[go: up one dir, main page]

WO2012022045A1 - Composés pyrrolopyrimidiniques et leurs utilisations - Google Patents

Composés pyrrolopyrimidiniques et leurs utilisations Download PDF

Info

Publication number
WO2012022045A1
WO2012022045A1 PCT/CN2010/076187 CN2010076187W WO2012022045A1 WO 2012022045 A1 WO2012022045 A1 WO 2012022045A1 CN 2010076187 W CN2010076187 W CN 2010076187W WO 2012022045 A1 WO2012022045 A1 WO 2012022045A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
alkyl
chosen
pharmaceutically acceptable
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2010/076187
Other languages
English (en)
Inventor
Wei-Guo Su
Wei Deng
Jinshui Li
Jianguo Ji
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hutchmed Ltd
Original Assignee
Hutchison Medipharma Ltd
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 Hutchison Medipharma Ltd filed Critical Hutchison Medipharma Ltd
Priority to PCT/CN2010/076187 priority Critical patent/WO2012022045A1/fr
Priority to US13/817,802 priority patent/US9346810B2/en
Priority to MX2013001970A priority patent/MX2013001970A/es
Priority to PCT/CN2011/078575 priority patent/WO2012022265A1/fr
Priority to SG2013009196A priority patent/SG187742A1/en
Priority to BR112013003864-0A priority patent/BR112013003864B1/pt
Priority to EP11817792.2A priority patent/EP2606051B1/fr
Priority to AU2011291185A priority patent/AU2011291185C1/en
Priority to RU2013104520/04A priority patent/RU2563644C2/ru
Priority to HK13107097.2A priority patent/HK1179953B/xx
Priority to NZ606751A priority patent/NZ606751A/en
Priority to JP2013524343A priority patent/JP5749341B2/ja
Priority to CA2808543A priority patent/CA2808543C/fr
Priority to KR1020137006853A priority patent/KR101541086B1/ko
Priority to CN201180040092.0A priority patent/CN103119045B/zh
Priority to PH1/2013/500299A priority patent/PH12013500299B1/en
Publication of WO2012022045A1 publication Critical patent/WO2012022045A1/fr
Anticipated expiration legal-status Critical
Priority to US15/134,223 priority patent/US10111875B2/en
Priority to US16/173,120 priority patent/US10369153B2/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to pharmaceutical field and, in particular, to certain pyrrolopyrimidine compounds, a composition containing said compound and the use thereof. These pyrrolopyrimidine compounds can effectively inhibit the activity of Jak kinases.
  • the Janus kinase (Jak) family is one of the well recognized families of non-receptor tyrosine kinases.
  • the Jak family may be activated by the binding of a cytokine to a cell surface receptor. Activated Jak may then initiate intracellular signaling cascades.
  • the Jak family and Signal Transducers and Activators of Transcription (STATs) are involved in the signaling pathways of a wide range of cytokines.
  • the Jak/STAT pathway has been shown to play a role in inflammatory diseases, such as, inflammatory diseases of the respiratory tract, multiple sclerosis, rheumatoid arthritis, asthma, inflammatory bowel disease, allergies, autoimmune diseases and other immune reactions.
  • the Jak/STAT pathway for example, JAK3/STAT, may also play a role in cancers.
  • Inhibitors of the Jak family are widely sought after and published for treatment or prevention of inflammatory diseases or cancers.
  • JAKs protein tyrosine kinases
  • JAK1 also known as Janus kinase- 1
  • JAK2 also known as Janus kinase-2
  • JAK3 also known as Janus kinase, leukocyte
  • JAKL also known as Janus kinase-2
  • TYK2 also known as protein-tyrosine kinase 2
  • the JAK proteins may range in size from 120 to 140 kDa and comprise seven conserved JAK homology (JH) domains; one of those can be a functional catalytic kinase domain, and another can be a pseudokinase domain potentially serving a regulatory function and/or serving as a docking site for STATs (Scott, Godshall et al. Clin.Diagn.Lab. Immunol, 9 (6): 1153-1159, 2002). While JAK1, JAK2 and TYK2 can be ubiquitously expressed, JAK3 is reported to be expressed, for example, in natural killer (NK) cells and not resting T cells, suggesting a role in lymphoid activation (Kawamura, M., D. W.
  • NK natural killer
  • the JAK/STAT pathway reportedly plays a role in the pathogenesis of the asthmatic response, chronic obstructive pulmonary disease, bronchitis, and other related inflammatory diseases of the lower respiratory tract.
  • the JAK/STAT pathway has also been implicated to play a role in inflammatory diseases/conditions of the eye including, but not limited to, ulceris, uveitis, scleritis, conjunctivitis, as well as chronic allergic responses. Therefore, inhibition of JAK kinases may have a beneficial role in the therapeutic treatment of those diseases.
  • Inhibition of the JAK kinases can be also envisioned to have therapeutic benefits in patients suffering from skin immune disorders such as psoriasis, and skin sensitization.
  • skin immune disorders such as psoriasis, and skin sensitization.
  • psoriasis vulgaris the most common form of psoriasis, it may have been generally accepted that activated T lymphocytes can be important for the maintenance of the disease and its associated psoriatic plaques (Gott Kunststoff, A. B., et al, Nat Rev Drug Disc, 4: 19-34, 2005).
  • Psoriatic plaques may contain a significant immune infiltrate, including leukocytes and monocytes, as well as multiple epidermal layers with increased keratinocyte proliferation.
  • Blocking signal transduction at the level of the JAK kinases may also hold promise for developing treatments for human cancers.
  • Cytokines of the interleukin 6 (IL-6) family which may activate the signal transducer gpl30, may be major survival and growth factors for human multiple myeloma (MM) cells.
  • the signal transduction of gpl30 is believed to involve JAK1, JAK2 and TYK2 and the downstream effectors STAT3 and the mitogen-activated protein kinase (MAPK) pathways.
  • JAK2 kinase activity and ERK2 and STAT3 phosphorylation may be inhibited. Furthermore, cell proliferation may be suppressed and apoptosis may be induced (De Vos, J., M. Jourdan, et al. "JAK2 tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogen-activated protein kinase (MAPK) and signal transducer and activator of
  • Myeloproliferative disorder may include polycythemia vera (PV), essential
  • thrombocythemia E, myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), and systemic mast cell disease (SMCD).
  • EMT thrombocythemia
  • MMM myeloid metaplasia with myelofibrosis
  • CML chronic myelogenous leukemia
  • CMML chronic myelomonocytic leukemia
  • HES hypereosinophilic syndrome
  • SMCD systemic mast cell disease
  • JAK2V617F kinase with a small molecule inhibitor ledto inhibition of proliferation of hematopoietic cells, suggesting that the JAK2 tyrosine kinase can be a potential target for pharmacologic inhibition in patients with PV, ET and MMM.
  • R 1 is chosen from hydrogen, alkyl, cycloalkyl and heterocycle
  • R is chosen from alkyl, aryl, cycloalkyl, heterocycle, heteroaryl, -C(0)R a , -C(0) R C c rR, d -S(0) n R f , and -S(0) n R c R d ,
  • R 1 and R 2 together with the N atom to which they are attached, form an optionally substituted 3- to 7-membered ring, which optionally comprises one or two additional heteroatoms and which is further optionally fused to an optionally substituted heteroaryl or optionally substituted aryl ring;
  • each of above said alkyl, aryl, cycloalkyl, heterocycle, heteroaryl in R 1 and R 2 is optionally substituted with one or more groups chosen from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -C(0)R a , -C(0)OR b , -CN, -C(0) R c R d , halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, - R c R d , - R e C(0)R a , - R e C(0)OR b , - R e C(0) R c R d , - R e S(0) n R f , - R e S(0) n R c R d , , - N0 2 , -OR b , -S(0)
  • n and n are independently chosen from 0, 1, and 2;
  • R a , R b , R c , R d , R e and R f are each independently chosen from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted haloalkyl, optionally substituted heteroaryl and optionally substituted heterocycle,
  • R c and R d with the nitrogen to which they are attached, combine to form a heterocycle ring, which is optionally substituted with one or more groups chosen from halo, lower alky, hydroxy, and lower alkoxy, wherein the heterocycle ring further optionally comprises one or two additional heteroatoms chosen from N, O and S;
