaments or pharmaceutical compositions for modulating cellular function or treating diseases. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.
- Fig. 1 is the result of the efficacy test of the psoriasis model induced by imiquimod cream in mice;
- Figure 2 shows the results of skin tissue section of the psoriasis model drug efficacy test induced by imiquimod cream in mice.
- NMR nuclear magnetic resonance
- MS mass spectrometry
- the measurement of LC-MS used Shimadzu LC-MS 2020 (ESI)).
- the HPLC measurement used a Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A).
- MPLC medium pressure preparative chromatography
- the thin layer chromatography silica gel plate is made of Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications of the thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
- Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
- the known starting materials of the present invention can be synthesized by adopting or following methods known in the art, or can be purchased from companies such as Annagy Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology and the like.
- TEA or Et 3 N triethylamine
- DIPEA N,N-diisopropylethylamine
- HOBt 1-hydroxybenzotriazole
- DCM dichloromethane
- PE petroleum ether
- EA or EtOAc ethyl acetate Ester
- THF tetrahydrofuran
- DMF N,N-dimethylformamide
- NMP N-methylpyrrolidone
- NMO N-methylmorpholine oxide
- MeOH methanol
- EtOH ethanol
- DMSO dimethylsulfoxide Sulfone
- TAF trifluoroacetic acid
- NaBH 4 sodium borohydride
- MsCl methylsulfonyl chloride
- DIBAL diisobutylaluminum hydride
- NBS N-bromosuccinimide
- NCS N-chlorobutane diimide
- DMS diisobutane diimide
- the reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the combined organic phases were concentrated to obtain the crude product. About 10% of the 1-5 in the crude product was unreacted.
- the crude product was dissolved in MeOH/THF/H 2 O( 1/1/1, a total of 150mL) solution, add K 2 OsO 4 (70mg, 0.19mmol), 0.5mmol of N-methylmorpholine oxide (NMO), the mixture was stirred at room temperature overnight, after the completion of the reaction, the reaction The liquid was concentrated, diluted with water, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine, concentrated to obtain crude product, which was separated and purified by silica gel column to obtain Intermediate 1-6 (313 mg, yield 59%).
- intermediate 3 can be obtained, MS m/z: 318(M+1) + .
- step 2 6-bromo-3-aminopyridine is replaced with 5-amino-2-bromo-3-fluoropyridine, and the operation of other reagents is the same, and can be obtained Intermediate Z3.
- step 2 is also processed by palladium Carbon-catalyzed hydrogenation is used to remove the Cbz protecting group, and in step 3, it is condensed with 1-methyl-5-pyrazolecarboxylic acid to obtain the corresponding example compounds in the table.
- step 2 is the same
- the Cbz protecting group is removed by catalytic hydrogenation with 10% palladium on carbon, and then condensed with 1-methyl-5-pyrazolecarboxylic acid in step 3, and then the Boc protecting group is removed by trifluoroacetic acid to obtain the example compound 24.
- Example compounds 25, 26 and 27 were replaced with different amino acids in the following table, and 4-(4-morpholinyl) was replaced with different amines in the table.
- Aniline is condensed with an amino acid
- step 2 is also subjected to palladium-carbon catalytic hydrogenation to remove the Cbz protecting group
- step 3 is condensed with 1-methyl-5-pyrazolecarboxylic acid to obtain Example compounds 25, 26 and 27 in the table.
- Example 28 (18.35mg, 0.034mmol, yield: 61%), MS m / z: 548.0 (M + 1) +.
- Example 32 Referring to the method of Example 28, using Intermediate 1 and ethyl 3-(4-aminophenyl)tetrahydrofuran-3-carboxylate as starting materials, the compound of Example 32 can be obtained, MS m/z: 576 (M +1) + . Similarly, intermediates 32-4 were condensed with various amines in the table below to give Examples 33-35.
- intermediate Z2 and intermediate 1 are condensed to obtain 37-1, and step 2 is also subjected to palladium-carbon catalytic hydrogenation to remove the Cbz protecting group to obtain 37 -2, the intermediate 37-2 of step 3 is condensed with 1-methyl-5-pyrazolecarboxylic acid to obtain 37-3, and finally the SEM protecting group is removed by trifluoroacetic acid to obtain the example compound 37 in the table.
