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EP-4735431-A2 - MK2 INHIBITORS AND METHODS OF MAKING AND USING THE SAME

EP4735431A2EP 4735431 A2EP4735431 A2EP 4735431A2EP-4735431-A2

Abstract

The present disclosure relates generally to certain compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions. The compounds and compositions provided herein may be used for the treatment or prevention of an autoimmune disease and/or inflammatory condition, including rheumatoid arthritis.

Inventors

  • ANESINI, Jason E.
  • SCHRIER, ADAM J.
  • VAN VELDHUIZEN, JOSHUA J.
  • BACHMAN, JAMES L.
  • BURCKLE, Alexander J.
  • CLARK, CHRISTOPHER T.
  • JONES, Kerry E.
  • KASUN, Zachary A.
  • LOYER-DREW, JENNIFER A.
  • NOTTE, GREGORY T.
  • SANGI, Michael S.

Assignees

  • GILEAD SCIENCES, INC.

Dates

Publication Date
20260506
Application Date
20240626

Claims (20)

  1. 1. A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein nng is C 6 .io aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl, or 4- to 10- membered heterocyclyl; each R 1 is independently halogen, -CD 3 , C 1-6 alkyl, C 2 _6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C 6 .io aryl, or 5- to 10-membered heteroaryl, -N(R 1a )(R 1a ), -CN, -OR 1a , -C(O)OR 1a , -C(O)R 1a , -C(O)N(R 1a XR 1a ), -N(R 1a )C(O)-R 1a , -N(R 1a )C(O)O-R 1a , -N(R 1a )C(O)N(R 1a )(R 1a ), -N=S(O)(R 1a )(R 1a ), -N(R 1a )S(O) 2 (R 1a ), -N(R 1a )S(O) 2 N(R 1a XR 1a ), -N(R 1a )S(O)2O(R 1a ), -OC(O)R 1a , -OC(O)OR 1a , -OC(O)N(R 1a )(R 1a ), -SR 1a , S(O)R 1a , -SF 5 , -S(OXNR 1a )R 1a , -S(NR 1a XNR 1a )R 1a , -S(O)(NR 1a )N(R 1a XR 1a ), -S(O)(N-CN)R 1a , -S(O) 2 R 1a , -S(O) 2 N(R 1a XR 1a ), -C(O)N(R 1a )S(O) 2 R 1a , -S(O) 2 N(R 1a )C(O)R 1a , or -P(O)(R 1a ) 2 , or two R 1 groups taken together with two adjacent atoms of ring to which they are attached form a C 3-10 cycloalkyl or 4- to 10-membered heterocyclyl, wherein each alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one to three halogen and is further optimally substituted with one to three R lg ; each R 1a is independently H, C 1-6 alkyl, C 3 _ 6 alkenyl, C 3 _6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, two R 1a groups taken together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one to three R 1i ; each R 1g is independently -CN, C 1-6 alkyl, C 2 _6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, -OR lh , -N(R lh XR lh ), -C(O)N(R lh XR lh ), -N(R lh )C(O)- R lh , -N(R lh )C(O)O-R lh , -N(R lh )C(O)N(R lh )(R lh ), -OC(O)N(R lh XR lh ), -N(R 1a )S(O) 2 (R 1a ), -S(O) 2 R lh , or -S(O) 2 N(R 1a XR 1a ), wherein each alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one to three R 1i ; each R lh is independently H, C 1-6 alkyl, C 2 _6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, or two R lh groups taken together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclyl, wherein each alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted with one to three R 11 ; each R 11 is independently halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3 .6 cycloalkyl, C 3.6 halocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or -O(C 3.6 cycloalkyl); L is a bond, -O-, -NR La -, -C(O)NR La -, -C(O)-, or Ci. 3 alkylene, wherein the alkylene is optionally substituted with one to three R Lb ; each R La is independently H, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-10 cycloalkyl; each R Lb is independently halogen, -OH, -OCH 3 , -NH 2 , or -CN ; each R Y is independently halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; or R Y and R 1 join together to form a C 3.6 cycloalkyl or 4- to 6-membered heterocyclyl, wherein each cycloalkyl and heterocyclyl is optionally substituted with one to three halogen; X is CR 3 or N; R 2 is H, halogen, C 1-6 alkyl, or C 3.6 cycloalkyl, wherein each alkyl and cycloalkyl is optionally substituted with one to three halogen; R 3 is H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or -O(C 3 .6 cycloalkyl); R 4 is H, -CN, C 1-6 alkyl, C 2-6 alkynyl, or C 3 .io cycloalkyl, wherein each alkyl, alkynyl, and cycloalkyl is optionally substituted with one to three R 4al ; each R 4al is independently halogen, -CN, -OR 4a2 , or -NR 4a2 R 4a2 ; each R 4a2 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3.6 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)O(C1. 