CN109963853A - One kind has the degradation active compound of tyrosine protein kinase JAK3 - Google Patents
One kind has the degradation active compound of tyrosine protein kinase JAK3 Download PDFInfo
- Publication number
- CN109963853A CN109963853A CN201880004075.3A CN201880004075A CN109963853A CN 109963853 A CN109963853 A CN 109963853A CN 201880004075 A CN201880004075 A CN 201880004075A CN 109963853 A CN109963853 A CN 109963853A
- Authority
- CN
- China
- Prior art keywords
- substituent group
- alkyl
- integer
- independently selected
- compound
- 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.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
Abstract
One kind having the degradation active compound of tyrosine protein kinase JAK3, and the structural formula of compound is shown in formula I, can be used for preparing the drug for the treatment of JAK3 related disease.
Description
The invention belongs to field of medicaments, have the active compound of degradation tyrosine protein kinase JAK3 and its preparation and application more particularly to one kind.
Janus kinases (JAKs) is to be present in intracellular non-receptor tyrosine protein kinase, particularly significant to multiple functions such as T cell growth, activation and steady-state adjustments, is played a crucial role in adjusting lymphohematological cell function.In mammal, which contains 4 principal home's family members, i.e. JAK1, JAK2, JAK3 and Tyk2.Wherein, JAK1, JAK2 and the Tyk2 wide expression in various histocytes, the JAK3 mainly high efficient expression in hematopoietic tissue, such as bone-marrow-derived lymphocyte, T lymphocyte, bone marrow cell and the thymocyte of activation.
Due to the extensive adjustment effect of JAK3-STAT signal path, organ-graft refection, heterograft, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, psoriasis (psoriasis), cancer, asthma, atopic dermatitis, type-1 diabetes mellitus and diabetic complication, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer disease, leukaemia, lymthoma, Huppert's disease, alopecia areata, many diseases such as leucoderma also relate to JAK3, JAK3 plays a crucial role in disease generation as signal transmitting member, the drug targets of this kind of disease are treated as exploitation in medicine research and development.
Therefore, those skilled in the art, which are dedicated to developing, is able to suppress the active compound of JAK3.
Summary of the invention
It is able to suppress and the compound for the JAK3 that degrades it is an object of the invention to provide a kind of, and its preparation and application.
In the first aspect of the present invention, provide a kind of such as following formula I compound represented or its pharmaceutically acceptable salt:
Wherein:
Indicate singly-bound；
Indicate singly-bound or double bond；
A missing is selected from C (=O), C (=O) X1, SOX1, SO
2The C of X1, with or without substituent group
1-8The C of alkyl, with or without substituent group
1-8The C of cyclic hydrocarbon radical and with or without substituent group
1-8Heterocyclic hydrocarbyl；Wherein X1 lacks or is selected from (CR
12R
13)
eO、(CR
12R
13)
eS and NR
14；Wherein R
12、R
13、R
14It is independently selected from the C of H, with or without substituent group
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical and with or without substituent group C
1-8Heterocyclic hydrocarbyl, e be 0 to 3 between integer (such as 1,2 or 3)；
W missing is selected from O, NR
17,-X2C (=O) X3 ,-X2S (=O)
gX3；Wherein R
17For H, the C of with or without substituent group
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical, with or without substituent group C
1-8Heterocyclic hydrocarbyl；Wherein X2, X3 are independent lacks or is selected from O, S, NR
18、(CH
2)
gO；The wherein integer that each g is 0 to 2；Wherein R
18For H, the C of with or without substituent group
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical, with or without substituent group C
1-8Heterocyclic hydrocarbyl；
Y is (CR
22R
23)
h、CHX4(CR
22R
23)
h, CX4=CH (CR
22R
23)
hOr (CR
22R
23)
h；Wherein h is the integer between 0 to 30；Wherein R
22、R
23It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical, with or without substituent group C
1-8Heterocyclic hydrocarbyl, with or without substituent group C
1-8Oxyl；Wherein X4 is H, halogen, cyano, nitro, hydroxyl, with or without substituent group C
1-8Oxyl, with or without substituent group C
1-8Hydrocarbon carbonyl oxygen, with or without substituent group C
1-8Amido, with or without substituent group C
1-8Ester group, with or without substituent group C
1-8Amino-carbonyl, with or without substituent group C
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical, with or without substituent group C
1-8Heterocyclic hydrocarbyl；
Z is (CR
24R
25)
i、CHX5(CR
24R
25)
i, CX5=CH (CR
24R
25)
iOr C ≡ C (CR
24R
25)
i；Wherein i is the integer between 0 to 30；Wherein R
24、R
25It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical, with or without substituent group C
1-8Heterocyclic hydrocarbyl, with or without substituent group C
1-8Oxyl；Wherein X5 is H, halogen, cyano, nitro, hydroxyl, with or without substituent group C
1-8Oxyl, with or without substituent group C
1-8Hydrocarbon carbonyl oxygen, with or without substituent group C
1-8Amido, with or without substituent group C
1-8Ester group, with or without substituent group C
1-8Amino-carbonyl, with or without substituent group C
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical, with or without substituent group C
1-8Heterocyclic hydrocarbyl；
B missing is selected from O, C=O, S, NR
15、-NR
15C (=O)-,-C (=O) NR
15,-C (=O) O-, OC (=O) O- ,-NR
15C (=O) O- ,-OC (=O) NR
15-、-NR
15C (=O) NR
16, with or without substituent group C
1-12Alkyl, with or without substituent group C
1-12Cyclic hydrocarbon radical and with or without substituent group C
1-12Heterocyclic hydrocarbyl；Wherein R
15、R
16It is independently selected from the C of H, with or without substituent group
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical and with or without substituent group C
1-8Heterocyclic hydrocarbyl；
X is selected from CR
19R
20, C (=O), S (=O), SO
2、NR
21；Wherein R
19、R
20It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical, with or without substituent group C
1-8Heterocyclic hydrocarbyl, with or without substituent group C
1-8Oxyl；Wherein R
21C selected from H, with or without substituent group
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical, with or without substituent group C
1-8Heterocyclic hydrocarbyl；
R
1、R
6、R
10It is each independently selected from the C of H, with or without substituent group
1-8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, with or without substituent group C
1-6Acyl group；
R
2、R
5It is independently selected from: hydrogen, OR
33、NR
34R
35, cyano, halogen, with or without substituent group C
1~8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, with or without substituent group C
1-6The amide groups of acyl group, with or without substituent group；Wherein R
33、R
34、R
35It is independently selected from the C of H, with or without substituent group
1~8Alkyl, with or without substituent group cyclic hydrocarbon radical, the heterocyclic hydrocarbyl of with or without substituent group；
R
3、R
7、R
8、R
9It is independently selected from: H, OR
27、NR
28R
29, cyano, halogen, nitro, with or without substituent group C
1-8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, X6S (=O)
kR
30, X6C (=O) R
31；Wherein k is the integer between 0 to 2；Wherein R
27, R
28, R
29, R
30, R
31It is independently selected from the C of H, with or without substituent group
1~8Alkyl, cyclic hydrocarbon radical, heterocyclic hydrocarbyl；Wherein X6 lacks or is selected from O, S, NR
32；Wherein R
32For H, the C of with or without substituent group
1-8Alkyl, the cyclic hydrocarbon radical of with or without substituent group and the heterocyclic hydrocarbyl of with or without substituent group；
R
4Selected from H, cyano, carboxyl, with or without substituent group C
1-8Alkyl, with or without substituent group hydrocarbon carbonyl oxygen；
A is the integer (such as 1,2,3,4,5) between 0 to 5；
B is the integer (such as 1,2,3) between 0 to 3；
C is the integer (such as 1,2,3,4,5,6,7,8,9) between 0 to 30；
D is the integer (such as 1,2,3,4,5,6,7,8,9) between 0 to 9.
In another preferred example, A is lacked；W is X2C (=O) X3, wherein X2 NR
18And X3 missing or X3 are NR
18And X2 is lacked；Y is (CR
22R
23)
h, wherein R
22、R
23It is independently selected from the C of H, hydroxyl, with or without substituent group
1-4Alkyl, h be 1 to 6 between integer；Z is (CR
24R
25)
i, wherein R
24、R
25It is independently selected from the C of H, hydroxyl, with or without substituent group
1-4Alkyl, i be 1 to 6 between integer；C is 0.