- intermediate 51-2 (7.2g, 14.78mmol), intermediate 2-isopropyl-3-pyrazolecarboxylic acid (2.73g, 17.74mmol) DMF (60ml) were added successively, and the ice bath stirring conditions HBTU (7.28 g, 19.22 mmol) and DIPEA (7.63 g, 59.14 mmol, 10.5 ml) were added in sequence, and the reaction was stirred for 10 mins under ice bath conditions, and the reaction was stirred at room temperature for 1 hr.
- HBTU 7.28 g, 19.22 mmol
- DIPEA 7.63 g, 59.14 mmol, 10.5 ml
- Example 1 General Route A With the amino acids in the table As the raw material, it is condensed with the corresponding amine in the table, and then catalyzed by palladium-carbon hydrogenation to remove the Cbz protecting group, and finally condensed with 1-methylpyrazole-5-carboxylic acid to obtain compounds 60-62.
- the present invention provides the following test examples.
- Test Example 1 IL-17A enzyme-linked immunosorbent assay (ELISA) experiment
- IL-17A (Sino Biological Inc. Cat# 12047-H07B) was incubated at 100 ⁇ l per well for 30 minutes at 37 degrees in a 96-well plate. The plate was washed 4 times with PBST (PBS, 0.05% Tween-20), 200 ⁇ l per well each time, and 200 ⁇ l of 5% skim milk was added to incubate for 30 minutes on a shaker at 25 degrees. Prepare compounds to be tested at 100X concentrations ranging from 0.003 ⁇ M to 30 ⁇ M.
- Test Example 2 Inhibition of human IL17A protein to induce HT-29 cells to produce chemokine GRO ⁇ /CXCL1
- the compound solution was administered to 3 rats at corresponding doses by intravenous injection/oral gavage, respectively.
- Rat anticoagulated whole blood was collected and plasma was separated;
- the compound was administered to 6 mice by intravenous injection/oral gavage at the corresponding dose, and the mice administered each route were divided into A /B two groups, in which the anticoagulated whole blood was collected from the mice in group A at 5min, 30min, 2h, and 8h after the administration, and the anticoagulated whole blood was collected from the mice in group B at 15min, 1h, 4h, and 24h after the administration, and separated. plasma.
- the compound solution was administered to 4 beagle dogs (2 males + 2 females) in each group by intravenous injection/oral gavage at corresponding doses, 5min, 15min, 30min, 1h after administration. , 2h, 4h, 8h, 12h, 24h, 36h to collect anticoagulated whole blood and separate plasma.
- Plasma concentrations of compounds were determined by standard curve calibration using LC-MS. Using Winnolin 5.2 software, the plasma concentration-time data were fitted to pharmacokinetic parameters, including elimination half-life (T1/2), area under the curve (AUClast), peak concentration (Cmax), apparent volume of distribution ( Vz), total clearance (Cl), absolute bioavailability (F%), etc.
- T1/2 elimination half-life
- AUClast area under the curve
- Vz apparent volume of distribution
- Cl total clearance
- F% absolute bioavailability
- the mouse back skin samples were collected, fixed in 4% paraformaldehyde, and stained with HE to investigate the protective effect of compound 51 on skin pathological damage (Fig. 2).
- the results of HE staining showed that the administration of compound 51 at 3, 10 and 30 mg/kg could inhibit the infiltration and damage of skin inflammatory cells induced by IMQ to different degrees.
- a model of encephalomyelitis was induced using MOG protein in 10-week female C57BL/6 mice. From the day before modeling, the compound solution of the present invention was administered by intragastric gavage (30 mg/kg) or intraperitoneal injection (3, 10, 30 mg/kg) once a day, or the IL17A antibody solution was administered by intraperitoneal injection every three days (first, 10 mg/kg twice, then 5 mg/kg); the control group and model group were given blank solvent. Daily scoring was performed according to the scoring system of the mouse encephalomyelitis model, and a scoring curve was drawn.
- mice brain and spinal cord samples were collected and fixed in 4% paraformaldehyde, and HE staining was performed to investigate the protective effect of the compound on the histopathological injury of the cerebral and spinal cord tissues.
