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JP-7856575-B2 - PHD inhibitor compounds, compositions, and their uses

JP7856575B2JP 7856575 B2JP7856575 B2JP 7856575B2JP-7856575-B2

Inventors

  • ポール イー． フレミング
  • トーマス ピー． ブライスデル
  • センカラ ラオ アッル

Assignees

  • アケビア セラピューティクス インコーポレイテッド

Dates

Publication Date
20260511
Application Date
20210319
Priority Date
20200320

Claims (20)

  1. Compound of formula A, or a pharmaceutically acceptable salt thereof, in the formula, Ar1 is a phenyl molecule substituted with one or more groups selected from halogens, CN, OH, and C1-3 alkyl groups optionally substituted with CN or one or more halogens. Ar 2 is a pyrido-2-yl substituted with one or more groups selected from NR 4 R 5 , NHR 11 ; OH; SO 2 R 6 ; SOR 7 R 8 ; SOR 9 ; (CH 2 ) p COOH; POR 12 R 13 ; C 3-6 cycloalkyl; C 3-6 heterocycloalkyl optionally substituted with a sulfonyl group or =O; C 1-3 alkyl optionally substituted with one or more halogens; and C 1-3 alkyl or heteroaryl optionally substituted with phenyl. R4 and R5 are each independently H or C1-3 alkyl . R 6 is C1-3 alkyl , NHCOR 15 , NR 16 , R 17 , or phenyl. R7 is C1-3 alkyl , C3-5 cycloalkyl, phenyl, or NR18 R19 . R 8 is NH or NCH 3 , R9 is a C1-3 alkyl group, R 11 is SO 2 R 22 , R12 and R13 are each independently C1-3 alkyl groups . R14 and R15 are each independently C1-3 alkyl , R16 and R17 are each independently C1-3 alkyl groups . R18 and R19 are each independently C1-3 alkyl groups . R 22 is NR 23 , R 24 , or a C1-3 alkyl group optionally substituted with a carboxyl group . R23 and R24 are each independently H or C1-3 alkyl . p is a compound or a pharmaceutically acceptable salt thereof, where p is 1, 2, or 3 .
  2. Ar 1 is, And in the formula, R1a is a C1-3 alkyl group optionally substituted with CN, halogen, OH, or CN. R1 is independently selected each time from the group consisting of hydrogen, halogen, CN, OH, and C1-3 alkyl groups optionally substituted with one or more halogens. Ar 2 is, And in the formula, R2 is independently selected each time from the group consisting of hydrogen, NR4R5 , OH, C1-3 alkyl, and C3-6 cycloalkyl. R3 is SO2 R6 , SOR7 R8 , SOR9 , ( CH2 ) pCOOH , NHR11 , POR12 R13 , or R 3 is, A cycloalkyl group selected from the group consisting of, or a heterocycloalkyl group optionally substituted with SO₂R₁₄ or =O, or R3 is either a cycloalkyl group or an optionally substituted heterocycloalkyl group. Selected from the group consisting of, R 3 is, A heteroaryl molecule optionally substituted with C1-3 alkyl or phenyl, or a C1-3 alkyl molecule optionally substituted with one or more halogens, selected from the group consisting of the following: R 6 is C1-3 alkyl, NHCOR 15 , NR 16 , R 17 , or phenyl. R7 is C1-3 alkyl, C3-5 cycloalkyl, phenyl, or NR18 R19 . R 8 is NH or NCH 3 , R 11 is SO 2 R 22 , R9 , R12 , R13 , R14 , and R15 are each independently C1-3 alkyl groups. R 22 is NR 23 , R 24 , or a C1-3 alkyl group optionally substituted with carboxyl. R4 , R5 , R16 , R17 , R18 , R19 , R23 , and R24 are each independently H or C1-3 alkyl. m is 1, 2, 3, or 4. n is 0, 1, 2, or 3. The compound according to claim 1, wherein p is 1, 2, or 3.
  3. Formula III: It has a structure that follows the formula, R1 is independently selected each time from the group consisting of hydrogen, halogen, CN, OH, and C1-3 alkyl groups optionally substituted with one or more halogens. R1a is a C1-3 alkyl group optionally substituted with CN, halogen, OH, or CN. R2 is independently selected each time from the group consisting of hydrogen, NR4R5 , OH, C1-3 alkyl, and C3-6 cycloalkyl. R3 is SO₂R₆ , SORₙR₄ , SOR₇ , ( CH₂ ) pCOOH , NHR₁₁ , POR₂R₁₃ , cycloalkyl , SO₂R₁₄ or heterocycloalkyl optionally substituted with =O, C₁ -3 alkyl or heteroaryl optionally substituted with phenyl, or C₁ -3 alkyl optionally substituted with one or more halogens. R4 and R5 are each independently H or C1-3 alkyl. R 6 is C1-3 alkyl, NHCOR 15 , NR 16 , R 17 , or phenyl. R7 is C1-3 alkyl, C3-5 cycloalkyl, phenyl, or NR18 R19 . R 8 is NH or NCH 3 , R9 is a C1-3 alkyl group, R 11 is SO 2 R 22 , R12 and R13 are each independently C1-3 alkyl groups. R14 is a C1-3 alkyl group, R15 is a C1-3 alkyl group. R16 and R17 are independently H or C1-3 alkyl. R18 and R19 are independently H or C1-3 alkyl. R 22 is NR 23 , R 24 , or a C1-3 alkyl group optionally substituted with a carboxyl group. R23 and R24 are independently H or C1-3 alkyl. m is 1, 2, 3, or 4. n is 0, 1, 2, or 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, or 3.
  4. Formula IV: It has a structure that follows the formula, R1 is independently selected each time from the group consisting of hydrogen, halogen, CN, and OH, or R1 is a C1-3 alkyl group optionally substituted with one or more halogens. R1a is a C1-3 alkyl group optionally substituted with CN, halogen, OH, or CN. R2 is independently selected each time from the group consisting of hydrogen, NR4R5 , OH, C1-3 alkyl, and C3-6 cycloalkyl. R4 and R5 are each independently H or C1-3 alkyl. R7 is C1-3 alkyl, C3-5 cycloalkyl, phenyl, or NR18 R19 . R 8 is NH or NCH 3 , R18 and R19 are each independently H or C1-3 alkyl. m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.
  5. Formula IVa: It has the structure, and in the formula, R 1a is CN or halogen, R2 is selected from the group consisting of hydrogen or C1-3 alkyl, R7 is C1-3 alkyl, C3-5 cycloalkyl, phenyl, or NR18 R19 . R 8 is NH or NCH 3 , The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R18 and R19 are each independently H or C1-3 alkyl.
  6. R 1a is Cl, R2 is CH3 , The compound according to claim 5, wherein R7 is CH3 , CH( CH3 ) 2 , CH2CH3 , cyclopropyl , or cyclopentyl, and/or R18 and R19 are each independently CH3 .
  7. Formula VI: It has a structure that follows the formula, R1 is independently selected each time from the group consisting of hydrogen, halogen, CN, OH, and C1-3 alkyl groups optionally substituted with one or more halogens. R1a is a C1-3 alkyl group optionally substituted with CN, halogen, OH, or CN. R2 is independently selected each time from the group consisting of hydrogen, NR4R5 , OH, C1-3 alkyl, and C3-6 cycloalkyl. R3 is a cycloalkyl group, or a heterocycloalkyl group optionally substituted with SO₂R₁₄ or =O. R4 and R5 are each independently H or C1-3 alkyl. R14 is a C1-3 alkyl group, m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.
  8. Formula VIa: It has the structure, and in the formula, R2 is hydrogen or C1-3 alkyl, R3 is either cycloalkyl or The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R3 is a heterocycloalkyl optionally substituted with SO2R14 or =O (where R14 is C1-3 alkyl).
  9. R 3 is A compound according to claim 8, selected from the group consisting of the following.
  10. The compound according to claim 8, wherein R2 is CH3 and/or R3 is cyclopropyl.
  11. Formula VII: It has a structure that follows the formula, R1 is independently selected each time from the group consisting of hydrogen, halogen, CN, OH, and C1-3 alkyl groups optionally substituted with one or more halogens. R1a is a C1-3 alkyl group optionally substituted with CN, halogen, OH, or CN. R2 is independently selected each time from the group consisting of hydrogen, NR4R5 , OH, C1-3 alkyl, and C3-6 cycloalkyl. R4 and R5 are each independently H or C1-3 alkyl. R 11 is SO 2 R 22 , R 22 is NR 23 , R 24 , or a C1-3 alkyl group optionally substituted with a carboxyl group. R23 and R24 are independently H or C1-3 alkyl. m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.
