1. A multilayer molded article comprising:
an innermost layer including;
a first polyarylene sulfide-derived resin, composition having 95% to 80% by mass of a polyarylene sulfide-derived resin and 5% to 20% by mass of an olefinic elastomer; and
an outer layer disposed on an outer-side of the innermost layer including a second polyarylene sulfide-derived resin composition having 5 to 35 parts by mass of reinforced fiber relative to 100 parts by mass of polyarylene sulfide resin composition.
2. The multilayer molded article according to claim 1, wherein the multilayer molded article is a multilayer blow molded article.
3. The multilayer molded article according to claim 1, wherein, the multilayer molded article is a multilayer cylindrical molded article.
4. The multilayer molded article according to claim 1, wherein the melt viscosity of the first polyarylene sulfide-derived resin composition is from 300 Pa\xb7s to 1500 Pa\xb7s.
5. The multilayer molded article according to claim 1, wherein the melt viscosity of the second polyarylene sulfide-derived resin, composition is from 450 Pa\xb7s to 800 Pa\xb7s.
6. The multilayer molded article according to claim 1, wherein the reinforced fiber is a glass fiber having an average fiber length of no greater than 3 mm.
7. The multilayer molded article according to claim 1, wherein the multilayer molded article is a three-dimensional blow molded article to be used as an internal, combustion engine pipe.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A compound of formula I:
156
or a pharmaceutically acceptable salt thereof, wherein:
W1 is nitrogen or CH, W2 is nitrogen or C(U)pRU, and W3 is nitrogen or C(V)qRV;
p and q are each independently 0 or 1;
RU and RV are each independently R or Ar1;
U and V are each independently a bond or a C1-6 alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by CO, CO2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO2, NRCONR, SO, SO2, NRSO2, SO2NR, NRSO2NR, O, S, or NR;
each occurrence of R is independently hydrogen or an optionally substituted C1-C4 aliphatic, or two R bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a 3-7 membered saturated, partially unsaturated, or fully unsaturated ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ar1 is a 5-7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein Ar1 is optionally substituted with m independent occurrences of Z-R5; wherein m is 0-5, Z is a bond or is a C1-C6 alkylidene chain wherein up to two methylene units of Z are optionally replaced by CO, CO2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO2, NRCONR, SO, SO2, NRSO2, SO2NR, NRSO2NR, O, S, or NR; and each occurrence of R5 is independently hydrogen, an optionally substituted aliphatic, heteroaliphatic, aryl or heteroaryl group, halogen, NO2, CN, OR, SR, N(R)2, NRCOR, NRCON(R)2, NRCO2R, COR, CO2R, OCOR, CON(R)2, OCON(R)2, SOR, SO2R, SO2N(R)2, NRSO2R, NRSO2N(R)2, COCOR, or COCH2COR;
R1 and R2 taken together and fused to ring B form a cyclic moiety selected from one of the following:
157
wherein each occurrence of RX is independently hydrogen, QR, or QnAr1; n is zero or one; and Q is an optionally substituted C1-4 alkylidene chain wherein one methylene unit of Q is optionally replaced by CO, CO2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO2, NRCONR, SO, SO2, NRSO2, SO2NR, NRSO2NR, O, S, or NR;
R3 is halogen, QR, QnCN, QnNO2, or QnAr1; and
R4 is Ar1, or T-Ar1;
wherein T is a C1-2 alkylidene chain wherein one methylene unit of T is optionally replaced by CO, CO2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO2, NRCONR, SO, SO2, NRSO2, SO2NR, NRSO2NR, O, S, or NR.
2. The compound of claim 1, wherein R1 and R2 taken together represent heterocycle i and RX is hydrogen or optionally substituted C1-6aliphatic.
3. The compound of claim 1, wherein RX is hydrogen, methyl, ethyl, propyl, n-butyl, tert-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C1-6alkyl substituted with N(R)2, or C1-6alkyl substituted with Ar1.
4. The compound of claim 1, wherein RX is hydrogen, methyl, or C1-2alkyl substituted with a group selected from optionally substituted phenyl, pyridyl, morpholino, piperidinyl, or piperazinyl.
5. The compound of claim 1, wherein R3 is hydrogen, halogen, QR or QAr1, wherein Q is a C1-3 alkylidene chain wherein one methylene unit of Q is optionally replaced by O, S, NHCO, or NR, and Ar1 is an optionally substituted 5-6 membered saturated, partially unsaturated, or fully unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
6. The compound of claim 1, wherein R3 is hydrogen, OH, OCH3, OCH2CH3, NHCOMe, NH2, NH(C1-4 aliphatic), N(C1-4 aliphatic)2, O(CH2)2morpholin-4-yl, O(CH2)2NH2, O(CH2)2NH(C1-4aliphatic), O(CH2)2N(C1-4 aliphatic)2, Br, Cl, or F.