- the new compound represented by formula I disclosed in the present invention exhibits good IL-17A inhibitory activity, and provides a new medicinal possibility for clinical treatment of diseases related to abnormal IL-17A activity.
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Abstract
Description
实施例 | F%(小鼠) | F%(大鼠) | F%(犬) |
51 | 56 | 46 | 58 |
Claims (22)
- 式I所示的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐:其中,R 1选自-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环)、-C 0~2亚烷基-C(O)R 11、-C 0~2亚烷基-C(O)NR 11R 12、-C 0~2亚烷基-C(O)OR 11、-C 0~2亚烷基-S(O)R 11、-C 0~2亚烷基-S(O)NR 11R 12、-C 0~2亚烷基-S(O)OR 11、-C 0~2亚烷基-S(O) 2R 11、-C 0~2亚烷基-S(O) 2NR 11R 12、-C 0~2亚烷基-S(O) 2OR 11、-C 0~2亚烷基-P(O)R 11R 12、-C 0~2亚烷基-P(O)(OR 11)R 12、-C 0~2亚烷基-P(O)(OR 11)(OR 12);其中亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R 1a取代;R 11、R 12分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R 1a取代;每个R 1a分别独立选自氢、卤素、氰基、=O、硝基、-C 1~6烷基、卤素取代的-C 1~6烷基、-C 0~2亚烷基-OR 1b、-C 0~2亚烷基-C(O)R 1b、-C 0~2亚烷基-C(O)NR 1bR 1c、-C 0~2亚烷基-NR 1bR 1c、-C 0~2亚烷基-NR 1bC(O)R 1c、-C 0~4亚烷基-S(O) 2R 1bR 1c、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R 1b取代;R 1b、R 1c分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基、=O、硝基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基);R 2、R 3分别独立选自氢、-C 1~6烷基、-C 0~2亚烷基-(3~10元环烷基);A环选自3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~10元芳杂环、5~12元螺环、5~12元螺杂环、5~12元桥环、5~12元桥杂环;其中环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个或三个独立的R A1取代;每个R A1分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基、=O、硝基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基)、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);B环选自3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~10元芳杂环、5~12元螺环、5~12元螺杂环、5~12元桥环、5~12元桥杂环;其中环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个或三个独立的R B1取代;每个R B1分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基、=O、硝基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基)、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);C环选自3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~10元芳杂环、5~12元螺环、5~12元螺杂环、5~12元桥环、5~12元桥杂环;其中环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个、三个或四个独立的R C1取代;每个R C1分别独立选自氢、卤素、氰基、=O、硝基、-C 1~6烷基、卤素取代的-C 1~6烷基、-C 0~2亚烷基-OR C2、-C 0~2亚烷基-C(O)R C2、-C 0~4亚烷基-C(O)NR C2R C3、-C 0~2亚烷基-NR C2R C3、-C 0~2亚烷基-NR C2C(O)R C3 2、3~10元环烷基、3~10元杂环烷基;其中烷基、亚烷基可进一步被一个、两个或三个独立的R C4取代;R C2、R C3分别独立选自氢、-C 1~6烷基、-C 0~2亚烷基-OR C4、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基);其中烷基、亚烷基、环烷基可进一步被一个、两个或三个独立的R C4取代;每个R C4分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基、=O、硝基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基);或者,当两个R C1连接在同一原子时,两个R C1可相连形成3~10元环烷基、3~10元杂环烷基;L选自O、S、CR D1R D1、NR L、NR LC(O)、NR LS(O)、NR LS(O) 2、C(O)NR L、C(O)、S(O)NR L、S(O) 2NR L或无;R L选自氢、-C 1~6烷基、-C 0~2亚烷基-(3~10元环烷基);D环选自3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~10元芳杂环、5~12元螺环、5~12元螺杂环、5~12元桥环、5~12元桥杂环或无;其中环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个或三个独立的R D1取代;L选自无且D环不选自无时,C环与D环直接相连;L和D环均选自无时,无-L-D的取代;每个R