  • each optionally substituted group above can be unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently chosen from C 1 -C4 alkyl, cycloalkyl, aryl, heterocycle, heteroaryl, aryl-Ci-C 4 alkyl-, heteroaryl-Ci-C 4 alkyl-, Ci-C 4 haloalkyl-, -OCi-C 4 alkyl, -OCi-C 4 alkylphenyl, -Ci-C 4 alkyl-OH, -Ci-C 4 alkyl-0-Ci-C 4 alkyl, -OCi-C 4 haloalkyl, halo, -OH, - H 2 , -Ci-C 4 alkyl- H 2 , -N(Ci-C 4 alkyl)(Ci-C 4 alkyl), - H(Ci-C 4 alkyl), -N(Ci-C 4
  • - HS0 2 (Ci-C 4 haloalkyl), in which each of phenyl, aryl, heterocycle, and heteroaryl is optionally substituted by one or more groups chosen from halo, cycloalkyl, heterocycle, Ci-C 4 alkyl, Ci-C 4 haloalkyl-, -OCi-C 4 alkyl, Ci-C 4 alkyl-OH, -Ci-C 4 alkyl-0-Ci-C 4 alkyl, -OCi-C 4 haloalkyl, cyano, nitro, - H 2 , -C0 2 H, -C(0)OCi-C 4 alkyl, -CON(Ci-C 4 alkyl)(Ci-C 4 alkyl), -CO H(Ci-C 4 alkyl), -CO H 2 , - HC(0)(Ci-C 4 alkyl), -N(Ci-C 4 alkyl)C(0)(Ci-C 4
  • R 1 is hydrogen or ethyl
  • R 2 is not acetyl
  • composition comprising at least one compound and/or at least one pharmaceutically acceptable salt described herein and at least one pharmaceutically acceptable carrier.
  • Also provided is a method of inhibiting the activity of at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2 comprising contacting at least one kinase with an effective amount of at least one compound and/or at least one pharmaceutically acceptable salt described herein.
  • a method of treating in a subject cancer responsive to inhibition of at least one kinase chosen from JAKl, JAK2, JAK3 and TYK2 comprising administering to the subject in need thereof an effective amount of at least one compound and/or at least one pharmaceutically acceptable salt described herein.
  • a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -CO H 2 is attached through the carbon atom.
  • alkyl refers to a straight or branched hydrocarbon, containing 1-10 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, w-propyl, / ' -propyl, «-butyl, / ' -butyl, and t-butyl.
  • “Lower alkyl” refers to a straight or branched
  • hydrocarbon containing 1-4 carbon atoms.
  • alkoxy is meant a straight or branched alkyl group of the indicated number of carbon atoms attached through an oxygen bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like.
  • Alkoxy groups will usually have from 1 to 6 carbon atoms attached through the oxygen bridge.
  • ""Lower alkoxy” refers to a straight or branched alkoxy, wherein the alkyl portion contains 1-4 carbon atoms.
  • alkenyl groups include, but are not limited to, vinyl, 2-propenyl, and 2-butenyl.
  • alkynyl herein refers to a C 2-10 straight or branched hydrocarbon, containing one or more C ⁇ C triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.
  • cycloalkyl refers to saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • the ring may be saturated or have one or more double bonds (i.e. partially unsaturated), but not fully conjugated, and not aryl, as defined herein.
  • bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and
  • tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.
  • aryl includes 5- and 6-membered carbocyclic aromatic rings fused to a 5- to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, provided that the point of attachment is at the carbocyclic aromatic ring.
  • Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals.
  • Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl" by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene" to the name of the
  • naphthylidene a corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
  • Aryl does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings are fused with a heterocyclic aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.
  • halo includes fluoro, chloro, bromo, and iodo
  • halogen includes fluorine, chlorine, bromine, and iodine
  • heteroaryl refers to aryl
  • 8- to 12-membered bicyclic rings containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring; and 11- to 14-membered tricyclic rings containing one or more, for example, from 1 to 4, or in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.
  • heteroaryl includes a 5- to 7-membered heterocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl ring.
  • bicyclic heteroaryl ring systems wherein only one of the rings contains one or more heteroatoms, the point of attachment may be at the heteroaromatic ring or the cycloalkyl ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • heteroaryl groups include, but are not limited to, (as numbered from the linkage position assigned priority 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4- pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 1-pyrazolyl, 2,3-pyrazolyl, 2,4-imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzoimidazolinyl, indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and 5,6,7,8- tetrahydroisoquinoline.
  • Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding "- idene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene.
  • Heteroaryl does not encompass or overlap with aryl as defined above.
  • Substituted heteroaryl also includes ring systems substituted with one or more oxide (- O " ) substituents, such as pyridinyl N-oxides.
  • heterocycle is meant a single aliphatic ring, usually with 3 to 7 ring atoms, containing at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms.
  • Heterocycle also refers to 5- to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S fused with 5- and 6-membered carbocyclic aromatic ring, provided that the point of attachment is at the heterocyclic ring.
  • the rings may be saturated or have one or more double bonds (i.e. partially unsaturated).
  • the heterocycle can be substituted by oxo.
  • the point of the attachment may be carbon or heteroatom in the heterocyclic ring.
  • a heterocycle is not a heteroaryl as defined herein.
  • Suitable heterocycles include, for example (as numbered from the linkage position assigned priority 1), 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, and 2,5-piperazinyl.
  • Morpholinyl groups are also contemplated, including 2-morpholinyl and 3 -morpholinyl (numbered wherein the oxygen is assigned priority 1).
  • Substituted heterocycle also includes ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1 -oxo- 1 -thiomorpholinyl and 1 , 1 -dioxo- 1 -thiomorpholinyl.
  • oxo moieties such as piperidinyl N-oxide, morpholinyl-N-oxide, 1 -oxo- 1 -thiomorpholinyl and 1 , 1 -dioxo- 1 -thiomorpholinyl.
  • substituted means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded.
  • a stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation as an agent having at least practical utility.
  • substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.
  • substituted with one or more groups refers to two hydrogens on the designated atom or group being independently replaced with two selections from the indicated group of substituents. In some embodiments, “substituted with one or more groups” refers to three hydrogens on the designated atom or group being independently replaced with three selections from the indicated group of substituents. In some embodiments, “substituted with one or more groups” refers to four hydrogens on the designated atom or group being independently replaced with four selections from the indicated group of substituents.
  • Compounds described herein include, but are not limited to, when possible, their optical isomers, such as enantiomers and diastereomerss, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers.
  • Racemates or mixtures of diastereomers can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (UPLC) column.
  • UPLC chiral high-pressure liquid chromatography
  • such compounds include Z- and E- forms (or cis- and trans- forms) of compounds with carbon- carbon double bonds.
  • the term "compound” is intended to include, to the extent they can be made without undue experimentation, all tautomeric forms of the compound.
  • Such compounds also include crystal forms including polymorphs and clathrates, to the extent they can be made by one of ordinary skill in the art without undue experimentation.
  • the term "salt" is intended to include all isomers, racemates, other mixtures, Z- and E-forms, tautomeric forms and crystal forms of the salt of the compound, to the extent they can be made by one of ordinary skill in the art without undue experimentation.