7. The compound of claim 1, wherein R3 is hydrogen.
8. The compound of claim 1, wherein R4 is a 6-membered saturated, partially unsaturated, or aryl ring having 0-3 nitrogens, a 9-10 membered bicyclic aryl ring having 0-2 nitrogen atoms, or a 5 membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each ring is optionally substituted.
9. The compound of claim 1, wherein R4 is optionally substituted phenyl, cyclohexyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, thiazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, indazolyl, or benzimidazolyl.
10. The compound of claim 1, wherein R4 is an optionally substituted phenyl group.
11. The compound of claim 8, wherein each occurrence of Z is independently a bond or a C1-4 alkylidene chain wherein one methylene unit of Z is optionally replaced by O, S, SO2, or NH; and each occurrence of R5 is independently hydrogen, C1-6 aliphatic, halogen, NO2, OR, N(R)2, or optionally substituted phenyl, pyridyl, or pyrimidinyl.
12. The compound of claim 8, wherein each occurrence of ZR5 is independently Cl, F, Br, methyl, ethyl, t-butyl, isopropyl, cyclopropyl, nitro, CN, OMe, OEt, CF3, NH2, phenyl, benzyl, benzyloxy, OH, methylene dioxy, SO2NH2, CONH2, CO2Me, phenoxy, O-pyridinyl, SO2phenyl, nitrophenoxy, aminophenoxy, S-dimethylpyrimidine, NHphenyl, NH-methoxyphenyl, pyridinyl, aminophenyl, phenol, chloro-fluoro-phenyl, dimethylaminophenyl, CF3-phenyl, dimethylphenyl, chlorophenyl, fluorophenyl, methoxyphenoxy, chlorophenoxy, ethoxyphenoxy, and fluorophenoxy.
13. The compound of claim 1, wherein (U)pRU and (V)qRV are each independently hydrogen, halogen, NO2, CN, OR, SR or N(R)2, or C1-4aliphatic optionally substituted with oxo, OR, SR, N(R)2, halogen, NO2 or CN.
14. The compound of claim 1, wherein (U)pRU and (V)qRV are each independently hydrogen, Me, OH, or OMe.
15. The compound of claim 1, wherein W1 is N or CH and compounds have the structure of Formula Ia or lb:
158
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1, wherein R4 is an optionally substituted phenyl group and compounds have the structure of Formula Ia or IIb:
159
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1, wherein R3 is hydrogen, and compounds have the general structure of Formula IIIa or IIIb:
160
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1, wherein R3 is hydrogen, and R1 and R2 taken together represent the heterocycle i and compounds have the general structure of Formula IVa or IVb:
161
or a pharmaceutically acceptable salt thereof.
19. The compound of any one of claims 15, 16, 17 or 18, wherein
i) R1 and R2 taken together represent the heterocycle i depicted above; where RX is defined according to one of the following groups:
a. hydrogen or optionally substituted C1-6aliphatic;
b. hydrogen, methyl, ethyl, propyl, n-butyl, tert-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C1-6alkyl substituted with N(R)2, or C1-6alkyl substituted with Ar1; or
c. hydrogen, methyl, or C1-2alkyl substituted with a group selected from optionally substituted phenyl, pyridyl, morpholino, piperidinyl, or piperazinyl.
ii) R3 is defined according to one of the following groups:
a. hydrogen, halogen, QR or QAr1, wherein Q is a C1-3 alkylidene chain wherein one methylene unit of Q is optionally replaced by O, S, NHCO, or NR, and Ar1 is an optionally substituted 5-6 membered saturated, partially unsaturated, or fully unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
b. hydrogen, OH, OCH3, OCH2CH3, NHCOMe, NH2, NH(C1-4 aliphatic), N(C1-4 aliphatic)2, O(CH2)2morpholin-4-yl, O(CH2)2NH2, O(CH2)2NH(C1-4 aliphatic), O(CH2)2N(C1-4 aliphatic)2, bromo, chloro, or fluoro; or
c. hydrogen;
iii) R4 is defined according to one of the following groups:
a. a 6-membered saturated, partially unsaturated, or aryl ring having 0-3 nitrogens, a 9-10 membered bicyclic aryl ring having 0-2 nitrogens, or a 5 membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each ring is optionally substituted;
b. an optionally substituted ring selected from phenyl, cyclohexyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, thiazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, indazolyl, or benzimidazolyl; or
c. an optionally substituted phenyl group;
iv) W1, W2 and W3 are defined according to one of the following groups:
a. W1 is nitrogen or CH, W2 is nitrogen or C(U)pRU, and W3 is nitrogen or C-(V)qRV;
b. W1 is nitrogen or CH, W2 is C(U)pRU, and W3 is C(V)qRV; or
c. W1 is nitrogen or CH and W2 and W3 are each CH; and
v) (U)pRU and (V)qRV groups are defined according to one of the following groups:
a. hydrogen, halogen, NO2, CN, OR, SR or N(R)2, or C1-4aliphatic optionally substituted with oxo, OR, SR, N(R)2, halogen, NO2 or CN;
b. hydrogen, Me, OH, OMe or N(R)2; or
c. both (U)pRU and (V)qRV are hydrogen.
