WO2022070288A1 - Composé bicyclique contenant de l'azote - Google Patents

Composé bicyclique contenant de l'azote Download PDF

Info

Publication number
WO2022070288A1
WO2022070288A1 PCT/JP2020/037047 JP2020037047W WO2022070288A1 WO 2022070288 A1 WO2022070288 A1 WO 2022070288A1 JP 2020037047 W JP2020037047 W JP 2020037047W WO 2022070288 A1 WO2022070288 A1 WO 2022070288A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
group
salt
halogeno
compound
Prior art date
Application number
PCT/JP2020/037047
Other languages
English (en)
Japanese (ja)
Inventor
浩一郎 新井
博憲 井上
好聖 高島
健一郎 鷹羽
明史 大村
公和 跡部
貴彦 伊藤
アンドリュー ジョン ポッター
ダニエル ポール マドックス
ニコラス フォロッペ
Original Assignee
旭化成ファーマ株式会社
ヴァーナリス （アールアンドディー） リミテッド
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 旭化成ファーマ株式会社, ヴァーナリス （アールアンドディー） リミテッド filed Critical 旭化成ファーマ株式会社
Priority to PCT/JP2020/037047 priority Critical patent/WO2022070288A1/fr
Publication of WO2022070288A1 publication Critical patent/WO2022070288A1/fr

