US2020385369A1PendingUtilityA1
New benzimidazoles derivatives as tec kinases family inhibitors
Est. expirySep 25, 2035(~9.2 yrs left)· nominal 20-yr term from priority
C07D 409/12C07D 235/32C07D 401/12A61K 47/02A61P 31/12C07D 413/12C07D 417/12A61P 37/00A61K 45/06A61P 29/00A61P 35/00C07D 409/14C07D 413/14C07D 403/12A61K 47/16
52
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Claims
Abstract
The present invention relates to a novel family of covalent kinases inhibitors. Compounds of this class have been found to have inhibitory activity against members of the Tec kinase family, particularly ITK, BTK, BMX, Tec and/or RLK. The present invention is directed to a compound of Formula I or pharmaceutically acceptable salt, solvate, solvate of salt, stereoisomer, tautomer, isotope, prodrug, complex or biologically active metabolite thereof, and its use in therapy.
Claims
exact text as granted — not AI-modified1 - 50 . (canceled)
51 . A method for treating a subject suffering from a protein kinase mediated disease, disorder, or condition associated with the activity of at least one kinase member of the Tec kinase family, comprising administering to the subject in need thereof a therapeutically effective amount of a compound having the structure of Formula I:
or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope, prodrug, or complex thereof, wherein
R is substituted or unsubstituted thiophenyl;
L is
wherein
ring B 1 is substituted or unsubstituted cycloalkyl;
R 1 is hydrogen, lower alkyl, or lower cycloalkyl; and
n is 0 or 1;
E is:
wherein:
Ra, Rb, and Rc are independently hydrogen, halogen, —CN, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; or
Ra and Rb, taken together with the carbon atoms to which they are attached, form a 3- to 8-membered substituted or unsubstituted cycloalkyl ring or form a 3- to 8-membered substituted or unsubstituted heterocyclic ring and Rc is selected as above; or
Rb and Rc, taken together with the carbon atom to which they are attached, form a 3- to 8-membered substituted or unsubstituted cycloalkyl ring or form a 3- to 8-substituted or unsubstituted membered heterocyclic ring and Ra is selected as above; or
Ra and Rb, taken together with the carbon atoms to which they are attached, form a triple bond and Rc is selected as above;
wherein
-L-E is:
X is a bond, alkylene, -(alkylene)-NR 2 —, -(alkylene)-NR 3 —, -(alkylene)-O—, —O—, —S—, —S(O) m —, —NR 2 —, —C(O)—, —C(O)O—, —C(O)NR 2 —, —C(O)ONR 2 —, or —S(O) m NR 2 —,
wherein:
R 2 is hydrogen, lower alkyl or lower cycloalkyl;
R 3 is —C(O)R 4 , —C(O)OR 4 or —S(O) m R 4 ;
R 4 is lower alkyl or lower cycloalkyl;
m is 1 or 2; and
Y is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl.
52 . The method of claim 51 , wherein R is:
53 . The method of claim 51 , wherein
R 1 is hydrogen or methyl; n is 0; E is:
wherein:
Ra, Rb, and Rc are independently hydrogen, halogen, —CN, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted heteroalkyl, or substituted or unsubstituted cycloalkyl.
54 . The method of claim 53 , wherein -L-E is
55 . The method of claim 51 , wherein E is
56 . The method of claim 51 , wherein —X—Y is:
(a) —CH 2 —NH—Y, where
Y is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl; or
(b) —CH 2 —NR 2 —Y, where
R 2 is hydrogen, lower alkyl, or lower cycloalkyl; and
Y is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl; or
(c) —C(O)—NR 2 —Y, where
R 2 is hydrogen, lower alkyl, or lower cycloalkyl; and
Y is selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaralkyl; or
(d) —NR 2 C(O)—Y, where
R 2 is hydrogen, lower alkyl, or lower cycloalkyl; and
Y is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl; or
(e) —NR 2 SO 2 —Y, where
R 2 is hydrogen, lower alkyl, or lower cycloalkyl; and
Y is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl; or
(f) —O—CH 2 —Y, where
Y is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl; or
(g) —CH 2 —NR 3 —Y, where
R 3 is —C(O)R 4 , —C(O)OR 4 or —S(O) m R 4 , wherein
m is 1 or 2;
R 4 is lower alkyl or lower cycloalkyl; and
Y is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl; or
(h) —CH 2 —Y where
Y is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl.
57 . The method of claim 51 , wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound having the structure of Formula IIa:
or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope, prodrug, or complex thereof, wherein
R is substituted or unsubstituted thiophenyl;
m is 0, 1, 2 or 3;
n 2 is 1, 2 or 3;
R 1 is hydrogen, lower alkyl or lower cycloalkyl; and
—X—Y is —CH 2 —NH—Y, —CH 2 —NR 2 —Y, —CH 2 —NR 3 —Y, —NR 2 C(O)—Y, —C(O)NR 2 —Y, or —CH 2 —Y, wherein
R 2 is hydrogen, lower alkyl, or lower cycloalkyl;
R 3 is —C(O)R 4 , —C(O)OR 4 or —S(O) m R 4 , wherein m is 1 or 2;
R 4 is lower alkyl or lower cycloalkyl; and
Y is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl.
58 . The method of claim 51 , wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound having one of the following structures:
Compound No.