  • “Pharmaceutically acceptable salts” include, but are not limited to salts with inorganic acids, such as hydrochlorate, phosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2- hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate such as acetate, HOOC- (CH 2 ) n -COOH where n is 0-4, and like salts.
  • pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base
  • a "solvate,” such as a “hydrate,” is formed by the interaction of a solvent and a compound.
  • the term “compound” is intended to include solvates, including hydrates, of compounds, to the extent they can be made by one of ordinary skill in the art by routine experimentation.
  • “salts” includes solvates, such as hydrates, of salts, to the extent they can be made by one of ordinary skill in the art by routine experimentation.
  • Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates, to the extent they can be made by one of ordinary skill in the art by routine experimentation.
  • a "chelate” is formed by the coordination of a compound to a metal ion at two (or more) points.
  • the term “compound” is intended to include chelates of compounds.
  • salts includes chelates of salts.
  • a "non-covalent complex” is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule.
  • complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).
  • Such non-covalent complexes are included in the term "compound ' .
  • hydrogen bond refers to a form of association between an electronegative atom (also known as a hydrogen bond acceptor) and a hydrogen atom attached to a second, relatively electronegative atom (also known as a hydrogen bond donor).
  • Suitable hydrogen bond donor and acceptors are well understood in medicinal chemistry (G. C. Pimentel and A. L. McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R. Taylor and O. Kennard, "Hydrogen Bond Geometry in Organic Crystals", Accounts of Chemical Research, 17, pp. 320- 326 (1984)).
  • group As used herein the terms "group”, “radical” or “fragment” are synonymous and are intended to indicate functional groups or fragments of molecules attachable to a bond or other fragments of molecules.
  • active agent is used to indicate a chemical substance which has biological activity.
  • an “active agent” is a chemical substance having
  • Treating refers to administering at least one compound and/or at least one pharmaceutically acceptable salt described herein to a subject that has a disease or disorder, or has a symptom of a disease or disorder, or has a predisposition toward a disease or disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect cancer, the symptoms of the disease or disorder, or the
  • the disease or disorder may be cancer. In some embodiments, the disease or disorder may be an inflammatory disease.
  • the term "effective amount” refers to an amount of at least one compound and/or at least one pharmaceutically acceptable salt described herein effective to "treat", as defined above, a disease or disorder in a subject.
  • the effective amount may cause any of the changes observable or measurable in a subject as described in the definition of "treating,” “treat,” “treatment” and “alleviation” above.
  • the effective amount can reduce the number of cancer or tumor cells; reduce the tumor size; inhibit or stop tumor cell infiltration into peripheral organs including, for example, the spread of tumor into soft tissue and bone; inhibit and stop tumor metastasis; inhibit and stop tumor growth; relieve to some extent one or more of the symptoms associated with the cancer, reduce morbidity and mortality; improve quality of life; or a combination of such effects.
  • An effective amount may be an amount sufficient to decrease the symptoms of a disease responsive to inhibition of at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2.
  • efficacy in vivo can, for example, be measured by assessing the duration of survival, time to disease progression (TTP), the response rates (RR), duration of response, and/or quality of life.
  • Effective amounts may vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, and co-usage with other agents.
  • the term “effective amount” may also refer to an amount of at least one compound and/or at least one pharmaceutically acceptable salt described herein effective to inhibit the activity of at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2.
  • the term “inhibition” indicates a decrease in the baseline activity of a biological activity or process.
  • “Inhibition of at least one kinase chosen from JAKl, JAK2, JAK3 and TYK2” refers to a decrease in the activity of the at least one kinase chosen from JAKl, JAK2, JAK3 and TYK2 as a direct or indirect response to the presence of at least one compound and/or at least one pharmaceutically acceptable salt described herein, relative to the activity of the at least one kinase chosen from JAKl, JAK2, JAK3 and TYK2 in the absence of the at least one compound and/or the at least one pharmaceutically acceptable salt thereof.
  • the decrease in activity may be due to the direct interaction of the at least one compound and/or at least one pharmaceutically acceptable salt described herein with the at least one kinase chosen from JAKl, JAK2, JAK3 and TYK2, or due to the interaction of the at least one compound and/or at least one pharmaceutically acceptable salt described herein, with one or more other factors that in turn affect the at least one kinase activity.
  • the presence of at least one compound and/or at least one pharmaceutically acceptable salt described herein may decrease the at least one kinase activity by directly binding to the at least one kinase, by causing (directly or indirectly) another factor to decrease the at least one kinase activity, or by (directly or indirectly) decreasing the amount of the at least one kinase present in the cell or organism.
  • R 1 is chosen from hydrogen, alkyl, cycloalkyl and heterocycle
  • R 2 is chosen from alkyl, aryl, cycloalkyl, heterocycle, heteroaryl, -C(0)R a , -C(0) R c R d , -S(0) n R f , and -S(0) n R c R d ,
  • R 1 and R 2 together with the N atom to which they are attached, form an optionally substituted 3- to 7-membered ring, which optionally comprises one or two additional heteroatoms and which is further optionally fused to an optionally substituted heteroaryl or optionally substituted aryl ring;
  • each of above said alkyl, aryl, cycloalkyl, heterocycle, heteroaryl in R 1 and R 2 is optionally substituted with one or more groups chosen from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -C(0)R a , -C(0)OR b , -CN, -C(0) R c R d , halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, - R c R d , - R e C(0)R a , - R e C(0)OR b , - R e C(0) R c R d , - R e S(0) n R f , - R e S(0) n R c R d , , - N0 2 , -OR b , -S(0)
  • n and n are independently chosen from 0, 1, and 2;
  • R a , R b , R c , R d , R e and R f are each independently chosen from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted haloalkyl, optionally substituted heteroaryl and optionally substituted heterocycle,
  • R c and R d with the nitrogen to which they are attached, combine to form a heterocycle ring, which is optionally substituted with one or more groups chosen from halo, lower alky, hydroxy, and lower alkoxy, wherein the heterocycle ring further optionally comprises one or two additional heteroatoms chosen from N, O and S;
  • each optionally substituted group above can be unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently chosen from C 1 -C4 alkyl, cycloalkyl, aryl, heterocycle, heteroaryl, aryl-Ci-C 4 alkyl-, heteroaryl-Ci-C 4 alkyl-, Ci-C 4 haloalkyl-, -OCi-C 4 alkyl, -OCi-C 4 alkylphenyl, -Ci-C 4 alkyl-OH, -Ci-C 4 alkyl-0-Ci-C 4 alkyl, -OCi-C 4 haloalkyl, halo, -OH, - H 2 , -Ci-C 4 alkyl- H 2 , -N(Ci-C 4 alkyl)(Ci-C 4 alkyl), - H(Ci-C 4 alkyl), -N(Ci-C 4
  • - HS0 2 (Ci-C 4 haloalkyl), in which each of phenyl, aryl, heterocycle, and heteroaryl is optionally substituted by one or more groups chosen from halo, cycloalkyl, heterocycle, Ci-C 4 alkyl, Ci-C 4 haloalkyl-, -OCi-C 4 alkyl, Ci-C 4 alkyl-OH, -Ci-C 4 alkyl-0-Ci-C 4 alkyl, -OCi-C 4 haloalkyl, cyano, nitro, - H 2 , -C0 2 H, -C(0)OCi-C 4 alkyl, -CON(Ci-C 4 alkyl)(Ci-C 4 alkyl), -CO H(Ci-C 4 alkyl), -CO H 2 , - HC(0)(Ci-C 4 alkyl), -N(Ci-C 4 alkyl)C(0)(Ci-C 4