Links

Images

Classifications

    • 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

Definitions

  • the present invention relates to a novel nitrogen-containing bicyclic compound or a drug containing them as an active ingredient.
  • Interleukin-1 receptor-related kinase 4 plays an important role in downstream signaling of Toll-like receptors (TLRs), interleukin-1 receptors (IL-1R), IL-18R and IL-33R. It is a protein kinase that plays a role (Non-Patent Document 1). Since the TLRs / IL-1 receptor family play important roles in inflammation and biological defense, this downstream signal is thought to play a major role in many diseases, including inflammatory and autoimmune diseases.
  • TLRs use pathogen-associated molecular patterns (PAMPs) derived from infectious microorganisms such as bacteria, fungi, parasites, and viruses as ligands. In addition, it recognizes and activates damage-associated molecular patterns (DAMPs) released from damaged and apoptotic cells.
  • PAMPs pathogen-associated molecular patterns
  • DAMPs damage-associated molecular patterns
  • MyD88 the adapter molecule MyD88 is recruited to a common intracellular region called the TIR (Toll / IL-1 receptor) region.
  • IRAK-4 is recruited to the receptor by interacting with MyD88 and initiates downstream signal transduction (Non-Patent Document 2).
  • IRAK-4 activates IRAK-1 and IRAK-2, and further regulates the production of inflammatory mediators such as cytokines and chemokines through the activation of signaling molecules such as NF-kB and MAPK downstream.
  • Non-Patent Document 3 It has been reported that human-derived cells lacking the IRAK-4 gene do not respond to TLRs agonists other than TLR3 and IL-1 ⁇ and IL-18 (Non-Patent Document 3). In addition, IRAK-4 gene-deficient mice do not respond to IL-1 ⁇ and IL-18 with TLRs agonists other than TLR3 (Non-Patent Document 4). On the other hand, in IRAK-1 gene-deficient mice and IRAK-2 gene-deficient mice, these signals are only partially suppressed (Non-Patent Document 5). Therefore, it is considered that IRAK-4 plays a central role in these signal transductions in the IRAK family.
  • Non-Patent Document 6 the kinase activity of IRAK-4 is essential for signal transduction involved in pathological conditions, and IRAK-4 inhibitors are acute and chronic inflammation, autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, and metabolic diseases such as gout and diabetes. , May show high efficacy in the treatment of diseases such as tumors.
  • the compound having IRAK-4 inhibitory activity for example, the compounds described in Patent Documents 1 to 6 are known.
  • the problem to be solved by the present invention is to provide a novel compound having IRAK-4 inhibitory activity. Another challenge is to provide a novel compound useful as an active ingredient of a pharmaceutical for preventing and / or treating a disease associated with IRAK-4 inhibition. Yet another subject is to provide a pharmaceutical containing the compound.
  • the compounds of the present invention represented by the following formula (1) have excellent IRAK-4 inhibitory activity, and these compounds have IRAK-. 4
  • it is useful for the prevention and / or treatment of diseases related to inhibition, and have completed the present invention.
  • R 1 is -H, -F, or methyl
  • R2 is —H, halogen, cyano, C 1-6 alkyl, halogeno C 1-6 alkyl, C 1-6 alkoxy, or halogeno C 1-6 alkoxy
  • Ar may be a 6-10-membered aryl or a 5-10-membered heteroaryl, wherein the Ar may be substituted with 1 to 3 identical or different substituents selected from the G1 group;
  • the G1 group includes -F, -Cl, hydroxy, cyano, C 1-3 alkyl, Harogeno C 1-3 alkyl, R Ar1 -OC 1-3 alkyl, R Ar1 -NR 11 -C 1-3 .
  • R Ar1 is a —H, C 1-6 alkyl, halogeno C 1-6 alkyl, or 3-7 member saturated ring group, wherein R Ar1 is the same or different from 1 to 3 selected from the G2 group.
  • the G2 group consists of -F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, oxo, C 1-3 alkoxy, halogeno C 1-3 alkoxy, and a 3-7-membered saturated ring group.
  • R 11 is -H, C 1-3 alkyl, halogeno C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, halogeno C 1-3 alkoxy C 1-3 alkyl, or 3-7 member saturated ring.
  • R 12 is a C 1-3 alkyl, a halogeno C 1-3 alkyl, a C 1-3 alkoxy C 1-3 alkyl, a halogeno C 1-3 alkoxy C 1-3 alkyl, or a 3-7 member saturated ring group.
  • R 13 is —H, phenyl, or a 5-6 member heteroaryl, said R 13 may be substituted with 1 to 3 identical or different substituents selected from the G3 group;
  • the G3 group is a group consisting of halogen, cyano, C 1-3 alkyl, and halogeno C 1-3 alkyl ;
  • Cy is the following general formula (1-1): Or it is a 3-7 member saturated heterocycle, the 3-7 member saturated heterocycle may be substituted with 1 to 3 identical or different substituents selected from the G4 group;
  • the G4 group consists of -F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, and hydroxy C 1-3 alkyl;
  • k is an integer of 1 or 2;
  • m is an integer of 1 to 3;
  • X is CR Cy3 or N;
  • RCy3 is -H, -F, or hydroxy;
  • RCy4 is -H, -F,
  • The-(CH 2 ) n -part may be substituted with 1 to 3 identical or different substituents selected from the group consisting of C 1-3 alkyl and halogeno C 1-3 alkyl; n is an integer from 0 to 2; R 21 and R 22 are independently -H, C 1-6 alkyl, halogeno C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, or 3-7, respectively.
  • R 21 and R 22 may be substituted with 1 to 3 identical or different substituents selected from the G2 group; Alternatively, R 21 and R 22 are combined to form a 4-7-membered saturated ring or a 7-11-membered spiro ring, and the 4-7-membered saturated ring and the 7-11-membered spiro ring are added to N and O and. It may have one or two identical or different heteroatoms or —S (O 2 ) — selected from the group consisting of N, and the 4-7-membered saturated ring and the 7-11-membered spiro ring may have.
  • the G5 groups include -F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogeno C 1-3 alkoxy, and -OC (O) R.
  • R 24 is -H, C 1-3 alkyl, halogeno C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, halogeno C 1-3 alkoxy C 1-3 alkyl, or 3-7 member saturated ring.
  • R 24 is a C 1-6 alkyl, a halogeno C 1-6 alkyl, a C 1-6 alkoxy C 1-6 alkyl, a halogeno C 1-6 alkoxy C 1-6 alkyl, or a 3-7 member saturated ring group.
  • R Cy4 and R Cy5 together form a 4-7-membered saturated ring, wherein the 4-7-membered saturated ring is 1-2 identical or different heteros selected from the group consisting of O and N. It may have an atom or —S (O 2 ) —, and the 4-7- membered saturated ring may be substituted with 1 to 3 identical or different substituents selected from the G5 group.
  • R Cy1 and R Cy2 are in the relationship of either (a) or (b); (A) R Cy1 and R Cy2 are independently -H, -F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, or C 1-3 alkoxy; (B) R Cy1 and R Cy2 together form a crosslink, a spiro ring, or a condensed ring, and the crosslinked, the spiro ring, and the condensed ring are selected from the group consisting of O and N 1-2. It may have the same or different heteroatoms, the crosslinks, spiro rings, and condensed rings being substituted with 1 to 3 identical or different substituents selected from the G4 group. May be good] The compound shown by or a salt thereof.
  • Ar is the following general formula (1-2): And; In equation (1-2), Y is CR Ar2 or N; R Ar2 is -H, -F, -Cl, hydroxy, cyano, C 1-6 alkyl, halogeno C 1-6 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkyl, -NH 2 , Or -NR 11 R 12 (R 11 and R 12 are synonymous with the above); R Ar3 and R Ar4 are independently -H, -F, -Cl, C 1-3 alkyl, or halogeno C 1-3 alkyl; R Ar5 is -H, -F, -Cl, hydroxy, cyano, C 1-6 alkyl, halogeno C 1-6 alkyl, R Ar1 -OC 1-3 alkyl, or -NR 11 R 12 (R Ar1 ). , R 11 and R 12 have the same meanings as described above).
  • R Ar5 is -CH2 -OR Ar1 (R Ar1 is synonymous with the above).
  • R Ar1 is synonymous with the above
  • R Ar1 is a -H, C 1-6 alkyl, or 3-7 member saturated ring group.
  • the R Ar1 may be substituted with 1 to 3 identical or different substituents selected from the G2 group ( G2 group is synonymous with the above), the compound according to the above [3] or a compound thereof. salt.
  • R Ar5 is -CH2 -OR Ar1 (R Ar1 is synonymous with the above), R Ar1 is a C 1-6 alkyl or 3-7 member saturated ring group, and the above R Ar1 .
  • R Ar1 is a C 1-6 alkyl or 3-7 member saturated ring group, and the above R Ar1 .
  • R Ar5 is -CH2 -OR Ar1 , R Ar1 is -H, and the R Ar1 is selected from the G2 group ( G2 group is synonymous with the above) 1 to 1.
  • R Ar5 is -CH2 -OR Ar1 , R Ar1 is C 1-6 alkyl, and the R Ar1 is selected from the G2 group ( G2 group is synonymous with the above).
  • the compound or salt thereof according to the above [3] which may be substituted with 1 to 3 identical or different substituents.
  • R Ar5 is -CH2 -OR Ar1
  • R Ar1 is a 3-7 - membered saturated ring group
  • the R Ar1 is from the G2 group ( G2 group is synonymous with the above).
  • R Ar5 is -CH2 -OR Ar1 , R Ar1 is C 3-7 cycloalkyl, and the R Ar1 is selected from the G2 group ( G2 group is synonymous with the above).
  • R Ar5 is -H, -F, -Cl, hydroxy, cyano, C 1-6 alkyl, halogeno C 1-6 alkyl, or -NR 11 R 12 (R 11 and R 12 are as described above.
  • R Ar1 is a C 1-6 alkyl or a 3-7 member saturated ring group, and the C 1-6 alkyl is substituted with 1 to 3 identical or different substituents selected from the G21 group.
  • the 3-7-membered saturated ring group may be substituted with 1 to 3 identical or different substituents selected from the G22 group;
  • Group G21 is a group consisting of -F, hydroxy, and 3-7 member saturated ring groups;
  • the G22 group is a group consisting of -F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, oxo, C 1-3 alkoxy, and a 3-7-membered saturated ring group.
  • R Ar1 is C 1-6 alkyl or C 3-7 cycloalkyl, and the C 1-6 alkyl is 1 to 3 identical or different substituents selected from the G21 group.
  • Group G21 is a group consisting of -F, hydroxy, and 3-7 member saturated ring groups
  • the G22 group is a group consisting of -F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, oxo, C 1-3 alkoxy, and a 3-7-membered saturated ring group. 4-7] or the compound according to any one of [5] or a salt thereof.
  • R Ar1 is C 1-6 alkyl or C 3-7 cycloalkyl, and the C 1-6 alkyl is 1 to 3 identical or different substituents selected from the G23 group. It may be substituted, and the C 3-7 cycloalkyl may be substituted with 1 to 3 identical or different substituents selected from the G24 group;
  • Group G 23 is a group consisting of -F, hydroxy, and C 3-7 cycloalkyl;
  • the G24 group is a group consisting of -F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, oxo, C 1-3 alkoxy, and C 3-7 cycloalkyl. -7], or the compound according to any one of [5] or a salt thereof.
  • R Cy1 and R Cy2 have the following relationship (a1); (A1) R Cy1 and R Cy2 are independently -H, hydroxy, or C 1-3 alkyl; The compound according to any one of the above [1] to [8] or a salt thereof. [9-3] The compound according to any one of the above [1] to [8] or a salt thereof, wherein R Cy1 and R Cy2 are related to the above (b).
  • R Cy1 and R Cy2 have the following relationship (b1); (B1) R Cy1 and R Cy2 together form a crosslink, which may have one or two identical or different heteroatoms selected from the group consisting of O and N. , The crosslink may be substituted with 1 to 3 identical or different substituents selected from the G4 group; The compound according to any one of the above [1] to [8] or a salt thereof.
  • R Cy1 and R Cy2 have the following relationship (b1-1); (B1-1) R Cy1 and R Cy2 are combined into the following general formulas (1-1-a-1) to (1-1-a-6):
  • the crosslinks may have one or two identical or different heteroatoms selected from the group consisting of O and N, and the crosslinks may be selected from the G4 group. It may be substituted with 1 to 3 identical or different substituents.
  • R Cy1 and R Cy2 have the following relationship (b2); (B2) R Cy1 and R Cy2 together form a spiro ring, the spiro ring having one or two identical or different heteroatoms selected from the group consisting of O and N. Also, the spiro ring may be substituted with 1 to 3 identical or different substituents selected from the G4 group; The compound according to any one of the above [1] to [8] or a salt thereof.
  • R Cy1 and R Cy2 have the following relationship (b2-1); (B2-1) R Cy1 and R Cy2 are combined into the following general formulas (1-1-b-1) to (1-1-b-7): A spiro ring of any of the above may be formed, and the spiro ring may be substituted with 1 to 3 identical or different substituents selected from the G4 group; The compound according to any one of the above [1] to [8] or a salt thereof.
  • R Cy1 and R Cy2 have the following relationship (b2-2); (B2-2) R Cy1 and R Cy2 are combined into the following general formula (1-1-b-1) or (1-1-b-3) :.
  • a spiro ring of any of the above may be formed, and the spiro ring may be substituted with 1 to 3 identical or different substituents selected from the G4 group; The compound according to any one of the above [1] to [8] or a salt thereof.
  • R Cy1 and R Cy2 have the following relationship (b3); (B3) R Cy1 and R Cy2 together form a fused ring, which has one or two identical or different heteroatoms selected from the group consisting of O and N. Also, the condensed ring may be substituted with 1 to 3 identical or different substituents selected from the G4 group; The compound according to any one of the above [1] to [8] or a salt thereof.
  • R Cy1 and R Cy2 are related to the above (b3-1); (B3-1) R Cy1 and R Cy2 are combined into the following general formulas (1-1-c-1) to (1-1-c-4): (X and R Cy4 are synonymous with the above)
  • the condensed ring may be substituted with 1 to 3 identical or different substituents selected from the G4 group.
  • X is CR Cy3 ( RCy3 is synonymous with the above); The compound according to any one of the above [1] to [9-10] or a salt thereof, wherein both R Cy1 and R Cy2 are ⁇ H. [11] The compound according to any one of the above [1] to [10] or a salt thereof, wherein R Cy3 is ⁇ H. [12] R Cy5 is ⁇ (CH 2 ) n ⁇ NR 11 R 12 (n, R 11 and R 12 are synonymous with the above), and ⁇ (CH 2 ) n ⁇ NR 21 R 22 in the above- (CH 2) n ⁇ NR 21 R 22.
  • n -part may be substituted with 1 to 3 identical or different substituents selected from the group consisting of C 1-3 alkyl and halogeno C 1-3 alkyl;
  • [12-2] The above-mentioned [1] to [11], wherein R Cy5 is- (CH 2 ) n -NR 21 R 22 (n, R 21 and R 22 have the same meanings as described above). Compound or salt thereof.
  • R Cy4 and R Cy5 are combined into the following general formulas (1-1-d-1) to (1-1-d-5): (X synonymous with the above)
  • the 4-7- membered saturated ring may be substituted with 1 to 3 identical or different substituents selected from the G5 group; [1] to [11] above, wherein R Cy1 and R Cy2 are independently ⁇ H, ⁇ F, hydroxy, C1-3alkyl , halogeno C1-3alkyl , or C1-3alkoxy .
  • Cy is the following general formula (1-1-1): (R 21 and R 22 are synonymous with the above); [1] to [14] above, wherein R Cy1 and R Cy2 are independently -H, -F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, or C 1-3 alkoxy.
  • R 21 and R 22 are independently -H, C 1-6 alkyl, halogeno C 1-6 alkyl, hydroxy C 1-6 alkyl, and C 1-6 alkoxy C 1-6 alkyl, respectively. , Or a 3-7-membered saturated ring group, wherein R 21 and R 22 may be substituted with 1 to 3 identical or different substituents selected from the G 2 group. 15] The compound or salt thereof according to any one of.
  • R 21 and R 22 are independently ⁇ H, C 1-6 alkyl, halogeno C 1-6 alkyl, hydroxy C 1-6 alkyl, or C 1-6 alkoxy C 1-6 .
  • R 21 and R 22 are combined to form a 4-7-membered saturated ring or a 7-11-membered spiro ring, and the 4-7-membered saturated ring and the 7-11-membered spiro ring are added to N.
  • It may have one or two identical or different heteroatoms or —S (O 2 ) — selected from the group consisting of O and N, the 4-7 membered saturated ring and 7-11.
  • R 21 and R 22 together form a 4-7-membered saturated ring, and the 4-7-membered saturated ring is selected from the group consisting of O and N in addition to N.
  • R 21 and R 22 are combined to form the following general formula (1-1-1-a-1) or (1-1-1-a-2):
  • the 4-membered or 5-membered saturated ring represented by the above may be formed, and the 4-membered or 5 -membered saturated ring may be substituted with 1 to 3 identical or different substituents selected from the G5 group; [1] to [15] above, wherein R Cy1 and R Cy2 are independently ⁇ H, ⁇ F, hydroxy, C1-3alkyl , halogeno C1-3alkyl , or C1-3alkoxy .
  • the G5 group is derived from -F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, and halogeno C 1-3 alkoxy.
  • R 21 and R 22 together form a 7-11-membered spiro ring, and the 7-11-membered spiro ring is selected from the group consisting of O and N in addition to N.
  • R 21 and R 22 are combined to form the following general formula (1-1-1-b-1) or (1-1-1-b-2):
  • the 7-membered spiro ring is represented by, and the 7-membered spiro ring may be substituted with 1 to 3 identical or different substituents selected from the G5 group; [1] to [15] above, wherein R Cy1 and R Cy2 are independently ⁇ H, ⁇ F, hydroxy, C1-3alkyl , halogeno C1-3alkyl , or C1-3alkoxy .
  • Cy is the following general formula (1-1-2): (R 21 and R 22 are synonymous with the above); [1] to [14] above, wherein R Cy1 and R Cy2 are independently -H, -F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, or C 1-3 alkoxy.
  • R 21 and R 22 are independently -H, C 1-6 alkyl, halogeno C 1-6 alkyl, hydroxy C 1-6 alkyl, and C 1-6 alkoxy C 1-6 alkyl, respectively.
  • R 21 and R 22 may be substituted with 1 to 3 identical or different substituents selected from the G2 group.
  • the compound according to any one of [16] or a salt thereof is the following general formula (1-1-2): (R 21 and R 22 are synonymous with the above); [1] to [14] above, wherein R Cy1 and R Cy2 are independently -H, -F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, or C
  • R 21 and R 22 are combined to form the following general formulas (1-1-2-a-1) to (1-1-2-a-4):
  • the 5-7-membered saturated ring may be substituted with 1 to 3 identical or different substituents selected from the G5 group to form any of the 5-7 -membered saturated rings represented by. ;
  • the compound according to any one of [16] or a salt thereof is any one of [16] or a salt thereof.
  • the G5 group is composed of -F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, and halogeno C 1-3 alkoxy.
  • [16-5] The compound according to any one of the above [1] to [16-4], wherein R Cy1 and R Cy2 are independently ⁇ H, hydroxy, or C1-3 alkyl, or a salt thereof. ..
  • [16-6] The compound according to any one of the above [1] to [16-4], wherein R Cy1 and R Cy2 are ⁇ H, or a salt thereof.
  • Cy is the following general formula (1-1-3):
  • R 25 is a C 1-3 alkyl, a halogeno C 1-3 alkyl, a hydroxy C 1-3 alkyl, a C 1-3 alkoxy C 1-3 alkyl, or a 3-7 member saturated ring group;
  • the spiro ring in formula (1-1-3) may be substituted with 1 to 3 identical or different substituents selected from the G4 group; [1] to [13] above, wherein R Cy1 and R Cy2 are independently -H, -F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, or C 1-3 alkoxy.
  • [17-2] The compound or salt thereof according to any one of the above [ 1 ] to [13] or [17], wherein the G4 group is a group consisting of ⁇ F.
  • [17-3] Of the above [1] to [13], [17], or [17-2], wherein R Cy1 and R Cy2 are independently ⁇ H, hydroxy, or C1-3 alkyl.
  • [17-4] The compound according to any one of the above [1] to [13], or [17] to [17-3], wherein R Cy1 and R Cy2 are ⁇ H, or a salt thereof.
  • [18] The compound according to any one of the above [1] to [17] or a salt thereof, wherein R 1 is ⁇ H.
  • [19] The compound according to any one of the above [1] to [18] or a salt thereof, wherein R 2 is ⁇ H.
  • Y is N; Even if R Ar1 is a C 1-6 alkyl or 3-7 member saturated ring group and the C 1-6 alkyl is substituted with 1 to 3 identical or different substituents selected from the G21 group. In addition, the 3-7-membered saturated ring group may be substituted with 1 to 3 identical or different substituents selected from the G22 group ( G21 group and G22 group have the same meanings as described above). ; The compound or salt thereof according to the above [4], wherein Cy is the formula (1-1-1) (R 21 and R 22 have the same meanings as described above).
  • Y is N; Even if R Ar1 is a C 1-6 alkyl or 4-5 member saturated ring group and the C 1-6 alkyl is substituted with 1 to 3 identical or different substituents selected from the G23 group. In addition, the 4-5-membered saturated ring group may be substituted with 1 to 3 identical or different substituents selected from the G 24 group (G 23 group and G 24 group have the same meanings as described above). ; The compound or salt thereof according to the above [4], wherein Cy is the formula (1-1-1) (R 21 and R 22 have the same meanings as described above).
  • Y is N;
  • R Ar1 may be a C 1-6 alkyl or a 5-membered saturated ring group, and the C 1-6 alkyl may be substituted with 1 to 3 identical or different substituents selected from the G23 group. Further, the 5-membered saturated ring group may be substituted with 1 to 3 identical or different substituents selected from the G24 group ( G23 group and G24 group have the same meanings as described above);
  • Y is N;
  • R Ar1 is C 1-6 alkyl, and the C 1-6 alkyl may be substituted with 1 to 3 identical or different substituents selected from the G 23 group (G 23 group is the same as above). Synonymous);
  • Cy is equation (1-1-1);
  • R 21 and R 22 are independently -H, C 1-6 alkyl, halogeno C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, or 3-7, respectively. It is a member-saturated ring group, and R 21 and R 22 may be substituted with 1 to 3 identical or different substituents selected from the G 2 group (G 2 group is synonymous with the above).
  • Y is N;
  • R Ar1 is cyclopentyl, and the cyclopentyl may be substituted with 1 to 3 identical or different substituents selected from the G 24 group (G 24 group is synonymous with the above);
  • Cy is equation (1-1-1);
  • R 21 and R 22 are independently -H, C 1-6 alkyl, halogeno C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, or 3-7, respectively. It is a member-saturated ring group, and R 21 and R 22 may be substituted with 1 to 3 identical or different substituents selected from the G 2 group (G 2 group is synonymous with the above).
  • Y is N;
  • R Ar1 may be a C 1-6 alkyl or a 5-membered saturated ring group, and the C 1-6 alkyl may be substituted with 1 to 3 identical or different substituents selected from the G23 group. Further, the 5-membered saturated ring group may be substituted with 1 to 3 identical or different substituents selected from the G24 group ( G23 group and G24 group have the same meanings as described above);