6 alkyl), or -C(O)N(R 4a3 ) 2 ; each R 4a3 is independently C 1-6 alkyl; is C 6-10 aryl or 5- to 10-membered heteroaryl; each R 5 is independently halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, -OR 5al , -N(R 5al ) 2 , -N(R 5al )C(O)(R 5al ), -C(O)N(R 5al ) 2 , -N(R 5al )S(O) 2 (R 5al ), -SO 2 N(R 5al ) 2 , -SO 2 (R 5al ), or -SR 5al , wherein each alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with one to three R 5bl ; each R 5al is independently H, C 1-6 alkyl, C 3-10 cycloalkyl, or 4- to 10-membered heterocyclyl, wherein each alkyl, cycloalkyl, and heterocyclyl is optionally substituted with one to three R 5b3 ; each R 5bl is independently halogen, -CN, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3 .io cycloalkyl, 4- to 10- membered heterocyclyl, -OR 5132 , or -N(R 5b2 ) 2 , wherein each alkyl, alkynyl, haloalkyl, cycloalkyl, and heterocycle is optionally substituted with one to three R 5b3 ; each R 5b2 is independently H, Ci- 6 alkyl, or C 3-10 cycloalkyl, wherein each alkyl and cycloalkyl is optionally substituted with one or two oxo and is further optionally substituted with one to three R 5b3 ; each R 5b3 is independently halogen, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, Ci- 6 alkoxy, C 1-6 haloalkoxy, C 3.6 cycloalkyl, C 3.6 halocycloalkyl, or -O(C 3.6 cycloalkyl); ring is C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-8 cycloalkyl, or 4- to 10- membered hetero cyclyl; each R 6 is independently oxo, halogen, -NO 2 , -N 3 , -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 .io cycloalkyl, 4- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, -OR 6al , -N(R 6al ) 2 , -N(R 6al ) 3 + , -C(O)R 6al , -C(O)OR 6al , -C(O)N(R 6al ) 2 , -N(R 6al )C(O)R 6al , -N(R 6al )C(O)OR 6al , N(R 6al )C(O)N(R 6al ) 2 , -N=S(O)(R 6al ) 2 , -N=S(O)N(R 6al ) 2 R 6al , -N(R 6al )S(O) 2 (R 6al ), -N(R 6al )S(O) 2 N(R 6al ) 2 , -N(R 6al )S(O) 2 O(R 6al ), -OC(O)R 6al , -OC(O)OR 6al , -OC(O)N(R 6al ) 2 , -Si(R 6al ) 3 , -SR 6al , -S(O)R 6al , -SF 5 , -S(O)(NR 6al )R 6al , -S(NR 6al ) 2 R 6al , -S(O)(NR 6al )N(R 6al ) 2 , -S(O)(N-CN)R 6al , -S(O) 2 R 6al , -S(O) 2 N(R 6al ) 2 , -C(O)N(R 6al )S(O) 2 R 6al , -S(O) 2 N(R 6al )C(O)R 6al , or -P(O)(R 6al ) 2 , or two R 6 groups taken together with two adjacent ( C ) atoms of ring ' to which they are attached form a C 3-10 cycloalkyl or a 4- to 10-membeied heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one to three halogen and is further optionally substituted with one to three R 6bl ; each R 6al is independently H, C 1-6 alkyl, C 3.6 alkenyl, C 3.6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, or two R 6al groups taken together with the atom or atoms to which they are attached form a 4- to 10-membered heterocyclyl, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one to three R 6bl ; each R 6bl is independently oxo, halogen, -NO 2 , -N 3 , -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, -OR 6b2 , -C(O)-R 6b2 , -C(O)O-R 6b2 , -C(O)N(R 6b2 ) 2 , -N(R 6b2 ) 2 , -N(R 6b2 ) 3 + , -N(R 6b2 )C(O)R 6b2 , -N(R 6b2 )C(O)OR 6b2 , -N(R 6b2 )C(O)N(R 6b2 ) 2 , -N=S(O)(R 6b2 ) 2 , -N(R 6b2 )S(O) 2 (R 6b2 ), -N(R 6b2 )S(O) 2 N(R 6b2 ) 2 , -N(R 6b2 )S(O) 2 O(R 6b2 ), -OC(O)R 6b2 , -OC(O)OR 6b2 , -OC(O)N(R 6b2 ) 2 , -Si(R 6b2 ) 3 , -SR 6b2 , -S(O)R 6b2 , -SF 5 , -S(O)(NR 6b2 )R 6b2 , -S(NR 6b2 ) 2 R 6b2 , -S(O)(NR 6b2 )N(R 6b2 ) 2 , -S(O)(N-CN)R 6b2 , -S(O) 2 R 6b2 , -S(O) 2 N(R 6b2 ) 2 , -C(O)N(R 6b2 )S(O)2R 6b2 , -S(O) 2 N(R 6b2 )C(O)R 6b2 , or -P(O)(R 6b2 ) 2 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one to three R 6cl ; each R 6b2 is independently H, C 1-6 alkyl, C 3.6 alkenyl, C 3.6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one to three R 6c2 ; each R 6cl and R 6c2 is independently oxo, halogen, -NO 2 , -N 3 , -CN, -OH, R 6dl , -O(R 6dl ), -OC(O)(R 6dl ), -NH 2 , -NH(R 6dl ), -N(R 6dl ) 2 , -C(O)(R 6dl ), -C(O)O(R 6dl ), -C(O)NH 2 , -C(O)NH(R 6dl ), -C(O)N(R 6dl ) 2 , -NHC(O)(R 6dl ), -NHC(O)O(R 6dl ), -NHC(O)NH(R 6dl ), -SH, -S(R 6dl ), -NHS(O)(R 6dl ), -N(R 6dl )(S(O)(R 6dl ), -S(O)N(R 6dl ) 2 , -S(O)(R 6dl ), -S(O)(NH)(R 6dl ), -S(O) 2 (R 6dl ), -S(O) 2 NH(R 6dl ), or -S(O) 2 N(R 6dl ) 2 ; each R 6dl is independently C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membeiedheterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl aryl, and heteroaryl is optionally substituted with one to three R 6el ; each R 6el is independently oxo, halogen, -NO 2 , -N 3 , -CN, -OH, -NH 2 , methyl, or halomethyl; wherein each heterocyclyl and heteroaryl independently has one to four ring heteroatoms each independently selected from N, O, and S; and m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3; and q is 0, 1, 2 or 3.
  2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is C 6-10 aryl or 5- to 10-membered heteroaryl.
  3. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring is R 1A is H or R 1 ; r is 0, 1, or 2; and s is 0 or 1.
  4. 4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring is
  5. 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, w herein each R 1 is independently halogen, -CD 3 , C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 6-membered heterocyclyl, - N(R 1a )(R 1a ), -CN, -OR 1a , -C(O)OR 1a , -C(O)N(R 1a )(R 1a ), -N(R 1a )C(O)-R 1a , -S(O) 2 N(R 1a )(R 1a ), - S(NR 1a )(O)(R 1a ), -N=S(O)(R 1a )(R 1a ), or two R 1 groups taken together with two adjacent atoms of ring to which they are attached form a 4- to 10-membered heterocyclyl, wherein each alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one to three halogen and is further optionally substituted with one to three R 1g .
  6. 6. The compound of any of claims 1-5, wherein R 1 or R 1A or both R 1 and R 1A are -CD 3 .
  7. 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, w herein ring is C 6-10 aryl.
  8. 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein ring is 5- to 10-membered heteroaryl.
  9. 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, w herein ring aryl.
  10. 10. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, w herein ring is 5- to 10-membered heteroaryl.
  11. 11. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein
  12. 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, or 3.
  13. 13. The compound, or a pharmaceutically acceptable salt thereof, selected from Table I or a pharmaceutically acceptable salt thereof.
  14. 14. A pharmaceutical composition comprising the compound of any one of claims 1 to 139, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  15. 15. The pharmaceutical composition of claim 14, further comprising one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof.
  16. 16. A method of inhibiting p38 MAP kinase activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 14 or 15.
  17. 17. A method of inhibiting MK2 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 14 or 15.
  18. 18. A method of treating a p38 MAP kinase-mediated disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 14 or 15.
  19. 19. A method of treating an MK2 -mediated disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 14 or 15.
  20. 20. A method of treating an autoimmune disorder, a chronic inflammatory disorder, an acute inflammatory disorder, an auto -inflammatory disorder, a fibrotic disorder, a metabolic disorder, a neoplastic disorder, a cardiovascular disorder, or a cerebrovascular disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 14 or 15.