In another preferred example, A is lacked；W missing is O；Y is (CR
22R
23)
h, wherein R
22、R
23It is independently selected from the C of H, hydroxyl, with or without substituent group
1-4Alkyl, h be 0 to 3 between integer；B is O；Z is (CR
24R
25)
i, wherein R
24、R
25It is independently selected from the C of H, hydroxyl, with or without substituent group
1-4Alkyl, i be 0 to 3 between integer；C is the integer between 1 to 6.
In another preferred example, A is C (=O) X1, and wherein X1 lacks or be selected from (CR
12R
13)
eAnd (CR O,
12R
13)
eS, wherein e is the integer between 0 to 2, R
12、R
13、R
14Independent is hydrogen or C
1-4Alkyl；W is O or NR
17, wherein R
17For the H or C of with or without substituent group
1-4Alkyl；Y is (CR
22R
23)
h, wherein R
22、R
23It is independently selected from the C of H, hydroxyl, with or without substituent group
1-4Alkyl, h be 0 to 3 between integer；Z is (CR
24R
25)
i, wherein R
24、R
25It is independently selected from the C of H, hydroxyl, with or without substituent group
1-4Alkyl, i be 0 to 3 between integer；B is O；C is the integer between 1 to 4.
In another preferred example, A SO
2X1, wherein X1 lacks or is selected from O and S；W is O；Y is (CR
22R
23)
h, wherein R
22、R
23It is independently selected from the C of H, hydroxyl, with or without substituent group
1-4Alkyl, h be 1 to 6 between integer；Z is (CR
24R
25)
i, wherein R
24、R
25It is independently selected from the C of H, hydroxyl, with or without substituent group
1-4Alkyl, i be 0 to 3 between integer；C is 0.
In another preferred example, A is lacked；W is NR
17, wherein R
17For the H or C of with or without substituent group
1-4Alkyl；Y is (CR
22R
23)
h, wherein R
22、R
23It is independently selected from the C of H, hydroxyl, with or without substituent group
1-4Alkyl, h be 0 to 3 between integer；Z is (CR
24R
25)
i, wherein R
24、R
25It is independently selected from the C of H, hydroxyl, with or without substituent group
1-4Alkyl, i be 0 to 4 between integer；B is O；C is the integer between 1 to 6.
In another preferred example, A is lacked；W missing；Y is (CR
22R
23)
h, wherein R
22、R
23It is independently selected from the C of H, hydroxyl, with or without substituent group
1-4Alkyl, h be 0 to 3 between integer；Z is (CR
24R
25)
i, wherein R
24、R
25It is independently selected from the C of H, hydroxyl, with or without substituent group
1-4Alkyl, i be 0 to 3 between integer；B is O；C is the integer between 1 to 10 (between preferably 1 to 6).
In another preferred example, A is C (=O) X1, and wherein X1 lacks or be selected from (CR
12R
13)
eAnd (CR O,
12R
13)
eS, wherein e is the integer between 0 to 2, R
12、R
13、R
14Independent is hydrogen or C
1-4Alkyl；W is O, NR
17,-X2C (=O) X3 or missing, wherein R
17For the H or C of with or without substituent group
1-4Alkyl；Y is CHX4 (CR
22R
23)
h, wherein R
22、R
23It is independently selected from the C of H, hydroxyl, with or without substituent group
1-4Alkyl, h be 0 to 3 between integer, X4 be cyano, nitro or hydroxyl；Z is (CR
24R
25)
i, wherein R
24、R
25It is independently selected from the C of H, hydroxyl, with or without substituent group
1-4Alkyl, i be 0 to 15 between integer；B is O；C is the integer between 0 to 10 (between preferably 0 to 6).
In another preferred example, any substituent group is selected from the group: halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C1-C6 alkoxy, unsubstituted or halogenated C2-C6 alkoxyalkyl, unsubstituted or halogenated C3-C8 naphthenic base, unsubstituted or halogenated C2-C6 alkyl-carbonyl, unsubstituted or halogenated C1-C6 alkylidene-hydroxyl, the alkyl-substituted amido of unsubstituted or C1-C6.
In another preferred example, A is C (=O)；Y is (CR
22R
23)
h, wherein R
22、R
23It is independently selected from H, hydroxyl, CN, h is the integer between 1 to 3；Preferably, R
22For H, R
23For CN, and h is 1.
In another preferred example, the compound structure such as Formulas I ' shown in:
Wherein, Formulas I ' in each group it is as defined above.
In another preferred example, shown in the compound structure such as Formulas I ":
Wherein, each group is as defined above in Formulas I ".
In another preferred example, in Formulas I, I ' or Formulas I ",
Indicate singly-bound.
In another preferred example, the X is C (=O).
In another preferred example, R
1It is selected from: the C of H and with or without substituent group
1-4Alkyl.
In another preferred example, R
2、R
5It is independently selected from: the C of hydrogen and with or without substituent group
1-4Alkyl.
In another preferred example, R
3It is selected from: the C of hydrogen and with or without substituent group
1-4Alkyl.
In another preferred example, R
6It is selected from: the C of hydrogen, with or without substituent group
1-4Alkyl, OR
29Wherein R
29C selected from H, with or without substituent group
1-6Alkyl.
In another preferred example, R
7It is selected from: the C of hydrogen, with or without substituent group
1-4Alkyl and NR
28R
29, wherein R
28R
29For the H or C of with or without substituent group
1-4Alkyl.
In another preferred example, R
8It is selected from: the C of hydrogen, halogen and with or without substituent group
1-4Alkyl.
In another preferred example, R
9It is selected from: the C of hydrogen, halogen and with or without substituent group
1-4Alkyl.
In another preferred example, R
10Be selected from: hydrogen, halogen, cyano, nitro and with or without substituent group C
1-4Alkyl.
In another preferred example, R
4Selected from H, cyano, with or without substituent group C
1-6Alkyl.
The second aspect of the present invention, provides a kind of pharmaceutical composition, and the composition contains compound described in first aspect or its pharmaceutically acceptable salt, prodrug and pharmaceutically acceptable carrier.
In another preferred example, the effective quantity refers to therapeutically effective amount or inhibits effective quantity, preferably 0.01~99.99%.
In another preferred example, described pharmaceutical composition also includes another or a variety of antitumor agents.
In another preferred example, pharmaceutical composition degradation JAK3.
In another preferred example, the pharmaceutical composition is for treating JAK3 activity or the relevant disease of expression quantity.
The third aspect of the present invention provides the purposes of compound as described in the first aspect of the invention, is used for:
(a) drug of preparation treatment disease relevant to JAK3 activity or expression quantity；
(b) preparation JAK3 targets degradation agent；
(c) the external non-therapeutic ground JAK3 that degrades；
(d) inhibit tumor cell proliferation to external non-therapeutic；And/or
(e) treatment disease relevant to JAK3 activity or expression quantity.
In another preferred example, the disease relevant to JAK3 activity or expression quantity is tumour or autoimmune disease.
In another preferred example, the activity to JAK3 or the relevant disease of expression quantity are selected from the group: organ-graft refection, xenograft rejection, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, psoriasis (psoriasis), cancer, asthma, atopic dermatitis, type-1 diabetes mellitus and diabetic complication, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer disease, leukaemia, lymthoma, Huppert's disease, alopecia areata and leucoderma etc..
The fourth aspect of the present invention provides a kind of preparation method of compound of formula I as described in the first aspect of the invention, comprising steps of
(a) it in atent solvent, is reacted with formula IV compound and Formula II compound, obtains compound of formula I；
In the above formulas, each group is as defined above, M
1For leaving group.
In another preferred example, the method also includes steps:
(b) it in atent solvent, is reacted with formula III compound and Formula V compound, obtains Formula II compound, M
1、M
2For leaving group.
The fifth aspect of the present invention, provide the method for JAK3 that degrades a kind of, comprising steps of applying a effective amount of compound of formula I as described in the first aspect of the invention or its pharmaceutically acceptable salt to effective object, or inhibit a effective amount of pharmaceutical composition as described in the fourth aspect of the present invention to inhibiting object to apply.
In another preferred example, the degradation is external non-therapeutic.