  12. The compound according to claim 11, wherein R2 is CH3 and/or R22 is NHCH3 , N( CH3 ) 2 , CH3 , CH2CH3 , or CH2COOH .
  13. Formula VIIa: It has the structure, and in the formula, R2 is hydrogen or C3-6 cycloalkyl, R 11 is SO 2 R 22 , R 22 is NR 23 , R 24 , or a C1-3 alkyl group optionally substituted with a carboxyl group. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein R23 and R24 are independently H or C1-3 alkyl.
  14. Formula VIII: It has a structure that follows the formula, R1 is independently selected each time from the group consisting of hydrogen, halogen, CN, OH, and C1-3 alkyl groups optionally substituted with one or more halogens. R1a is a C1-3 alkyl group optionally substituted with CN, halogen, OH, or CN. R2 is independently selected each time from the group consisting of hydrogen, NR4R5 , OH, C1-3 alkyl, and C3-6 cycloalkyl. R3 is a heteroaryl compound optionally substituted with a C1-3 alkyl or phenyl compound. R4 and R5 are each independently H or C1-3 alkyl. m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.
  15. Formula VIIIa: It has the structure, and in the formula, R 3 is, The compound according to claim 14, or a pharmaceutically acceptable salt thereof, which is a heteroaryl optionally substituted with C1-3 alkyl or phenyl, selected from the group consisting of the above.
  16. Formula X: It has a structure that follows the formula, R1 is independently selected each time from the group consisting of hydrogen, halogen, CN, OH, and C1-3 alkyl groups optionally substituted with one or more halogens. R1a is a C1-3 alkyl group optionally substituted with CN, halogen, OH, or CN. R2 is independently selected each time from the group consisting of hydrogen, NR4R5 , OH, C1-3 alkyl, and C3-6 cycloalkyl. R4 and R5 are each independently H or C1-3 alkyl. R9 is a C1-3 alkyl group, m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.
  17. The compound according to claim 16, wherein R9 is CH3 .
  18. Formula XI: It has a structure that follows the formula, R1 is independently selected each time from the group consisting of hydrogen, halogen, CN, OH, and C1-3 alkyl groups optionally substituted with one or more halogens. R1a is a C1-3 alkyl group optionally substituted with CN, halogen, OH, or CN. R2 is independently selected each time from the group consisting of hydrogen, NR4R5 , OH, C1-3 alkyl, and C3-6 cycloalkyl. R4 and R5 are each independently H or C1-3 alkyl. m is 1, 2, 3, or 4. n is 0, 1, 2, or 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, or 3.
  19. Equation XII: It has a structure that follows the formula, R1 is independently selected each time from the group consisting of hydrogen, halogen, CN, OH, and C1-3 alkyl groups optionally substituted with one or more halogens. R1a is a C1-3 alkyl group optionally substituted with CN, halogen, OH, or CN. R2 is independently selected each time from the group consisting of hydrogen, NR4R5 , OH, C1-3 alkyl, and C3-6 cycloalkyl. R4 and R5 are each independently H or C1-3 alkyl. m is 1, 2, 3, or 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.
  20. Equation XIII: It has a structure that follows the formula, R1 is independently selected each time from the group consisting of hydrogen, halogen, CN, OH, and C1-3 alkyl groups optionally substituted with one or more halogens. R1a is a C1-3 alkyl group optionally substituted with CN, halogen, OH, or CN. R2 is independently selected each time from the group consisting of hydrogen, NR4R5 , OH, C1-3 alkyl, and C3-6 cycloalkyl. R4 and R5 are each independently H or C1-3 alkyl. R12 is a C1-3 alkyl group. R13 is a C1-3 alkyl group, The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, or 4.