D1分别独立选自氢、卤素、氰基、=O、硝基、-C 1~6烷基、卤素取代的-C 1~6烷基、-C 0~2亚烷基-OR D2、-C 0~2亚烷基-C(O)R D2、-C 0~2亚烷基-C(O)NR D2R D3、-C 0~2亚烷基-NR D2R D3、-C 0~2亚烷基-NR D2C(O)R D3、-C 0~4亚烷基-OP(O)(OH) 2、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个R D4取代;R D2、R D3分别独立选自氢、C 1~6烷基、-C 0~2亚烷基-OR D4、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个R D4取代;每个R D4分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基、=O、硝基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基)、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);其中,C环选自苯环,L选自无时,D环不选自5~6元芳杂环。
- 根据权利要求1所述的化合物,其特征在于:C环选自5~6元芳杂环;其中5~6元芳杂环可进一步被一个、两个或三个独立的R C1取代;每个R C1分别独立选自氢、卤素、氰基、=O、硝基、-C 1~6烷基、卤素取代的-C 1~6烷基、-OR C2、-C(O)R C2、-C(O)NR C2R C3、-NR C2R C3、-NR C2C(O)R C3 2、3~6元环烷基、3~6元杂环烷基。
- 根据权利要求1所述的化合物,其特征在于:D环选自5~6元环烷基、5~6元杂环烷基、苯环、5~6元芳杂环或无;其中环烷基、杂环烷基、苯环、芳杂环可进一步被一个、两个或三个独立的R D1取代。
- 根据权利要求1所述的化合物,其特征在于:C环选自苯环;其中苯环可进一步被一个、两个或三个独立的R C1取代;每个R C1分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基;L选自无;D环选自3~10元环烷基、3~10元杂环烷基、5~10元芳环、7~10元芳杂环、5~12元螺环、5~12元螺杂环、5~12元桥环、5~12元桥杂环或无;其中环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个或三个独立的R D1取代。
- 根据权利要求1所述的化合物,其特征在于:式I所述的化合物如式II所示:其中,R 1选自-C(O)R 11、-C(O)NR 11R 12、-C(O)OR 11、-S(O)R 11、-S(O)NR 11R 12、-S(O)OR 11、-S(O) 2R 11、-S(O) 2NR 11R 12、-S(O) 2OR 11、-P(O)R 11R 12、-P(O)(OR 11)R 12、-P(O)(OR 11)(OR 12);R 11、R 12分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R 1a取代;每个R 1a分别独立选自氢、卤素、氰基、=O、硝基、-C 1~6烷基、卤素取代的-C 1~6烷基、 -C 0~2亚烷基-OR 1b、-C 0~2亚烷基-C(O)R 1b、-C 0~2亚烷基-C(O)NR 1bR 1c、-C 0~2亚烷基-NR 1bR 1c、-C 0~2亚烷基-NR 1bC(O)R 1c、-C 0~4亚烷基-S(O) 2R 1bR 1c、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R 1b取代;R 1b、R 1c分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基、=O、硝基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基);R 2、R 3分别独立选自氢、-C 1~6烷基、-C 0~2亚烷基-(3~10元环烷基);A环选自3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~10元芳杂环、5~12元螺环、5~12元螺杂环、5~12元桥环、5~12元桥杂环;其中环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个或三个独立的R A1取代;每个R A1分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基、=O、硝基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基)、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);B环选自3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~10元芳杂环、5~12元螺环、5~12元螺杂环、5~12元桥环、5~12元桥杂环;其中环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个或三个独立的R B1取代;每个R B1分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基、=O、硝基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基)、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);C环选自5~6元芳杂环;其中芳杂环可进一步被一个、两个、三个或四个独立的R C1取代;每个R C1分别独立选自氢、卤素、氰基、=O、硝基、-C 1~6烷基、卤素取代的-C 1~6烷基、-C 0~2亚烷基-OR C2、-C 0~2亚烷基-C(O)R C2、-C 0~2亚烷基-C(O)NR C2R C3、-C 0~2亚烷基-NR C2R C3、-C 0~2亚烷基-NR C2C(O)R C3 2、3~10元环烷基、3~10元杂环烷基;其中烷基、亚烷基可进一步被一个、两个或三个独立的R C4取代;R C2、R C3分别独立选自氢、-C 1~6烷基、-C 0~2亚烷基-OR C4、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基);其中烷基、亚烷基、环烷基可进一步被一个、两个或三个独 立的R C4取代;每个R