  • R 1 is hydrogen or ethyl
  • R 2 is not acetyl
  • m is 1.
  • R 1 is chosen from alkyl and cycloalkyl, each of which is optionally substituted with one or more groups chosen from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -C(0)R a , -C(0)OR b , -CN, -C(0) R c R d , halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, - R c R d , - R e C(0)R a , - R e C(0)OR b , - R e C(0) R c R d , - R e S(0) n R f , - R e S(0) n R c R d , , - N0 2 , -OR b , -S(0) n R
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more groups chosen from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -C(0)R a , -C(0)OR b , -CN, -C(0)NR c R d , halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, -NR c R d , -NR e C(0)R a , - NR e C(0)OR b , -NR e C(0)NR c R d , -NR e S(0) n R f , -NR e S(0) n NR c R d , , -N0 2 , -OR b , -S(0) n R f ,
  • R 2 is alkyl or cycloalkyl, each of which is optionally substituted with one or more groups chosen from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -C(0)R a , -C(0)OR b , -CN, -C(0)NR c R d , halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, -NR c R d , -NR e C(0)R a , - NR e C(0)OR b , -NR e C(0)NR c R d , -NR e S(0) n R f , -NR e S(0) n NR c R d , , -N0 2 , -OR b , -S(0) n R
  • R 2 is -C(0)R a , -C(0)NR c R d , or-S(0) n NR c R d , wherein R a , R c , and R d are each independently chosen from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted haloalkyl, optionally substituted heteroaryl and optionally substituted heterocycle,
  • R c and R d with the nitrogen to which they are attached, combine to form a heterocycle ring, which is optionally substituted with one or more groups chosen from halo, lower alky, hydroxy, and lower alkoxy, wherein the heterocycle ring further optionally comprises one or two additional heteroatoms chosen from N, O and S.
  • each of which is optionally substituted with one or more groups chosen from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted haloalkyl, -C(0)R a , - C(0)OR b , -CN, -C(0)NR c R d , halo, optionally substituted heterocycle, optionally substituted heteroaryl, -NR c R d , -NR e C(0)R a , -NR e C(0)OR b , -NR e C(0)NR c R d , -NR e S(0) n R f , - NR e S(0) n NR c R d , , -N0 2 , -OR b , -S(0) n R f , and -S(0) n NR c R d .
  • each of which is optionally substituted with one or more groups chosen from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted haloalkyl, -C(0)R a , - C(0)OR b , -CN, -C(0) R c R d , halo, optionally substituted heterocycle, optionally substituted heteroaiyl, - R c R d , - R e C(0)R a , - R e C(0)OR b , - R e C(0) R c R d , - R e S(0) n R f , - R e S(0) n NR c R d , , -N0 2 , -OR b , -S(0) n R f , and -S(0) n R c R d .
  • R 2 is
  • R 2 is
  • R 1 is chosen from C1-3 alkyl, allyl, propargyl, and cyclopropyl, each of which is optionally substituted with one or more groups chosen from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -C(0)R a , -C(0)OR b , -CN, -C(0)NR c R d , halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaiyl, -NR c R d , -NR e C(0)R a , -NR e C(0)OR b , -NR e C(0)NR c R d , -NR e S(0) n R f , -
  • R 1 is methyl.
  • the absolute stereocenter bearing the -N(R 1 )(R 2 ) group is the R- isomer.
  • At least one compound chosen from compounds 1 to 260 and/or at least one pharmaceutically acceptable salt thereof is also provided.
  • compounds of formula (1) can react with compounds of formula (2), wherein m is as defined herein, in the presence of a base, such as but not limited to K 2 C0 3 , Na 2 C0 3 , NaH, Et 3 N or diisopropylethylamine (DIPEA), to give compounds of formula (3).
  • a base such as but not limited to K 2 C0 3 , Na 2 C0 3 , NaH, Et 3 N or diisopropylethylamine (DIPEA)
  • DIPEA diisopropylethylamine
  • N-Boc group in compound of formula (3) can be deprotected to give the compound of formula (4) that can subsequently react with R X and R 2 X, wherein X is CI.
  • R 1 and R 2 are as defined herein, in the presence of a base, such as but not limited to K 2 C0 3 , Na 2 C0 3 , Cs 2 C0 3 , NaH, t-BuONa, t- BuOK, Et 3 N, or diisopropylethylamine (DIPEA), to give the compound of formula (I).
  • a base such as but not limited to K 2 C0 3 , Na 2 C0 3 , Cs 2 C0 3 , NaH, t-BuONa, t- BuOK, Et 3 N, or diisopropylethylamine (DIPEA)
  • DIPEA diisopropylethylamine
  • Pd(OAc) 2 Pd 2 (dba) 3 or Pd(PPh 3 ) 4 and a ligand, such as but not limited to Ph 3 P, f Bu 3 P, 2,2'- bis(diphenylphosphino)- 1 , 1 '-binaphthalene (BINAP), 1 , 1 '-bis(diphenylphosphino)ferrocene (dppf) or l,3-bis(2,6-dipropylphenyl)-lH-imidazol-3-ium chloride, can be used as a catalyst to improve the reaction efficiency.
  • a ligand such as but not limited to Ph 3 P, f Bu 3 P, 2,2'- bis(diphenylphosphino)- 1 , 1 '-binaphthalene (BINAP), 1 , 1 '-bis(diphenylphosphino)ferrocene (dppf) or l,3-bis(2,6-dipropy
  • compound of formula (7) can react with compound of formula (5) under the conditions described in Scheme I to give compound of formula (8).
  • compound of formula (8) can also be prepared by the reactions of compound of formula (7) with compound of formula (9), wherein R la and R lb are selected from H, alkyl, cycloalkyl, aryl heteroaryl, or R la and R lb together with the attached carbon atom to form a cycloalkyl or heterocycloalkyl ring.
  • Compound of formula (8) can react with compound of formula (6) under the conditions described in Scheme I to give compound of formula (10).
  • N-Boc group in compound of formula (10) can be deprotected to give compound of formula (1 1) that can further react with compound of formula (1) in the presence a base, such as but not limited to K 2 CO 3 , Na 2 C0 3 , Cs 2 C0 3 , NaH, t-BuONa, t-BuOK, Et 3 N, or diisopropylethylamine
  • a base such as but not limited to K 2 CO 3 , Na 2 C0 3 , Cs 2 C0 3 , NaH, t-BuONa, t-BuOK, Et 3 N, or diisopropylethylamine
  • a palladium reagent such as but not limited to PdCl 2 , Pd(OAc) 2 Pd 2 (dba) 3 or Pd(PPh 3 ) 4 , and a ligand, such as but not limited to Ph 3 P, f Bu 3 P, 2,2'-bis(diphenylphosphino)- ⁇ , -binaphthalene (BINAP), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos), l, l'-bis(diphenylphosphino)ferrocene (dppf) or l,3-bis(2,6-dipropylphenyl)-lH-imidazol-3-ium chloride, can be used as a catalyst to improve the reaction efficiency.
  • a palladium reagent such as but not limited to PdCl 2 , Pd(OAc) 2 Pd 2 (dba) 3 or Pd(PPh 3
  • Scheme III shows that compound of formula (3) can react with LiAlH to give compound of (12) that can further react with compound of formula (5) under similar conditions as described in Scheme I to give compound of formula (13).
  • the compounds thus obtained can be further modified at their peripheral positions to provide the desired compounds. Synthetic chemistry transformations are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser 's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.
  • the at least one compound and/or at least one pharmaceutically acceptable salt described herein can be purified by column chromatography, high performance liquid chromatography, crystallization, or other suitable methods.
  • composition comprising at least one compound and/or at least one pharmaceutically acceptable salt described herein, and at least one pharmaceutically acceptable carrier.
  • a composition comprising at least one compound and/or at least one pharmaceutically acceptable salt described herein can be administered in various known manners, such as orally, parenterally, by inhalation spray, or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • An oral composition can be any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions and solutions.
  • Commonly used carriers for tablets include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added to tablets.
  • useful diluents include lactose and dried corn starch.
  • the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.
  • a sterile injectable composition e.g., aqueous or oleaginous suspension
  • a sterile injectable composition can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable Intermediate can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable dispersing or wetting agents such as, for example, Tween 80
  • the sterile injectable Intermediate can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable dispersing or wetting agents such as, for example, Tween 80