  • Cy is equation (1-1-1); R 21 and R 22 are combined to form a 4-7-membered saturated ring or a 7-11-membered spiro ring, and the 4-7-membered saturated ring and the 7-11-membered spiro ring are O and N in addition to N.
  • Y is N;
  • R Ar1 is C 1-6 alkyl, and the C 1-6 alkyl may be substituted with 1 to 3 identical or different substituents selected from the G 23 group (G 23 group is the same as above). Synonymous);
  • Cy is equation (1-1-1);
  • R 21 and R 22 are combined to form a 4-7-membered saturated ring or a 7-11-membered spiro ring, and the 4-7-membered saturated ring and the 7-11-membered spiro ring are O and N in addition to N.
  • Y is N;
  • R Ar1 is cyclopentyl, and the cyclopentyl may be substituted with 1 to 3 identical or different substituents selected from the G 24 group (G 24 group is synonymous with the above);
  • Cy is equation (1-1-1);
  • R 21 and R 22 are combined to form a 4-7-membered saturated ring or a 7-11-membered spiro ring, and the 4-7-membered saturated ring and the 7-11-membered spiro ring are O and N in addition to N. It may have 1 to 2 identical or different heteroatoms or —S (O 2 ) — selected from the group consisting of the 4-7-membered saturated ring and the 7-11-membered spiro ring. It may be substituted with 1 to 3 identical or different substituents selected from the 5 groups ( G5 group is synonymous with the above); the compound or salt thereof according to the above [4].
  • a pharmaceutical composition for the prevention and / or treatment of rheumatism wherein the compound according to any one of the above [1] to [30] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising an acceptable carrier.
  • a method for preventing and / or treating rheumatism in a mammal wherein an effective amount of the compound according to any one of the above [1] to [30] or a pharmaceutically acceptable salt thereof is used.
  • a method comprising the step of administering to a mammal.
  • the "compound represented by the formula (1) or a salt thereof” (hereinafter, may be simply referred to as “the compound of the present invention”) has excellent IRAK-4 inhibitory activity. Also, certain embodiments of the compounds of the invention show high selectivity for other kinases, especially FLT3. Moreover, certain embodiments of the compounds of the invention show low genotoxicity. In addition, certain embodiments of the compounds of the invention can be used as active ingredients in pharmaceuticals for the prevention and / or treatment of diseases associated with IRAK-4 inhibition, such as the prevention and / or treatment of autoimmune diseases. Furthermore, certain embodiments of the compounds of the invention can be used as reagents with IRAK-4 inhibitory activity.
  • the carbon atom is simply “C”
  • the hydrogen atom is “H”
  • the oxygen atom is “O”
  • the sulfur atom is “S”
  • the nitrogen atom is “N”.
  • the carbonyl group is simply “-C (O)-”
  • the carboxyl group is “-COO-”
  • the sulfinyl group is “-S (O)-”
  • the sulfonyl group is "-S (O) 2- ".
  • the ether bond may be represented by “-O-” and the thioether bond may be represented by "-S-” (in this case, "-” represents the bond).
  • the alkyl may be a saturated hydrocarbon group that is linear, branched, cyclic, or a combination thereof.
  • methyl, ethyl, propyl, butyl, their isomers [normal (n), iso (iso), secondary (sec), tertiary (t), etc.], or cycloalkyl such as cyclopropyl or cyclobutyl are exemplified.
  • the alkyl include an alkyl having 1 to 6 carbon atoms.
  • an alkyl having 1 to 3 carbon atoms is exemplified.
  • An alkyl having 1 to 6 carbon atoms may be referred to as a C 1-6 alkyl.
  • alkoxy may be linear, branched, cyclic, or a combination thereof, alkyloxy.
  • alkoxy an alkoxy having 1 to 6 carbon atoms is exemplified.
  • alkoxy having 1 to 3 carbon atoms is exemplified.
  • Alkoxy having 1 to 6 carbon atoms may be referred to as C 1-6 alkoxy.
  • Alkylene also includes linear or branched alkylene.
  • alkylene examples include linear or branched alkylene.
  • methylene, ethylene, propylene, butylene, methylmethylene, ethylmethylene, methylethylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene, or 1-methylbutylene are exemplified.
  • the alkylene examples include an alkylene having 1 to 6 carbon atoms.
  • an alkylene having 1 to 3 carbon atoms is exemplified.
  • An alkylene having 1 to 6 carbon atoms may be referred to as a C 1-6 alkylene.
  • the "halogen” is fluoro (-F), chloro (-Cl), bromo (-Br), or iodine (-I).
  • -F or -Cl is exemplified.
  • -F is exemplified.
  • halogeno is meant substituted with the same or different 1-7 halogens. In another aspect, it means that they are substituted with the same or different 1-5 halogens. In yet another embodiment, it means that it is substituted with 1 to 3 halogens. In yet another embodiment, it means that it is substituted with one halogen. It is exemplified that it is substituted with ⁇ F.
  • aromatic ring is not particularly limited as long as it is a ring having aromaticity, and examples thereof include monocyclic to tricyclic aromatic rings.
  • aromatic ring include an aromatic hydrocarbon ring or an aromatic heterocycle. Specifically, benzene, naphthalene, phenanthrene, thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, pyrazole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrimidinone, indol, isoindole.
  • Indazole quinoline, isoquinoline, benzimidazole, benzotriazole, benzothiophene, benzofuran, benzothiazole, phthalazine, quinoxalin, pyrolopyridine, or carbazole.
  • aromatic ring group include a monovalent group formed by removing any one hydrogen atom from the aromatic ring. It may be a monocyclic to tricyclic aromatic ring group. For example, aryl or heteroaryl are exemplified.
  • the "aryl” may be a monocyclic to tricyclic aromatic hydrocarbon ring group.
  • Aryl also contains an aromatic hydrocarbon ring group condensed with a saturated hydrocarbon ring described later.
  • 6-14 member aryl is exemplified.
  • Another embodiment is exemplified by 6-10 member aryls.
  • Yet another embodiment is exemplified by 6-membered aryl.
  • phenyl, naphthyl, anthranil, phenanthrenyl, fluorenyl, indanyl, or 1,2,3,4-tetrahydronaphthalenyl are exemplified.
  • Another embodiment is phenyl and yet another embodiment is naphthyl. Indanyl and 1,2,3,4-tetrahydronaphthalenyl are included in 6-10 member aryls.
  • heteroaryl may be a monocyclic to tricyclic aromatic heterocyclic group containing 1 to 4 heteroatoms as ring-constituting atoms. Examples of the heteroatom include O, S, or N. 5-14 member heteroaryl is exemplified. As another embodiment, 5-10-membered heteroaryl is exemplified. Yet another embodiment is exemplified by 5-6 member heteroaryl.
  • Benzoimidazolyl benzotriazolyl, benzothienyl, benzofuranyl, benzothiazolyl, phthalazinyl, quinoxalinyl, pyrrolopyridyl, or carbazolyl.
  • saturated ring examples include a saturated hydrocarbon ring or a saturated heterocycle.
  • the saturated ring may have a crosslink or may be condensed with the aromatic ring.
  • the "saturated hydrocarbon ring” may be a monocyclic to tricyclic saturated hydrocarbon ring.
  • a 3-10 member saturated hydrocarbon ring is exemplified.
  • a 3-7-membered saturated hydrocarbon ring is exemplified.
  • Yet another embodiment is exemplified by a 5- or 6-membered saturated hydrocarbon ring.
  • the saturated hydrocarbon ring may have a crosslink or may be condensed with the aromatic ring. Specifically, cyclopropane, cyclobutane, cyclopentane, cyclohexane, or adamantane are exemplified.
  • the "saturated heterocycle” may be a monocyclic to tricyclic saturated heterocycle containing 1 to 4 heteroatoms as ring-constituting atoms. Examples of the heteroatom include O, S, or N.
  • a 3-10 member saturated heterocycle is exemplified.
  • a 3-7 member saturated heterocycle is exemplified.
  • Yet another embodiment is exemplified by a 5- or 6-membered saturated heterocycle.
  • the saturated heterocycle may have a crosslink or may be condensed with the aromatic ring.
  • tetrahydropyran tetrahydrofuran
  • piperidine pyrrolidine
  • azetidine oxetane
  • aziridine oxylan
  • tetrahydrothiopyran tetrahydrothiophene
  • morpholine oxazepan, or piperazine.
  • a “condensed ring” is a cyclic compound in which two or more rings share two or more atoms and are bonded to each other, and the two or more rings are independently 3-7-membered saturated rings. Is exemplified by the cyclic compound.
  • the fused ring can have 1-3 heteroatoms selected from O, S, and N.
  • a condensed ring a cyclic compound in which two rings share two adjacent atoms is exemplified.
  • the "spiro ring” is exemplified by a cyclic compound containing one carbon atom common to the two rings, wherein the two rings are independently 3-7-membered saturated rings.
  • the spiro ring can have 1-3 heteroatoms selected from O, S, and N. When the number of atoms constituting the spiro ring is 7 to 11, the spiro ring may be referred to as a 7-11-membered spiro ring. Examples of the spiro ring include a 7-13-membered spiro ring. As another embodiment, a 7-11-membered spiro ring is exemplified. Yet another embodiment is exemplified by a 7-9 member spiro ring.
  • the "saturated ring group” is a monovalent group formed by removing any one hydrogen atom from the saturated ring, or a monovalent group formed by removing one hydrogen atom from each of two different ring-constituting atoms in the saturated ring.
  • a divalent group can be mentioned.
  • Saturated hydrocarbon ring groups or saturated heterocyclic groups are exemplified.
  • a 3-10-membered saturated ring group is exemplified.
  • a 3-7-membered saturated ring group is exemplified.
  • Yet another embodiment is exemplified by a 5- or 6-membered saturated ring group.
  • the "saturated hydrocarbon ring group” is a monovalent group formed by removing any one hydrogen atom from the saturated hydrocarbon ring, or one each from two different ring-constituting atoms in the saturated hydrocarbon ring.
  • a divalent group formed by excluding a hydrogen atom can be mentioned. It may be a monocyclic to tricyclic saturated hydrocarbon ring group.
  • the saturated hydrocarbon ring group may have a crosslink or may be condensed with the aromatic ring.
  • a 3-10-membered saturated hydrocarbon ring group is exemplified.
  • a 3-7-membered saturated hydrocarbon ring group is exemplified.
  • Yet another embodiment is exemplified by a 5- or 6-membered saturated hydrocarbon ring group.
  • the monovalent group examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl.
  • the divalent group specifically, among the specific examples of the above monovalent group, the divalent group obtained by further removing the hydrogen atom from the ring-constituting atom different from the ring-constituting atom excluding the hydrogen atom is used. Can be mentioned.
  • the "saturated heterocyclic group” is a monovalent group formed by removing any one hydrogen atom from the saturated heterocycle, or one hydrogen atom from each of two different ring-constituting atoms in the saturated heterocycle.
  • a divalent group that can be excluded can be mentioned. It may be a saturated heterocyclic group of monocyclic to tricyclic rings containing 1 to 4 heteroatoms as ring-constituting atoms.
  • the saturated heterocyclic group may have a crosslink or may be condensed with the aromatic ring. Examples of the heteroatom include O, S, or N.
  • a 3-10-membered heterocyclic group is exemplified. As another embodiment, a 3-7 member saturated heterocyclic group is exemplified.
  • Yet another embodiment is exemplified by a 5- or 6-membered saturated heterocyclic group.
  • the monovalent group include tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahydrothiopyranyl, tetrahydrothienyl, morpholinyl, or piperazinyl.
  • the "partially unsaturated ring group” may be any ring as long as a part of the saturated ring group is unsaturated, and is a partially unsaturated hydrocarbon ring group (partially unsaturated hydrocarbon ring group) or a partially unsaturated ring.
  • Heterocyclic groups (partially unsaturated heterocyclic groups) are exemplified.
  • a 3-10 member partially unsaturated ring group is exemplified.
  • a 3-7 member partially unsaturated ring group is exemplified.
  • Yet another embodiment is exemplified by a 5- or 6-membered partially unsaturated ring group.
  • the “partially unsaturated hydrocarbon ring group” may be any group as long as a part of the saturated hydrocarbon ring group is unsaturated. Specific examples thereof include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and bicyclooctatrienyl.
  • the "partially unsaturated heterocyclic group” may be any group as long as a part of the saturated heterocyclic group is unsaturated. Specific examples thereof include dihydropyranyl, dihydrofuranyl, dihydrothiopyranyl, dihydrothienyl, 1,2-dihydroquinolyl, or 1,2,3,4-tetrahydroquinolyl.
  • isomers include all of them unless otherwise specified.
  • alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene, and alkynylene include linear and branched chains.
  • isomers based on double bonds, rings, or fused rings (E or Z isomers, or cis or trans isomers), isomers based on the presence of asymmetric carbons (R- or S-isomers, ⁇ ).
  • the bonds of the two substituents are as follows: When described in a stereoscopic arrangement shown by a thick solid line and a thick broken line as shown in the above description, the above description is described in the following two optically active substances: Means a mixture of.
  • R 1 are ⁇ H, ⁇ F, and methyl.
  • —H or —F is exemplified.
  • —H is exemplified.
  • R 2 include —H, halogen, cyano, C 1-6 alkyl, halogeno C 1-6 alkyl, C 1-6 alkoxy, or halogeno C 1-6 alkoxy.
  • —H, halogen, cyano, C 1-6 alkyl, or halogeno C 1-6 alkyl is exemplified.
  • Yet another embodiment is exemplified by —H, —F, cyano, C 1-3 alkyl, or fluoro C 1-3 alkyl.
  • —H is exemplified.
  • Ar examples of Ar are 6-10-membered aryl and 5-10-membered heteroaryl.
  • phenyl or 5-6 member heteroaryl is exemplified.
  • Yet another embodiment is exemplified by 5-6 member heteroaryl.
  • examples of the 6-10-membered aryl in Ar include phenyl, naphthyl, or indanyl. Another embodiment is phenyl.
  • Examples of the 5-10-membered heteroaryl in Ar include thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, pyridone-yl, pyrimidinone-yl, and the like.
  • Examples thereof include indrill, isoindrill, indazolyl, quinolyl, isoquinolyl, benzoimidazolyl, benzotriazolyl, benzothienyl, benzofuranyl, benzothiazolyl, phthalazinyl, quinoxalinyl, or pyrrolopyridyl.
  • thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridone-yl, or pyrimidinone-yl are exemplified.
  • Yet another embodiment exemplifies thienyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, or pyrazinyl.
  • Yet another embodiment is exemplified by thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyridyl, or pyrimidinyl. Yet another embodiment is exemplified by thiazolyl, isothiazolyl, pyridyl, or pyrimidinyl. Yet another embodiment is exemplified by pyridyl or pyrimidinyl. Yet another embodiment is exemplified by pyrimidinyl.
  • the Ar may be substituted with 1 to 3 identical or different substituents selected from the G1 group.
  • the G1 group includes -F, -Cl, hydroxy, cyano, C 1-3 alkyl, halogeno C 1-3 alkyl, R Ar1 -OC 1-3 alkyl, and R Ar1 -NR 11 -C 1- .
  • the G11 group consisting of alkyl and -NR 11 R 12 is exemplified. Yet another embodiment is exemplified by the G12 group consisting of -F, -Cl, hydroxy, cyano, C 1-3 alkyl, halogeno C 1-3 alkyl, and R Ar1 -OC 1-3 alkyl. ..
  • -C (O) NR 11 R 12 , -C (O) NH 2 , -NR 11 S (O 2 ) R 12 , -S (O 2 ) NR 11 R 12 , -NH 2 , -S (O 2 ) NH 2 , -NR 11 R 12 , and -NHC (O) NHR 13 are exemplified by the G13 group.
  • Yet another embodiment is exemplified by R Ar1 -OC 1-3 alkyl.
  • Yet another embodiment is exemplified by R Ar1 -O-methyl.
  • R Ar1 examples include —H, C 1-6 alkyl, halogeno C 1-6 alkyl, and 3-7 member saturated ring groups.
  • a C 1-6 alkyl or 3-7 member saturated ring group is exemplified.
  • C 1-6 alkyl Yet another embodiment is exemplified by cyclobutyl or cyclopentyl.
  • cyclopentyl Yet another embodiment is exemplified by a 3-7 member saturated ring group.
  • Examples of the 3-7-membered saturated ring group include C 3-7 cycloalkyl or a 3-7 member saturated heterocyclic group.
  • Examples of the 3-7-membered saturated heterocyclic group include oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, or piperazinyl.
  • tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, or morpholinyl is exemplified.
  • Yet another embodiment is exemplified by tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, or piperidinyl. Yet another embodiment is exemplified by tetrahydrofuranyl or pyrrolidinyl.
  • the R Ar1 may be substituted with 1 to 3 identical or different substituents selected from the G2 group.
  • the G 2 group consists of -F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, oxo, C 1-3 alkoxy, halogeno C 1-3 alkoxy, and 3-7 member saturated ring groups.
  • a group is exemplified.
  • the G21 group consisting of —F, hydroxy, and 3-7 member saturated ring groups is exemplified.
  • Yet another embodiment is exemplified by the G22 group consisting of —F, hydroxy, C1-3alkyl , halogeno C1-3alkyl , oxo, C1-3alkoxy , and 3-7-membered saturated ring groups. ..
  • Yet another embodiment is exemplified by the G23 group consisting of —F, hydroxy, or C 3-7 cycloalkyl.
  • Yet another embodiment is exemplified by the G24 group consisting of —F, hydroxy, or cyclopropyl.
  • R 11 examples include -H, C 1-3 alkyl, halogeno C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, halogeno C 1-3 alkoxy C 1-3 alkyl, or 3-7 members. Saturated ring groups are exemplified. As another embodiment, —H, C 1-3 alkyl, halogeno C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, or halogeno C 1-3 alkyl are exemplified. Yet another embodiment is exemplified by a 3-7 member saturated ring group.
  • R 12 examples include C 1-3 alkyl, halogeno C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, halogeno C 1-3 alkoxy C 1-3 alkyl, or 3-7-membered saturated ring group. Is exemplified. As another embodiment, C 1-3 alkyl, halogeno C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, or halogeno C 1-3 alkyl are exemplified. Yet another embodiment is exemplified by a 3-7 member saturated ring group. Examples of the 3-7-membered saturated ring group in R 11 and R 12 include C 3-7 cycloalkyl or a 3-7 member saturated heterocyclic group. As another embodiment, cyclopropyl, cyclobutyl, or oxetanyl is exemplified.
  • R 13 examples are —H, phenyl, or 5-6 member heteroaryl.
  • Examples of the 5-6-membered heteroaryl include thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridadinyl.
  • Another embodiment of R13 is exemplified by phenyl or trifluoromethylphenyl.
  • the R 13 may be substituted with 1 to 3 identical or different substituents selected from the G3 group.
  • the G3 group include a group consisting of halogen, cyano, C 1-3 alkyl, and halogeno C 1-3 alkyl .
  • the G31 group consisting of ⁇ F, cyano, methyl, and trifluoromethyl is exemplified.
  • Examples of Y include CR Ar2 or N.
  • CR Ar2 is exemplified.
  • N is exemplified.
  • R Ar2 include -H, -F, -Cl, hydroxy, cyano, C 1-6 alkyl, halogeno C 1-6 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkyl, and -NH.
  • 2 or -NR 11 R 12 (R 11 and R 12 have the same meanings as described above) is exemplified.
  • —H, —F, —Cl, hydroxy, cyano, C 1-6 alkyl, halogeno C 1-6 alkyl, or —NH 2 is exemplified.
  • Yet another embodiment is exemplified by —H, —F, hydroxy, C1-3alkyl , halogeno C1-3alkyl , or —NH2 .
  • Yet another embodiment is exemplified by hydroxy, hydroxyethyl, hydroxymethyl.
  • R Ar3 and R Ar4 are -H, -F, -Cl, C 1-3 alkyl, or halogeno C 1-3 alkyl, respectively.
  • —H, —F, C 1-3 alkyl, or halogeno C 1-3 alkyl, respectively are exemplified independently.
  • —H, —F, methyl, or trifluoromethyl are exemplified independently of each other.
  • Yet another embodiment is exemplified by —H, —F, or methyl.
  • —H is exemplified.
  • R Ar5 examples include -H, -F, -Cl, hydroxy, cyano, C 1-6 alkyl, halogeno C 1-6 alkyl, R Ar1 -OC 1-3 alkyl, or -NR 11 R 12 (R).
  • Ar1 , R11 , and R12 have the same meanings as described above).
  • R Ar1 -OC 1-3 alkyl is exemplified.
  • R Ar1 -OC 1-3 alkyl examples include the following.
  • R Ar1 -OC 1-3 alkyl specifically, for example, the following is exemplified.
  • Cy examples include formula (1-1) or a 3-7-membered saturated heterocycle.
  • an integer of 1 or 2 is exemplified. In another embodiment, an integer of 2 is exemplified.
  • m an integer of 1 to 3 is exemplified. In another embodiment, an integer of 2 is exemplified.
  • Examples of X are CR Cy3 or N. As another embodiment, CR Cy3 is exemplified. As yet another embodiment, N is exemplified.
  • Examples of RCy3 include —H, —F, and hydroxy.
  • —H is exemplified.
  • Examples of RCy4 include ⁇ H, ⁇ F, hydroxy, C1-3alkyl , halogeno C1-3alkyl , C1-3alkoxy C1-3alkyl , and hydroxyC1-3alkyl .
  • —H, —F, hydroxy, or C1-3alkyl are exemplified.
  • —H is exemplified.
  • Examples of RCy5 are —H, —F, 5-6 member heteroaryl, or ⁇ (CH 2 ) n ⁇ NR 21 R 22 or absent.
  • Examples of the 5-6 member heteroaryl include pyrazole, imidazole, thiazole, or isothiazole.
  • —H, —F, 5-6 member heteroaryl, or ⁇ (CH 2 ) n ⁇ NR 21 R 22 is exemplified.
  • ⁇ (CH 2 ) n ⁇ NR 21 R 22 is exemplified.
  • R Cy5 does not exist, for example, R Cy1 and R Cy2 together form a condensed ring represented by the following formulas (1-1-c-1) to (1-1-c-4). The case of doing is exemplified. At this time, the condensed ring can be formed by assuming that R Cy1 or R Cy2 is bonded instead of R Cy5 to the ring-constituting carbon atom to which R Cy5 is bonded.
  • The-(CH 2 ) n -part in the- (CH 2 ) n -NR 21 R 22 is the same or different from 1 to 3 selected from the group consisting of C 1-3 alkyl and halogeno C 1-3 alkyl. It may be substituted with a substituent.
  • n an integer of 0 to 2 is exemplified.
  • Examples of the-(CH 2 ) n -NR 21 R 22 include -CH 2 -NR 21 R 22 .
  • -NR 21 R 22 is exemplified.
  • the R 21 and R 22 are independently -H, C 1-6 alkyl, halogeno C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, or 3 respectively.
  • a -7-membered saturated ring group is exemplified.
  • —H, C 1-6 alkyl, halogeno C 1-6 alkyl, hydroxy C 1-6 alkyl, or C 1-6 alkoxy C 1-6 alkyl are exemplified.
  • Yet another embodiment is exemplified by —H, C 1-3 alkyl, or halogeno C 1-3 alkyl, hydroxy C 1-3 alkyl, or C 1-3 alkoxy C 1-3 alkyl.
  • Yet another embodiment is exemplified by a 3-7 member saturated ring group. Examples of the 3-7-membered saturated ring group include C 3-7 cycloalkyl or a 3-7 member saturated heterocyclic group.