Description

MK2 INHIBITORS AND METHODS OF MAKING AND USING THE SAME CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63/511,147, filed June 29, 2023, the contents of which is incorporated herein in its entirety. FIELD This disclosure relates generally to novel MK2 inhibiting compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions. In some embodiments, the novel MK2 inhibiting compounds provided herein may be used in the treatment of certain diseases and disorders, including, but not limited to, inflammatory conditions. BACKGROUND Mitogen-activated protein kinases (MAPK) are a conserved family of enzymes that relay and propagate external stimuli, using phosphorylation cascades to generate a coordinated cellular response to the environment. The MAPK are proline -directed serine/threonine-specific protein kinases that regulate cellular activities, such as gene expression, mitosis, differentiation, and cell survival/apoptosis. To date, four distinct classes of mammalian MAPK have been identified: the extracellular signaling kinases (ERK1 and 2), the c-junN-terminal kinase- 1 (JNK1-3), the p38 MAPK (p38a, P, y, and 6), and ERK5. The MAPK are activated by the dual phosphorylation of Thr and Tyr residues within a TXY activation motif by coordinated dual- specificity MAPKK, where X is Glu, Pro, and Gly in ERK, JNK, and p38 MAPK, respectively. MAPK are 60-70% identical to each other, yet differ in their activation loop sequences and sizes. The activation loop is adjacent to the enzyme-active site, and its phosphorylation allows the enzyme to reposition active-site residues into the optimal orientation for substrate binding and catalysis. Downstream substrates of MAPK include mitogen-activated protein -kinase-activated protein (MAPKAP) kinases and transcription factors, the phosphorylation of which, either directly or indirectly, regulates gene expression at several points, including transcription, nuclear export, and mRNA stability and translation. The cellular consequences of MAPK activation include inflammation, apoptosis, differentiation, and proliferation. Distinct genes encode four p38 MAPK in humans: p38a, P, y, and 6. Significant amino acid sequence homology is observed among the 4 isoforms, with 60 -75 overall sequence identity and > 90% identity within the kinase domains. Tissue- selective expression is observed, with p38y found predominantly in skeletal muscle, p386 in the testes, pancreas, and small intestine. In contrast, p38a and are more ubiquitously expressed. p38 MAPK is the major isoform involved in the immune and inflammatory response. As such its function is critical for the production and activity of multiple proinflammatory cytokines, including TNFa, IL-1, IL-6, and IL-8, in cells such as macrophages, monocytes, synovial cells, and endothelial cells. p38 MAPK is also responsible for the induction of key inflammatory enzymes such as COX2 and iNOS, the major sources of eicosanoids and nitric oxide at sites of inflammation, respectively. Additionally, the p38 MAPK pathway regulates the expression of matrix metalloproteinases (MMP), including MMP2, MMP9, and MMP13. The use of selective and potent inhibitors has facilitated the discovery of several families of p38 MAPK substrates, including transcription facto is. MAPKAP kinases, and other enzymes. p38 MAPK can directly phosphorylate several transcription factors, such as myocyte - specific enhancer binding factor 2C (MEF2C), CHOP, peroxisome proliferator- activated receptor (PPAR) a, PPAR y co-activator 1 and p53. These transcription factors are involved in cellular functions such as apoptosis, gluconeogenesis, and synthesis of enzymes involved in fatty acid oxidation. p38 MAPK is also involved in the direct or indirect phosphorylation of enzyme substrates, such as cytosolic phospholipase A2, and the Cdc25 phosphatases, which are involved in the activation of cyclin -dependent protein kinase activity and cellcycle regulation. Therefore in addition to its role in the inflammatory response, p38 MAPK has other functions associated with normal and abnormal cell growth and survival as well as cellular function and homeostasis. The MAPKAP kinases (MK2, MK3, and PRAK) are selectively phosphorylated by p38 MAPK, while the phosphorylation of MSK1 /2, MNK1/2, and RSKb is catalyzed by both p38 MAPK and ERK. MK2, MK3, and PRAK, once phosphorylated and activated by p38 MAPK, share similar substrate specificities. All of these kinases can phosphorylate the small heat-shock protein Hsp27. Studies have shown that the PRAK- and MK3 -deficient mice do not display any resistance to endotoxic shock or a decrease in lipopolysaccharide-(LPS)-induced cytokine production. In contrast, MK2 -deficient mice show a resistance to endotoxic shock and an impaired inflammatory response, as well as a significant