  • the sterile injectable Intermediate can also be a sterile injectable solution or suspension in
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or di-glycerides).
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the Intermediate of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.
  • An inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • a topical composition can be formulated in form of oil, cream, lotion, ointment and the like.
  • suitable carriers for the composition include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (greater than C12).
  • the pharmaceutically acceptable carrier is one in which the active ingredient is soluble.
  • Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired.
  • transdermal penetration enhancers may be employed in those topical formulations. Examples of such enhancers can be found in U.S. Patents 3,989,816 and 4,444,762.
  • Creams may be formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of an oil, such as almond oil, is admixed.
  • An example of such a cream is one which includes about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil.
  • Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool.
  • a vegetable oil such as almond oil
  • An example of such an ointment is one which includes about 30% by weight almond oil and about 70% by weight white soft paraffin.
  • a pharmaceutically acceptable carrier refers to a carrier that is compatible with active ingredients of the composition (and in some embodiments, capable of stabilizing the active ingredients) and not deleterious to the subject to be treated.
  • solubilizing agents such as cyclodextrins (which form specific, more soluble complexes with the at least one compound and/or at least one pharmaceutically acceptable salt described herein), can be utilized as pharmaceutical excipients for delivery of the active ingredients.
  • examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow # 10.
  • Suitable in vitro assays can be used to preliminarily evaluate the efficacy of the at least one compound and/or at least one pharmaceutically acceptable salt described herein, in inhibiting the activity of at least one kinase chosen from JAKl, JAK2, JAK3 and TYK2.
  • the at least one compound and/or at least one pharmaceutically acceptable salt described herein can further be examined for efficacy in treating cancer or inflammatory disease by in vivo assays.
  • the compounds described herein, and/or the pharmaceutically acceptable salts thereof can be administered to an animal (e.g., a mouse model) having cancer or inflammatory disease and its therapeutic effects can be accessed. Based on the results, an appropriate dosage range and administration route for animals, such as humans, can also be determined.
  • the method comprises contacting the at least one kinase with an amount of at least one compound and/or at least one pharmaceutically acceptable salt described herein effective to inhibit the activity of the at least one kinase chosen from JAK1, JAK2, JA 3 and TYK2.
  • the at least one compound and/or at least one pharmaceutically acceptable salt described herein can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in subjects with cancer.
  • cancer refers to a cellular disorder characterized by uncontrolled or disregulated cell proliferation, decreased cellular
  • cancer includes, but is not limited to, solid tumors and bloodborne tumors.
  • cancer encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels.
  • cancer further encompasses primary and metastatic cancers.
  • Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer;
  • breast cancer including metastatic breast cancer
  • prostate cancer including androgen-dependent and androgen-independent prostate cancer
  • renal cancer including, e.g., metastatic renal cell carcinoma
  • hepatocellular cancer including lung cancer, including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (B AC), and adenocarcinoma of the lung
  • ovarian cancer including, e.g., progressive epithelial or primary peritoneal cancer
  • cervical cancer gastric cancer; esophageal cancer; head and neck cancer, including, e.g., squamous cell carcinoma of the head and neck; skin cancer, including e.g., malignant melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; soft tissue sarcoma; and thyroid carcinoma.
  • skin cancer including e.g., malignant melanoma
  • neuroendocrine cancer including metastatic neuroendocrine tumors
  • brain tumors including, e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma
  • bone cancer soft tissue sarcoma
  • thyroid carcinoma thyroid carcinoma
  • Non-limiting examples of hematologic malignancies include acute myeloid leukemia (AML); chronic myelogenous leukemia (CML), including accelerated CML and CML blast phase (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM);
  • AML acute myeloid leukemia
  • CML chronic myelogenous leukemia
  • ALL acute lymphoblastic leukemia
  • CLL chronic lymphocytic leukemia
  • HD Hodgkin's disease
  • NHL non-Hodgkin's lymphoma
  • NHL multiple myeloma
  • MDS myelodysplastic syndromes
  • A refractory anemia
  • RARS refractory anemia with ringed siderblasts
  • RAEB refractory anemia with excess blasts
  • RAEB-T RAEB in transformation
  • myeloproliferative syndromes include, but are not limited to, lung cancer, head and neck cancer, colorectal cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, stomach cancer, kidney cancer, liver cancer, brain cancer, bone cancer, and leukemia.
  • the at least one compound and/or at least one pharmaceutically acceptable salt described herein can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in subjects with an inflammatory disease or inflammatory disorder.
  • inflammatory disease or "inflammatory disorder” refers to pathological states resulting in inflammation, typically caused by neutrophil chemotaxis.
  • disorders include inflammatory skin diseases including psoriasis and atopic dermatitis; systemic scleroderma and sclerosis; responses associated with inflammatory bowel disease (IBD) (such as Crohn's disease and ulcerative colitis); ischemic reperfusion disorders including surgical tissue reperfusion injury, myocardial ischemic conditions such as myocardial infarction, cardiac arrest,
  • cranial trauma hypovolemic shock; asphyxia; adult respiratory distress syndrome; acute-lung injury; Behcet's Disease; dermatomyositis; polymyositis; multiple sclerosis (MS); dermatitis; meningitis; encephalitis; uveitis; osteoarthritis; lupus nephritis; autoimmune diseases such as rheumatoid arthritis (RA), Sjorgen's syndrome, vasculitis; diseases involving leukocyte diapedesis; central nervous system (CNS) inflammatory disorder, multiple organ injury syndrome secondary to septicaemia or trauma; alcoholic hepatitis; bacterial pneumonia;
  • RA rheumatoid arthritis
  • CNS central nervous system
  • antigen-antibody complex mediated diseases including glomerulonephritis; sepsis; sarcoidosis; immunopathologic responses to tissue/organ transplantation; inflammations of the lung, including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF), and cystic fibrosis; etc.
  • diseases including glomerulonephritis; sepsis; sarcoidosis; immunopathologic responses to tissue/organ transplantation; inflammations of the lung, including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF), and cystic fibrosis; etc.
  • IPF idiopathic pulmonary fibrosis
  • the preferred indications include, without limitation, chronic inflammation, autoimmune diabetes, rheumatoid arthritis (RA), rheumatoid spondylitis, gouty arthritis and other arthritic conditions, multiple sclerosis (MS), asthma, systemic lupus erythematosus, adult respiratory distress syndrome, Behcet's disease, psoriasis, chronic pulmonary inflammatory disease, graft versus host reaction, Crohn's Disease, ulcerative colitis, inflammatory bowel disease (IBD), Alzheimer's disease, and pyresis, along with any disease or disorder that relates to inflammation and related disorders.
  • MS multiple sclerosis
  • asthma systemic lupus erythematosus
  • adult respiratory distress syndrome Behcet's disease
  • psoriasis chronic pulmonary inflammatory disease
  • graft versus host reaction Crohn's Disease
  • ulcerative colitis inflammatory bowel disease
  • IBD inflammatory bowel disease