  • C 4-6 cycloalkyl or 4-6 member saturated heterocyclic group is exemplified.
  • Yet another embodiment exemplifies cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, or piperazinyl.
  • Yet another embodiment is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, or pyrrolidinyl.
  • the R 21 and R 22 may be substituted with 1 to 3 identical or different substituents selected from the G 2 group.
  • Examples of the G 2 group include aspects of the G 21 to G 24 groups in addition to the G 2 group.
  • the R 21 and R 22 can be combined to form a 4-7-membered saturated ring or a 7-11-membered spiro ring.
  • the 4-7-membered saturated ring and the 7-11-membered spiro ring contain 1 to 2 identical or different heteroatoms or -S (O 2 )- selected from the group consisting of O and N. You may have.
  • azetidine, pyrrolidine, piperidine, morpholine, oxazepan, or piperazine, or the carbon atoms constituting these 4-7-membered saturated rings were replaced with —S (O 2 ) ⁇ 4.
  • a 7-membered saturated ring is exemplified.
  • Azetidine, pyrrolidine, or piperidine is exemplified as another embodiment of the 4-7-membered saturated ring, particularly when RCy5 is ⁇ CH2 -NR 21 R22 .
  • Yet another embodiment is exemplified by azetidine or pyrrolidine.
  • azetidine, pyrrolidine, piperidine, morpholine, or oxazepan is exemplified as another embodiment of the 4-7-membered saturated ring, particularly when RCy5 is ⁇ NR 21 R 22 .
  • the R 21 and R 22 together form a 4-7-membered saturated ring, and the 4-7-membered saturated ring is added to N, and one or two selected from the group consisting of O and N. Examples of cases having the same or different heteroatoms are as follows. In this case, the 4-7-membered saturated ring is morpholine. (K, m, n, X, R Cy1 , R Cy2 , and R Cy 4 are synonymous with the above)
  • the 7-11-membered spiro ring is a cyclic compound containing one carbon atom common to the two rings, and the two rings are independently 3-7-membered saturated rings.
  • the present invention is not particularly limited as long as the number of atoms constituting the cyclic compound is 3-7, but the following examples are given.
  • the R 21 and R 22 together form a 7-11-membered spiro ring, and the 7-11-membered spiro ring is added to N, and one or two selected from the group consisting of O and N.
  • Examples of cases having the same or different heteroatoms are as follows. (K, m, n, X, R Cy1 , R Cy2 , and R Cy 4 are synonymous with the above)
  • the 4-7-membered saturated ring and the 7-11- membered spiro ring may be substituted with 1 to 3 identical or different substituents selected from the G5 group.
  • the G5 group includes -F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogeno C 1-3 alkoxy, and -OC (O).
  • a group consisting of R 24 , —S (O 2 ) NH 2 , and a 3-7 member saturated ring group is exemplified.
  • -F hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogeno C 1-3 alkoxy, and -OC (O).
  • the G52 group consisting of R24 is exemplified.
  • the G53 group consisting of R24 is exemplified.
  • Yet another embodiment is exemplified by the G54 group consisting of —F, hydroxy, C1-3alkyl , C1-3alkoxy , and —OC (O) R24 .
  • Yet another embodiment is exemplified by the G55 group consisting of —F, hydroxy, methyl, methoxy, and trifluoromethyl.
  • Examples of the 3-7- membered saturated ring group in the G5 group include C 3-7 cycloalkyl or a 3-7-membered saturated heterocyclic group.
  • C 4-6 cycloalkyl or 4-6 member saturated heterocyclic group is exemplified.
  • Yet another embodiment exemplifies cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, or piperazinyl.
  • Yet another embodiment exemplifies cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, or pyrrolidinyl. Yet another embodiment is exemplified by cyclopropyl, cyclobutyl, oxetanyl, or azetidinyl.
  • R 23 in the G5 group examples include —H, C 1-3 alkyl, halogeno C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, halogeno C 1-3 alkoxy C 1-3 alkyl, or A 3-7 member saturated ring group is exemplified.
  • —H, C 1-3 alkyl, halogeno C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, or halogeno C 1-3 alkoxy C 1-3 alkyl are exemplified.
  • Yet another embodiment is exemplified by —H, C 1-3 alkyl, or halogeno C 1-3 alkyl.
  • Examples of the 3-7-membered saturated ring group include cyclopropyl, cyclobutyl, and oxetanyl.
  • R 24 in the G5 group examples include C 1-6 alkyl, halogeno C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, halogeno C 1-6 alkoxy C 1-6 alkyl, or 3-7.
  • a member saturated ring group is exemplified.
  • C 1-6 alkyl, halogeno C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, or halogeno C 1-6 alkoxy C 1-6 alkyl are exemplified.
  • Yet another embodiment is exemplified by —H, C 1-6 alkyl, or halogeno C 1-6 alkyl.
  • Examples of the 3-7-membered saturated ring group include cyclopropyl, cyclobutyl, and oxetanyl.
  • Cy when X is C, k and m are integers of 2, and R Cy5 is ⁇ (CH 2 ) n ⁇ NR 21 R 22 , Cy is exemplified as having the following relationship. To. (N, R Cy1 , R Cy2 , R Cy4 , R 21 and R 22 are synonymous with the above)
  • the relationship (A) may be referred to as a cis relationship, and the relationship (B) may be referred to as a transformer relationship.
  • the relationship (A) is exemplified.
  • Yet another embodiment is exemplified by the relationship (B).
  • R Cy4 and R Cy5 can be combined to form a 4-7-membered saturated ring.
  • the 4-7-membered saturated ring may have 1-2 identical or different heteroatoms or —S (O 2 ) — selected from the group consisting of O and N.
  • C 4-7 cycloalkyl or 4-7-membered saturated heterocycle, or carbon atoms constituting these 4-7-membered saturated rings are replaced with —S (O 2 ) ⁇ .
  • An example is a ring.
  • cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, azetidine, pyrrolidine, piperidine, morpholine, oxazepan, or piperazine, or the carbon atoms constituting these 4-7-membered saturated rings are -S.
  • a 4-7-membered saturated ring replaced with (O 2 )- is exemplified.
  • cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, azetidine, pyrrolidine, piperidine, morpholine, oxazepan, or piperazine are exemplified.
  • the RCy4 and RCy5 together form a 4-7-membered saturated ring, and the 4-7-membered saturated ring is added to N, and one or two identical rings selected from the group consisting of O and N.
  • the following may be exemplified as a case of having a different heteroatom.
  • the 4-7-membered saturated ring is morpholine. (K, m, X, R Cy1 and R Cy2 are synonymous with the above)
  • the 4-7- membered saturated ring may be substituted with 1 to 3 identical or different substituents selected from the G5 group.
  • Examples of the G5 group include aspects of the G51 to G54 groups in addition to the G5 group.
  • R Cy1 and R Cy2 are related to either (a) or (b).
  • R Cy1 and R Cy2 are independently -H, -F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, or C 1-3 alkoxy.
  • R Cy1 and R Cy2 together form a crosslink, a spiro ring, or a condensed ring, and the crosslinked, the spiro ring, and the condensed ring are selected from the group consisting of O and N 1-2. It may have the same or different heteroatoms, the crosslinks, spiro rings, and condensed rings being substituted with 1 to 3 identical or different substituents selected from the G4 group. May be good.
  • R Cy1 and R Cy2 are independently exemplified by -H, -F, hydroxy, C 1-3 alkyl, or halogeno C 1-3 alkyl, respectively. Will be done.
  • —H, —F, hydroxy, or C1-3alkyl are exemplified.
  • Yet another embodiment is exemplified by —H, —F, or hydroxy.
  • —H is exemplified.
  • R Cy1 and R Cy2 are in the relationship (b), R Cy1 and R Cy2 together form a crosslink, a spiro ring, or a condensed ring.
  • the crosslink, spiro ring, and condensed ring may have one or two identical or different heteroatoms selected from the group consisting of O and N.
  • R Cy1 and R Cy2 forming a crosslink together are exemplified by Cy1 and R Cy2 forming a crosslink with C1-3 alkylene or Harogeno C1-3 alkylene together.
  • forming a crosslink with C 1-3 alkylene is exemplified.
  • Yet another embodiment is exemplified by forming a crosslink with methylene or ethylene.
  • R Cy1 and R Cy2 bonded to a common ring-constituting carbon atom together form a 3-7-membered saturated ring.
  • forming a saturated hydrocarbon ring is exemplified.
  • Yet another embodiment is exemplified by forming a saturated heterocycle.
  • Yet another embodiment is exemplified by cyclopropane, cyclobutane, oxetane, or azetidine.
  • R Cy1 and R Cy2 bonded to adjacent ring-constituting carbon atoms together form a 3-7-membered saturated ring.
  • a 3-7-membered saturated hydrocarbon ring is exemplified.
  • forming a 3-7 member saturated heterocycle is exemplified by forming a 3-7 member saturated heterocycle.
  • Yet another embodiment is exemplified by cyclopropane, cyclobutane, oxetane, or azetidine. (X and R Cy4 are synonymous with the above)
  • R Cy1 and R Cy2 together form a condensed ring represented by the above formulas (1-1-c-1) to (1-1-c-4), the ring to which R Cy5 is bonded is formed.
  • a condensed ring can be formed by assuming that R Cy1 or R Cy2 is bonded to the constituent carbon atom instead of R Cy5 .
  • the crosslinks, spiro rings, and condensed rings may be substituted with 1 to 3 identical or different substituents selected from the G4 group.
  • R Cy1 and R Cy2 are combined to form a spiro ring or a fused ring, the ring (conventional ring) to which R Cy1 and R Cy2 are originally bonded, and R Cy1 and R Cy2 are combined.
  • 1 to 3 identical or different substituents selected from the G4 group are substituted, any of the two rings can be substituted. In another embodiment, it can be replaced with a new ring. In yet another embodiment, it can be replaced with a conventional ring.
  • Examples of the G4 group include a group consisting of -F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, and hydroxy C 1-3 alkyl.
  • the G 41 group consisting of ⁇ F, hydroxy, C 1-3 alkyl, halogeno C 1-3 alkyl, and hydroxy C 1-3 alkyl is exemplified.
  • the G42 group consisting of —F, hydroxy, C 1-3 alkyl, and halogeno C 1-3 alkyl.
  • Yet another embodiment is exemplified by the G43 group consisting of -F, hydroxy, methyl, ethyl, and trifluoromethyl.
  • the Cy is exemplified by a 3-7-membered saturated heterocycle.
  • the 3-7-membered saturated heterocycle include oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, or piperazinyl.
  • tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, or morpholinyl is exemplified.
  • tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, or piperidinyl is exemplified.
  • tetrahydrofuranyl or pyrrolidinyl is exemplified.
  • the 3-7-membered saturated heterocycle may be substituted with 1 to 3 identical or different substituents selected from the G4 group.
  • Examples of the G4 group include aspects of the G41 to G43 groups in addition to the G4 group.
  • R 25 examples include C 1-3 alkyl, halogeno C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, and 3-7 member saturated ring groups.
  • C 1-3 alkyl or Harogeno C 1-3 alkyl is exemplified.
  • Methyl, ethyl, or trifluoromethyl are exemplified.
  • the spiro ring in the formula (1-1-3) may be substituted with 1 to 3 identical or different substituents selected from the G4 group.
  • the G4 group include aspects of the G41 to G43 groups in addition to the G4 group.
  • One to three identical or different substituents selected from the G4 group are substituted on a 4 -membered saturated heterocycle (azetidine ring) formed by combining RCy4 and RCy5 . Is exemplified.
  • the saturated ring or the spiro ring having N as a constituent atom may be substituted with 1 to 3 identical or different substituents selected from the G5 group.
  • the G5 group include aspects of the G51 to G55 groups in addition to the G5 group.
  • the "compound represented by the formula (1)” is generally understood as a free compound represented by the formula (1). Moreover, the following salt can be mentioned as the salt.
  • the type of the salt of the compound represented by the formula (1) is not particularly limited, and may be either an acid addition salt or a base addition salt, or may be in the form of an intramolecular counterion. ..
  • a pharmaceutically acceptable salt is preferable as the salt.
  • the salt of the compound represented by the formula (1) is a pharmaceutically acceptable salt.
  • the acid addition salt examples include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, or formic acid, acetic acid, propionic acid, oxalic acid, and malonic acid. , Succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, citric acid, malic acid, tartrate acid, dibenzoyl tartrate acid, mandelic acid, maleic acid, fumaric acid, aspartic acid, or acid addition salt with an organic acid such as glutamate. Is included.
  • the base addition salt examples include a base addition salt with an inorganic base such as sodium, potassium, magnesium, calcium and aluminum, and a base addition salt with an organic base such as methylamine, 2-aminoethanol, arginine, lysine or ornithine. Etc. can be exemplified. However, it is needless to say that the type of salt is not limited to these and can be appropriately selected by those skilled in the art.
  • the compounds of the present invention include the form of hydrates.
  • the compounds of the present invention also include the form of anhydrate.
  • the compounds of the present invention include the form of solvates.
  • the compound of the present invention also includes the form of a solvate.
  • the compounds of the present invention include crystalline morphology.
  • the compound of the present invention also includes an amorphous form.
  • the compounds of the invention also include forms labeled with various radioactive or non-radioactive isotopes. More specifically, the compound of the present invention contains an anhydride and solvate of "the compound represented by the formula (1)", or a hydrate and / or a solvate thereof, or crystals thereof. including.
  • the compound of the present invention contains an anhydride and a solvate of "a salt of a compound represented by the formula (1)", or a hydrate and / or a solvate of the salt thereof, or further comprises crystals thereof. include.
  • the compound of the present invention may also contain a pharmaceutically acceptable prodrug of "the compound represented by the formula (1)".
  • a pharmaceutically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions.
  • examples of the group forming a prodrug for a hydroxyl group and an amino group include an acyl group and an alkoxycarbonyl group.
  • Examples of the group forming a prodrug for the carboxyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an s-butyl group, a t-butyl group and an amino group. Examples thereof include a methylamino group, an ethylamino group, a dimethylamino group, or a diethylamino group.
  • a group that appropriately forms a prodrug according to a conventional method into any one or more arbitrary groups selected from the hydroxyl group and the amino group in the compound of the present invention, for example, using a prodrug-forming reagent such as a corresponding halide. If desired, it can be produced by isolation and purification according to a conventional method as appropriate. Further, it is also possible to introduce a group that appropriately forms a prodrug according to a conventional method by using a prodrug-forming reagent such as an alcohol or an amine corresponding to the carboxyl group in the compound of the present invention.
  • a prodrug-forming reagent such as an alcohol or an amine corresponding to the carboxyl group in the compound of the present invention.
  • the compound represented by the formula (1) can be produced according to a known method, for example, a method shown below, a method according to these, or a method shown in Examples. It should be noted that the compound as a raw material in each of the following production methods is commercially available, or a known method described in, for example, "Compendium of Organic Synthesis Methods, Vol. I-XII (Wiley-Interscience)". Can be manufactured using.
  • the reaction for compound synthesis of the present invention is carried out in a suitable solvent selected according to a known method. Suitable solvents do not react substantially with the starting material, intermediates, or products at the temperature at which the reaction takes place (eg, temperatures ranging from the melting point to the boiling point of the solvent).
  • the reaction can be carried out in a single solvent or a mixed solvent. A solvent suitable for each reaction is used.
  • the reaction can be followed by an appropriate method according to known methods.
  • the product is a spectroscopic method, such as a nuclear magnetic resonance apparatus (NMR) such as 1H or 13C , an infrared spectrophotometer (IR), a mass spectrometer (MS), high performance liquid chromatography ( It can be tracked using HPLC), thin layer chromatography (TLC), and the like.
  • NMR nuclear magnetic resonance apparatus
  • IR infrared spectrophotometer
  • MS mass spectrometer
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • the compound represented by the formula (1) and its intermediates can be produced by the synthetic method described below. Unless otherwise specified, the following reaction formulas and R 1 , R 2 , R cy1 , R cy2 , R Ar1 , Cy, and Ar described above have the same meanings as described above.
  • the compound of the present invention may be produced by a method other than the method described in the present specification by appropriately utilizing the method described in the present specification and the common general technical knowledge in the art.
  • the reaction formulas and examples are intended for illustration purposes and do not limit the scope of the present invention.
  • the compound of the present invention represented by the formula (1) can be produced, for example, according to the following reaction scheme.
  • “STEP” means a process, and for example, “STEP 1" means a process 1.
  • the compound represented by the formula (1) represents, for example, reaction scheme 1 (in the formula of each compound, LG 1 represents a leaving group such as, for example, -Cl, -Br, -I, OTf, OMs, or OTs. Further, halogen can be produced by the method described in (indicating -Cl, -Br, or -I).
  • the compounds represented by the formulas (2)-(4) are commercially available or can be produced according to known methods, for example, the methods shown below, or methods similar thereto.
  • the compound represented by the formula (1) can be produced by a coupling reaction with the compound represented by the formula (2) using a metal catalyst. More specifically, it can be produced by Negishi coupling or the like between the compound represented by the formula (2) and the reagent represented by Cy-M.
  • the M represents a substituent that can be reacted by various couplings such as ZnI, MgBr, boronic acid, and boronic acid ester.
  • the compound represented by the formula (2) and the reagent represented by Cyus -M may be reacted by Suzuki-Miyaura coupling or the like to reduce the unsaturated bond on Cyus .
  • the compound represented by the formula (1) can be produced.
  • Cyus -M M is similar to the above, and Cyus indicates a substituent in which a part on Cy is substituted with an unsaturated bond, for example, cyclohexene boronic acid.
  • X on Cy N
  • the compound is produced by a reaction of the compound represented by the formula (2) with the corresponding amine represented by Cy—H by a reaction such as Ulman coupling or Buchwald-Hartwig coupling. Can be done.
  • these Cy-M, Cyus -M, and Cy-H are collectively referred to as Cy- GE -M / H.
  • the substituent of the substituent Cy can be converted into the compound represented by the formula (1) by further conversion, for example, deprotection, reduction, reductive amination, alkylation, fluorination and the like. ..
  • the compound represented by the formula (2) is a compound represented by the formula (3), such as iodination using N-iodosuccinimide, N-iodosaccharin, iodine, or bromoization using N-bromosuccinimide. It can be manufactured by performing halogenation.
  • the reaction solvent for example, acetonitrile, DMF, dichloromethane and the like can be used.
  • the reaction temperature can usually be 0 ° C to 100 ° C.
  • the compound represented by the formula (3) can be produced by a coupling reaction with the compound represented by the formula (4) using a metal catalyst.
  • the compound represented by the formula (3) can be reacted using the reagent represented by Ar-M.
  • M in Ar-M is synonymous with the above.
  • palladium can be used as the metal catalyst.
  • Reagents Ar-M are commercially available or can be prepared according to known methods.
  • As the coupling reaction for example, Suzuki-Miyaura coupling, Negishi coupling, Kumada coupling, Sonogashira coupling, Ulman coupling, Buchwald-Hartwig coupling and the like can be used.
  • the compound represented by the formula (1) is, for example, reaction scheme 2 (in the formula of each compound, LG 2 represents a leaving group such as, for example, OTf, OMs, or OTs, and hallo is -Cl,-. Br, or -I.
  • LG 2 represents a leaving group such as, for example, OTf, OMs, or OTs, and hallo is -Cl,-. Br, or -I.
  • PG can be produced by the method described in Greene's Protective Groups in Organic Synthesis, John Wiley and Sons (2014 edition). can.
  • the compounds represented by the formulas (5)-(9) are commercially available or can be produced according to known methods, for example, the methods shown below, or methods similar thereto.
  • the compound represented by the formula (1) can be produced by a coupling reaction with the compound represented by the formula (5) using a metal catalyst.
  • the compound represented by the formula (5) can be reacted using the reagent represented by Ar-M.
  • Reagent Ar-M has the same meaning as described above.
  • palladium can be used as the metal catalyst.
  • Reagents Ar-M are commercially available or can be prepared according to known methods.
  • As the coupling reaction for example, Suzuki-Miyaura coupling, Negishi coupling, Kumada coupling, Sonogashira coupling, Ulman coupling, Buchwald-Hartwig coupling and the like can be used.
  • the substituent of the substituent Cy can be converted into the compound represented by the formula (1) by further conversion, for example, deprotection, reduction, reductive amination, alkylation, fluorination and the like. ..
  • the compound represented by the formula (5) is obtained by sulfonylating the compound represented by the formula (6) in the presence of a base using trifluoromethanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonimide) or the like. It can be manufactured by.