In another preferred example, when applying a effective amount of compound of formula I as described in the first aspect of the invention or its pharmaceutically acceptable salt to effective object, the inhibition effective quantity is 0.001-500nmol/L, preferably 0.01-200nmol/L.
The sixth aspect of the present invention, provide a kind of method for treating disease relevant to JAK3 activity or expression quantity, the described method includes: to the compound of formula I as described in the first aspect of the invention for the treatment of object application therapeutically effective amount, or the pharmaceutical composition as described in the 4th invention of the invention.
In another preferred example, the object is mammal；Preferably, the mammal is behaved.
In another preferred example, the disease relevant to JAK3 activity or expression quantity is tumour or autoimmune disease.
In another preferred example, the activity to JAK3 or the relevant disease of expression quantity are selected from the group: organ-graft refection, xenograft rejection, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, psoriasis (psoriasis), cancer, asthma, atopic dermatitis, type-1 diabetes mellitus and diabetic complication, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer disease, leukaemia, lymthoma, Huppert's disease, alopecia areata and leucoderma etc..
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and it can be combined with each other between each technical characteristic specifically described in below (e.g. embodiment), to form a new or preferred technical solution.Due to space limitations, I will not repeat them here.
The present inventor after extensive and in-depth study, is prepared for a kind of compound with structure shown in Formulas I, and find it with JAK3 degrading activity.And the compound is at much lower concentrations, degradation can be generated to JAK3, activity is quite excellent, thus can be used for treating disease such as tumour relevant to JAK3 activity or expression quantity.The present invention is completed on this basis.
The present invention provides the purposes of a kind of noval chemical compound and its tyrosine protein kinase JAK3 that degrades.The compound of the present invention can degrade JAK3, and it can be used as JAK3 degradation agent two and wave immunoregulation effect, and the diseases such as rheumatoid arthritis, psoriasis, psoriasis arthropathica, ankylosing spondylitis, atopic dermatitis, keratoconjunctivitis sicca and Crohn disease for treating mammal.
Term
In the present invention, term " C
1-8Alkyl " refers to the functional group for containing only two kinds of carbon, hydrogen atoms, wherein the number of carbon atom is 1~8.Alkyl can be regarded as corresponding hydrocarbon and lose remaining free radical after a hydrogen atom, can be alkyl, naphthenic base, alkenyl or alkynyl etc.；Its structure can be straight chain, branch or ring-type；It can be aliphatic, be also possible to aromatic.
Term " C
1-6Alkyl " refers to the linear or branched alkyl group with 1~6 carbon atom, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, sec-butyl, tert-butyl, or similar group.
The term as used herein " alkoxy " includes O- alkyl, and " alkyl " therein is as defined above.
Term used herein " halogenated " unless otherwise directed, including fluoro, chloro, bromo or iodo.
The compound of the present invention can contain double bond.When containing this kind of double bond, the compound of the present invention exists with or mixtures thereof cis-, trans-.
Halogen described herein includes fluorine, chlorine, bromine and iodine.
Unless otherwise directed, the moieties of alkyl and alkoxy referred to herein can be straight chain, branch or cricoid.
In the present invention, term " cyclic hydrocarbon radical " refers to the functional group containing two kinds of carbon, hydrogen atoms.Including naphthenic base, cycloalkenyl (at least containing a carbon-carbon double bond) and aryl.They can be monocycle, bicyclic and polycyclic.They can be loop coil, be also possible to condensed ring.
In the present invention, term " heterocyclic hydrocarbyl " refers to containing carbon, hydrogen and at least one heteroatomic functional group in addition to carbon, hydrogen.Including Heterocyclylalkyl, heterocycloalkenyl (at least containing a carbon-carbon double bond) and heteroaryl.One or more ring member nitrogen atoms in ring are hetero atom.Hetero atom can be O, N and S atom and their various combinations.They can be monocycle, bicyclic and polycyclic.They can be loop coil, be also possible to condensed ring.
In the present invention, term " substituent group " includes but is not limited to fluorine, chlorine, bromine, cyano, hydroxyl, amino, C
1-6Oxyl, C
1-6Halohydrocarbyl, C
1-6Acyl group, C
1-6Sulfonyl.
The term as used herein " oxyl " refers to O- alkyl, and " alkyl " therein is as defined above.
The term as used herein " hydrocarbon carbonyl oxygen " refers to C (=O) O- alkyl, and " alkyl " therein is as defined above.
The term as used herein " amido " refers to N (H or alkyl 1) (H or alkyl 2), and " alkyl " therein is as defined above.
The term as used herein " amino-carbonyl " refers to C (=O)-amido, and " amido " therein is as defined above.
The term as used herein " amide groups " refers to N (H or alkyl)-C (=O)-alkyl, and " alkyl " therein is as defined above.
In the present invention, term " containing ", "comprising" or " comprising " indicate that various composition can be applied in mixture or composition of the invention together.Therefore, term " mainly by ... form " and " consist of " were included in term " containing ".
In the present invention, term " pharmaceutically acceptable " ingredient refers to suitable for people and/or animal and without excessive bad side reaction (such as toxicity, stimulation and allergy), that is, has the substance of reasonable benefit/risk ratio.
In the present invention, term " effective quantity " refers to therapeutic agent treatment, alleviates or prevent the amount of target disease or situation, or shows the detectable amount for treating or preventing effect.Combination for therapeutic agent and/or therapeutic agent that figure and health status, the property and degree of illness and selection that the accurate effective quantity of certain an object depends on the object are given.Therefore, it is useless for preassigning accurate effective quantity.However, can determine the effective quantity with routine experiment for the situation that Mr. Yu gives, clinician can judge.
Herein, except place is illustrated, term " substitution " refers to that one or more hydrogen atoms on group are replaced by substituent group selected from the group below: halogen, unsubstituted or halogenated C
1-6Alkyl, unsubstituted or halogenated C
2-6Acyl group, unsubstituted or halogenated C
1-6Alkyl-hydroxyl.
Unless stated otherwise, in the present invention, the compound occurred is intended to including all possible optical isomer, such as the compound of single chiral or the mixture (i.e. racemic modification) of various different chipal compounds.Among all compounds of the invention, each asymmetric carbon atom can be optionally the mixture of R configuration or S configuration or R configuration and S configuration.
As used herein, term " the compounds of this invention " refers to Formulas I compound represented.The term further includes and various crystalline forms, pharmaceutically acceptable salt, hydrate or the solvate of compound of formula I.
As used herein, term " pharmaceutically acceptable salt " refers to that the compounds of this invention and acid or alkali are formed by the salt for being suitable as drug.Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is the salt that the compounds of this invention and acid are formed.The acid for suitably forming salt includes but is not limited to: the inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzene methanesulfonic acid, the organic acids such as benzene sulfonic acid；And the acidic amino acids such as aspartic acid, glutamic acid.