C4分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基、=O、硝基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基);D环选自3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~10元芳杂环、5~12元螺环、5~12元螺杂环、5~12元桥环、5~12元桥杂环;其中环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个或三个独立的R D1取代;每个R D1分别独立选自氢、卤素、氰基、=O、硝基、-C 1~6烷基、卤素取代的-C 1~6烷基、-C 0~2亚烷基-OR D2、-C 0~2亚烷基-C(O)R D2、-C 0~2亚烷基-C(O)NR D2R D3、-C 0~2亚烷基-NR D2R D3、-C 0~2亚烷基-NR D2C(O)R D3、-C 0~4亚烷基-OP(O)(OH) 2、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个R D4取代;R D2、R D3分别独立选自氢、C 1~6烷基、-C 0~2亚烷基-OR D4、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个R D4取代;每个R D4分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基、=O、硝基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基)、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环)。
- 根据权利要求1所述的化合物,其特征在于:式I所述的化合物如式III所示:其中,R 1选自-C(O)R 11、-C(O)NR 11R 12、-C(O)OR 11、-S(O)R 11、-S(O)NR 11R 12、-S(O)OR 11、-S(O) 2R 11、-S(O) 2NR 11R 12、-S(O) 2OR 11、-P(O)R 11R 12、-P(O)(OR 11)R 12、-P(O)(OR 11)(OR 12);R 11、R 12分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R 1a取代;每个R 1a分别独立选自氢、卤素、氰基、=O、硝基、-C 1~6烷基、卤素取代的-C 1~6烷基、-C 0~2亚烷基-OR 1b、-C 0~2亚烷基-C(O)R 1b、-C 0~2亚烷基-C(O)NR 1bR 1c、-C 0~2亚烷基-NR 1bR 1c、 -C 0~2亚烷基-NR 1bC(O)R 1c、-C 0~4亚烷基-S(O) 2R 1bR 1c、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R 1b取代;R 1b、R 1c分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基、=O、硝基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基);R 2、R 3分别独立选自氢、-C 1~6烷基、-C 0~2亚烷基-(3~10元环烷基);A环选自3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~10元芳杂环、5~12元螺环、5~12元螺杂环、5~12元桥环、5~12元桥杂环;其中环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个或三个独立的R A1取代;每个R A1分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基、=O、硝基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基)、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);B环选自3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~10元芳杂环、5~12元螺环、5~12元螺杂环、5~12元桥环、5~12元桥杂环;其中环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个或三个独立的R B1取代;每个R B1分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基、=O、硝基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基)、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);C环选自6元芳环、5~6元芳杂环;其中芳环、芳杂环可进一步被一个、两个、三个或四个独立的R C1取代;每个R C1分别独立选自氢、卤素、氰基、=O、硝基、-C 1~6烷基、卤素取代的-C 1~6烷基、-C 0~2亚烷基-OR C2、-C 0~2亚烷基-C(O)R C2、-C 0~2亚烷基-C(O)NR C2R C3、-C 0~2亚烷基-NR C2R C3、-C 0~2亚烷基-NR C2C(O)R C3 2、3~10元环烷基、3~10元杂环烷基;其中烷基、亚烷基可进一步被一个、两个或三个独立的R C4取代;R C2、R C3分别独立选自氢、-C 1~6烷基、-C 0~2亚烷基-OR C4、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基);其中烷基、亚烷基、环烷基可进一步被一个、两个或三个独立的R C4取代;每个R C4分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基、=O、硝基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基);D环选自3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~12元螺环、5~12元螺杂环、5~12元桥环、5~12元桥杂环;其中环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个或三个独立的R D1取代;每个R D1分别独立选自氢、卤素、氰基、=O、硝基、-C 1~6烷基、卤素取代的-C 1~6烷基、-C 0~2亚烷基-OR D2、-C 0~2亚烷基-C(O)R D2、-C 0~2亚烷基-C(O)NR D2R D3、-C 0~2亚烷基-NR D2R D3、-C 0~2亚烷基-NR D2C(O)R D3、-C 0~4亚烷基-OP(O)(OH) 2、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个R D4取代;R D2、R D3分别独立选自氢、C 1~6烷基、-C 0~2亚烷基-OR D4、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个R D4取代;每个R D4分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基、=O、硝基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基)、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环)。