  • a base diisopropylethylamine or the like can be used.
  • the reaction solvent for example, 1,4-dioxane, DMF, dichloromethane and the like can be used.
  • the reaction temperature can usually be ⁇ 78 ° C. to 100 ° C.
  • the compound represented by the formula (6) can be produced by deprotecting the compound represented by the formula (7).
  • the deprotection reaction may be carried out according to a known method, for example, the method described in Greene's Protective Groups in Organic Synthesis, John Wiley and Sons (2014 edition), and the like.
  • the compound represented by the formula (7) can be produced by a coupling reaction with the compound represented by the formula (8) using a metal catalyst.
  • the compound represented by the formula (7) can be produced by a coupling reaction between the compound represented by the formula (8) and the reagent represented by Cy GE -M / H.
  • the reagent Cy GE -M / H has the same meaning as described above.
  • palladium can be used as the metal catalyst.
  • the reagent Cy GE -M / H is commercially available or can be prepared according to known methods.
  • As the coupling reaction for example, Suzuki-Miyaura coupling, Negishi coupling, Kumada coupling, Sonogashira coupling, Ulman coupling, Buchwald-Hartwig coupling and the like can be used.
  • the compound represented by the formula (8) is a compound represented by the formula (9), such as iodination using N-iodosuccinimide, N-iodosaccharin, iodine, or bromoization using N-bromosuccinimide. It can be manufactured by performing halogenation.
  • the reaction solvent for example, acetonitrile, DMF, dichloromethane and the like can be used.
  • the reaction temperature can usually be 0 ° C to 100 ° C.
  • the compound in which L is represented by -Cl, -Br, -I, or -O-PG is a compound.
  • reaction scheme 3 in the formula of each compound, L represents a halogen represented by -Cl, -Br, or -I, or a protected hydroxyl group represented by -O-PG.
  • PG represents Greene. It can be manufactured by the method described in's Protective Groups in Organic Synthesis, John Wiley and Sons (2014 edition)).
  • the compounds represented by the formulas (11)-(13) are commercially available or can be produced according to known methods, for example, the methods shown below, or methods similar thereto.
  • the compound represented by the formula (10) can be produced by decarboxylating the compound represented by the formula (11) by heating in the presence of an acid.
  • an acid for example, sulfuric acid can be used.
  • Water can be used as the reaction solvent.
  • the reaction temperature can usually be 50 ° C to 150 ° C.
  • the compound represented by the formula (11) can be produced by cyclizing the compound represented by the formula (12) with propiolic acid in the presence of a base.
  • a base for example, potassium carbonate can be used.
  • DMF can be used as the reaction solvent.
  • the reaction temperature can usually be 0 ° C to 100 ° C.
  • the compound represented by the formula (12) can be produced by reacting the compound represented by the formula (13) with O- (mesitylene sulfonyl) hydroxylamine. Chloroform and dichloromethane can be used as the reaction solvent. The reaction temperature can usually be 0 ° C to 50 ° C. Further, among the compounds represented by the formula (10), the compound in which L is -OTf, -OMs, or -OTs has, for example, the protecting group of the compound in which L is -O-PG in the formula (10) has been removed. After that, it can be produced by converting the hydroxyl group into Tf, Ms, or Ts.
  • the compound (14) in which Cy is represented by the formula (1-1-2) is, for example, reaction scheme 4 (LG 2 in the formula of each compound is, for example, OTf, OMs, etc. Or, it indicates a leaving group such as OTs.
  • hallo indicates -Cl, -Br, or -I.
  • PG Greene's Protective Groups in Organic Synthesis, John Wiley and Sons (2014 edition). It can be manufactured by the method described in (showing the protective group listed in).
  • the compound represented by (14)-(21) is commercially available or can be produced according to a known method, for example, the method shown below, or a method similar thereto.
  • the compound represented by the formula (14) can be produced by a reductive amination reaction of the compound represented by the formula (15). For example, it can be produced by forming an imine in the presence of R 11 R 12 NH followed by a reduction reaction of the imine with sodium triacetoxyborohydride. THF and dichloromethane can be used as the reaction solvent. The reaction temperature can usually be 0 ° C to 80 ° C. Substituents R 11 R 12 can convert the compound represented by the formula (14) by further conversion, for example, deprotection, reduction, alkylation, fluorination and the like.
  • the compound represented by the formula (15) can be produced by deprotecting the compound represented by the formula (16).
  • the deprotection reaction may be carried out according to a known method, for example, the method described in Greene's Protective Groups in Organic Synthesis, John Wiley and Sons (2014 edition), and the like.
  • the compound represented by the formula (16) can be produced by a coupling reaction with the compound represented by the formula (17) using a metal catalyst.
  • the compound represented by the formula (17) can be reacted using the reagent represented by Ar-M.
  • Reagent Ar-M has the same meaning as described above.
  • palladium can be used as the metal catalyst.
  • Reagents Ar-M are commercially available or can be prepared according to known methods.
  • As the coupling reaction for example, Suzuki-Miyaura coupling, Negishi coupling, or the like can be used.
  • the compound represented by the formula (17) is obtained by sulfonylating the compound represented by the formula (18) in the presence of a base using trifluoromethanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonimide) or the like. It can be manufactured by.
  • a base diisopropylethylamine or the like can be used.
  • the reaction solvent for example, 1,4-dioxane, DMF, dichloromethane and the like can be used.
  • the reaction temperature can usually be ⁇ 78 ° C. to 100 ° C.
  • the compound represented by the formula (18) can be produced by deprotecting the compound represented by the formula (19).
  • the deprotection reaction may be carried out according to a known method, for example, the method described in Greene's Protective Groups in Organic Synthesis, John Wiley and Sons (2014 edition), and the like.
  • the compound represented by the formula (19) can be produced by hydrogenating the compound represented by the formula (20) in the presence of a palladium catalyst.
  • a palladium catalyst examples include methanol and ethyl acetate.
  • the reaction can usually be carried out at a temperature of room temperature to 80 ° C., and can be reacted under a pressure of 100 atm from normal pressure.
  • the compound represented by the formula (20) can be produced by a coupling reaction with the compound represented by the formula (8) using a metal catalyst.
  • the compound represented by the formula (20) can be reacted using the reagent represented by the formula (21).
  • M in the formula (21) has the same meaning as described above.
  • palladium can be used as the metal catalyst.
  • the compounds represented by the formula Ar-M are commercially available or can be prepared according to known methods.
  • As the coupling reaction for example, Suzuki-Miyaura coupling, Negishi coupling, or the like can be used.
  • the compound (22) in which Cy is represented by the general formula (1-1-1) is, for example, reaction scheme 5 (LG 2 in the formula of each compound is, for example, OTf, OMs. , Or a leaving group such as OTs.
  • PG is produced by the method described in Greene's Protective Groups in Organic Synthesis, John Wiley and Sons (2014 edition). can do.
  • the compounds represented by the formulas (19) and (22)-(28) are commercially available or can be produced according to known methods, for example, the methods shown below, or methods similar thereto.
  • the compound represented by the formula (22) can be produced by a coupling reaction with the compound represented by the formula (23) using a metal catalyst.
  • the compound represented by the formula (23) can be reacted using the reagent represented by Ar-M.
  • Reagent Ar-M reagent has the same meaning as described above.
  • palladium can be used as the metal catalyst.
  • Reagents Ar-M are commercially available or can be prepared according to known methods.
  • As the coupling reaction for example, Suzuki-Miyaura coupling, Negishi coupling, or the like can be used.
  • Substituents R 11 R 12 can convert the compound represented by the formula (22) by further conversion, for example, deprotection, reduction, alkylation, fluorination and the like.
  • the compound represented by the formula (23) is obtained by sulfonylating the compound represented by the formula (24) in the presence of a base using trifluoromethanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonimide) or the like. It can be manufactured by.
  • a base diisopropylethylamine or the like can be used.
  • the reaction solvent for example, 1,4-dioxane, DMF, dichloromethane and the like can be used.
  • the reaction temperature can usually be ⁇ 78 ° C. to 100 ° C.
  • the compound represented by the formula (24) can be produced by deprotecting the compound represented by the formula (25).
  • the deprotection reaction may be carried out according to a known method, for example, the method described in Greene's Protective Groups in Organic Synthesis, John Wiley and Sons (2014 edition), and the like.
  • the compound represented by the formula (25) can be produced by a reductive amination reaction of the compound represented by the formula (26).
  • it can be produced by forming an imine in the presence of R 11 R 12 NH followed by a reduction reaction of the imine with sodium triacetoxyborohydride.
  • THF and dichloromethane can be used as the reaction solvent.
  • the reaction temperature can usually be 0 ° C to 80 ° C.
  • the compound represented by the formula (26) can be produced by reacting the compound represented by the formula (27) under acidic conditions.
  • acid for example, hydrochloric acid can be used. THF and acetonitrile can be used as the reaction solvent.
  • the reaction temperature can usually be 0 ° C to 100 ° C.
  • the compound represented by the formula (27) can be produced by increasing the carbon content of the compound represented by the formula (28) by a Wittig reaction using (methoxymethyl) triphenylphosphonium chloride under basic conditions.
  • the base for example, potassium tert-butoxide can be used.
  • THF can be used as the reaction solvent.
  • the reaction temperature can usually be 0 ° C to 80 ° C.
  • the compound represented by the formula (28) can be produced by deprotecting the compound represented by the formula (19).
  • the deprotection reaction may be carried out according to a known method, for example, the method described in Greene's Protective Groups in Organic Synthesis, John Wiley and Sons (2014 edition), and the like.
  • Ar is represented by the formula (1-2)
  • Y in the formula is represented by N
  • R Ar3 and R Ar4 are both ⁇ H
  • R Ar5 is ⁇ CH2 -OR Ar1 .
  • Compound (29) indicates, for example, reaction scheme 6 (in the formula, LG 1 indicates a leaving group such as, for example, -Cl, -Br, -I, OTf, OMs, or OTs, and LG 2 indicates a leaving group. For example, it indicates a leaving group such as OTf, OMs, or OTs.
  • PG indicates a protective group published in Greene's Protective Groups in Augmented Science, John Wiley and Sons (2014 edition). It can be manufactured by the method.
  • the compounds represented by the formulas (29)-(33) are commercially available or can be produced according to known methods, for example, the methods shown below, or methods similar thereto.
  • the compound represented by the formula (29) can be produced by alkylating the compound represented by the formula (30) under basic conditions.
  • the compound represented by the formula (30) can be reacted using the reagent represented by R Ar1 -LG 1 .
  • R Ar1 -LG 1 is commercially available or can be manufactured according to known methods.
  • As the base for example, sodium hydride or sodium hydroxide can be used.
  • As the catalyst for example, tetrabutylammonium chloride can be used.
  • As the reaction solvent THF, DMF, or dichloromethane can be used.
  • the reaction temperature can usually be 0 ° C to 80 ° C.
  • the compound represented by the formula (29) can be converted by further conversion, for example, deprotection, reduction, alkylation, fluorination and the like. can.
  • the compound represented by the formula (29) can be produced by etherifying the compound represented by the formula (31) under basic conditions.
  • the compound represented by the formula (31) can be reacted using the reagent represented by R Ar1 -OH.
  • As the base for example, sodium hydride or sodium hydroxide can be used.
  • As the catalyst for example, tetrabutylammonium chloride can be used.
  • As the reaction solvent THF, DMF, or dichloromethane can be used.
  • the reaction temperature can usually be 0 ° C to 80 ° C.
  • the compound represented by the formula (31) can be produced by sulfonylating the compound represented by the formula (30) under basic conditions.
  • the base for example, triethylamine can be used.
  • the sulfonylating agent mesylloride can be used.
  • THF can be used as the reaction solvent.
  • the reaction temperature can usually be 0 ° C to 80 ° C.
  • the compound represented by the formula (30) can be produced by deprotecting the compound represented by the formula (32).
  • the deprotection reaction may be carried out according to a known method, for example, the method described in Greene's Protective Groups in Organic Synthesis, John Wiley and Sons (2014 edition), and the like.
  • the compound represented by the formula (32) can be produced by a coupling reaction with the compound represented by the formula (5) using a metal catalyst.
  • the compound represented by the formula (5) can be reacted using the reagent represented by the formula (33).
  • M in the formula is synonymous with the above.
  • palladium can be used as the metal catalyst.
  • the compound represented by the formula (33) is commercially available or can be produced according to a known method.
  • As the coupling reaction for example, Suzuki-Miyaura coupling, Negishi coupling and the like can be used.
  • the compound represented by the formula (34) is, for example, reaction scheme 7 (in the formula of each compound, LG 1 is, for example, -Cl, -Br, -I, OTf, OMs, Alternatively, it indicates a leaving group such as OTs. Further, Z indicates a boron derivative such as boronic acid B (OH) 2 or a boronic acid ester)).
  • the compounds represented by the formulas (35)-(37) are commercially available or can be produced according to known methods, for example, the methods shown below, or methods similar thereto.
  • the compound represented by the formula (34) can be produced by CH borylizing the compound represented by the formula (35) using an iridium catalyst.
  • the borane source for example, bis (pinacolato) diborone can be used.
  • THF can be used as the reaction solvent.
  • the reaction temperature can usually be 20 ° C to 80 ° C.
  • the compound represented by the formula (35) can be produced by etherifying the compound represented by the formula (36) under basic conditions.
  • the compound represented by the formula (36) can be produced by reacting with the reagent represented by R Ar1 -OH.
  • the base for example, sodium hydride or sodium hydroxide can be used.
  • the catalyst for example, tetrabutylammonium chloride can be used.
  • the reaction solvent THF, DMF, or dichloromethane can be used.
  • the reaction temperature can usually be 0 ° C to 80 ° C.
  • the compound represented by the formula (36) can be produced by subjecting the compound represented by the formula (37) to halogenation including chlorolation.
  • the chlorolytic agent for example, thionyl chloride can be used.
  • Dichloromethane can be used as the reaction solvent.
  • the reaction temperature can usually be 0 ° C to 40 ° C.
  • the compound represented by the formula (38) is, for example, reaction scheme 8 (Ar / LG 1 in the formula of each compound represents the above-mentioned Ar or LG 1 and FG 1 ).
  • a substituent that can be converted into an amine structure by a reduction, deprotection reaction followed by an amination reaction, such as a group, is shown as a protective group for an aldehyde group, for example, Greene's Protective Groups in Organic Synthesis, John Wiley and Sons. (2014 version) can be used as a protective group) can be produced by the method described in.
  • the compounds represented by the formulas (38)-(41) are commercially available or can be produced according to known methods, for example, the methods shown below, or methods similar thereto.
  • the compound represented by the formula (38) can be produced by reducing the compound represented by the formula (39).
  • a reduction method for example, a method of reacting a hydrogen source in the presence of a palladium catalyst can be used.
  • the hydrogen source for example, hydrogen gas, 1-methyl-1,4-cyclohexadiene, gamma terpinene, triethylsilane and the like can be used. Toluene and ethanol can be used as the reaction solvent.
  • the reaction temperature can usually be 0 ° C to 110 ° C.
  • a method of reacting the above-mentioned hydrogen source in the presence of an acid can be used.
  • the acid for example, bis (trifluoromethanesulfonyl) imide or trifluoromethanesulfonic acid can be used.
  • the reaction solvent THF, chlorobenzene and the like can be used.
  • the reaction temperature can usually be 0 ° C to 110 ° C.
  • the compound represented by the formula (39) can be produced under acidic conditions by an alkenylation reaction between the compound represented by the formula (41) and the compound represented by the formula (40).
  • the acid include 10-campar sulfonic acid, trifluoromethanesulfonic acid, paratoluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, pentafluoropropionic acid, bromide-acetic acid mixture, gadrinium trifluoromethanesulfonate and aluminum chloride. Can be used.
  • reaction solvent toluene, orthoxylene, anisole, chlorobenzene, 4-methyltetrahydropyran, and cyclopentyl methyl ether can be used.
  • additive that promotes the reaction magnesium sulfate, diphosphorus pentoxide, molecular sieve, and trifluoromethanesulfonic anhydride can be used.
  • the reaction temperature can usually be 40 ° C to 140 ° C.
  • the method for producing the compound of the present invention is not limited to the method described here.
  • the compound of the present invention can be produced by modifying or converting a substituent of a compound that is a precursor thereof by combining one or a plurality of reactions described in ordinary chemical literature and the like.
  • examples of the method for producing a compound containing asymmetric carbon include a production method by asymmetric reduction, and a commercially available (or known method or known method) in which the portion corresponding to the asymmetric carbon is optically active in advance.
  • examples thereof include a method using a raw material compound (which can be prepared according to the above), a method of optically resolution by an enzyme, or a method of producing an optically active compound.
  • the method is, for example, high performance liquid chromatography (HPLC) using an optically active column, supercritical fluid chromatography (SFC), or a salt formed with an optically active reagent and separated by fractional crystallization.
  • HPLC high performance liquid chromatography
  • SFC supercritical fluid chromatography
  • a salt formed with an optically active reagent and separated by fractional crystallization there are a classical optical fractionated crystallization method for releasing the formation of the salt, or a method for separating and purifying the diastereomers produced by condensing with an optically active reagent and then decomposing them again.
  • the optically active compound of the present invention can be produced by subsequently carrying out the production method shown above.
  • a salt pharmaceutically acceptable by known means for example, an inorganic salt with sodium or the like or triethylamine. It is also possible to use an organic salt such as (organic salt).
  • an inorganic salt when an inorganic salt is obtained, it is preferable to dissolve the compound of the present invention in water containing a hydroxide, a carbonate, a bicarbonate and the like corresponding to the desired inorganic salt.
  • the reaction may be mixed with a water-miscible inert organic solvent such as methanol, ethanol, acetone or dioxane.
  • a solution of sodium salts can be obtained by using sodium hydroxide, sodium carbonate or sodium bicarbonate.
  • the compound when the compound contains an amino group contained in the compound or a basic functional group other than the compound, or when an aromatic ring having a basic property itself (for example, a pyridine ring) is contained.
  • They can also be pharmaceutically acceptable salts (eg, salts with inorganic acids such as hydrochloric acid or salts with organic acids such as acetic acid) by known means.
  • salts with inorganic acids such as hydrochloric acid or salts with organic acids such as acetic acid
  • the reaction may be mixed with a water-miscible inert organic solvent such as methanol, ethanol, acetone or dioxane.
  • a solution of hydrochloride can be obtained by using hydrochloric acid.
  • the solution may be evaporated, or a water-miscible organic solvent having a certain degree of polarity such as n-butanol, ethylmethylketone, etc. may be added to obtain the solid salt.
  • a water-miscible organic solvent having a certain degree of polarity such as n-butanol, ethylmethylketone, etc.
  • the various compounds described in the present invention can be purified by known methods, for example, various chromatographies (columns, flash columns, thin layers, high-performance liquids, supercritical fluids).
  • a certain aspect of the compound of the present invention has IRAK-4 inhibitory activity and can be used as an IRAK-4 inhibitor. That is, certain embodiments of the compounds of the invention can be used as pharmaceuticals for the prevention and / or treatment of diseases associated with IRAK-4 inhibition. More specifically, the diseases associated with IRAK-4 inhibition are those that are successful with IRAK-4 inhibition, more specifically TLRs or IL-1 family signaling systems.