Compound and its pharmaceutically acceptable salt
The present invention relates to compounds of Formula I or its pharmaceutically acceptable salts；
Wherein:
Indicate singly-bound；
Indicate singly-bound or double bond；
A missing is selected from C (=O), C (=O) X1-, SOX1-, SO
2The C of X1-, with or without substituent group
1-8The C of alkyl, with or without substituent group
1-8The C of cyclic hydrocarbon radical and with or without substituent group
1-8Heterocyclic hydrocarbyl；Wherein X1 lacks or is selected from (CR
12R
13)
eO、(CR
12R
13)
eS and NR
14；Wherein R
12、R
13、R
14It is independently selected from the C of H, with or without substituent group
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical and with or without substituent group C
1-8Heterocyclic hydrocarbyl, e be 0 to 3 between integer；
W missing is selected from O, NR
17,-X2C (=O) X3 ,-X2S (=O)
gX3；Wherein R
17For H, the C of with or without substituent group
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical, with or without substituent group C
1-8Heterocyclic hydrocarbyl；Wherein X2, X3 are independent lacks or is selected from O, S, NR
18；The wherein integer that g is 0 to 2；Wherein R
18For H, the C of with or without substituent group
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical, with or without substituent group C
1-8Heterocyclic hydrocarbyl；
Y is (CR
22R
23)
h、CHX4(CR
22R
23)
h, CX4=CH (CR
22R
23)
hOr (CR
22R
23)
h；Wherein h is the integer between 0 to 30；Wherein R
22、R
23It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical, with or without substituent group C
1-8Heterocyclic hydrocarbyl, with or without substituent group C
1-8Oxyl；Wherein X4=H, halogen, cyano, nitro, hydroxyl, with or without substituent group C
1-8Oxyl, with or without substituent group C
1-8Hydrocarbon carbonyl oxygen, with or without substituent group C
1-8Amido, with or without substituent group C
1-8Ester group, with or without substituent group C
1-8Amino-carbonyl, with or without substituent group C
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical, with or without substituent group C
1-8Heterocyclic hydrocarbyl；
Z is (CR
24R
25)
i、CHX5(CR
24R
25)
i, CX5=CH (CR
24R
25)
iOr C ≡ C (CR
24R
25)
i；Wherein i is the integer between 0 to 30；Wherein R
24、R
25It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical, with or without substituent group C
1-8Heterocyclic hydrocarbyl, with or without substituent group C
1-8Oxyl；Wherein X5=H, halogen, cyano, nitro, hydroxyl, with or without substituent group C
1-8Oxyl, with or without substituent group C
1-8Hydrocarbon carbonyl oxygen, with or without substituent group C
1-8Amido, with or without substituent group C
1-8Ester group, with or without substituent group C
1-8Amino-carbonyl, with or without substituent group C
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical, with or without substituent group C
1-8Heterocyclic hydrocarbyl；
B missing is selected from O, C=O, S, NR
15、-NR
15C (=O)-,-C (=O) NR
15,-C (=O) O-, OC (=O) O- ,-NR
15C (=O) O- ,-OC (=O) NR
15-、-NR
15C (=O) NR
16, with or without substituent group C
1-12Alkyl, with or without substituent group C
1-12Cyclic hydrocarbon radical and with or without substituent group C
1-12Heterocyclic hydrocarbyl；Wherein R
15、R
16It is independently selected from the C of H, with or without substituent group
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical and with or without substituent group C
1-8Heterocyclic hydrocarbyl；
X is selected from CR
19R
20, C (=O), S (=O), SO
2、NR
21；Wherein R
19、R
20It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical, with or without substituent group C
1-8Heterocyclic hydrocarbyl, with or without substituent group C
1-8Oxyl；Wherein R
21C selected from H, with or without substituent group
1-8Alkyl, with or without substituent group C
1-8Cyclic hydrocarbon radical, with or without substituent group C
1-8Heterocyclic hydrocarbyl；
R
1、R
6、R
10It is each independently selected from the C of H, with or without substituent group
1-8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, with or without substituent group C
1-6Acyl group；
R
2、R
5It is independently selected from: hydrogen, OR
33、NR
34R
35, cyano, halogen, with or without substituent group C
1~8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, with or without substituent group C
1-6The amide groups of acyl group, with or without substituent group；Wherein R
33、R
34、R
35It is independently selected from the C of H, with or without substituent group
1~8Alkyl, with or without substituent group cyclic hydrocarbon radical, the heterocyclic hydrocarbyl of with or without substituent group；
R
3、R
7、R
8、R
9It is independently selected from: H, OR
27、NR
28R
29, cyano, halogen, nitro, with or without substituent group C
1-8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, X6S (=O)
kR
30, X6C (=O) R
31；Wherein k is the integer between 0 to 2；Wherein R
27, R
28, R
29, R
30, R
31It is independently selected from the C of H, with or without substituent group
1~8Alkyl, cyclic hydrocarbon radical, heterocyclic hydrocarbyl；Wherein X6 lacks or is selected from O, S, NR
32；Wherein R
32For H, the C of with or without substituent group
1-8Alkyl, the cyclic hydrocarbon radical of with or without substituent group and the heterocyclic hydrocarbyl of with or without substituent group；
R
4Selected from H, cyano, carboxyl, with or without substituent group C
1-8Alkyl, with or without substituent group hydrocarbon carbonyl oxygen；
A is the integer (such as 1,2,3,4,5) between 0 to 5；
B is the integer (such as 1,2,3) between 0 to 3；
C is the integer (such as 1,2,3,4,5,6,7,8,9) between 0 to 30；
D is the integer (such as 1,2,3,4,5,6,7,8,9) between 0 to 9.
Unless otherwise instructed, integer described herein can be 0,1,2,3,4,5,6,7,8 or 9.
In another preferred example, each C1-8 cyclic hydrocarbon radical is preferably C3-8 cyclic hydrocarbon radical (such as C3-8 naphthenic base).
In another preferred example, each C1-8 heterocyclic hydrocarbyl is preferably C3-8 heterocyclic hydrocarbyl (the 4-10 membered heterocycloalkyl such as containing 3-8 carbon atom).
It is preferably carried out in mode at of the invention one, the compound is selected from the group:
The compound of the present invention packet can form pharmaceutically acceptable salt with inorganic acid, organic acid or alkali.The inorganic acid includes but is not limited to hydrochloric acid, hydrobromic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid etc.；The organic acid includes but is not limited to methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzene sulfonic acid, p- toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, lactic acid, tartaric acid, malonic acid, glycolic, succinic acid and propionic acid etc.；The alkali includes but is not limited to inorganic salts and amine.
Term pharmaceutically acceptable salt refers to according to medical judgment suitable for contacting the tissue of people and mammal and without those of excessive toxicity, stimulation, allergic reaction etc. salt.Pharmaceutically acceptable salt is well known in the art.
Present invention also contemplates that the pharmaceutical composition of pro-drug containing a compound of formula I.Pro-drug includes such compound, and wherein precursor molecule is covalently bound on free carboxy, hydroxyl, amino or the amido of compound of formula I by carbonic acid ester bond, urethane bond, amido bond, alkyl ester bond, phosphoric acid ester bond, phosphoramidic acid ester bond.
The preparation of compound
Preparation method
The preparation method of formula I structural compounds is described more particularly below, but these specific methods do not form any restrictions to the present invention.Various synthetic methods describing in the present specification or known in the art can also optionally be combined and are easily made by the compounds of this invention, and such combination can readily be carried out by those skilled in the art in the invention.
Following reaction process illustrates the preparation of the compounds of this invention.Unless otherwise directed, A, B, W, Y, Z, X, a, b, c, d, R in reaction process and the discussion below
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、R
9、R
10It is as defined above.
In general, the slave formula III as described in following proposal obtains the compound of Formulas I:
In compound II, when W is ether, formula III (W1=OH) can be used and prepared under alkali effect with the direct nucleophilic displacement of fluorine of the intermediate containing leaving group, or reaction prolonged using light reacts with alcohol and prepare；When W is ester, carbamate (NHCO
2) when, formula III (W1=OH) can be used and react preparation with acyl chlorides, Acibenzolar (amide), carboxylic acid, isocyanates under alkali effect；When W is amine, formula III (W1=NH can be used
2) prepared under alkali effect with the direct nucleophilic displacement of fluorine of the intermediate containing leaving group, formula III (W1=NH can also be used
2) with aldehyde/ketone reductive amination process is carried out to prepare；When W is amide, alkoxy carbonyl group amine (OCONH) and urea, formula III (W1=NH can be used
2) under alkali effect with corresponding acyl chlorides, Acibenzolar (amide), carboxylic acid, isocyanates react preparation.
It, can be with directly replacing or prepared by reduction amination when A and nitrogen-atoms are keyed with C-N in compound I；When A and nitrogen-atoms are connected in a manner of amide, urea, carbamate, sulfonamide, sulphamide, can be prepared with corresponding acyl chlorides, Acibenzolar (amide), carboxylic acid, isocyanates, sulfonic acid chloride, chlorosulfuric acid.
In general, the case where according to connection structure A and W, compound I can also react to obtain by elder generation formula IV and intermediate chain link, then with formula III.Chemical synthesis process used is same as above.
Formula III, IV compound can be obtained by known synthetic method or be easy through commercially available acquisition.
The application of compound of formula I
The compound of formula I can be used for one or more purposes below:
(a) drug of preparation treatment disease relevant to JAK3 activity or expression quantity；
(b) preparation JAK3 targets degradation agent；
(c) the external non-therapeutic ground JAK3 that degrades；
(d) inhibit tumor cell proliferation to external non-therapeutic；And/or
(e) treatment disease (such as autoimmune disease) relevant to JAK3 activity or expression quantity.