- 根据权利要求1所述的化合物,其特征在于:式I所述的化合物如式IV所示:其中,R 1选自-C(O)R 11;R 11选自 其中,R 11选自的环可进一步被一个、两个或三个独立的R 1a取代;每个R 1a分别独立选自氢、卤素、氰基、-C 1~6烷基、卤素取代的-C 1~6烷基、3~6元环烷基、-C 0~2亚烷基-OR 1b;R 1b选自氢、C 1~6烷基、卤素取代的C 1~6烷基。R 2、R 3分别独立选自氢、-C 1~6烷基;R D2、R D3分别独立选自氢、C 1~6烷基、-C 0~2亚烷基-OR D4、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个R D4取代;每个R D4分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基、=O、硝基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基)、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基)、-C 0~2亚烷基-(5~10元芳环)、-C 0~2亚烷基-(5~10元芳杂环)。
- 根据权利要求1所述的化合物,其特征在于:式I所述的化合物如式V所示:其中,R 1选自-C(O)R 11;R 11选自 其中,R 11选自的环可进一步被一个、两个或三个独立的R 1a取代;每个R 1a分别独立选自氢、卤素、氰基、-C 1~6烷基、卤素取代的-C 1~6烷基、3~6元环烷基、-C 0~2亚烷基-OR 1b;R 1b选自氢、C 1~6烷基、卤素取代的C 1~6烷基。R 2、R 3分别独立选自氢、-C 1~6烷基;R C1选自-C 0~4亚烷基-C(O)NR C2R C3;R C2、R C3分别独立选自氢、-C 1~6烷基、-C 0~2亚烷基-OR C4、-C 0~2亚烷基-(3~10元环烷基)、-C 0~2亚烷基-(3~10元杂环烷基);其中烷基、亚烷基、环烷基可进一步被一个、两个或三个独立的R C4取代;每个R C4分别独立选自氢、C 1~6烷基、卤素取代的C 1~6烷基、卤素、氰基、=O、硝基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基)。
- 权利要求1-19任一项所述的化合物、或其氘代化合物、或其立体异构体、或其药学 上可接受的盐在制备治疗IL-17A介导的疾病的药物中的用途。
- 权利要求20所述的用途,其特征在于:所述IL-17A介导的疾病是与炎症、自身免疫性疾病、感染性疾病、癌症、癌前期综合征相关的疾病中的一种或几种。
- 一种药物组合物,其特征在于:它是以权利要求1~19任一项所述的化合物、或其立体异构体、或其氘代化合物、或其药学上可接受的盐,加上药学上可接受的辅料制备而成的制剂。
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WO2023283453A1 (en) * | 2021-07-09 | 2023-01-12 | Dice Alpha, Inc. | Phenyl acetamide based il-17a modulators and uses thereof |
WO2023025783A1 (en) | 2021-08-23 | 2023-03-02 | Leo Pharma A/S | Small molecule modulators of il-17 |
WO2024121427A1 (en) * | 2022-12-09 | 2024-06-13 | Sanofi | Therapeutic compounds |
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WO2023111181A1 (en) | 2021-12-16 | 2023-06-22 | Leo Pharma A/S | Small molecule modulators of il-17 |
WO2023166172A1 (en) | 2022-03-04 | 2023-09-07 | Leo Pharma A/S | Small molecule modulators of il-17 |
WO2024115662A1 (en) | 2022-12-02 | 2024-06-06 | Leo Pharma A/S | Small molecule modulators of il-17 |
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WO2023283453A1 (en) * | 2021-07-09 | 2023-01-12 | Dice Alpha, Inc. | Phenyl acetamide based il-17a modulators and uses thereof |
WO2023025783A1 (en) | 2021-08-23 | 2023-03-02 | Leo Pharma A/S | Small molecule modulators of il-17 |
WO2024121427A1 (en) * | 2022-12-09 | 2024-06-13 | Sanofi | Therapeutic compounds |
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EP4177249A4 (en) | 2024-07-24 |
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AU2021306755A1 (en) | 2023-02-09 |
KR20230021083A (ko) | 2023-02-13 |
CA3184924A1 (en) | 2022-01-13 |
EP4177249A1 (en) | 2023-05-10 |
AU2021306755B2 (en) | 2024-05-30 |
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US20230159465A1 (en) | 2023-05-25 |
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