  • the disease is not particularly limited as long as it is a disease that can be prevented and / or treated by suppressing the production of inflammatory mediators such as TNF ⁇ and IL-6 due to the inhibition of TNF ⁇ .
  • the IRAK-4 inhibitory activity can be measured, for example, by the method shown in Test Example 1 or 2 described later.
  • the disease related to IRAK-4 inhibition is not particularly limited as long as it is a disease that is successful by IRAK-4 inhibition, but specifically, for example, acute or chronic inflammation, autoimmune disease (rheumatoid arthritis, systemic erythematosus, lupus). Nephritis, etc.), autoimmune diseases (TNF receptor-related periodic syndrome (TRAPS), familial Mediterranean fever, cryopyrin-related periodic fever syndrome, high IgD syndrome, etc.), metabolic diseases (gout, etc.), etc. are exemplified. ..
  • a certain aspect of the compound of the present invention has a TLR / IL-1 ⁇ signal inhibitory action as shown in a test example described later, and is useful as an active ingredient of a drug.
  • certain embodiments of the compounds of the invention are preferably used for the prevention and / or treatment of diseases involving IRAK-4 signals.
  • Some embodiments of the compounds of the invention show high selectivity for other kinases.
  • other kinases include FLT3, ITK, CK2, IKKb, JAK1, Syk, PKC ⁇ , or p38.
  • FLT3 is exemplified in particular. It is confirmed by, for example, a cytokine production suppression test using immune cells or a collagen-induced arthritis model that certain aspects of the pharmaceuticals of the present invention are useful for the prevention and / or treatment of diseases involving IRAK-4 signals. be able to. Specifically, the method described in Test Example 3 described later is exemplified.
  • a certain aspect of the pharmaceutical of the present invention can be prepared as a pharmaceutical containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, for example, a compound administered as a prodrug or a pharmaceutical product.
  • a pharmaceutically acceptable salt undergoes metabolism in vivo to produce the compound represented by the formula (1) or the pharmaceutically acceptable salt thereof is also included in the scope of the pharmaceutical product of the present invention.
  • the route of administration of certain aspects of the pharmaceutical of the present invention is not particularly limited, but for example, oral administration, subcutaneous administration, intradermal administration, intramuscular injection, intravenous administration, nasal administration, intravaginal administration, transrectal administration, or It can be appropriately selected from local administration to the affected area.
  • the compound represented by the formula (1) or the pharmaceutically acceptable salt thereof may be used as it is, but the compound represented by the formula (1) or the pharmaceutically acceptable salt thereof may be used. It is preferred to add one or more pharmaceutically acceptable carriers to prepare and administer the pharmaceutical composition. Further, as the active ingredient of the pharmaceutical product of the present invention, a hydrate or solvate of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof may be used.
  • Examples of the dosage form for formulating the pharmaceutical composition include tablets, powders, granules, syrups, suspensions, capsules, inhalants, injections and the like, and for the production thereof, Various carriers corresponding to these formulations are used.
  • carriers for oral preparations may include excipients, binders, lubricants, fluidity promoters, or colorants.
  • Examples of the inhalant include a method of inhaling the powder of the pharmaceutical composition or a chemical solution in which the pharmaceutical composition is dissolved or suspended in a solvent as it is, or a method of atomizing and inhaling using a sprayer called an atomizer or a nebulizer. Be done.
  • an injection or the like generally distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, propylene glycol, polyethylene glycol or the like can be used as the diluent. Further, if necessary, a bactericide, a preservative, a stabilizer, an tonicity agent, a painless agent, or the like may be added. An inclusion compound in which the compound of the present invention is included in cyclodextrin may be prepared and used as the pharmaceutical of the present invention.
  • an appropriate dosage form may be appropriately selected and administered by an appropriate route.
  • it can be orally administered in the form of tablets, powders, granules, syrups, suspensions, capsules and the like. It can also be administered trans-airway in the form of an inhalant. It can also be administered subcutaneously, intradermally, intravascularly, intramuscularly, or intraperitoneally in the form of an injection containing an infusion.
  • it can be administered transmucosally in the form of a sublingual agent or a suppository, and can be administered transdermally in the form of a gel, lotion, ointment, cream, spray or the like. It can also be administered as a sustained-release preparation, such as a sustained-release injection or an implantable preparation (eg, a film preparation, etc.).
  • the administration period of a certain aspect of the drug of the present invention is not particularly limited, but in principle, it is administered during the period when the clinical symptoms of the disease are judged to occur, and it is generally continued for several weeks to one year. be. However, it is possible to further extend the administration period depending on the pathological condition, or it is possible to continue administration even after the recovery of clinical symptoms. Furthermore, even if clinical symptoms are not manifested, it can be administered prophylactically at the discretion of the clinician.
  • the dose of a certain aspect of the drug of the present invention is not particularly limited, but for example, when the drug of the present invention is orally administered, it is generally possible to administer 0.01 to 1000 mg of the active ingredient per adult. can. In that case, the administration frequency can be from once every 6 months to daily administration, preferably once / day.
  • the daily and / or single dose, administration period, and frequency of administration are the patient's age, weight, physical health, type and severity of the disease to be treated, route of administration, and dosage form (active ingredient of the carrier). It may be increased or decreased as appropriate according to conditions such as sustained release of.
  • an aspect of the drug of the present invention may be used at the same time as or at the same time as one or more selected drugs shown below. It can be changed and used together. Further, certain aspects of the pharmaceutical of the present invention can also be prepared and administered as a so-called combination drug together with the agents exemplified above.
  • the combination is not only an administration form as a complete mixture of active ingredients as in a typical composition, but also an administration form in a non-mixed combination in which each active ingredient is separately administered from a plurality of containers arranged therein. It also includes kits and packaging.
  • drugs examples include immunosuppressive agents (tachlorimus, cyclosporin, rapamycin, mofetyl mycophenolate, interferon preparations, cyclophosphamide, azathiopurine, methotrexate, etc.) and anti-inflammatory agents (steroids).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • ibuprofen ibuprofen, selecoxib
  • disease-modifying antirheumatic drugs gold preparation, methotrexate
  • biopharmaceuticals used as therapeutic agents for autoimmune diseases, drugs for uric acid metabolism disorders (corhitin, probenecid, bucolome, etc.) , Benzbromalon, alloprinol, etc.), hypoglycemic agents (alogliptin, nateglinide, acarbose, metformin, pyoglitazone, insulin preparations, etc.), antihypertensive agents (imidapril, balsartan, candesartan, etc.) Bronchial dilators (adrenaline ⁇ 2 agonists such as salmetherol and salbutamol, anticholinergic drugs ipratropium, thiotropium, etc.), allergic disease therapeutic agents (theophylline, etc.), antiallergic drugs (fexoquinazine, epinastine, olopatazine, loratazine, cetilidine, bepot
  • Ethyl icosapanthate, etc. Ethyl icosapanthate, etc.
  • neurotransmitter regulators donevezil, galantamine, memantin, etc.
  • antioxidants vitamin E, acetylcysteine, carnitine, betaine, pentoxyphyllin, etc.
  • antibiotics ⁇ -lactam, ⁇ -lactam, etc.
  • Various preparations such as macrolide, tetracycline, aminoglycoside, quinolone, chloramphenicol, etc. ). It can also be used in combination with various drugs created in the future. These combination drugs are not limited to any clinically significant combination.
  • a certain aspect of the compound of the present invention contains a compound having excellent safety (various toxicity and safety pharmacology), pharmacokinetic performance, etc., and its usefulness as an active ingredient of a pharmaceutical can be confirmed by the following methods, for example. ..
  • Safety-related tests include, for example, those listed below, but are not limited to this example. Cytotoxicity test (test using HL60 cells and hepatocytes, etc.), genotoxicity test (Ames test, mouse phosphorformer TK test, chromosomal abnormality test, micronucleus test, etc.), skin sensitization test (Buehler method, GPMT method, etc.) , APT method, LLNA test, etc.), Skin photosensitivity test (Adjuvant and Strip method, etc.), Eye irritation test (single instillation, short-term continuous instillation, repeated instillation, etc.), Safety pharmacology test for cardiovascular system (, etc.) Telemetry method, APD method, hERG inhibition evaluation method, etc.), safety pharmacology test for central nervous system (FOB method, modified Irwin method, etc.), safety pharmacology test for respiratory system (measurement method by respiratory function measuring device, blood gas) (Measurement method by analyzer, etc.), general toxicity
  • the tests related to pharmacokinetic performance include, for example, those listed below, but are not limited to this example.
  • Inhibition or induction test of chitochrome P450 enzyme, cell permeability test (test using CaCO-2 cells, MDCK cells, etc.), drug transporter ATPase assay, oral absorption test, blood concentration transition measurement test, metabolism test (stable) Includes sex tests, metabolic molecular species tests, reactivity tests, etc.), solubility tests (solubility test by turbidity method, etc.), etc.
  • a certain aspect of the compound of the present invention is useful as an active ingredient of a pharmaceutical by conducting a cytotoxicity test.
  • the cytotoxicity test include methods using various cultured cells such as HL-60 cells, which are pre-human leukemia cells, primary isolated cultured cells of liver cells, and neutrophil fractions prepared from human peripheral blood. This test can be performed by the method described below, but is not limited to this description. Prepare cells as a cell suspension of 105 to 107 cells / ml, and dispense 0.01 mL to 1 mL of the suspension into microtubes or microplates.
  • a solution in which the compound was dissolved was added therein in an amount of 1/100 to 1 times the amount of the cell suspension, and the final concentration of the compound was, for example, 0.001 ⁇ M to 1000 ⁇ M in a cell culture medium at 37 ° C. Incubate under 5% CO 2 for 30 minutes to several days. After the culture is completed, the cell viability is evaluated using the MTT method or the WST-1 method (Ishiyama, M., et al., In Vitro Toxicology, 8, p.187, 1995). By measuring the cytotoxicity of a compound to cells, its usefulness as an active ingredient of a drug can be confirmed.
  • genotoxicity tests include the Ames test, the mouse phosphorformer TK test, the chromosomal aberration test, and the micronucleus test.
  • the Ames test is a method for determining sudden reversion mutations by culturing the bacteria on a culture dish mixed with a compound using Salmonella or Escherichia coli of the specified bacterial species (1999, Pharmaceutical Trial No. 1604). Refer to II-1. Genotoxicity test, etc. from the "Genotoxicity test guideline").
  • the mouse lymphoma TK test is a gene mutation ability detection test targeting the thymidine kinase gene of mouse lymphoid L5178Y cells (1999, Pharmaceutical Cons No. 1604, "Genetic Toxicity Test Guidelines" II-3. Mouse phosphorus. Formal TK test; Clive, D. et al., Mutat. Res., 31, pp.17-29, 1975; Cole, J., et al., Mutat.Res., 111, pp.371-386, 1983 Etc.).
  • the chromosomal aberration test is a method of co-culturing cultured mammalian cells and a compound, then immobilizing the cells, staining the chromosomes, and observing the cells to determine the activity that causes the chromosomal aberration (1999 Pharmaceutical Trial No. 1).
  • the micronucleus test evaluates the ability to form micronuclei due to chromosomal abnormalities, and is based on the method using rodents (in vivo test) (1999, Pharmaceutical Review No. 1604, "Genotoxicity Test Guidelines". II-4.
  • a certain aspect of the compound of the present invention is useful as an active ingredient of a pharmaceutical.
  • the Buehler method (Buehler, E.V. Arch.Dermatol., 91, pp.171-177, 1965) and GPMT method (maximization method) are used as skin sensitization tests using guinea pigs. (Magnusson, B. et al., J. Invest. Dermatol., 52, pp.268-276, 1969)) or APT method (adjuvant & patch method (Sato, Y.
  • a skin photosensitization test As a skin light sensitization test, a skin light sensitization test using a guinea pig (see “Explanation of non-clinical test guidelines for pharmaceuticals 2002", Yakuji Nippo Co., Ltd. 2002, 1-9: Skin light sensitization test, etc.) Adjuvant and S Tori p method (Ichikawa, H. et al., J. Invest. Dermatol., 76, pp.498-501, 1981), Harber method (Harber, L.C., Arch).
  • a certain aspect of the compound of the present invention is useful as an active ingredient of a pharmaceutical.
  • eye irritation tests a single eye drop test method using rabbit eyes, monkey eyes, etc. (single instillation only once), a short-term continuous instillation test method (instillation in a short period of multiple times at regular intervals), and a repeated instillation test method (instillation at regular intervals) (Fukui, N. et al., Gendai no Rinsho, 4 (7), pp), which improves eye irritation symptoms for a certain period of time after instillation.
  • There is a method of evaluation according to .277-289, 1970 By clarifying the ocular irritation of the compound by using any one or more of these methods, the usefulness as an active ingredient of a drug can be confirmed.
  • a certain aspect of the compound of the present invention is useful as an active ingredient of a drug by conducting a safety pharmacological test on the cardiovascular system.
  • a safety pharmacological test for the cardiovascular system the telemetry method (method for measuring the effects of compound administration without anesthesia on electrocardiogram, heart rate, blood pressure, blood flow, etc. (Shigeru Kanno, Hirokazu Bureau, Yoshiyoshi Nakata) Ed. Animal electrocardiogram, echocardiography, blood pressure, and pathological examination for basic and clinical use (2003 Maruzen Co., Ltd.), APD method (method for measuring cardiomyocyte action potential duration (Muraki, K. et al.). , AM. J.
  • hERG inhibition evaluation method Patch clamp method (Chachin, M. et al., Nippon Yakurigaku Zasshi, 119, pp.345-351, 2002), Binding assay method (Gilbert, JD et al., J. Pharm. Tox. Methods, 50, pp) .187-199, 2004), Rb + efflex assay method (Cheng, CS et al., Drug Develop. Indust.
  • a certain aspect of the compound of the present invention is useful as an active ingredient of a drug by conducting a safety pharmacological test on the central nervous system.
  • the FOB method (Mattson, J. L. et al., J. American College of Technology, 15 (3), pp.239-254, 1996) is a safety pharmacological test for the central nervous system. ), Modified Irwin (method for evaluating general symptoms and behavioral observation (Irwin, S. Comprehensive Observational Assessment (Berl.) 13, pp.222-257, 1968), etc.
  • a certain aspect of the compound of the present invention is useful as an active ingredient of a drug by conducting a safety pharmacological test on the respiratory system.
  • Safety for the respiratory system As a pharmacological test, a measurement method using a respiratory function measuring device (measurement of respiratory rate, tidal volume, minute ventilation, etc.) (Drorbaugh, J.E. et al., Pediatrics, 16, pp.81- 87, 1955; Epstein, M.A.
  • the general toxicity test is a single or repeated (multiple days) oral administration of a compound dissolved or suspended in an appropriate solvent using rodents such as rats and mice or non-rods such as monkeys and dogs. It is a method of observing the general condition of an administered animal and evaluating clinical chemical changes and pathological histological changes by intravenous administration or the like. By clarifying the general toxicity of the compound using these methods, the usefulness as an active ingredient of a pharmaceutical can be confirmed.
  • the reproductive developmental toxicity test is a test that examines the induction of adverse effects on the reproductive development process of compounds using rodents such as rats and mice or non-rods such as monkeys and dogs ("Explanation of non-clinical test guidelines 2002"). See Yakuji Nippo, 2002, 1-6: Reproductive Developmental Toxicity Test, etc.). Reproductive developmental toxicity tests include tests on fertility and early embryonic development until implantation, tests on prenatal and postnatal development and maternal function, and tests on embryo / fetal development (2000, Pharmaceutical Cons No. 1834, Attachment). Please refer to [3] Reproductive developmental toxicity test) etc. from "Guidelines for Pharmaceutical Toxicity Test Method". By clarifying the reproductive developmental toxicity of the compound using these test methods, its usefulness as an active ingredient of a drug can be confirmed.
  • cytochrome P450 enzymes Gomez-Lechon, MJ et al., Curr. Drug Metab. 5 (5), pp. It can be confirmed by performing 443-462, 2004.
  • cytochrome P450 enzymes for example, a cytochrome P450 enzyme of each molecular species or a human P450 expression system microsome prepared from cells or prepared by using a recombinant is used, and the enzyme activity is compounded in vitro.
  • the reactive metabolites are trapped as dGSH adducts by incubating the human liver microsome and the compound in the presence of NADPH and glutathione (dGSH) fluorescently labeled with a dansyl group, and the fluorescence intensity is increased.
  • dGSH NADPH and glutathione
  • a method for comprehensively detecting peaks caused by reactive metabolites from the amount of dGSH adduct produced Junping Gan. Et al., Chem. Res. Toxicol. 2005, 18, 896-903
  • 14C labeled compound is incubated with human liver microsomes in the presence of NADPH to measure covalently bound activity to proteins (Baillie TA, Drug Metabolizing Enzymes.
  • a cell permeability test for example, a method of measuring the cell membrane permeability of a compound in an in vitro cell culture system using Caco-2 cells (Delie, F. et al., Crit. Rev. Ther. Drug Carrier Syst., 14, pp. 221-286, 1997; Yamashita, S. et al., Eur. J. Pham. Sci., 10, pp.195-204, 2000; Ingels, F.M. et al., J. Pham. Sci.
  • a certain aspect of the compound of the present invention is useful as an active ingredient of a drug, for example, by performing a drug transporter ATPase assay as an ATP-Binding Cassette (ABC) transporter.
  • a drug transporter ATPase assay a method for investigating whether a compound is a substrate for P-gp using a P-glycoprotein (P-gp) baculovirus expression system (Germann, U.A., Methods Enzymol., 292, pp.427-41, 1998) and so on.
  • a transport test using oocytes collected from Xenopus laevis as a Solute Carrier Transporter (SLC) transporter.
  • SLC Solute Carrier Transporter
  • Examples of the transport test include a method of investigating whether or not a compound is a substrate of OATP2 using OATP2-expressing Oocytes (Tamai I. et. Al., Pharm Res. 2001 Sep; 18 (9): 1262-1269). ..
  • the usefulness as an active ingredient of a drug can be confirmed.
  • a certain aspect of the compound of the present invention is useful as an active ingredient of a pharmaceutical.
  • an oral absorption test using rodents, monkeys, dogs, etc., a certain amount of the compound is dissolved or suspended in an appropriate solvent, the blood concentration after oral administration is measured over time, and the compound is taken orally.
  • Examples include a method for evaluating blood transferability by administration using the LC-MS / MS method (edited by Kenichi Harada et al., "Latest Mass Spectrometry for Life Sciences", Kodansha Scientific 2002, etc.). By clarifying the oral absorbability of the compound using these methods, the usefulness as an active ingredient of a drug can be confirmed.
  • a certain aspect of the compound of the present invention is useful as an active ingredient of a pharmaceutical by conducting a blood concentration transition measurement test.
  • a compound is orally or parenterally administered to rodents, monkeys, dogs, etc. (for example, intravenously, intramuscularly, intraperitoneally, subcutaneously, transdermally, instilled or nasally).
  • the transition of the concentration of the compound in the blood after administration to is measured using the LC-MS / MS method (edited by Kenichi Harada et al., "Latest Mass Spectrometry for Life Science", Kodansha Scientific 2002, etc.). The method etc. can be mentioned.
  • the usefulness as an active ingredient of a drug can be confirmed.
  • a certain aspect of the compound of the present invention is useful as an active ingredient of a pharmaceutical.
  • a blood stability test method (a method for predicting metabolic clearance in vivo from the metabolic rate of a compound in hepatic microsomes of humans or other animal species (Shou, W. Z. et al.,) J. Mass Spectrom., 40 (10), pp.1347-1356, 2005; Li, C. et al., Drug Metab. Dispos., 34 (6), 901-905, 2006) etc.) , Metabolism molecular species test method, reactive metabolite test method and the like.
  • a certain aspect of the compound of the present invention is useful as an active ingredient of a pharmaceutical by conducting a solubility test.
  • the evaluation of solubility in water exemplifies a method of confirming under acidic conditions, neutral conditions, or basic conditions, and further includes confirming a change in solubility depending on the presence or absence of bile acid.
  • a solubility test a solubility test method by the turbidity method (Lipinski, C.A. et al., Adv. Drug Deliv. Rev., 23, pp.3-26, 1997; Bevan, C.D. et al., Anal. Chem. , 72, pp.1781-1787, 2000) and so on.