In another preferred example, the activity to JAK3 or the relevant disease of expression quantity are organ-graft refection, heterograft, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, psoriasis (psoriasis), cancer, asthma, atopic dermatitis, type-1 diabetes mellitus and diabetic complication, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer disease, leukaemia, lymthoma, Huppert's disease, alopecia areata, leucoderma etc..
Compound of formula I of the invention can be used for preparing a kind of pharmaceutical composition, and the pharmaceutical composition includes: (i) a effective amount of compound of formula I or its pharmaceutically acceptable salt；(ii) pharmaceutically acceptable carrier.
In another preferred example, the effective quantity refers to therapeutically effective amount or inhibits effective quantity.
The method that compound of formula I of the invention can be also used for inhibition or the cloth JAK3 that degrades, the inhibition is that the inhibition of external non-therapeutic is also possible to therapeutic inhibition.
In another preferred example, when to inhibiting object application to inhibit a effective amount of compound of formula I of the invention or its pharmaceutically acceptable salt, the inhibition effective quantity is 0.001-500nmol/L, preferably 0.01-200nmol/L.
Particularly, the present invention also provides a kind of methods for the treatment of and JAK3 activity or the relevant disease of expression quantity, which comprises applies the compound of formula I of therapeutically effective amount to treatment object or described contains pharmaceutical composition of the compound of formula I as effective component.
Pharmaceutical composition and method of administration
Since the compounds of this invention can degrade JAK3 significantly to play to JAK3 inhibitory activity, therefore the compounds of this invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and containing the pharmaceutical composition that the compounds of this invention is main active can be used for treating, prevent and alleviates by JAK3 is active or the relevant disease of expression quantity.According to the prior art, the compounds of this invention can be used for treating the disease including tumour etc..
Pharmaceutical composition of the invention includes the compounds of this invention or its pharmacologically acceptable salt and pharmacologically acceptable excipient or carrier within the scope of safe and effective amount.Wherein " safe and effective amount " refers to: the amount of compound is enough to be obviously improved the state of an illness, and is unlikely to generate serious side effect.In general, pharmaceutical composition contains 1-2000mg the compounds of this invention/agent, more preferably, contain 5-200mg the compounds of this invention/agent.Preferably, described is " one " for a capsule or tablet.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solids or liquid filler or gelatinous mass, they are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity.In " compatibility " referred to herein as composition each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the drug effect of compound.Pharmaceutically acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame oil, peanut oil, olive oil), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite), emulsifier
Wetting agent (such as lauryl sodium sulfate), colorant, flavoring agent, stabilizer, antioxidant, preservative, apirogen water.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representative method of application includes (but being not limited to): in oral, tumor, rectum, parenteral (intravenous, intramuscular or subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid dosage forms, reactive compound is mixed at least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or mixed with following compositions: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) adhesive, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizer, for example, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates and sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as cetanol and glycerin monostearate；(h) adsorbent, for example, kaolin；Or mixtures thereof (i) lubricant, for example, talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl sodium sulfate,.In capsule, tablet and pill, dosage form also may include buffer.
Coating and shell material preparation can be used in solid dosage forms such as tablet, sugar-pill, capsule, pill and granule, such as casing and other materials well known in the art.They may include opacifying agent, also, the release of reactive compound or compound can discharge in certain a part in the digestive tract in a delayed fashion in this composition.The example of adoptable embedding component is polymeric material and wax material.When necessary, reactive compound can also be with one of above-mentioned excipient or a variety of formation microencapsulation forms.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture.In addition to active compounds, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, solubilizer and emulsifier, example is known, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethylformamide and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or the mixture of these substances etc..
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweetener, tender taste agent and fragrance.
In addition to active compounds, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.Suitable aqueous and nonaqueous carrier, diluent, solvent or excipient includes water, ethyl alcohol, polyalcohol and its suitable mixture.
The dosage form of the compounds of this invention for local administration includes ointment, powder, patch, stock solution and inhalant.Active constituent is aseptically mixed together with physiologically acceptable carrier and any preservative, buffer, or the propellant that may be needed when necessary.
The compounds of this invention can be administered alone, or be administered in combination with other pharmaceutically acceptable compounds.
When using pharmaceutical composition, it is the mammal (such as people) that the compounds of this invention of safe and effective amount is applicable to treatment, dosage is the effective dosage pharmaceutically thought when wherein applying, for the people of 60kg weight, day dosage is usually 1~2000mg, preferably 5~500mg.Certainly, specific dosage is also contemplated that the factors such as administration route, patient health situation, within the scope of these are all skilled practitioners technical ability.
Main advantages of the present invention include:
1. providing a kind of compound shown in formula I.
2. the JAK3 degradation agent and its preparation and application, the inhibitor that provide a kind of structure novel are degradable JAK3 at much lower concentrations.
3. providing the pharmaceutical composition of a kind for the treatment of and JAK3 activity related diseases.
Present invention will be further explained below with reference to specific examples.It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are weight percent and parts by weight.
The preparation of 1 compound 3 of embodiment
Step 1:
2.14g 6- bromine caproyl chloride and 1.37g pomalidomide are dissolved in 50ml THF (tetrahydrofuran), 8h is stirred at reflux, is down to room temperature, is dried in vacuo to obtain compound (1) 2.19g for 40 DEG C after concentration.MS(ESI):450[M+H]
+。
Step 2:
By 1g compound (1), 1.28g compound (2) and 2.6g DIPEA (N, N- diisopropylethylamine) it is dissolved in 50ml DMF (N, dinethylformamide) in, 80 DEG C of stirring 6h, it is down to room temperature, compound (3) 810mg, yield: 65.6% are chromatographed to obtain through column after concentration.MS(ESI):615[M+H]
+。
1H NMR(400MHz,CD
3OD) δ 8.61 (d, J=8Hz, 1H), 8.11 (s, 1H), 7.72 (m, 1H), 7.54 (d, J=8Hz, 1H), 7.10 (d, J=4Hz, 1H), 6.63 (s, 1H), 5.14 (dd, J=12,4Hz, 1H), 3.48 (br, 3H), 3.37 (s, 1H), 2.50-3.10 (m, 10H), 2.32 (m, 1H), 2.16 (m, 1H), 1.25-2.00 (m, 9H), 1.03 (d, J=8Hz, 3H).
The preparation of 2 compound 7 of embodiment
Step 1:
By 4- hydroxyl Thalidomide 100mg, triethylene glycol list benzyl oxide 96mg, triphenylphosphine 100mg are dissolved in the anhydrous THF of 10ml, DIAD (diisopropyl azodiformate) 95mg are added dropwise, reacts at room temperature 2h.Decompression removes THF, obtains compound (4) 110mg after column chromatographic purifying.MS(ESI):497[M+H]
+。
Step 2:
100mg compound (4) and 10%Pd-C 100mg are added in methanol 10ml, room temperature hydrogenated over night.Filtering, filtrate concentration, residue obtain compound (5) 40mg after column chromatographic purifying.MS(ESI):407[M+H]
+。
Step 3:
Compound (5) 30mg is dissolved in methylene chloride 5ml, Dess-martin oxidant 47mg is added, reacts at room temperature 3h.NaHCO is added
3Saturated aqueous solution and Na
2S
2O
3Saturated aqueous solution stirs 5min, organic layer is separated, through anhydrous Na
2S
2O
3It is dry, it is concentrated to dryness, obtains compound (6) and be directly used in the next step.
After compound (6) are dissolved with methylene chloride 7ml, it is added raw material (2) 36mg and NaBH (OAc)
323mg, room temperature reaction overnight, remove methylene chloride under reduced pressure, obtain compound (7) after column chromatographic purifying, and 20mg.MS (ESI): 634 [M+H]
+。
1H NMR (hydrochloride, 400MHz, D
2O) δ 8.09 (d, J=1.6Hz, 1H), 7.45-7.62 (m, 1H), 7.18 (dd, J=12.0,7.2Hz, 1H), 7.07 (m, 2H), 6.54-6.70 (m, 1H), 4.90-5.08 (m, 2H), 4.12 (m, 2H), 3.30-3.85 (m, 14H), 3.20 (s, 3H), 2.73 (m, 2H), 2.42 (m, 2H), 2.09 (m, 2H), 1.73 (m, 1H), (1.00 d, J=8.0Hz, 3H).