  • Alzheimer's disease Alzheimer's disease
  • the at least one compound and/or at least one pharmaceutically acceptable salt described herein can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in subjects with an autoimmune disease.
  • autoimmune disease refers to a disease or disorder arising from and/or directed against an individual's own tissues or organs, or a co-segregate or manifestation thereof, or resulting condition therefrom.
  • autoimmune diseases include, but are not limited to, lupus, myasthenia gravis, multiple sclerosis (MS), rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease, asthma and idiopathic thrombocytopenic purpura, and myeloid proliferative disorder, such as myelofibrosis, PV / ET (Post-Polycythemia / Essential Thrombocythemia Myelofibrosis).
  • the at least one compound and/or at least one pharmaceutically acceptable salt described herein is administered in conjunction with another therapeutic agent.
  • the other therapeutic agent is one that is normally administered to patients with the disease or condition being treated.
  • the other therapeutic agent may be an anti-inflammatory agent or an anti-neoplastic agent, depending on the disease or condition being treated.
  • the at least one compound and/or at least one pharmaceutically acceptable salt described herein may be administered with the other therapeutic agent in a single dosage form or as a separate dosage form.
  • the other therapeutic agent may be administered prior to, at the same time as, or following administration of the at least one compound and/or at least one pharmaceutically acceptable salt described herein.
  • At least one compound and/or at least one pharmaceutically acceptable salt described herein is administered in conjunction with an anti-inflammatory agent.
  • anti-inflammatory agents include corticosteroids (e.g., fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide or budesonide), disease-modifying agents (e.g., antimalarials, methotrexate, sulfasalazine, mesalamine, azathioprine, 6-mercaptopurine, metronidazole, injectable and oral gold, or D- penicillamine), non-steroidal antiinflammatory drugs (e.g., acetominophen, aspirin, sodium salicylate, sodium cromoglycate, magnesium salicylate, choline magnesium salicylate, salicylsalicylic acid, ibuprofen, naproxen, diclofenac, diflunisal
  • corticosteroids e.g
  • At least one compound and/or at least one pharmaceutically acceptable salt described herein is administered in conjunction with an anti-neoplastic agent.
  • an anti-neoplastic agent refers to any agent that is administered to a subject with cancer for purposes of treating the cancer.
  • Nonlimiting examples of anti-neoplastic agents include: radiotherapy; immunotherapy; DNA damaging chemotherapeutic agents; and chemotherapeutic agents that disrupt cell replication.
  • Non-limiting examples of DNA damaging chemotherapeutic agents include
  • topoisomerase I inhibitors e.g., irinotecan, topotecan, camptothecin and analogs or metabolites thereof, and doxorubicin
  • topoisomerase II inhibitors e.g., etoposide, teniposide, and daunorubicin
  • alkylating agents e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, methotrexate, mitomycin C, and cyclophosphamide
  • DNA intercalators e.g., cisplatin, oxaliplatin, and carboplatin
  • DNA intercalators and free radical generators such as bleomycin
  • nucleoside mimetics e.g., 5- fluorouracil, capecitibine, gemcitabine, fludarabine,
  • Chemotherapeutic agents that disrupt cell replication include: paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, and related analogs; thalidomide and related analogs (e.g., CC-5013 and CC-4047); protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib); proteasome inhibitors (e.g., bortezomib); F-kappa B inhibitors, including inhibitors of I kappa B kinase; antibodies which bind to proteins overexpressed in cancers and thereby downregulate cell replication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab); and other inhibitors of proteins or enzymes known to be upregulated, over-expressed or activated in cancers, the inhibition of which downregulates cell replication.
  • Lawesson's reagent 2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-l, 3,2,4- dithiadiphosphetane
  • the tile compound was prepared according to the procedure of Compound 23 (B) using 3 -(( lR,2R)-2-hydroxy-2, 3 -dihydro- lH-inden- 1 -yl)- 1 -methyl- 1 - ((R) - 1 -(7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2, 3- ⁇ JJpyrimidin-4-yl)pyrrolidin-3-yl)urea. MS (m/z): 393 (M+H) + .
  • the first compound (compound 136)from the column was collected and confirmed to be (R)-5-ethoxy-N-methyl-N-(l-(7-((2-(trimethylsilyl)ethoxy)-methyl)-7H- pyrrolo[2,3- ⁇ JJpyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine [MS (m/z), 470 (M+l) + , 21 mg, 41.1% yield) and the later compound(compound 143) from the column was isolated and concentrated to give the title compound (22 mg, 47.8% yield). MS (m/z), 426 (M+l) +
  • the tile compound was prepared according to the procedure of Compound 163 (A) using (R)-6-(l-(7H-pyrrolo[2,3-i3 ⁇ 4pyrimidin-4-yl)pyrrolidin-3-ylamino)-5-nitronicotinonitrile. MS (m/z): 321 (M+H) + .
  • the tile compounds was prepared according to the procedure of Compound 164 using R)-6-( 1 -(7H-pyrrolo [2,3 - ⁇ JJpyrimidin-4-yl)pyrrolidin-3 -ylamino)-5 -amino nicotinonitrile.
  • tile compounds was prepared according to the procedure of Compound 23 (B) using (R)-N 5 -(4-fluorobenzyl)-N -methyl- ⁇
  • tile compounds was prepared according to the procedure of Compound 23 (B) using (R)-N,N-dimethyl-6-(methyl(l-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- ⁇ JJpyrimidin-4-yl)pyrrolidin-3-yl)amino)pyridine-3 -sulfonamide.
  • JAKl/2/3 kinase assay are performed in vitro using Kit-Tyr 6 Peptide (Invitrogen, Cat.No. PV4122).
  • TYK2 kinase assay are performed in vitro using Z'-LYTETM Kinase Assay Kit-Tyr 3 Peptide (Invitrogen, Cat.No. PV3192).
  • Recombinant human JAKl/2/3 or TYK2 catalytic domains are from Invitrogen (Cat No. PV4774/PV4210/PV3855/PV4790); All reactions (20 pL) are started by adding 2.5 ⁇ . of the testing compound in 4% DMSO solution, 5 ⁇ .
  • IL-6-induced STAT3 phosphorylation HepG2 cells (SIBS) are seeded in 96 well plates at 5.4 ⁇ 10 3 cells per well in Serum Free DMEM media overnight and incubated in the presence or absence of various concentrations of diluted compound for 30 min at 37 °C, 5% C02. Cells were stimulated by adding 10 ng/ml human recombinant IL-6 to each well for 15 minutes at 37°C, 5% C02. Cells are then fixed in 2% paraformaldehyde for 45 minutes at room temperature and incubated in ice-cold methanol for 30 minutes. After washing in PBS, cells are incubated with rabbit anti-phospho-STAT3 (Y705) (Cell Signaling
  • TF-1 cells (ATCC) are plated in 96 well plates at 1 * 10 4 cells per well in 10% FBS RPMI-1640 media at 37 °C, 5% C02 for 3 hours. Cells were incubated in the presence or absence of various concentrations of diluted compound for 30 min at 37 °C, 5% C02. Cells were stimulated by adding 10 ng/ml human recombinant IL-3 to each well for 30 minutes at 37°C, 5% C02. Cells are then fixed in 2% paraformaldehyde for 45 minutes at room temperature and incubated in ice-cold methanol for 30 minutes.
  • Ramos cells are plated in 96 well plates at l .O lO 4 cells per well 10% FBS RPMI-1640 and incubated at 37 °C, 5% C02 for 3 hours. Cells were incubated with compounds for 30 minutes prior to stimulation with interleukin-4 (lOng/ml final) for an additional 30 minutes. Cells are then fixed in 2% paraformaldehyde for 45 minutes and incubated in ice-cold methanol for 30 minutes. After washing in PBS, cells are incubated with rabbit anti-phospho-STAT6 (Y641) (Cell
  • Inhibition (%) 100-((inhibitor treatment -cell) / (stimulator -cell)) x 100
  • Inhibitor treatment represents cell activation percentage of wells treated by both compound and stimulator (IL-6, IL-3 or IL-4);
  • Cell represents the cell activation percentage of wells treated by neither compound nor stimulator (IL-6, IL-3 or IL-4).
  • Stimulator represents the cell activation percentage of wells treated by stimulator (IL-6, IL-3 or IL-4) only.
  • Most of the compounds disclosed herein inhibited at least one kinase chosen from JAKl, JAK2, JAK3 and TYK2 in the cellular assays with IC 50 ⁇ 10.0 uM.

