Search

JP-7857232-B2 - Bifunctional degradation products of hematopoietic precursor kinases and their therapeutic use

JP7857232B2JP 7857232 B2JP7857232 B2JP 7857232B2JP-7857232-B2

Inventors

  • シュナトナ， ハンター ピー．
  • シャーン－ナンス， ガレン ポール
  • ミッチェル， スコット エー．
  • ビューエル， ジョン

Assignees

  • ニューリックス セラピューティクス，インコーポレイテッド
  • ギリアード サイエンシーズ， インコーポレイテッド

Dates

Publication Date
20260512
Application Date
20210505
Priority Date
20200506

Claims (20)

  1. Structure of formula (Ic) A compound having or a pharmaceutically acceptable salt thereof, Here, L is a linker moiety having 2 to 24 continuously covalently bonded atoms of a length selected from the group consisting of C, O, N, and S, and LHM is a ligase harness moiety, which is a compound or pharmaceutically acceptable salt thereof that targets CRBN or VHL.
  2. L, And in the formula, t is 0, 1, 2, 3, 4, 5, 6, or 7, q is 0, 1, 2, 3, 4, 5, 6, or 7, L1 is a direct bond, -C(O)NH-, or -C(O)-, L2 is -C(O)NH-, -O-, or -NH-. The compound according to claim 1.
  3. L has the following structure The compound according to claim 2, having one of the above.
  4. L, And in the formula, w is 1, 2, or 3, v is 1 or 2, p is 1, 2, 3, 4, or 5, Y1 is a direct bond, -( CH2 ) p- , or -O-, Y2 is a direct bond, -( CH2 ) p- , -C(O)-, or -C(O) -CH2- , X3 and X4 are independently N or C(R), where R is H or C1-3 alkyl. L4 is either a direct bond, -NH-, -NHC(O)-, or L4 is The compound according to claim 1.
  5. L has the following structure The compound according to claim 4, having one of the above.
  6. L has the following structure The compound according to claim 1, which is one of the following.
  7. The LHM targets CRBN, and has the structure of formula (Id). A compound according to any one of claims 1 to 6 having [in the formula, W is -C( Rg )- or -N-, Z1 is -C(O) - , -C(S)-, -C(NR g )-, -C(R g ) ²- , -C(R g ) ²- C(O)-, -C(O)-N(R g )-, -CR g =CR g- , -C(R g ) =N-, -C(R g ) ² -C(S)-, or -C(R g ) ² -C(R g ) ²- , and q is 0, 1 or 2, R g is hydrogen or C1-6 alkyl, Ra is C1-6 alkyl, halo, halo- C1-6 alkyl, -N( Rg ) 2 , CN, nitro, -O- C1-4 alkyl, or hydroxyl.
  8. The LHM has the following structure The compound according to claim 7, having one of the above.
  9. The LHM targets VHL and has the structure of formula (Ie) or (If). A compound according to any one of claims 1 to 6 having [in the formula, p is either 0 or 1, R j is an unsubstituted 5-6 member heteroaryl or a 5-6 member heteroaryl substituted with 1-3 R ks . Each R k is independently a halo, oxo, -CN, -OH, C1-6 alkyl, C3-8 cycloalkyl, or -O- C1-6 alkyl. Each Re is independently hydrogen, C1-6 alkyl, or C3-8 cycloalkyl. R b is hydrogen or hydroxyl, R c is -C(O)R f , R f is an unsubstituted C1-6 alkyl or a C1-6 alkyl substituted with a halo or -CN or an unsubstituted C3-8 cycloalkyl or a C3-8 cycloalkyl substituted with a halo or -CN , and R g is hydrogen .
  10. The LHM has the following structure The compound according to claim 9, having one of the above.
  11. below: A compound according to claim 1, selected from the group consisting of the following.
  12. Structure of formula (IIc) A compound having or a pharmaceutically acceptable salt thereof, Here, L is a linker portion having 2 to 24 continuously covalently bonded atoms of a length selected from the group consisting of C, O, N, and S, and LHM is a ligase harness portion that targets CRBN or VHL. A compound or a pharmaceutically acceptable salt thereof.
  13. L, And in the formula, t is 0, 1, 2, 3, 4, 5, 6, or 7, q is 0, 1, 2, 3, 4, 5, 6, or 7, L1 is a direct bond, -C(O)NH-, or -C(O)-, L2 is -C(O)NH-, -O-, or -NH-. The compound according to claim 12.
  14. The compound according to claim 13, wherein t is 0, q is 5 or 7, L1 is -C(O)NH-, and L2 is -O- or -NH-.
  15. The aforementioned LHM targets VHL, and has the structure of formula (If). A compound according to any one of claims 12 to 14 having [in the formula, p is either 0 or 1, R j is an unsubstituted 5-6 member heteroaryl or a 5-6 member heteroaryl substituted with 1-3 R ks . Each R k is independently a halo, oxo, -CN, -OH, C1-6 alkyl, C3-8 cycloalkyl, or -O- C1-6 alkyl. Each Re is independently hydrogen, C1-6 alkyl, or C3-8 cycloalkyl. R b is hydrogen or hydroxyl, R c is -C(O)R f , where R f is an unsubstituted C1-6 alkyl or a C1-6 alkyl substituted with a halo or -CN, or an unsubstituted C3-8 cycloalkyl or a C3-8 cycloalkyl substituted with a halo or -CN , and R g is hydrogen .
  16. The aforementioned LHM is one of the following structures The compound according to claim 15, having the following characteristics.
  17. The LHM targets CRBN, and has the structure of formula (Id). A compound according to any one of claims 12 to 14 having [in the formula, W is -C( Rg )- or -N-, Z1 is -C(O) - , -C(S)-, -C(NR g )-, -C(R g ) ²- , -C(R g ) ²- C(O)-, -C(O)-N(R g )-, -CR g =CR g- , -C(R g ) =N-, -C(R g ) ² -C(S)-, or -C(R g ) ² -C(R g ) ²- , and q is 0, 1 or 2, R g is hydrogen or C1-6 alkyl, Ra is C1-6 alkyl, halo, haloC1-6 alkyl, -N( Rg ) 2 , CN, nitro, hydroxyl, or -O- C1-4 alkyl.
  18. The compound according to claim 17, wherein W is -CH- and Z1 is -C(O)-, -CH2- , -CH2 -C(O)-, or -CH=CH-.
  19. The aforementioned LHM is one of the following structures The compound according to claim 18, having the following characteristics.
  20. below: A compound according to claim 12, selected from the above.