The preparation of 3 compound 10 of embodiment
Step 1:
2- (2- (2- bromine oxethyl) ethyoxyl) benzyl acetate 174mg, potassium carbonate 100mg, potassium iodide 20mg and pomalidomide 100mg are added in 20ml DMF (n,N-Dimethylformamide), 80 DEG C of reactions are overnight.Reaction solution obtains compound (8) 113mg after column chromatographic purifying.MS(ESI):510[M+H]
+。
Step 2:
100mg compound (8) and 10%Pd-C100mg are added in 10ml methanol, room temperature hydrogenated over night.Filtering, filtrate concentration, residue obtain compound (9) 73mg after column chromatographic purifying.MS (ESI anion): 418 [M-H]
-。
Step 3:
Compound (9) 50mg and raw material (2) 30mg are dissolved in methylene chloride 5ml, HOBt (I-hydroxybenzotriazole) 20mg and EDC (1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride) 40mg is added, room temperature reaction is overnight.It removes methylene chloride under reduced pressure, obtains compound (10) after column chromatographic purifying, 50mg.MS (ESI): 647 [M+H]
+。
1H NMR (400MHz, CDCl3) δ 10.63 (br, 1H), 9.84 (br, 1H), 8.22 (d, J=1.2Hz, 1H), (7.43 t, J=7.6Hz, 1H), 7.06 (dd, J=7.2,1.2Hz, 1H), 6.97 (d, J=2.8Hz, 1H), 6.82 (d, J=8.4Hz, 1H), 6.51 (d, J=3.6Hz, 1H), 6.42 (m, 1H), 5.12 (br, 1H), 4.91 (m, 1H), 4.55 (br, 2H), 3.89 (m, 4H), 3.64 (s, 3H), 3.51 (br, 2H), (3.38 m, 3H), 2 .50-3.01 (m, 6H), 2.25 (br, 1H), 2.10 (m, 1H), 1.86 (br, 1H), 1.64 (br, 1H), 0.96 (d, J=6.8Hz, 3H).
The preparation of 4 compound 13 of embodiment
Step 1:
Raw material (2) 200mg is dissolved in methylene chloride 20ml, triethylamine 100mg and 5- benzyloxy pentane sulfonic acid chloride 180mg is added, room temperature reaction is overnight.Evaporating solvent under reduced pressure, after column chromatographic purifying compound (11) 187mg.MS(ESI):486 [M+H]
+。
Step 2:
180mg compound (11) and 10%Pd-C 180mg are added in methanol 20ml, room temperature hydrogenation is stayed overnight.Filtering, filtrate are concentrated, and obtain compound (12) 134mg.MS (ESI): 396 [M+H] after column chromatographic purifying
+。
Step 3:
4- hydroxyl Thalidomide 50mg, triphenylphosphine 50mg and compound (12) 50mg are dissolved in 5ml anhydrous tetrahydro furan, DIAD (diisopropyl azodiformate) 50mg is added dropwise, reacts at room temperature 3h.Decompression removes tetrahydrofuran, obtains compound (13) 33mg after column chromatographic purifying.MS(ESI):652[M+H]
+。
1H NMR (hydrochloride, 400MHz, D
2O) δ 8.11 (d, J=2.0Hz, 1H), 7.43-7.61 (m, 1H), 7.20 (dd, J=11.6,6.8Hz, 1H), 7.08 (m, 2H), 6.60-6.71 (m, 1H), 5.02 (m, 2H), 4.54 (m, 1H), 4.02 (m, 2H), 3.85 (m, 2H), 3.18 (s, 3H), 2.72-3.12 (m, 4H), 2.15-2.50 (m, 4H), 1.28-2.06 (m, 9H), 0.96 (d, J=7.6Hz, 3H).
The preparation of 5 compound 17 of embodiment
The first step
4- fluorine Thalidomide (2.00g) is added in 3- amino -1- propyl alcohol (10.00g), microwave reaction 0.5 hour, reaction solution is diluted with methylene chloride (50ml), 0.5M dilute hydrochloric acid, water, saturated common salt water washing are successively used, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, residue silica gel column purification, 0.60g compound 14 is obtained, is yellow solid, yield: 25%.MS(ESI):331[M+H]
+。
Second step
Compound 17 (200mg) and diisopropylethylamine (150mg) are dissolved in methylene chloride (10ml), is added dropwise methane sulfonyl chloride (80mg), is added rear reaction solution and continue to be stirred overnight.Reaction solution 0.5M dilute hydrochloric acid and saturated common salt water washing, organic phase is concentrated under reduced pressure, residue is dissolved in anhydrous N, dinethylformamide (10ml), it is added under the cooling of (226mg) ice-water bath of tropsch imatinib free alkali 16 and 60% sodium hydride (40mg) is added portionwise, it is slowly increased to room temperature, is stirred overnight.Reaction solution is concentrated under reduced pressure, and residue prepares plate with silica gel and purifies to obtain 16mg compound 17, is yellow solid, yield: 4.2%.MS(ESI):626[M+H]
+。
Similarly, following compound is prepared by the method for similar above-described embodiment:
The activity of the Western blot detection compound degradation JAK3 albumen of embodiment 6
Cell strain: Jurkat cell strain uses the RPMI1640 culture containing 10% calf serum to be based on 37 DEG C, 5%CO
2, culture in saturated humidity incubator.
DMSO control group, compound intervention group (10 μM) are set, handle the cell pyrolysis liquid that 100 μ L pre-cooling is added after collecting cell for 24 hours, 30min is cracked on ice, extracts total protein of cell, and bicinchoninic acid (BCA) method measurement protein concentration is simultaneously quantified.Conventional glue, loading, electrophoresis, then transferring film, closing, it is separately added into rabbit-anti people JAK3 (1: 500), 4 DEG C of overnight incubations, are added the goat anti-rabbit igg (1: 5000) of horseradish peroxidase-labeled after rinsing, ECL developer solution develops the color after rinsing, Bio-Rad gel imaging system scanning imagery, software processing analysis.With the control of glyceraldehyde phosphate dehydrogenase (GAPDH) internal reference.
Gray analysis is carried out to each band using Image J software, calculates the degradation rate of degradation JAK3 albumen.
Compound see the table below the degrading activity of JAK3 albumen in Jurkat cell:
| Compound number | Degrading activity | Compound number | Degrading activity |
| 3 | ++++ | 22 | ++++ |
| 7 | +++ | 23 | ++++ |
| 10 | +++ | 24 | +++ |
| 14 | +++ | 25 | +++ |
| 15 | ++++ | 26 | ++++ |
| 18 | +++ | 27 | ++++ |
| 19 | +++ | 28 | +++ |
| 20 | +++ | 29 | +++ |
| 21 | +++ | 30 | ++++ |
Remarks: in above table, "-" is represented without degrading activity, and "+" represents degradation rate as 10%-30%, and " ++ " represents degradation rate as 30%-50%, and " +++ " represents degradation rate as 50%-90%, and " ++++" represents degradation rate and be greater than 90%.
The inhibiting effect that 7 CCK8 method of embodiment detection formula compound is proliferated Jurkat cell (human leukemia T lymphocyte)
In vitro with CCK8 method measuring compound to the inhibited proliferation of Jurkat cell.Specific step is as follows:
It takes Jurkat cell to be incubated in 1640 culture mediums of 10% calf serum, is inoculated in 96 orifice plates, 2 × 10
5Cells/well is placed in 37 DEG C, 5%CO
2In incubator.Compound is dissolved in dimethyl sulfoxide (DMSO), concentration is obtained and is the solution of 10mM, then be diluted to required concentration with phosphate buffer, be separately added into above-mentioned 96 orifice plate, each 2 hole of concentration, every 10 μ l of hole, each concentration makees two parallel testings.It is added in plate after DMSO accordingly to be made to gradient dilution, as control.
By above-mentioned 96 orifice plate in 37 DEG C, 5%CO
2After cultivating 48 hours in cell incubator, 10 μ l CCK8 solution are added in every hole, continue to keep the temperature 1~4 hour in the incubator.Measure 465nm absorbance value.