Landscapes

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

Abstract

Cette invention concerne des composés pyrrolopyrimidiniques et des procédés d'utilisation associés. L'invention concerne, en particulier, certains composés pyrrolopyrimidiniques doués de l'activité d'inhibition des kinases JAK. L'invention concerne, par ailleurs, les compositions pharmaceutiques contenant ces composés pyrrolopyrimidiniques et l'utilisation de ces composés dans le traitement des maladies inflammatoires et du cancer.
PCT/CN2010/076187 2010-08-20 2010-08-20 Composés pyrrolopyrimidiniques et leurs utilisations Ceased WO2012022045A1 (fr)

Priority Applications (18)

Application Number Priority Date Filing Date Title
PCT/CN2010/076187 WO2012022045A1 (fr) 2010-08-20 2010-08-20 Composés pyrrolopyrimidiniques et leurs utilisations
HK13107097.2A HK1179953B (en) 2010-08-20 2011-08-18 Pyrrolopyrimidine compounds and uses thereof
NZ606751A NZ606751A (en) 2010-08-20 2011-08-18 Pyrrolopyrimidine compounds and uses thereof
PCT/CN2011/078575 WO2012022265A1 (fr) 2010-08-20 2011-08-18 Composés de pyrrolopyrimidine et leurs utilisations
SG2013009196A SG187742A1 (en) 2010-08-20 2011-08-18 Pyrrolopyrimidine compounds and uses thereof
BR112013003864-0A BR112013003864B1 (pt) 2010-08-20 2011-08-18 Compostos de pirrolpirimidina, composição e uso dos mesmos
EP11817792.2A EP2606051B1 (fr) 2010-08-20 2011-08-18 Composés de pyrrolopyrimidine et leurs utilisations
AU2011291185A AU2011291185C1 (en) 2010-08-20 2011-08-18 Pyrrolopyrimidine compounds and uses thereof
RU2013104520/04A RU2563644C2 (ru) 2010-08-20 2011-08-18 Пирролопиримидиновые соединения и их применения
US13/817,802 US9346810B2 (en) 2010-08-20 2011-08-18 Pyrrolopyrimidine compounds and uses thereof
MX2013001970A MX2013001970A (es) 2010-08-20 2011-08-18 Compuestos de pirrolopirimidina y usos de los mismos.
JP2013524343A JP5749341B2 (ja) 2010-08-20 2011-08-18 ピロロピリミジン化合物およびその使用
CA2808543A CA2808543C (fr) 2010-08-20 2011-08-18 Composes de pyrrolopyrimidine et leurs utilisations
KR1020137006853A KR101541086B1 (ko) 2010-08-20 2011-08-18 피롤로피리미딘 화합물 및 그 용도
CN201180040092.0A CN103119045B (zh) 2010-08-20 2011-08-18 吡咯并嘧啶化合物及其用途
PH1/2013/500299A PH12013500299B1 (en) 2010-08-20 2011-08-18 Pyrrolopyrimidine compounds and uses thereof
US15/134,223 US10111875B2 (en) 2010-08-20 2016-04-20 Pyrrolopyrimidine compounds and uses thereof
US16/173,120 US10369153B2 (en) 2010-08-20 2018-10-29 Pyrrolopyrimidine compounds and uses thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2010/076187 WO2012022045A1 (fr) 2010-08-20 2010-08-20 Composés pyrrolopyrimidiniques et leurs utilisations

Publications (1)

Publication Number Publication Date
WO2012022045A1 true WO2012022045A1 (fr) 2012-02-23

Family

ID=45604698

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2010/076187 Ceased WO2012022045A1 (fr) 2010-08-20 2010-08-20 Composés pyrrolopyrimidiniques et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2012022045A1 (fr)

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2485589A4 (fr) * 2009-09-04 2013-02-06 Biogen Idec Inc Inhibiteurs hétéroaryles de btk
WO2013130890A1 (fr) * 2012-02-29 2013-09-06 Amgen Inc. Composés hétérobicycliques et leur utilisation en tant qu'inhibiteurs de la phosphodiestérase
US8957078B2 (en) 2013-03-15 2015-02-17 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8969360B2 (en) 2013-03-15 2015-03-03 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9012462B2 (en) 2008-05-21 2015-04-21 Ariad Pharmaceuticals, Inc. Phosphorous derivatives as kinase inhibitors
US9273077B2 (en) 2008-05-21 2016-03-01 Ariad Pharmaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
US9309250B2 (en) 2011-06-22 2016-04-12 Vertex Pharmaceuticals Incorporated Substituted pyrrolo[2,3-b]pyrazines as ATR kinase inhibitors
US9340546B2 (en) 2012-12-07 2016-05-17 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9585886B2 (en) 2010-12-16 2017-03-07 Calchan Limited ASK1 inhibiting pyrrolopyrimidine derivatives
US9611283B1 (en) 2013-04-10 2017-04-04 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in ALK-driven cancers
KR20170044202A (ko) 2014-09-02 2017-04-24 니뽄 신야쿠 가부시키가이샤 피라졸로티아졸 화합물 및 의약
US9663519B2 (en) 2013-03-15 2017-05-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9670215B2 (en) 2014-06-05 2017-06-06 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
WO2017150477A1 (fr) 2016-03-01 2017-09-08 日本新薬株式会社 Cristal de composé présentant une activité d'inhibition de jak
US9834518B2 (en) 2011-05-04 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US9834571B2 (en) 2012-05-05 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
CN107973807A (zh) * 2018-01-19 2018-05-01 唐山学院 一种三唑并苯并噻唑衍生物及其制备方法和应用
US10160760B2 (en) 2013-12-06 2018-12-25 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
CN109563097A (zh) * 2016-11-23 2019-04-02 无锡福祈制药有限公司 一种7H-吡咯并[2,3-d]嘧啶类化合物的晶型、盐型及其制备方法
US10508113B2 (en) 2018-03-12 2019-12-17 Abbvie Inc. Inhibitors of tyrosine kinase 2 mediated signaling
WO2020092015A1 (fr) 2018-11-02 2020-05-07 University Of Rochester Atténuation thérapeutique d'une infection épithéliale
CN111362975A (zh) * 2015-05-28 2020-07-03 施万生物制药研发Ip有限责任公司 作为jak激酶抑制剂的萘啶化合物
CN113214278A (zh) * 2016-10-03 2021-08-06 杭州高光制药有限公司 新型Jak1选择性抑制剂及其用途
US11179394B2 (en) 2014-06-17 2021-11-23 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of Chk1 and ATR inhibitors
CN114591333A (zh) * 2020-12-04 2022-06-07 广州嘉越医药科技有限公司 一种吡咯并嘧啶类化合物的制备方法
US11351149B2 (en) 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11464774B2 (en) 2015-09-30 2022-10-11 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of DNA damaging agents and ATR inhibitors
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
CN115515591A (zh) * 2020-04-15 2022-12-23 派拉米德生物科学公司 用于制备酪氨酸受体激酶抑制剂的方法
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
US12084453B2 (en) 2021-12-10 2024-09-10 Incyte Corporation Bicyclic amines as CDK12 inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1305479A (zh) * 1998-06-19 2001-07-25 辉瑞产品公司 吡咯并[2,3－d]嘧啶化合物
WO2010034740A1 (fr) * 2008-09-23 2010-04-01 Palau Pharma, S.A. Dérivés (r)-3-(n,n-diméthylamino)pyrrolidine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1305479A (zh) * 1998-06-19 2001-07-25 辉瑞产品公司 吡咯并[2,3－d]嘧啶化合物
WO2010034740A1 (fr) * 2008-09-23 2010-04-01 Palau Pharma, S.A. Dérivés (r)-3-(n,n-diméthylamino)pyrrolidine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KEVIN D. ET AL.: "Design of selective", ATP-COMPETITIVE INHIBITORS OF AKT, vol. 53, no. 12, 19 May 2010 (2010-05-19), pages 4615 - 4622 *