20. The compound of claim 19, wherein each occurrence of Z is independently a bond or a C1-4 alkylidene chain wherein one methylene unit of Z is optionally replaced by O, S, SO2, or NH; and each occurrence of R5 is independently hydrogen, C1-6 aliphatic, halogen, NO2, OR, N(R)2, or optionally substituted phenyl, pyridyl, and pyrimidinyl.
21. The compound of claim 19, wherein each occurrence of ZR5 is independently Cl, F, Br, methyl, ethyl, t-butyl, isopropyl, cyclopropyl, nitro, CN, OMe, OEt, CF3, NH2, phenyl, benzyl, benzyloxy, OH, methylene dioxy, SO2NH2, CONH2, CO2Me, phenoxy, O-pyridinyl, SO2phenyl, nitrophenoxy, aminophenoxy, S-dimethylpyrimidine, NHphenyl, NH-methoxyphenyl, pyridinyl, aminophenyl, phenol, chloro-fluoro-phenyl, dimethylaminophenyl, CF3-phenyl, dimethylphenyl, chlorophenyl, fluorophenyl, methoxyphenoxy, chlorophenoxy, ethoxyphenoxy, or fluorophenoxy.
22. The compound of claim 1, having the formula IVa, wherein RX is hydrogen or optionally substituted C1-6aliphatic; m is 0, 1 or 2; and ZR5 is Cl, F, Br, methyl, ethyl, t-butyl, isopropyl, cyclopropyl, nitro, CN, OMe, OEt, CF3, NH2, phenyl, benzyl, benzyloxy, OH, methylene dioxy, SO2NH2, CONH2, CO2Me, phenoxy, O-pyridinyl, SO2phenyl, nitrophenoxy, aminophenoxy, S-dimethylpyrimidine, NHphenyl, NH-methoxyphenyl, pyridinyl, aminophenyl, phenol, chloro-fluoro-phenyl, dimethylaminophenyl, CF3-phenyl, dimethylphenyl, chlorophenyl, fluorophenyl, methoxyphenoxy, chlorophenoxy, ethoxyphenoxy, or fluorophenoxy.
23. The compound of claim 1, selected from one of the following compounds:
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24. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
25. The composition of claim 24, further comprising an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, a treatment for Alzheimer’s Disease, a treatment for Parkinson’s Disease, an agent for treating Multiple Sclerosis (MS), a treatment for asthma, an agent for treating schizophrenia, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an agent for treating a blood disorder, or an agent for treating an immunodeficiency disorder.
26. A method of inhibiting JAK-3 kinase activity in:
(a) a patient; or
(b) a biological sample;
which method comprises administering to said patient, or contacting said biological sample with a compound of claim 1 or a composition of claim 24.
27. A method of treating or lessening the severity of a disease or disorder selected from an immune response, an autoimmune disease, a neurodegenerative, or a solid or hematologic malignancy comprising administering to a subject in need thereof a compound of claim 1 or a composition of claim 24.
28. The method of claim 27, wherein the disease or disorder is selected from an allergic or type I hypersensitivity reaction, asthma, transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, multiple sclerosis, Familial amyotrophic lateral sclerosis (FALS), leukemia, or lymphoma.
29. The method of claim 28, comprising the further step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, a treatment for Alzheimer’s Disease, a treatment for Parkinson’s Disease, an agent for treating Multiple Sclerosis (MS), a treatment for asthma, an agent for treating schizophrenia, an antiinflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an agent for treating a blood disorder, or an agent for treating an immunodeficiency disorder, wherein:
said additional therapeutic agent is appropriate for the disease being treated; and
said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.