Description

Cross-reference of related applications: This application claims priority to U.S. Provisional Application No. 63/021,045, filed 6 May 2020, which is incorporated herein by reference in its entirety. Background Technology The present invention provides a novel bifunctional compound for proteolytic degradation of hematopoietic precursor kinase (HPK1), and a method for treating HPK1-modulated diseases. Description of Related Technologies: Cancer immunology utilizes antibodies that are inhibitors of immune checkpoint receptors CTLA4, PD-1, and PD-L1. Targeted disruption of these checkpoint pathways releases immune cells from critical regulatory pathways, enabling a boost in the immune response against cancer cells. While current therapies utilizing these antibodies have shed light on significant and persistent responses to many different cancers, they have also been highlighted by low overall response rates (<25%). Improvements in these response rates have been achieved through combinations of checkpoint blockade with other immunoactivators or cell-based therapies. STE20 serine/threonine kinase 1, a hematopoietic precursor kinase belonging to the germinal center kinase family, regulates the function of diverse immune populations, including T cells, B cells, and dendritic cells (Hu et al., Gens Dev, 1996; Alzabin et al., J Immunol 2009). In T cells, HPK1 acts as a negative regulator of T cell receptor (TCR) signaling by phosphorylating SLP76 on serine 376, thereby inducing association between SLP76 and the 14-3-3 protein and leading to the dissociation of the signaling complex (Di Bartolo et al., JEM 2007) (Liou et al., Immunity 2000; Sauer et al., JBC 2001). Further supporting the role of HPK1 as a negative regulator of TCR signaling, mouse HPK1-deficient T cells or HPK1 kinase-inactive mutant T cells exhibit enhanced ERK1/2 activation and effector cytokine secretion compared to their wild-type counterparts upon TCR activation (Shui et al., Nat Immunol 2007, Hernandez et al., Cell Reports 2018). Therefore, targeting HPK1 degradation can provide therapeutic opportunities in enhancing antitumor immunity and increasing the response to checkpoint receptor blockade. Hu et al., Gens Dev, 1996, Alzabin et al., J Immunol 2009Shui et al., Nat Immunol 2007, Hernandez et al., Cell Reports 2018 Detailed Description Specific degradation of HPK1 has been achieved by using heterobifunctional small molecules to recruit HPK1 to a ubiquitin ligase, thereby promoting ubiquitination and proteasome degradation of HPK1. Accordingly, the Specified Bifunctional Compounds are provided, each comprising an HPK1 binder covalently conjugated via a linker to a ligase harness portion (LHM) for targeting a ubiquitin ligase. Preferably, the LHM targets cereblon (CRBN) or von Hipper-Lindau (VHL) protein, which are substrate-recognizing subunits of two universally expressed, biologically important kaline ring E3 ubiquitin ligase complexes. See, for example, WO2019/099926, WO2020/023851, and U.S. Patent Application Publication No. 2019/0192668. One embodiment is a bifunctional compound of formula (I). or provides a pharmaceutically acceptable salt, isotopic form, isolated stereoisomer, or mixture thereof [wherein, m is 0, 1, 2, 3, or 4. n is 0, 1, 2, 3, 4, 5, or 6. A is a C3-7 monocyclic cycloalkyl ring, or a 4-6 member monocyclic heterocyclyl ring having one or two heteroatoms independently selected from N, O, and S. L is a linker moiety having 2 to 24 continuously covalently bonded atoms of a length selected from the group consisting of C, O, N, and S. LHM is the ligature harness part. R11 is, i) selected from the group consisting of -OH, halogens, oxo, C1-3 alkyl, and C1-3 alkoxy, or ii) a 4-6 member monocyclic heterocyclil having one or two heteroatoms independently selected from N, O, and S (where the 4-6 member monocyclic heterocyclil is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogens, oxo, C1-3 alkyl, and C1-3 alkoxy), iii)-S(O) 2 C 1-6 alkyl, iv)-S(O) 2 C 3-7 monocyclic cycloalkyl, v) C1-6 alkyl groups optionally substituted with 1-3 groups independently selected from -CN, -OH , halogens, C1-3 alkoxys, and C3-7 monocyclic cycloalkyls, or vi) -C(O) R21 And, Each R12 is independently selected from -OH, halogen, C1-3 alkyl, and C1-3 alkoxy. R 21 is, i) H, ii) C3-7 monocyclic or cross-linked bicyclic cycloalkyls (where the C1-3 alkyl groups are optionally substituted with 1-3 groups independently selected from -OH, -OH, halogens, C1-3 alkyls, and C1-3 alkoxys), iii) A 4- to 6-membered monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S (where the 4- to 6-membered monocyclic heterocycline is optionally substituted with one to three groups independently selected from -CN, -OH, halogens, oxo, C1-3 alkyl, and C1-3 alkoxy), iv) A 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S (where the 5-6 member monocyclic heteroaryl