  • a certain aspect of the compound of the present invention is useful as an active ingredient of a pharmaceutical by examining, for example, upper gastrointestinal tract disorder, renal dysfunction and the like.
  • a pharmacological test on the upper gastrointestinal tract the effect on the gastric mucosa can be investigated using a fasted rat gastric mucosal injury model.
  • Pharmacological tests for renal function include a method for measuring renal blood flow and glomerular filtration rate [Physiology, 18th Edition (Spectral Hall), 1986, Chapter 17].
  • Examples and the like examples and test Examples
  • All purchased reagents were used without further purification.
  • the purchased anhydrous solvent was used without further drying.
  • BIOTAGE Dalton was used as an MS detector connected to Yamazen's medium pressure preparative purification system SmartFlash or BIOTAGE's medium pressure preparative purification system Isolera ONE.
  • As the column either SNAP Ultra manufactured by Biotage or DispoPack AT manufactured by YMC was used. In some cases, it was purified using BondElute SCX manufactured by Agilent as an ion exchange resin.
  • the BondElute SCX may be abbreviated as SCX below.
  • SCX As an example of the use of SCX, after washing the cartridge with methanol and dichloromethane, the crude product is dissolved in a minimum volume solvent (for example, a mixed solvent of dichloromethane-methanol) and adsorbed. Then, the impurities are washed away with methanol while applying pressure, and the product is eluted with 2.0 M ammonia-methanol.
  • a minimum volume solvent for example, a mixed solvent of dichloromethane-methanol
  • TLC thin layer chromatography
  • Precoated silica gel 60 F254 manufactured by Merck, product number 5715-1M
  • PTLC phosphomolybdic acid
  • NMR nuclear magnetic resonance apparatus
  • ppm parts per million
  • 1H integral value
  • multiplex term s, singlet; d, doublet; t, triplet; q, quartet; qui, quintet; m. , Multiplet; br, broad; dd, double doublet, etc.
  • LCMS liquid chromatograph mass spectrometry spectrum
  • LC-MS liquid chromatograph mass spectrometry spectrum
  • ESI electrospray
  • the liquid chromatography apparatus an Aquacity ⁇ Ltra Performance LC system manufactured by Waters was used.
  • the separation column ACQUITY UPLC BEH C18 2.1 ⁇ 50 mm 1.7 ⁇ m (manufactured by Waters) was used.
  • the crude reaction mixture was filtered through cerite, and the obtained filtrate was concentrated under reduced pressure.
  • the obtained residue was dissolved in chloroform, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the mixture was stirred at 60 ° C. for 18 hours.
  • the crude reaction mixture was diluted with ethyl acetate (100 mL) and washed with 10% saline (200 mL).
  • the aqueous layer was extracted again with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate, filtered through cerite, and concentrated under reduced pressure.
  • tert-butyl 7- (5-hydroxypyrazolo [1,5-a] pyridin-3-yl) -2-azaspiro [3,5] nonane-2-carboxylate (intermediate A-3-3; 0. 50 g, 1.4 mmol) was dissolved in 1,4-dioxane (7 mL), N, N-diisopropylethylamine (0.98 mL, 5.6 mmol), N-phenylbis (trifluoromethanesulfonimide) (0.68 g, 2.1 mmol) was added, and the mixture was stirred at room temperature for 16 hours.
  • the crude reaction mixture was diluted with ethyl acetate (15 mL) and washed with 10% saline (20 mL). The aqueous layer was extracted again with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate, filtered through cerite, and concentrated under reduced pressure.
  • Example a-01-02 tert-butyl 7- (5- (pyrimidine-5-yl) pyrazolo [1,5-a] pyridin-3-yl) -2-azaspiro [3, 5]
  • the crude product tert-butyl 7- (5- (pyrimidine-5-yl) pyrazolo [1,5-a] pyridine- 3-Il) -2-Azaspiro [3,5]
  • Nonane-2-carboxylate Example a-03-01 was used to synthesize and crude product (S) -7- (5- (3).
  • tert-butyl 7- (5- (2- (hydroxymethyl) pyrimidin-5-yl) pyrazolo [1,5-a] pyridin-3-yl) -2-azaspiro [3,5] nonane-2-carboxylate (Intermediate A-3-7; 0.10 g, 0.22 mmol) was dissolved in DMF (2 mL), and sodium hydride (33 mg, 55% by weight, 0.83 mmol) and 1-bromopropane (33 mg, 55% by weight, 0.83 mmol) under ice-cooling were used. 70 ⁇ L) was added, and the mixture was stirred for 3 hours. The reaction mixture was heated to room temperature, stirred for another hour, and methanol was added to stop the reaction.
  • the obtained refined product was dissolved in dichloromethane (2 mL), TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 3 hours.
  • the obtained crude reaction mixture was concentrated under reduced pressure and purified using SCX to obtain a crude product.
  • the obtained crude product was dissolved in dichloromethane (2 mL), 37% aqueous formalin solution (0.050 mL, 0.67 mmol) and sodium triacetoxyborohydride (24 mg, 0.11 mmol) were added, and the mixture was stirred at room temperature for 4 hours. ..
  • reaction solution was cooled to 0 ° C., imidazole (156 g, 2.29 mol) and TBS chloride (207 g, 1.38 mol) were sequentially added, and the mixture was stirred at room temperature for 1 and a half hours.
  • the obtained crude reaction mixture was cooled to 0 ° C., water (530 mL) was added, the mixture was filtered through cerite, extracted with ethyl acetate, and then the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
  • optical isomers were separated and analyzed under the following chiral HPLC conditions to obtain each optically active substance having an optical purity of 99.7% ee or more.
  • Sorting conditions Column: CHIRALART Cellulose-SC (10um) 245x150mm I. D. , Eluent: heptane / 2-propanol (80/20) (v / v), flow rate: 518 mL / min, temperature: 24 ° C., detection: UV (245 nm), load: 180 mL (9 g) Analytical conditions; Column: CHIRALART Cellulose-SC (5um) 250x4.6mm I. D.
  • Example a-07-01 tert-butyl 7- (5-(((((1S, 2S) -2-((tert-butyldimethylsilyl) oxy) cyclopentyl) oxy) methyl) pyrimidine-5- Il) Pyrazolo [1,5-a] Pyridine-3-yl) -2-Azaspiro [3,5] Nonane-2-carboxylate
  • tert-butyl 7- (5- (5-aminopyridine-yl) pyrazolo [1,5-a] pyridin-3-yl) -2-azaspiro [3,5] nonane-2-carboxylate (Exa-) 09-01; 50 mg, 115 ⁇ mol) was dissolved in dichloromethane (1 mL), phenyl isocyanate (153 ⁇ L, 153 ⁇ mol) was added, and the mixture was stirred at room temperature for 20 hours.
  • tert-butyl 7- (5-hydroxypyrazolo [1,5-a] pyridin-3-yl) -2-azaspiro [3,5] nonane-2-carboxylate (intermediate A-3-3; 1 g, 2.8 mmol) was dissolved in acetonitrile (28 mL), N-bromosuccinimide (582 mg, 3.1 mmol) was added, and the mixture was stirred at room temperature for 4 minutes. A saturated aqueous sodium thiosulfate solution was added to the obtained crude reaction mixture, and the mixture was extracted with ethyl acetate.
  • tert-butyl 7- (4-bromo-5-hydroxypyrazolo [1,5-a] pyridin-3-yl) -2-azaspiro [3,5] nonan-2-carboxylate (intermediate B-2-) 1; 442 mg, 1.0 mmol) is dissolved in dichloromethane (10 mL), N, N-diisopropylethylamine (260 ⁇ L, 1.5 mmol) and benzyloxymethyl chloride (168 ⁇ L, 1.2 mmol) are added, and the mixture is stirred at room temperature for 1 hour. bottom.
  • tert-butyl 7- (5-((benzyloxy) methoxy) -4-bromopyrazolo [1,5-a] pyridin-3-yl) -2-azaspiro [3,5] nonane-2-carboxylate (intermediate) B-2-2; 101 mg, 181 ⁇ mol), trimethylboroxin (45 ⁇ L, 363 ⁇ mol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (15 mg, 18 ⁇ mol), cesium carbonate (89 mg, 272 ⁇ mol) was added to DME (1.5 mL) and water (0.3 mL). The mixture is irradiated with microwaves at 110 ° C.
  • tert-butyl 7- (5-((benzyloxy) methoxy) -4-methylpyrazolo [1,5-a] pyridin-3-yl) -2-azaspiro [3,5] nonane-2-carboxylate (intermediate) B-2-3; 76 mg, 154 mmol) was dissolved in ethyl acetate (1.5 mL) and 10% palladium carbon (76 mg) was added. Hydrogen was introduced into the reaction mixture, and the mixture was stirred at room temperature for 2 days. Methanol (1.5 mL) and 10% palladium carbon (76 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour.
  • the obtained crude reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • 5-Bromo-4-fluoropyrazolo [1,5-a] pyridine (intermediate B-1--3; 300 mg, 1.4 mmol) was dissolved in methanol (13 mL) and a 28% sodium methoxide-methanol solution (1). (2.8 mL, 14 mmol) was added, and the mixture was stirred at room temperature for 20 hours. The reaction was diluted with 10% saline (100 mL) and extracted twice with dichloromethane (30 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 5-bromo-4-methoxypyrazolo [1,5-a] pyridine (291 mg, yield 92%).
  • Example b-04-01 tert-butyl 7- (4-methoxy-5-(2-((2-propoxymethyl) pyrimidin-5-yl) pyrazolo [1,5-a] pyridin-3-yl)) -2-Azaspiro [3,5] Nonane-2-carboxylate
  • Example b-04-02 4-Methoxy-5- (2-propoxymethyl) pyrimidin-5-yl) -3- (2-azaspiro [3,5] nonane-7-yl) pyrazolo [1,5-yl) a] Pyridine
  • Example b-04-03 4-Methoxy-3- (2-methyl-2-azaspiro [3,5] nonane-7-yl) -5- (2-propoxymethyl) pyrimidin-5-yl) pyrazolo [ 1,5-a] Pyridine
  • the crude reaction mixture was diluted with ethyl acetate (50 mL) and washed with 10% saline (100 mL). The aqueous layer was extracted again with ethyl acetate (100 mL), and the combined organic layer was dried over anhydrous sodium sulfate, filtered through cerite, and concentrated under reduced pressure.
  • Example c-01-01 (S) -1-((5- (3- (trans-4- (1,4-oxazepan-4-yl) cyclohexyl)) pyrazolo [1,5-a] pyridine-5 -Il) pyrimidine-2-yl) methoxy) butane-2-ol
  • reaction mixture was cooled to 0 ° C., methanol (135 mL) was added dropwise over 6 minutes, and the mixture was stirred at room temperature for 3 hours.
  • the organic layer is dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the crude product 1- (trans-4- (5- (benzyloxy) pyrazolo [1,5-a] pyridin-3-yl) cyclohexyl.
  • Example d-01-02 (1S, 2S) -2-((5- (3- (trans-4-((dimethylamino) methyl) cyclohexyl) pyrazolo [1,5-a] pyridin-5-yl) ) Pyrimidine-2-yl) Methoxy) Cyclopentane-1-ol
  • Trimethylsulfonium iodide (4.8 g, 23.5 mmol) was dissolved in THF (50 mL), an n-butyllithium solution (2.6 M hexane solution, 9 mL, 23 mmol) was added at 0 ° C., and the mixture was stirred for 30 minutes.
  • the reaction solution was cooled to ⁇ 45 ° C. and 4- (5- (benzyloxy) pyrazolo [1,5-a] pyridin-3-yl) cyclohexane-1-one (intermediate D-1-2; 5.0 g). , 15.6 mmol) in THF (100 mL) was added and stirred overnight at room temperature.
  • Trans-4- (5- (benzyloxy) pyrazolo [1,5-a] pyridin-3-yl) cyclohexane-1-carbaldehyde (intermediate D-1--4; 960 mg) was dissolved in THF (9 mL).
  • 2-Methylpropane-2-sulfinamide (417 mg) was added, then trisborate (2,2,2-trifluoroethyl) (1 mL) was added, and the mixture was stirred at room temperature for 5 hours.
  • Saturated aqueous sodium hydrogen carbonate was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained crude product was purified by automatic silica gel column chromatography using amino silica gel (eluent; hexane-ethyl acetate) to purify (S) -1- (trans-4- (5- (benzyl)).
  • Oxy) pyrazolo [1,5-a] pyridin-3-yl) cyclohexyl) -N, N-dimethylethane-1-amine (170 mg, yield 58%) was obtained.
  • (2S) -1-((5- (3- (4- (methoxymethylene) cyclohexyl) pyrazolo [1,5-a] pyridin-5-yl) pyrimidin-2-yl) methoxy) butane-2- Synthesized by using all (intermediate D-2-1; 284 mg), the crude product (S) -4- (5-(2-((2-hydroxybutoxy) methyl) pyrimidin-5-yl) Pyrazolo [1,5-a] pyridin-3-yl) cyclohexane-1-carbaldehyde (135 mg) was obtained.
  • LCMS (LC-1); RT 1.27, m / z 409 [M + H] +
  • Example d-02-01 (S) -1-((5- (3- (4-((diethylamino) methyl) cyclohexyl) pyrazolo [1,5-a] pyridin-5-yl) pyrimidine-2- Il) methoxy) butane-2-ol
  • Imidazole (330 mg, 4.82 mmol) and TBS chloride (545 mg, 3.62 mmol) were added thereto, and the mixture was stirred at room temperature for 6 hours. Then, imidazole (330 mg, 4.82 mmol) and TBS chloride (545 mg, 3.62 mmol) were added, and the mixture was stirred at room temperature for 52 hours. Further, imidazole (330 mg, 4.82 mmol) and TBS chloride (545 mg, 3.62 mmol) were added, and the mixture was stirred at room temperature for 24 hours.
  • Example d-03-01 (1S, 2S) -2-((5- (3- (trans-4-((dimethylamino) methyl) cyclohexyl) pyrazolo [1,5-a] pyridin-5-yl) ) Pyrimidine-2-yl) Methoxy) -4,4-difluorocyclopentane-1-ol
  • reaction mixture is crudely purified using automatic silica gel column chromatography (eluent; chloroform-methanol), purified by HPLC, and then subjected to silica gel column chromatography using amino silica gel (eluent; chloroform: methanol).
  • silica gel column chromatography using amino silica gel (eluent; chloroform: methanol).
  • 1-((trans-4- (5-(((((1S, 2S) -2-hydroxycyclopentyl) oxy) methyl) pyrimidin-5-yl) pyrazolo [1,5-a) ] Pyridine-3-yl) cyclohexyl) methyl) azetidine-3-yl propionate (6.8 mg, yield 13%) was obtained.
  • reaction mixture was crudely purified using automatic silica gel column chromatography (eluent; chloroform-methanol), and then a part (45 mg) of the crude product was purified by HPLC to 2-((5- (5-().
  • 3- Trans-4-((dimethylamino) methyl) cyclohexyl) pyrazolo [1,5-a] pyridin-5-yl) pyrimidin-2-yl) methoxy) cyclopentane-1-one (26.9 mg) Obtained.
  • Example d-05-02 (1S, 2S) -2-((5- (3- (trans-4-((dimethylamino) methyl) cyclohexyl) pyrazolo [1,5-a] pyrimidin-5-yl) ) Pyrimidine-2-yl) Methoxy) Cyclopentylmethanesulfonate
  • Example d-05-03 (1R, 2S) -2-((5- (3- (trans-4-((dimethylamino) methyl) cyclohexyl) pyrazolo [1,5-a] pyridin-5-yl) ) Pyrimidine-2-yl) methoxy) cyclopentyl acetate
  • Example d-05-04 (1R, 2S) -2-((5- (3- (trans-4-((dimethylamino) methyl) cyclohexyl) pyrazolo [1,5-a] pyridin-5-yl) ) Pyrimidine-2-yl) Methoxy) Cyclopentane-1-ol
  • the diastereomixture (3) containing trans-4- (4,4,5,5-tetramethyll-1,3-dioxolane-2-yl) cyclohexane-1-ol (intermediate E-2-4). .7 g) was dissolved in THF (32 mL), imidazole (1.6 g, 24 mmol) and triphenylphosphine (6.3 g, 24 mmol) were added, and the mixture was cooled to 0 ° C. A solution of iodine (6.1 g, 24 mmol) in THF (30 mL) was added dropwise over 50 minutes under cooling to 0 ° C. The reaction solution was stirred at 0 ° C.
  • Lithium chloride (196 mg, 4.63 mmol) was dried under reduced pressure at 100 ° C. for 1 hour and cooled to room temperature.
  • Zinc (powder) (420 mg, 6.45 mmol) was added thereto, and the mixture was dried under reduced pressure at 100 ° C. for 1 and a half hours. Then, it is cooled to room temperature under an argon atmosphere, THF (2.8 mL, dehydration), 1,2-dibromoethane (26 ⁇ L, 64.5 ⁇ mol), chlorotrimethylsilane (8 ⁇ L, 64.5 ⁇ mol), 2- (cis-4-4).
  • a 1N aqueous sodium hydroxide solution and saturated aqueous sodium hydrogen carbonate solution were added to the aqueous layer at 0 ° C. to make the pH basic, and then the mixture was extracted with chloroform.
  • the organic layer is dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, roughly purified using automatic silica gel column chromatography (eluent; chloroform-methanol), purified by HPLC, and desalted using SCX (1S, 2S).
  • Example e-03-01 1-(5-(((((1S, 2S) -2-((tert-butyldimethylsilyl) oxy) cyclopentyl) oxy) methyl) pyrimidin-5-yl) pyrazolo [1,5-a] Pyridin-3-yl) -4,4-difluorocyclohexane-1-ol
  • Example e-03-02 (1S, 2S) -2-((5- (3- (4,4-difluorocyclohexyl) pyrazolo [1,5-a] pyridin-5-yl) pyrimidine-2-yl) ) Methoxy) cyclopentane-1-ol
  • Examples f-01-01 5-(2-(((((1S, 2S) -2-((tert-butyldimethylsilyl) oxy) cyclopentyl) oxy) methyl) pyrimidin-5-yl) -3-( Trans-4- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole-3-yl) cyclohexyl) pyrazolo [1,5-a] pyridine
  • Example f-01-02 (1S, 2S) -2-((5- (3- (trans-4- (1H-pyrazole-5-yl) cyclohexyl)) pyrazolo [1,5-a] pyridine-5 -Il) pyrimidin-2-yl) methoxy) cyclopentane-1-ol
  • Trans-2-((5- (3- (trans-4 (hydroxymethyl) cyclohexyl) pyrazolo [1,5-a] pyridin-5-yl) pyrimidin-2-yl) methoxy) cyclopentylacetate (intermediate F- 2-2; Triethylamine (88 mg, 0.868 mmol) and methylloride (99 mg, 0.868 mmol) were added to a dichloromethane solution of 200 mg, 0.434 mmol) at room temperature, and the mixture was stirred for 16 hours. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example f-02-01 (1S, 2S) -2-((5- (3- (trans-4- (methoxymethyl) cyclohexyl) pyrazolo [1,5-a] pyridin-5-yl) pyridin-) 2-Il) Methoxy) Cyclopentane-1-ol
  • Example f-03-01 Trans-2-((5- (3- (trans-4-((S) -1-hydroxyethyl) cyclohexyl) pyrazolo [1,5-a] pyridin-5-yl)) Pyrimidine-2-yl) methoxy) cyclopentyl acetate
  • Example f-03-02 Trans-2-((5- (3- (trans-4-((S) -1-hydroxyethyl) cyclohexyl) pyrazolo [1,5-a] pyridin-5-yl)) Pyrimidine-2-yl) methoxy) cyclopentane-1-ol
  • Example g-01-01 tert-butyl 7- (5-(((((1S, 2S) -2-((tert-butyldimethylsilyl) oxy) cyclopentyl) oxy) methyl) pyrimidine-5- Il) Pyrazolo [1,5-a] Pyridine-3-yl) -5,5-dimethyl-2,7-diazaspiro [3.5] Nonane-2-carboxylate
  • Example g-01-02 (1S, 2S) -2-((5- (3- (5,5-dimethyl-2,7-diazaspiro [3.5] nonane-7-yl) pyrazolo [1, 5-a] Pyridine-5-yl) Pyrimidine-2-yl) Methoxy) Cyclopentane-1-ol
  • tert-butyl 7- (5-(2-(((((1S, 2S) -2-((tert-butyldimethylsilyl) oxy) cyclopentyl) oxy) methyl) pyrimidine-5-yl) pyrazolo [1,5-yl) a] Pyridine-3-yl) -5,5-dimethyl-2,7-diazaspiro [3.5] nonane-2-carboxylate (Example g-01-01; 7.8 mg, 115 ⁇ mol) in THF (1 mL). ), 2N Hydrochloric acid (5 mL) was added, and the mixture was stirred at room temperature for 16 hours.
  • Trans-4- (5- (benzyloxy) pyrazolo [1,5-a] pyridin-3-yl) cyclohexane-1-carbaldehyde (intermediate D-1--4; 5 g, 14.9 mmol) in acetonitrile (150 mL) ), Add tert-butylcarbamate (5.25 g, 44.9 mmol), triethylsilane (7.2 mL, 44.9 mmol), trifluoroacetic acid (3.32 mL, 43.4 mmol), and add 16 at 50 ° C. Stirred for hours.
  • the obtained crude product was purified by reverse phase HPLC (column: XB-C18, column size: 50x250 mm, particle size: 10 ⁇ m, mobile phase A: 10 mmol ammonium hydrogencarbonate aqueous solution, mobile phase B). : Acetonitrile, gradient: 10% B to 40% B (30 minutes), 40% B to 65% B (15 minutes), flow rate: 100 mL / min, detection: UV210, 254 nm).
  • the fraction containing the desired product was lyophilized and (1S, 2S) -2-((5- (3- (trans-4-((dimethyl-d6 amino) methyl) cyclohexyl) pyrazolo [1,5-a] pyridine).
  • ⁇ Test Example 1 Measurement of human IRAK-4 inhibitory activity> (1) Measurement method The activity of human IRAK-4 (Invitrogen, Cat.PV3362) is the phosphorylation of the IRAK-4 peptide substrate (biotin-KKKKRFSFKKSFKKC) in the presence of 10 ⁇ M ATP (Sigma Aldrich, Cat.A7699). -Measured by the FRET method. The enzymatic reaction was performed in a reaction buffer consisting of 50 mM HEPES (pH 7.2), 1 mM DTT, 0.1 mM Na 3 VO 4 , 5 mM MgCl 2 , 1 mM MnCl 2 , and 0.1% bovine serum albumin.
  • test compound was added to a reaction buffer containing 1 nM IRAK-4, 0.5 ⁇ M peptide substrate, and 10 ⁇ M ATP, and incubated at 23 ° C. for 30 minutes.
  • Europium cryptotate-labeled antibody 0.3 ⁇ g / mL, antibody prepared using IRAK-4 peptide substrate as antigen
  • streptavidin-XL665 2 ⁇ g / mL, CisBio, Cat.610SAXLB
  • 50 mM HEPES pH 7.2.
  • THP-1 LPS-stimulated TNF ⁇ production inhibition test using human acute monocytic leukemia-derived cell line THP-1>
  • Measurement method in the THP-1 assay the effect of the test compound on TNF ⁇ production induced by LPS stimulation can be evaluated.
  • THP-1 cells ATCC, Cat. TIB-202
  • 20 ⁇ L of test compound was added, and 1 in a 5% CO 2 incubator at 37 ° C. Incubated for hours.
  • 20 ⁇ L of LPS final concentration 2.5 ng / mL, Sigma, Cat. L2630
  • the plates were centrifuged, and 100 ⁇ L of the supernatant was taken from each well and used for evaluation of the amount of TNF ⁇ by HTRF (Cisbio, Cat. 62TNFPEB).
  • HTRF Transgene, Cat. 62TNFPEB
  • To measure the amount of TNF ⁇ dilute the supernatant 2-fold with medium, add 10 ⁇ L to a 384-well plate, add anti-TNF ⁇ -criptate (5 ⁇ L) and anti-TNF ⁇ -XL665 (5 ⁇ L), and let stand overnight. bottom. The fluorescence intensity ratio at a wavelength of 620/665 nm was measured with a microplate reader, and the amount of TNF ⁇ in the supernatant was calculated by a calibration curve.
  • the TNF ⁇ production suppression rate when LPS is not added is 100%
  • the TNF ⁇ production suppression rate when the test compound is not added is 0%
  • the IC50 of the test compound is used as 4 parameters of the data analysis software XLfit (ID Business Solutions Ltd.). It was determined using a compound model.
  • Cell viability was measured using a 96-well plate after removing 100 ⁇ L of the supernatant, and the effect of the off-target effect by the test compound was evaluated. After adding 5 ⁇ L of CCK-8 (Dojindo, Cat.CK04-10) and incubating at 37 ° C. for 1 hour, the absorbance at 450 nm was measured with a microplate reader. The cell viability when no LPS was added was set to 100%, and the IC 50 of the test compound was determined using XLfit. It should be noted that each operation and condition during measurement can be appropriately changed within a range that can be understood by those skilled in the art and does not significantly affect the measurement.
  • Rat collagen-induced arthritis model> (1) Measurement method An 8-week-old female Lewis rat (SLC Inc.) was immunized with bovine type II collagen (CII, Collagen Technology Workshop, product number K41) to induce arthritis. A one-to-one mixed emulsion of incomplete Freund's adjuvant (Difco, Cat. 263910) and CII 3 mg / mL solution was prepared, and 0.3 mL per rat was 0.1 mL at three locations in the ridge and the roots of both hind limbs. Injected one by one.
  • incomplete Freund's adjuvant Difco, Cat. 263910
  • CII 3 mg / mL solution was prepared, and 0.3 mL per rat was 0.1 mL at three locations in the ridge and the roots of both hind limbs. Injected one by one.
  • the footpad volume of both hind limbs of the animal was measured using a Plethysmometer every other day from the start of administration, and the effect of the test compound was evaluated.
  • prednisolone prednisolone SIGMA, Cat. P6004
  • the average value of the footpad volume ratio of each group to the Normal group on each measurement day was calculated using Excel2010 (Microsoft) and graphed using GraphPadPrism7.03 (GraphPad Software, Inc.).
  • the Normal group was defined as a 100% inhibitory control, and the solvent-administered group was defined as a 0% inhibitory control.
  • the compound of the general formula (1) or a salt thereof has excellent IRAK-4 inhibitory activity, and is useful as an active ingredient of a drug for the prevention and / or treatment of diseases related to IRAK-4 inhibition.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne : un composé de formule générale (1) qui présente une activité inhibitrice de l'IRAK-4 et qui est utile en tant que principe actif d'un médicament pour prévenir et/ou traiter une maladie liée à l'inhibition de l'IRAK-4 ; ou un sel de celui-ci.
PCT/JP2020/037047 2020-09-30 2020-09-30 Composé bicyclique contenant de l'azote WO2022070288A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JP2020/037047 WO2022070288A1 (fr) 2020-09-30 2020-09-30 Composé bicyclique contenant de l'azote