Description

Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62/992,616, filed on 20 March 2020, which is incorporated herein by reference in its entirety. Hypoxia is a condition or state in which the supply of oxygen is insufficient for normal life functions, for example, a low supply of arterial blood oxygen. Hypoxia can lead to cellular dysfunction and structural tissue damage. Activation of cellular defense mechanisms during hypoxia is mediated by HIF (hypoxia-inducible factor) proteins. In response to hypoxia, HIFα levels increase in most cells due to a decrease in HIFα prolyl hydroxylation. Prolyl hydroxylation of HIFα is achieved by a family of proteins variously called prolyl hydroxylase domain-containing proteins (PHD1, 2, and 3), also known as HIF prolyl hydroxylase (HPH-3, 2, and 1) or EGLN-2, 1, and 3. PHD proteins are oxygen sensors and regulate HIF stability in an oxygen-dependent manner. The three PHD isoforms function differently in their regulation of HIF and may have roles in other non-HIF-related regulation. In fact, numerous studies have demonstrated that stabilizing HIF can reduce tissue inflammation and promote tissue repair. Therefore, compounds that can inhibit the activity of PHD proteins may be particularly beneficial in new therapies (Lee et al. (2019) Exp. Mol. Med. 51:68). Novel small molecule PHD inhibitors useful in treating diseases including those of the heart (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lungs (e.g., acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), liver (e.g., acute liver failure, liver fibrosis, and cirrhosis), and kidneys (e.g., acute kidney injury and chronic kidney disease) are described herein. The present invention provides, in particular, novel small molecule inhibitors of PHD that are useful in treating diseases including, but not limited to, diseases of the heart (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lungs (e.g., acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), liver (e.g., acute liver failure, hepatic fibrosis, and cirrhosis), and kidneys (e.g., acute kidney injury and chronic kidney disease). In one embodiment, the structure follows formula (A), A compound having a pharmaceutically acceptable salt thereof is provided herein, in the formula, Ar1 is an aryl or heteroaryl group optionally substituted with one or more groups selected from halogens, CN, OH, CN, C1-3 alkyl groups optionally substituted with one or more halogens, and C1-3 alkoxy groups. Ar2 is a pyrido-2-yl optionally substituted with one or more groups selected from halogens; aminos; amides; OH; sulfonyl groups; sulfinyl groups; carbonyl groups; phosphoryl groups; C3-6 cycloalkyls; C3-6 heterocycloalkyls optionally substituted with sulfonyl groups or =O ; C1-3 alkyls optionally substituted with carbonyl or one or more halogens; and heteroaryls optionally substituted with C1-3 alkyls or phenyl. In the embodiment, Ar 1 is And in the formula, X is N or CR 1a , Y and Z are independently CH or N. R1a is a C1-3 alkyl group optionally substituted with H, CN, halogen, C1-3 alkoxy, OH, or CN. R1 is independently selected each time from the group consisting of hydrogen, halogen, CN, OH, C1-3 alkyl and C1-3 alkoxy optionally substituted with one or more halogens. m is 1, 2, 3, or 4. In the embodiment, Ar 1 is as follows: . In the embodiment, Ar 1 is In the formula, R 1a is H, CN, halogen, C1-3 alkoxy, OH, or a C1-3 alkyl group optionally substituted with CN. In this embodiment, R1a is H, CN, halogen, C1-3 alkoxy, OH, or a C1-3 alkyl group optionally substituted with CN. In the embodiment, R1 is independently selected each time from the group consisting of hydrogen, halogen, CN, OH, C1-3 alkyl, and C1-3 alkoxy, which are optionally substituted with one or more halogens. In the embodiment, Ar 2 is And in the formula, R2 is independently selected each time from the group consisting of hydrogen, halogen , NR4R5 , OH, C1-3 alkyl, and C3-6 cycloalkyl. R3 is SO₂R₆ , SORₙR₄ , SOR₇R₁ , COR₁₀ , ( CH₂ ) pCOOH , NHR₁₀ , POR₁₂R₁₀ , halogen, cycloalkyl , SO₂R₁₄ or heterocycloalkyl optionally substituted with = O, C₁ -3 alkyl or heteroaryl optionally substituted with phenyl, or C₁ -3 alkyl optionally substituted with one or more halogens. R 6 is C1-3 alkyl, NHCOR 15 , NR 16 , R 17 , or phenyl. R7 is C1-3 alkyl, C3-5 cycloalkyl, phenyl, or NR18 R19 . R 8 is NH or NCH 3 , R10 is C1-3 alkyl or NHSO2 R20 , R 11 is COR 21 or SO 2 R 22 . R9 , R12 , R13 , R14 , R15 , and R20 are each independently C1-3 alkyl groups. R21 is a heterocycloalkyl, cycloalkyl, or C1-3 alkyl group. R 22 is NR 23 , R 24 , or a C1-3 alkyl group optionally substituted with carboxyl. R4 , R5 , R16 , R17 , R18 , R19 , R23 , and R24 are each independently H or C1-3 alkyl. p is 1, 2, or 3