Comparative survival rate of cells after compound is handled is calculated according to absorbance value.
Compound is calculated to the IC of Jurkat cell by software
50。
The compound of synthesis is shown in Table 1 to the in-vitro multiplication inhibiting effect of Jurkat cell:
Table 1
| Compound number | IC 50(μM) |
| 3 | 20 |
| 7 | 100 |
| 10 | 60 |
| 14 | 10 |
| 15 | 8 |
The above result shows that the compound of synthesis has the good activity for inhibiting Jurkat cell.
The internal resisting rheumatoid arthritis activity of 8 compound of embodiment (15)
In vivo using full Freund's adjuvant induction Wistar rat rheumatoid arthritis as model, the resisting rheumatoid arthritis effect of measurement compound (15).Specific step is as follows:
1) test specimen
Sample: compound (15).
2) preparation method
Sample: compound (15), when preparation, are dissolved with normal saline solution
3) animal and adjuvant
Wistar rat 24, male, weight 170-200g.
Adjuvant: full Freund's adjuvant (CFA), Sigma.
4) test method
Wistar rat is divided into 4 groups, every group 6 at random.Respectively blank control group, model group, compound (15) group (20mg/kg ip administration), tropsch imatinib positive controls (20mg/kg po administration).Rheumatoid arthritis is induced in the left back vola pedis intracutaneous injection CFA 0.15mL of rat.11st day beginning drug treatment after rat modeling, once a day, the 20th day treatment end.Left back sufficient volume is measured after treatment end, calculates foot swelling inhibiting rate.
5) test result
Compound (15) is shown in Table 2 to the foot swelling inhibiting rate of full Freund's adjuvant induced rat rheumatoid arthritis:
Table 2
| Group | Foot swelling inhibiting rate (%) |
| Blank control group | - |
| Model group | - |
| Compound (15) | 49 |
| Positive control (tropsch imatinib) | 29 |
Above experiment in vivo is the result shows that compound (15) has good resisting rheumatoid arthritis activity in vivo, and activity is significantly higher than positive control medicine tropsch imatinib.
All references mentioned in the present invention is incorporated herein by reference, as if each reference was individually incorporated by reference.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can make various modifications or changes to the present invention, these equivalent forms also fall within the scope of the appended claims of the present application.
Claims (10)
- A kind of such as following formula I compound represented or its pharmaceutically acceptable salt:Wherein:--- indicate singly-bound；Indicate singly-bound or double bond；A missing is selected from C (=O), C (=O) X1, SOX1, SO 2The C of X1, with or without substituent group 1-8The C of alkyl, with or without substituent group 1-8The C of cyclic hydrocarbon radical and with or without substituent group 1-8Heterocyclic hydrocarbyl；Wherein X1 lacks or is selected from (CR 12R 13) eO、(CR 12R 13) eS and NR 14；Wherein R 12、R 13、R 14Independent is the C of H, with or without substituent group 1-8Alkyl, with or without substituent group C 1-8Cyclic hydrocarbon radical and with or without substituent group C 1-8Heterocyclic hydrocarbyl, e be 0 to 3 between integer；W missing is selected from O, NR 17, X2C (=O) X3, X2S (=O) gX3；Wherein R 17For H, the C of with or without substituent group 1-8Alkyl, with or without substituent group C 1-8Cyclic hydrocarbon radical, with or without substituent group C 1-8Heterocyclic hydrocarbyl；Wherein X2, X3 are independent lacks or is selected from O, S, NR 18、(CH 2) gO；The wherein integer that g is 0 to 2；Wherein R 18For H, the C of with or without substituent group 1-8Alkyl, with or without substituent group C 1-8Cyclic hydrocarbon radical, with or without substituent group C 1-8Heterocyclic hydrocarbyl；Y is (CR 22R 23) h、CHX4(CR 22R 23) h, CX4=CH (CR 22R 23) hOr (CR 22R 23) h；Wherein h is the integer between 0 to 30；Wherein R 22、R 23It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group 1-8Alkyl, with or without substituent group C 1-8Cyclic hydrocarbon radical, with or without substituent group C 1-8Heterocyclic hydrocarbyl, with or without substituent group C 1-8Oxyl；Wherein X4 is H, halogen, cyano, nitro, hydroxyl, with or without substituent group C 1-8Oxyl, with or without substituent group C 1-8Hydrocarbon carbonyl oxygen, with or without substituent group C 1-8Amido, with or without substituent group C 1-8Ester group, with or without substituent group C 1-8Amino-carbonyl, with or without substituent group C 1-8Alkyl, with or without substituent group C 1-8Cyclic hydrocarbon radical, with or without substituent group C 1-8Heterocyclic hydrocarbyl；Z is (CR 24R 25) i、CHX5(CR 24R 25) i, CX5=CH (CR 24R 25) iOr C ≡ C (CR 24R 25) i；Wherein i is the integer between 0 to 30；Wherein R 24、R 25It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group 1-8Alkyl, with or without substituent group C 1-8Cyclic hydrocarbon radical, with or without substituent group C 1-8Heterocyclic hydrocarbyl, with or without substituent group C 1-8Oxyl；Wherein X5 is H, halogen, cyano, nitro, hydroxyl, with or without substituent group C 1-8Oxyl, with or without substituent group C 1-8Hydrocarbon carbonyl oxygen, with or without substituent group C 1-8Amido, with or without substituent group C 1-8Ester group, with or without substituent group C 1-8Amino-carbonyl, with or without substituent group C 1-8Alkyl, with or without substituent group C 1-8Cyclic hydrocarbon radical, with or without substituent group C 1-8Heterocyclic hydrocarbyl；B missing is selected from O, C=O, S, NR 15、NR 15C (=O), C (=O) NR 15, C (=O) O, OC (=O) O, NR 15C (=O) O, OC (=O) NR 15、NR 15C (=O) NR 16, with or without substituent group C 1-12Alkyl, with or without substituent group C 1-12Cyclic hydrocarbon radical and with or without substituent group C 1-12Heterocyclic hydrocarbyl；Wherein R 15、R 16It is independently selected from the C of H, with or without substituent group 1-8Alkyl, with or without substituent group C 1-8Cyclic hydrocarbon radical and with or without substituent group C 1-8Heterocyclic hydrocarbyl；X is selected from CR 19R 20, C (=O), S (=O), SO 2、NR 21；Wherein R 19、R 20It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group 1-8Alkyl, with or without substituent group C 1-8Cyclic hydrocarbon radical, with or without substituent group C 1-8Heterocyclic hydrocarbyl, with or without substituent group C 1-8Oxyl；Wherein R 21C selected from H, with or without substituent group 1-8Alkyl, with or without substituent group C 1-8Cyclic hydrocarbon radical, with or without substituent group C 1-8Heterocyclic hydrocarbyl；R 1、R 6、R 10It is each independently selected from the C of H, with or without substituent group 1-8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, with or without substituent group C 1-6Acyl group；R 2、R 5It is independently selected from: hydrogen, OR 33、NR 34R 35, cyano, halogen, with or without substituent group C 1~8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, with or without substituent group C 1-6The amide groups of acyl group, with or without substituent group；Wherein R 33、R 34、R 35It is independently selected from the C of H, with or without substituent group 1~8Alkyl, with or without substituent group cyclic hydrocarbon radical, the heterocyclic hydrocarbyl of with or without substituent group；R 3、R 7、R 8、R 9It is independently selected from: H, OR 27、NR 28R 29, cyano, halogen, nitro, with or without substituent group C 1-8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, X6S (=O) kR 30, X6C (=O) R 31；Wherein k is the integer between 0 to 2；Wherein R 27, R 28, R 29, R 30, R 31It is independently selected from the C of H, with or without substituent group 1~8Alkyl, cyclic hydrocarbon radical, heterocyclic hydrocarbyl；Wherein X6 lacks or is selected from O, S, NR 32；Wherein R 32For H, the C of with or without substituent group 1-8Alkyl, the cyclic hydrocarbon radical of with or without substituent group and the heterocyclic hydrocarbyl of with or without substituent group；R 4Selected from H, cyano, carboxyl, with or without substituent group C 1-8Alkyl, with or without substituent group hydrocarbon carbonyl oxygen；A is the integer between 0 to 5；B is the integer between 0 to 3；C is the integer between 0 to 30；D is the integer between 0 to 9.