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2020/037047 WO2022070288A1 (fr) 2020-09-30 2020-09-30 Composé bicyclique contenant de l'azote

Publications (1)

Publication Number Publication Date
WO2022070288A1 true WO2022070288A1 (fr) 2022-04-07

Family

ID=80951280

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2020/037047 WO2022070288A1 (fr) 2020-09-30 2020-09-30 Composé bicyclique contenant de l'azote

Country Status (1)

Country Link
WO (1) WO2022070288A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016011390A1 (fr) * 2014-07-18 2016-01-21 Biogen Ma Inc. Agents d'inhibition de l'irak 4
WO2017108723A2 (fr) * 2015-12-22 2017-06-29 F. Hoffmann-La Roche Ag Dérivés pyrazolo [1,5 a]pyrimidine en tant que modulateurs d'irak 4
WO2020173739A1 (fr) * 2019-02-25 2020-09-03 Galapagos Nv Dérivés de pyrazolopyridine utilisés comme inhibiteurs de pask

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016011390A1 (fr) * 2014-07-18 2016-01-21 Biogen Ma Inc. Agents d'inhibition de l'irak 4
WO2017108723A2 (fr) * 2015-12-22 2017-06-29 F. Hoffmann-La Roche Ag Dérivés pyrazolo [1,5 a]pyrimidine en tant que modulateurs d'irak 4
WO2020173739A1 (fr) * 2019-02-25 2020-09-03 Galapagos Nv Dérivés de pyrazolopyridine utilisés comme inhibiteurs de pask

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BUCKLEY, G. M. ET AL.: "IRAK -4 inhibitors. Part III: A series of imidazo[1,2-a]pyridines", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 18, no. 12, 2008, pages 3656 - 3660, XP022707452, DOI: 10.1016/j.bmcl.April.2008.042 *
DATABASE Registry ANONYMOUS : "Pyrazolo[1,5-a]pyridine, 3-[4-(1-methylethyl)-1-piperazinyl]-5-phenyl- ", XP055931894, retrieved from STN Database accession no. RN 2469193-56-2 *

Similar Documents

Publication Publication Date Title
US11459330B2 (en) Substituted bicyclic heterocyclic compounds as PRMT5 inhibitors
KR102454308B1 (ko) PI3Kδ 관련 장애의 치료를 위한 피라졸로피리미딘 유도체의 용도
JP2020114868A (ja) Ｊａｋ１阻害剤としてのピペリジン−４−イルアゼチジン誘導体
WO2013026025A1 (fr) Dérivés de cyclohexyl-azétidine en tant qu'inhibiteurs de la jak
US9796725B2 (en) Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
KR20180109842A (ko) 화합물
KR101947289B1 (ko) 신규 피롤로피리미딘 화합물 또는 그의 염, 및 이것을 함유하는 의약 조성물, 특히 nae 저해 작용에 기초하는 종양 등의 예방제 및/또는 치료제
WO2011028685A1 (fr) Dérivés hétérocycliques de pyrazol-4-yl-pyrrolo[2,3-d] pyrimidines en tant qu'inhibiteurs de janus kinase
JP6986032B2 (ja) Ｊａｋ阻害剤としてのピロロピリミジン化合物の結晶
RU2764980C2 (ru) Бициклические амины в качестве новых ингибиторов jak-киназы
JP2021515773A (ja) ＰＩ３Ｋ−γ阻害剤としてのアミノピラジンジオール化合物
AU2014234908B2 (en) N-(2-cyano heterocyclyl)pyrazolo pyridones as Janus kinase inhibitors
JP2022525749A (ja) Ｊａｋキナーゼ阻害剤及びその調製方法、並びにその医薬分野での使用
TW202110848A (zh) 取代的稠合雙環類衍生物、其製備方法及其在醫藥上的應用
WO2022070288A1 (fr) Composé bicyclique contenant de l'azote
CN118139864A (zh) 新化合物
TW202327581A (zh) 含氮雙環化合物
WO2022070289A1 (fr) Composé bicyclique contenant de l'azote qui contient de la pyrimidine
WO2022070287A1 (fr) Composé macrocyclique
TW202328123A (zh) 含有嘧啶之含氮雙環化合物
RU2818822C1 (ru) Макроциклическое соединение
EP4419203A1 (fr) Modulateurs tricycliques de la gpr65
WO2023086800A1 (fr) Composés hétérocycliques utilisés en tant que récepteur de déclenchement exprimé sur des agonistes de cellules myéloïdes 2 et procédés d'utilisation
WO2023285583A1 (fr) Dérivés de 5,6,7,8-tétrahydro-2,6- et 2,7-naphtyridine destinés à être utilisés dans le traitement de maladies sensibles à la modulation du transporteur de citrate
EA039962B1 (ru) Гетероарил-замещенные пирроло[2,3-d]пиримидины в качестве ингибиторов янус-киназы

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20956216

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20956216

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP