WO2018096525A2 - Composés hétéroaryle et utilisations associées - Google Patents

Composés hétéroaryle et utilisations associées Download PDF

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Publication number
WO2018096525A2
WO2018096525A2 PCT/IB2018/052089 IB2018052089W WO2018096525A2 WO 2018096525 A2 WO2018096525 A2 WO 2018096525A2 IB 2018052089 W IB2018052089 W IB 2018052089W WO 2018096525 A2 WO2018096525 A2 WO 2018096525A2
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Prior art keywords
deuterium
compound
formula
hydrogen
compounds
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PCT/IB2018/052089
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WO2018096525A3 (fr
Inventor
Peter Anthony CICALA
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Celgene Corporation
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Priority to PCT/IB2018/052089 priority Critical patent/WO2018096525A2/fr
Publication of WO2018096525A2 publication Critical patent/WO2018096525A2/fr
Publication of WO2018096525A3 publication Critical patent/WO2018096525A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention provides compounds, and compositions thereof, useful as inhibitors of protein kinases.
  • Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).
  • protein kinases mediate intracellular signaling by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli.
  • Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H 2 O 2 ), cytokines (e.g., interleukin-1 (IL-1) and tumor necrosis factor a (TNF-a)), and growth factors (e.g., granulocyte macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF)).
  • IL-1 interleukin-1
  • TNF-a tumor necrosis factor a
  • growth factors e.g., granulocyte macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF)
  • An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.
  • R 7 , R 7' , R 8a , R 8a' , R 8 , R 8 ' , R 9a , R 9a' , R 9 , R 9 ' , R xa , R x , R x ' , R xc , R ya , R ya' , R y andR y ' is as defined herein.
  • Compounds of the present invention are useful for treating a variety of diseases, disorders or conditions, associated with abnormal cellular responses triggered by protein kinase-mediated events. Such diseases, disorders, or conditions include those described herein.
  • Compounds provided by this invention are also useful for the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors.
  • the present invention provides certain compounds, and compositions thereof, useful as protein kinase inhibitors.
  • the present invention provides certain 2,4-disubstituted pyrimidine compounds which inhibit activity of one or more protein kinases, including Janus kinase ("JAK").
  • JNK Janus kinase
  • R 8 ' , R 9a , R 9a' , R 9 , R 9 ' , R xa , R x , R x ' , R xc , R ya , R ya' , R y andR y ' is independently selected from hydrogen or deuterium;
  • R 7 , R 7' , R 8a , R 8a' , R 8 , R 8 ' , R 9a , R 9a' , R 9 , R 9 ' , R xa , R x , R x ' , R xc , R ya , R ya' , R y andR y ' is deuterium.
  • the present invention provides a compound of Formula I, wherein the compound is a co
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci_ 4 alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • an inhibitor is defined as a compound that binds to and /or inhibits the target protein kinase with measurable affinity.
  • an inhibitor has an IC 50 and/or binding constant of less about 50 ⁇ , less than about 1 ⁇ , less than about 500 nM, less than about 100 nM, or less than about 10 nM.
  • measurable affinity and “measurably inhibit,” as used herein, means a measurable change in JAK activity between a sample comprising a compound of the present invention, or composition thereof, and an equivalent sample comprising JAK, in the absence of said compound, or composition thereof.
  • Deuterium (D or 2 H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as a mixture of the isotopes 1H (hydrogen or protium), D ( 2 H or deuterium), and T ( 3 H or tritium).
  • hydrogen in hydrogen-containing chemical compounds actually represents a mixture of hydrogen and about 0.015% deuterium.
  • deuterium-enriched compounds are prepared via synthesis utilizing appropriately enriched starting materials.
  • deuterium-enriched or deuterium enrichment refer to a compound, or a particular site of said compound, which comprises deuterium in an amount that is greater than its natural isotopic abundance (0.015%).
  • the present invention provides compounds comprising deuterium at a given site, wherein the percentage or level of deuterium incorporation is greater than its natural isotopic abundance. [0019] According to one aspect, the present invention provides a compound of Formula I:
  • R 2 is R 2c ;
  • R 8 ' , R 9a , R 9a' , R 9 , R 9 ' , R xa , R x , R x ' , R xc , R ya , R ya' , R y andR y ' is independently selected from hydrogen or deuterium;
  • R 7 , R 7' , R 8a , R 8a' , R 8 , R 8 ' , R 9a , R 9a' , R 9 , R 9 ' , R xa , R x , R x ' , R xc , R ya , R ya' , R y andR y ' is deuterium.
  • R la is deuterium. In some embodiments, R l is deuterium. In some embodiments, R lc is deuterium. In some embodiments, each of R la , R l , and R lc is deuterium. In some embodiments, each of R la , R l , and R lc is deuterium and each of R 2a , R 2 , T?2C ?3b ?3c ?4 ?4' ?4" ?5 T?6 ?6' ?7 TJV x?8a T?8a' ?8b ?8b' ?9a ?9a' ?9b ?9b' ?xa x j xb
  • R x ' , R xc , R ya , R ya' , R y andR y ' is hydrogen.
  • R 2a is deuterium. In some embodiments, R 2 is deuterium. In some embodiments, R 2c is deuterium. In some embodiments, each of R 2a , R 2 , and R 2c is deuterium. In some embodiments, each of R 2a , R 2 , and R 2c is deuterium and each of R la , R l ,
  • R x ' , R xc , R ya , R ya' , R y andR y ' is hydrogen.
  • R 3a is deuterium. In some embodiments, R 3 is deuterium. In some embodiments, R 3c is deuterium. In some embodiments, each of R 3a , R 3 , and R 3c is deuterium. In some embodiments, each of R 3a , R 3 , and R 3c is deuterium and each of R la , R l ,
  • R x ' , R xc , R ya , R ya' , R y andR y ' is hydrogen.
  • each of R la , R l , R lc , R 2a , R 2 , R 2c , R 3a , R 3 , and R 3c is deuterium.
  • R 4 is deuterium. In some embodiments, R 4 is deuterium. In some embodiments, R 4 is deuterium. In some embodiments, R 4 is deuterium. In some embodiments, each of each of R 4 , R 4 , and R 4 is deuterium and each of R la , R l , R lc , R 2a , R 2 , R 2c , R 3a , R 3 , R 3c , R 5 , R 6 , R 6' , R 7 , R 7' , R 8a , R 8a' , R 8 , R 8 ' , R 9a , R 9a' , R 9 , R 9 ' , R xa , R x , R x ' , R xc , R ya , R ya' , R y andR y ' is hydrogen.
  • R 6 is deuterium. In some embodiments, R 6 is deuterium. In some embodiments, each of R 6 and R 6 is deuterium. In some embodiments, each of R 6 and R 6 is deuterium and each of R la , R l , R lc , R 2a , R 2 , R 2c , R 3a , R 3 , R 3c , R 4 , R 4' , R 4" , R 5 , R 7 , R 7' , R 8a , R 8a' , R 8 , R 8 ' , R 9a , R 9a' , R 9 , R 9 ' , R 9 , R 9 ' , R xa , R x , R x ' , R xc , R ya , R ya' , R y andR y ' is hydrogen.
  • R 7 is deuterium. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is deuterium.
  • each of R and R is deuterium. In some embodiments, each of R and R is deuterium and each of R la , R l , R lc , R 2a , R 2 , R 2c , R 3a , R 3 , R 3c , R 4 , R 4' , R 4" , R 5 , R 6 , R 6' , R 8a , R 8a' , R 8 , R 8 ' , R 9a , R 9a' , R 9 , R 9 ' , R 9 , R 9 ' , R xc , R ya , R ya' , R y andR y ' is hydrogen.
  • R 8a is deuterium. In some embodiments, R 8a is deuterium. In some embodiments, R 8 is deuterium. In some embodiments, R 8 is deuterium. In some embodiments, each of R 8a and R 8a is deuterium. In some embodiments, each of R 8 and R 8 is deuterium. In some embodiments, each of R 8a , R 8a , R 8 , and R 8 is deuterium and each of R la ,
  • R x ' , R xc , R ya , R ya' , R y andR y ' is hydrogen.
  • R 9a is deuterium. In some embodiments, R 9a is deuterium. In some embodiments, R 9 is deuterium. In some embodiments, R 9 is deuterium. In some embodiments, each of R 9a and R 9a is deuterium. In some embodiments, each of R 9 and R 9 is deuterium.
  • each of R 9a , R 9a , R 9 , and R 9 is deuterium and each of R la , x j lb ?lc ?2a ?2b ?2 ?3a ?3b ?3 ?4 4' ?4" ?5 ?6 6' ?7 V ?8a r j Sa' ?8b ?8b' x j xa x j xb
  • R x ' , R xc , R ya , R ya' , R y andR y ' is hydrogen.
  • R xa is deuterium. In some embodiments, R xa is deuterium and each of R la , R l , R lc , R 2a , R 2 , R 2c , R 3a , R 3 , R 3c , R 4 , R 4' , R 4" , R 5 , R 6 , R 6' , R 7 , R 7' , R 8a , R 8a' , R 8 , R 8 ' , R 9a , R 9a' , R 9 , R 9 , R 9 ' , R x , R x ' , R xc , R ya , R ya' , R y andR y ' is hydrogen.
  • R x is deuterium. In some embodiments, R x is deuterium. In some embodiments, each of R x and R x is deuterium and each of R la , R l , R lc , R 2a , R 2 , R 2c , R 3a ,
  • R y and R y is hydrogen.
  • R ya is deuterium. In some embodiments, R ya is deuterium. In some embodiments, each of R ya and R ya' is deuterium and each of R la , R l , R lc , R 2a , R 2 , R 2c , R 3a , n b 3 4 4' T?4" 5 TJ6 TJ6' TJV V x j 8a r?9a x j 9a' x j xa x j xb r j xb' , K
  • R y , and R y is hydrogen.
  • R y is deuterium. In some embodiments, R y is deuterium. In some embodiments, each of R y and R y ' is deuterium and each of R la , R l , R lc , R 2a , R 2 , R 2c , R 3a ,
  • R ya , and R ya' is hydrogen.
  • each of R 4 , R 4 , R 4 is hydrogen and each of R 1 , R 2 and R 3 is -C3 ⁇ 4. Accordingly, in some embodiments, the present invention provides a compound of Formula Il-a:
  • each of R 6 , R 6' , R 7 , R 7' , R 8a , R 8a' , R 8 , R 8 ' , R 9a , R 9a' , R 9 , R 9 ' , R xa , R x , R x ' , R xc , R ya , R ya' , R y and R y is independently selected from hydrogen or deuterium;
  • R 6 , R 6' , R 7 , R 7' , R 8a , R 8a' , R 8 , R 8 ' , R 9a , R 9a' , R 9 , R 9 ' , R xa , R x , R x ' , R xc , R ya , R ya' , R y andR y ' is deuterium.
  • each of R 4 , R 4 , R 4 is hydrogen and each of R 1 , R 2 and R 3 is -CH 3 . Accordingly, in some embodiments, the present invention provides a compound of Formula Ill-a:
  • each of R 6 , R 6' , R 7 , R 7' , R 8a , R 8a' , R 8 , R 8 ' , R 9a , R 9a' , R 9 , R 9 ' , R xa , R x , R x ' , R xc , R ya , R ya' , R y and R y is independently selected from hydrogen or deuterium.
  • each of R 4 , R 4 , R 4 is hydrogen and each of R 1 , R 2 and R 3 is -CD 3 . Accordingly, in some embodiments, the present invention provides a compound of Formula Il-b or Formula Ill-b:
  • each of R 6 , R 6' , R 7 , R 7' , R 8a , R 8a' , R 8 , R 8 ' , R 9a , R 9a' , R 9 , R 9 ' , R xa , R x , R x ' , R xc , R ya , R ya' , R y and R y is independently selected from hydrogen or deuterium.
  • each of R 4 , R 4 , R 4 is deuterium and each of R 1 , R 2 and R 3 is -C3 ⁇ 4. Accordingly, in some embodiments, the present invention provides a compound of Formula II-c or Formula III-c:
  • each of R 6 , R 6' , R 7 , R 7' , R 8a , R 8a' , R 8 , R 8 ' , R 9a , R 9a' , R 9 , R 9 ' , R xa , R x , R x ' , R xc , R ya , R ya' , R y and R y is independently selected from hydrogen or deuterium.
  • each of R 4 , R 4 , R 4 is deuterium and each of R 1 , R 2 and R 3 is -CD 3 . Accordingly, in some embodiments, the present invention provides a compound of Formula Il-d or Formula Ill-d:
  • each of R 66 ,, R 6 ', R 7 R 7 ', R 8a , R 8a ', R 8 , R 8 ', R 9a , R 9a ', R 9 , R 9 ', R xa , R x , R x ', R xc , R ya , R ya ', R y and R y is independently selected from hydrogen or deuterium
  • Table 1 sets forth compounds of Formula Il-a, Il-b, II-c, and II-d wherein each of R 6 , R 6 , R 7 and R 7 is hydrogen.
  • Table 2 sets forth compounds of Formula Il-a, Il-b, II-c, and ⁇ - d wherein each of R 6 and R 6 is hydrogen and each of R 7 and R 7 is deuterium.
  • Table 3 sets forth compounds of Formula Il-a, Il-b, II-c, and II-d wherein each of R 6 and R 6 is deuterium and each of R 7 and R 7 is hydrogen.
  • Table 4 sets forth compounds of Formula Il-a, Il-b, II-c, and II- d wherein each of R 6 , R 6 , R 7 and R 7 is deuterium. It will be appreciated that each row in Table 1 , Table 2, Table 3, and Table 4 represents four discrete compounds. For example, row 1 in Table 1 represents compounds II-a-1, ⁇ -b-l, II-c-1 and II-d-1:
  • R 7 is hydrogen