Structure
1
3
6
18
58
62
63
64
65
68
70
71
81
or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope, prodrug, or complex thereof.
59 . The method of claim 51 , wherein the at least one kinase member of the Tec kinase family is ITK, BTK, BMX, RLK, or a combination thereof.
60 . The method of claim 51 , further comprising administering a therapeutically effective amount of at least one additional active pharmaceutical ingredient for the treatment of cancer, an autoimmune disease, an allergic disease, an inflammatory disease, or a viral infection.
61 . The method of claim 51 , wherein the protein kinase mediated disease, disorder, or condition is cancer, an autoimmune disease, an allergic disease, an inflammatory disease, or a viral infection.
62 . The method of any one of claims 51 - 61 , wherein the protein kinase mediated disease, disorder, or condition is lung inflammation, allergic asthma, pneumonia, psoriasis, atopic dermatitis, uveitis, dry eye disease, arthritis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, Still's disease, juvenile arthritis, type I diabetes, inflammatory bowel disease, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Basedow's disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's disease, Takayasu arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener granuloma, alopecia universalis, Burchett disease, chronic fatigue syndrome, dysautonomia, endometriosis, interstitial cystitis, myotonia, vulvodynia, pemphigus, allergy, anaphylaxis, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, inflammatory bowel disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis nephritis, oophoritis, orchitis, osteitis, osteoarthritis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis, HIV/AIDS, influenza, T-cell lymphomas, T-cell leukemias, peripheral T-cell lymphoma, Seazry syndrome/cutaneous T-cell lymphoma, acute lymphoblastic leukemia, adult T-cell leukemia/lymphoma, NK/T-cell lymphoma, nasal type or aggressive NK-cell leukemia, or a combination thereof.
63 . A method of modulating or inhibiting in a subject protein kinase activity associated with at least one kinase member of the Tec kinase family, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula 1:
or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope, prodrug, or complex thereof, wherein
R is substituted or unsubstituted thiophenyl;
L is
wherein
ring B 1 is substituted or unsubstituted cycloalkyl;
R 1 is hydrogen, lower alkyl, or lower cycloalkyl; and
n is 0 or 1;
E is:
wherein:
Ra, Rb, and Rc are independently hydrogen, halogen, —CN, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; or
Ra and Rb, taken together with the carbon atoms to which they are attached, form a 3- to 8-membered substituted or unsubstituted cycloalkyl ring or form a 3- to 8-membered substituted or unsubstituted heterocyclic ring and Rc is selected as above; or
Rb and Rc, taken together with the carbon atom to which they are attached, form a 3- to 8-membered substituted or unsubstituted cycloalkyl ring or form a 3- to 8-substituted or unsubstituted membered heterocyclic ring and Ra is selected as above; or
Ra and Rb, taken together with the carbon atoms to which they are attached, form a triple bond and Rc is selected as above;
wherein
-L-E is:
X is a bond, alkylene, -(alkylene)-NR 2 —, -(alkylene)-NR 3 —, -(alkylene)-O—, —O—, —S—, —S(O) m —, —NR 2 —, —NR 3 —, —C(O)—, —C(O)O—, —C(O)NR 2 —, —C(O)ONR 2 —, or S(O) m NR 2 —,
wherein:
R 2 is hydrogen, lower alkyl or lower cycloalkyl;
R 3 is —C(O)R 4 , —C(O)OR 4 or —S(O) m R 4 ;
R 4 is lower alkyl or lower cycloalkyl;
m is 1 or 2; and
Y is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl.
64 . A method of inhibiting in a cell or a tissue a protein kinase associated with at least one kinase member of the Tec kinase family, comprising contacting the cell or tissue with a compound of Formula 1:
or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope, prodrug, or complex thereof, wherein
R is substituted or unsubstituted thiophenyl;
L is
wherein
ring B 1 is substituted or unsubstituted cycloalkyl;
R 1 is hydrogen, lower alkyl, or lower cycloalkyl; and
n is 0 or 1;
E is:
wherein:
Ra, Rb, and Rc are independently hydrogen, halogen, —CN, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; or
Ra and Rb, taken together with the carbon atoms to which they are attached, form a 3- to 8-membered substituted or unsubstituted cycloalkyl ring or form a 3- to 8-membered substituted or unsubstituted heterocyclic ring and Rc is selected as above; or
Rb and Rc, taken together with the carbon atom to which they are attached, form a 3- to 8-membered substituted or unsubstituted cycloalkyl ring or form a 3- to 8-substituted or unsubstituted membered heterocyclic ring and Ra is selected as above; or
Ra and Rb, taken together with the carbon atoms to which they are attached, form a triple bond and Rc is selected as above;
wherein
-L-E is:
X is a bond, alkylene, -(alkylene)-NR 2 —, -(alkylene)-NR 3 —, -(alkylene)-O—, —O—, —S—, —S(O) m —, —NR 2 —, —NR 3 —, —C(O)—, —C(O)O—, —C(O)NR 2 —, —C(O)ONR 2 —, or S(O) m NR 2 —,
wherein:
R 2 is hydrogen, lower alkyl or lower cycloalkyl;
R 3 is —C(O)R 4 , —C(O)OR 4 or —S(O) m R 4 ;
R 4 is lower alkyl or lower cycloalkyl;
m is 1 or 2; and
Y is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl.Cited by (0)
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