Cited By (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9273077B2 (en) 2008-05-21 2016-03-01 Ariad Pharmaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
US9012462B2 (en) 2008-05-21 2015-04-21 Ariad Pharmaceuticals, Inc. Phosphorous derivatives as kinase inhibitors
EP2485589A4 (fr) * 2009-09-04 2013-02-06 Biogen Idec Inc Inhibiteurs hétéroaryles de btk
US9029359B2 (en) 2009-09-04 2015-05-12 Biogen Idec Ma, Inc. Heteroaryl Btk inhibitors
US9585886B2 (en) 2010-12-16 2017-03-07 Calchan Limited ASK1 inhibiting pyrrolopyrimidine derivatives
US9834518B2 (en) 2011-05-04 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US9309250B2 (en) 2011-06-22 2016-04-12 Vertex Pharmaceuticals Incorporated Substituted pyrrolo[2,3-b]pyrazines as ATR kinase inhibitors
US9174992B2 (en) 2012-02-29 2015-11-03 Amgen Inc. Heterobicyclic compounds
WO2013130890A1 (fr) * 2012-02-29 2013-09-06 Amgen Inc. Composés hétérobicycliques et leur utilisation en tant qu'inhibiteurs de la phosphodiestérase
US9834571B2 (en) 2012-05-05 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US11370798B2 (en) 2012-12-07 2022-06-28 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9340546B2 (en) 2012-12-07 2016-05-17 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10392391B2 (en) 2012-12-07 2019-08-27 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9650381B2 (en) 2012-12-07 2017-05-16 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US12187731B2 (en) 2012-12-07 2025-01-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US11117900B2 (en) 2012-12-07 2021-09-14 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9718827B2 (en) 2012-12-07 2017-08-01 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10787452B2 (en) 2012-12-07 2020-09-29 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9663519B2 (en) 2013-03-15 2017-05-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8969360B2 (en) 2013-03-15 2015-03-03 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8957078B2 (en) 2013-03-15 2015-02-17 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9611283B1 (en) 2013-04-10 2017-04-04 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in ALK-driven cancers
US10815239B2 (en) 2013-12-06 2020-10-27 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US11485739B2 (en) 2013-12-06 2022-11-01 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10160760B2 (en) 2013-12-06 2018-12-25 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10800781B2 (en) 2014-06-05 2020-10-13 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10093676B2 (en) 2014-06-05 2018-10-09 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9670215B2 (en) 2014-06-05 2017-06-06 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US11179394B2 (en) 2014-06-17 2021-11-23 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of Chk1 and ATR inhibitors
US9937176B2 (en) 2014-09-02 2018-04-10 Nippon Shinyaku Co., Ltd. Pyrazolothiazole compound and medicine comprising same
KR20170044202A (ko) 2014-09-02 2017-04-24 니뽄 신야쿠 가부시키가이샤 피라졸로티아졸 화합물 및 의약
US9999622B2 (en) 2014-09-02 2018-06-19 Nippon Shinyaku Co., Ltd. Pyrazolothiazole compound and medicine comprising same
CN111362975A (zh) * 2015-05-28 2020-07-03 施万生物制药研发Ip有限责任公司 作为jak激酶抑制剂的萘啶化合物
CN111362975B (zh) * 2015-05-28 2022-04-05 施万生物制药研发Ip有限责任公司 作为jak激酶抑制剂的萘啶化合物
US11464774B2 (en) 2015-09-30 2022-10-11 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of DNA damaging agents and ATR inhibitors
WO2017150477A1 (fr) 2016-03-01 2017-09-08 日本新薬株式会社 Cristal de composé présentant une activité d'inhibition de jak
US10822350B2 (en) 2016-03-01 2020-11-03 Nippon Shinyaku Co., Ltd. Crystal of compound having JAK-inhibiting activity
KR20180116341A (ko) 2016-03-01 2018-10-24 니뽄 신야쿠 가부시키가이샤 Jak 저해 작용을 갖는 화합물의 결정
US11377453B2 (en) 2016-03-01 2022-07-05 Nippon Shinyaku Co., Ltd. Crystal of compound having JAK-inhibiting activity
CN113214278A (zh) * 2016-10-03 2021-08-06 杭州高光制药有限公司 新型Jak1选择性抑制剂及其用途
CN113214278B (zh) * 2016-10-03 2022-10-28 杭州高光制药有限公司 新型Jak1选择性抑制剂及其用途
CN109563097B (zh) * 2016-11-23 2021-05-14 无锡福祈制药有限公司 一种7H-吡咯并[2,3-d]嘧啶类化合物的晶型、盐型及其制备方法
CN109563097A (zh) * 2016-11-23 2019-04-02 无锡福祈制药有限公司 一种7H-吡咯并[2,3-d]嘧啶类化合物的晶型、盐型及其制备方法
US12357639B2 (en) 2017-09-22 2025-07-15 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
CN107973807B (zh) * 2018-01-19 2020-07-10 唐山学院 一种三唑并苯并噻唑衍生物及其制备方法和应用
CN107973807A (zh) * 2018-01-19 2018-05-01 唐山学院 一种三唑并苯并噻唑衍生物及其制备方法和应用
US10508113B2 (en) 2018-03-12 2019-12-17 Abbvie Inc. Inhibitors of tyrosine kinase 2 mediated signaling
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
WO2020092015A1 (fr) 2018-11-02 2020-05-07 University Of Rochester Atténuation thérapeutique d'une infection épithéliale
CN115515591A (zh) * 2020-04-15 2022-12-23 派拉米德生物科学公司 用于制备酪氨酸受体激酶抑制剂的方法
US11351149B2 (en) 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds
US11452711B2 (en) 2020-09-03 2022-09-27 Pfizer Inc. Nitrile-containing antiviral compounds
US11541034B2 (en) 2020-09-03 2023-01-03 Pfizer Inc. Nitrile-containing antiviral compounds
CN114591333A (zh) * 2020-12-04 2022-06-07 广州嘉越医药科技有限公司 一种吡咯并嘧啶类化合物的制备方法
CN114591333B (zh) * 2020-12-04 2023-08-01 广州嘉越医药科技有限公司 一种吡咯并嘧啶类化合物的制备方法
US12084453B2 (en) 2021-12-10 2024-09-10 Incyte Corporation Bicyclic amines as CDK12 inhibitors

Similar Documents

Publication Publication Date Title
US10369153B2 (en) Pyrrolopyrimidine compounds and uses thereof
WO2012022045A1 (fr) Composés pyrrolopyrimidiniques et leurs utilisations
CN102372717B (zh) 吡咯并嘧啶类化合物及其用途
AU2014351413B2 (en) Pyrrolopyrrolone derivatives and their use as BET inhibitors
WO2012167423A1 (fr) Pyridopyrazines substituées en tant que nouveaux inhibiteurs de syk
JP2023145547A (ja) Ｃｄ７３阻害剤、その製造方法と応用
JP2022502438A (ja) Ｆｇｆｒ４阻害剤及びその使用
WO2020228823A1 (fr) Nouveaux composés amides et leurs utilisations
CN116323582B (zh) 杂芳环类化合物及其用途
CN116249696B (zh) 嘧啶酮类化合物及其用途
TWI401258B (zh) 吡咯並嘧啶類化合物及其用途
HK1179953B (en) Pyrrolopyrimidine compounds and uses thereof
TW201311682A (zh) 稠合雜芳基化合物及其用途

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: 10856043

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: 10856043

Country of ref document: EP

Kind code of ref document: A1