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Abstract

La présente invention concerne des composés, des compositions pharmaceutiquement acceptables de ces composés, et des méthodes d'utilisation correspondantes.
PCT/IB2018/052089 2018-03-27 2018-03-27 Composés hétéroaryle et utilisations associées WO2018096525A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109232440A (zh) * 2018-01-16 2019-01-18 深圳市塔吉瑞生物医药有限公司 用于抑制激酶活性的二苯氨基嘧啶类化合物

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015117053A1 (fr) * 2014-01-31 2015-08-06 Dana-Farber Cancer Institute, Inc. Dérivés de diaminopyrimidine benzènesulfone et leurs utilisations
US10316049B2 (en) * 2015-12-17 2019-06-11 Gilead Sciences, Inc. Tank-binding kinase inhibitor compounds

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109232440A (zh) * 2018-01-16 2019-01-18 深圳市塔吉瑞生物医药有限公司 用于抑制激酶活性的二苯氨基嘧啶类化合物
WO2019140953A1 (fr) * 2018-01-16 2019-07-25 深圳市塔吉瑞生物医药有限公司 Composé de diphénylaminopyrimidine inhibant l'activité kinase
EP3578555A4 (fr) * 2018-01-16 2019-12-11 Shenzhen Targetrx, Inc. Composé de diphénylaminopyrimidine inhibant l'activité kinase
CN111892543A (zh) * 2018-01-16 2020-11-06 深圳市塔吉瑞生物医药有限公司 用于抑制激酶活性的二苯氨基嘧啶类化合物
JP2021510717A (ja) * 2018-01-16 2021-04-30 深▲チェン▼市塔吉瑞生物医薬有限公司Ｓｈｅｎｚｈｅｎ ＴａｒｇｅｔＲｘ， Ｉｎｃ． キナーゼ活性を阻害するためのジフェニルアミノピリミジン系化合物
US11384069B2 (en) 2018-01-16 2022-07-12 Shenzhen Targetrx, Inc. Diphenylaminopyrimidine compound for inhibiting kinase activity
JP7169005B2 (ja) 2018-01-16 2022-11-10 深▲チェン▼市塔吉瑞生物医薬有限公司 キナーゼ活性を阻害するためのジフェニルアミノピリミジン系化合物

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