- Compound as described in claim 1 or its pharmaceutically acceptable salt, it is characterised in that:In the Formulas I, A missing；W is X2C (=O) X3, wherein X3 NR 18And X2 missing or X2 are NR 18And X3 is lacked；Y is (CR 22R 23) h, wherein R 22、R 23It is independently selected from the C of H, hydroxyl, with or without substituent group 1-4Alkyl, h be 1 to 6 between integer；Z is (CR 24R 25) i, wherein R 24、R 25It is independently selected from the C of H, hydroxyl, with or without substituent group 1-4Alkyl, i be 1 to 6 between integer；C is 0；OrIn the Formulas I, A missing；W missing is O；Y is (CR 22R 23) h, wherein R 22、R 23It is independently selected from the C of H, hydroxyl, with or without substituent group 1-4Alkyl, h be 0 to 3 between integer；B is O；Z is (CR 24R 25) i, wherein R 24、R 25It is independently selected from the C of H, hydroxyl, with or without substituent group 1-4Alkyl, i be 0 to 3 between integer；C is the integer between 1 to 6；OrIn the Formulas I, A is C (=O) X1, and wherein X1 lacks or be selected from (CR 12R 13) eAnd (CR O, 12R 13) eS, wherein e is the integer between 0 to 2, R 12、R 13、R 14Independent is hydrogen or C 1-4Alkyl；W is O or NR 17, wherein R 17For the H or C of with or without substituent group 1-4Alkyl；Y is (CR 22R 23) h, wherein R 22、R 23It is independently selected from the C of H, hydroxyl, with or without substituent group 1-4Alkyl, h be 0 to 3 between integer；Z is (CR 24R 25) i, wherein R 24、R 25It is independently selected from the C of H, hydroxyl, with or without substituent group 1-4Alkyl, i be 0 to 3 between integer；B is O；C is the integer between 1 to 4；OrIn the Formulas I, A SO 2X1, wherein X1 lacks or is selected from O and S；W is O；Y is (CR 22R 23) h, wherein R 22、R 23It is independently selected from the C of H, hydroxyl, with or without substituent group 1-4Alkyl, h be 1 to 6 between integer；Z is (CR 24R 25) i, wherein R 24、R 25It is independently selected from the C of H, hydroxyl, with or without substituent group 1-4Alkyl, i be 0 to 3 between integer；C is 0；OrIn the Formulas I, A missing；W is NR 17, wherein R 17For the H or C of with or without substituent group 1-4Alkyl；Y is (CR 22R 23) h, wherein R 22、R 23It is independently selected from the C of H, hydroxyl, with or without substituent group 1-4Alkyl, h be 0 to 3 between integer；Z is (CR 24R 25) i, wherein R 24、R 25It is independently selected from the C of H, hydroxyl, with or without substituent group 1-4Alkyl, i be 0 to 4 between integer；B is O；C is the integer between 1 to 6；OrIn the Formulas I, A missing；W missing；Y is (CR 22R 23) h, wherein R 22、R 23It is independently selected from the C of H, hydroxyl, with or without substituent group 1-4Alkyl, h be 0 to 3 between integer；Z is (CR 24R 25) i, wherein R 24、R 25It is independently selected from the C of H, hydroxyl, with or without substituent group 1-4Alkyl, i be 0 to 3 between integer；B is O；C is the integer between 1 to 10 (between preferably 1 to 6).
- Compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that in Formulas I, X is C (=O).
- Compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that R 1It is selected from: the C of H and with or without substituent group 1-4Alkyl.
- Compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that R 4Selected from H, cyano, with or without substituent group C 1-6Alkyl.
- Compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that the compound is selected from the group:
- A kind of pharmaceutical composition, which is characterized in that the composition contains compound described in claim 1 or its pharmaceutically acceptable salt, prodrug and pharmaceutically acceptable carrier.
- The purposes of a kind of compound as described in claim 1 or its pharmaceutically acceptable salt, is used for:(a) drug of preparation treatment disease relevant to JAK3 activity or expression quantity；(b) preparation JAK3 targets degradation agent；(c) the external non-therapeutic ground JAK3 that degrades；(d) inhibit tumor cell proliferation to external non-therapeutic；And/or(e) treatment disease relevant to JAK3 activity or expression quantity.
- Purposes as claimed in claim 8, which is characterized in that the disease relevant to JAK3 activity or expression quantity is tumour or autoimmune disease.
- A kind of method of external degradation JAK3, the described method includes: applying a effective amount of compound of formula I as described in claim 1 or its pharmaceutically acceptable salt to effective object, or inhibit a effective amount of pharmaceutical composition as claimed in claim 7 to inhibiting object to apply.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710783074.0A CN109422751B (en) | 2017-09-03 | 2017-09-03 | Compound with activity of degrading tyrosine protein kinase JAK3 |
| CN2017107830740 | 2017-09-03 | ||
| PCT/CN2018/103708 WO2019042443A1 (en) | 2017-09-03 | 2018-09-02 | Compound having tyrosine protein kinase jak3-degradation activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109963853A true CN109963853A (en) | 2019-07-02 |
| CN109963853B CN109963853B (en) | 2022-04-22 |
Family
ID=65512838
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710783074.0A Active CN109422751B (en) | 2017-09-03 | 2017-09-03 | Compound with activity of degrading tyrosine protein kinase JAK3 |
| CN201880004075.3A Active CN109963853B (en) | 2017-09-03 | 2018-09-02 | Compound with activity of degrading tyrosine protein kinase JAK3 |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710783074.0A Active CN109422751B (en) | 2017-09-03 | 2017-09-03 | Compound with activity of degrading tyrosine protein kinase JAK3 |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN109422751B (en) |
| WO (1) | WO2019042443A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109422751B (en) * | 2017-09-03 | 2022-04-22 | 上海美志医药科技有限公司 | Compound with activity of degrading tyrosine protein kinase JAK3 |
| CN114478532A (en) * | 2020-10-26 | 2022-05-13 | 上海美志医药科技有限公司 | Targeted Btk degradation compound and anti-tumor application thereof |
Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1767533A1 (en) * | 2000-12-27 | 2007-03-28 | Celgene Corporation | N-{(2-(2,6-dioxo(3-piperidyl)-1,3-dioxo-2,3-dihydro-1H-isoindolin-4-yl)methyl}cyclopropylcarboxamide as TNF inhibitor |
| CN103119045A (en) * | 2010-08-20 | 2013-05-22 | 和记黄埔医药（上海）有限公司 | Pyrrolopyrimidine compounds and uses thereof |
| CN103502249A (en) * | 2011-05-17 | 2014-01-08 | 普林斯匹亚生物制药公司 | Azaindole derivatives as tyrosine kinase inhibitors |
| CN104736569A (en) * | 2012-01-12 | 2015-06-24 | 耶鲁大学 | Compounds & methods for the enhanced degradation of targeted proteins & other polypeptides by an e3 ubiquitin ligase |
| CN104853754A (en) * | 2012-11-20 | 2015-08-19 | 普林斯匹亚生物制药公司 | Azaindole derivatives as jak3 inhibitors |
| CN105712998A (en) * | 2014-12-05 | 2016-06-29 | 上海润诺生物科技有限公司 | Azaindole derivatives, preparation method and applications thereof in medicine |
| CN106458993A (en) * | 2014-04-14 | 2017-02-22 | 阿尔维纳斯股份有限公司 | Imide-based modulators of proteolysis and associated methods of use |
| WO2017176958A1 (en) * | 2016-04-06 | 2017-10-12 | The Regents Of The University Of Michigan | Monofunctional intermediates for ligand-dependent target protein degradation |
| WO2017180417A1 (en) * | 2016-04-12 | 2017-10-19 | The Regents Of The University Of Michigan | Bet protein degraders |
| WO2018119441A1 (en) * | 2016-12-23 | 2018-06-28 | Arvinas, Inc. | Egfr proteolysis targeting chimeric molecules and associated methods of use |
| CN109422751A (en) * | 2017-09-03 | 2019-03-05 | 上海美志医药科技有限公司 | One kind has the degradation active compound of tyrosine protein kinase JAK3 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UA110324C2 (en) * | 2009-07-02 | 2015-12-25 | Genentech Inc | Jak inhibitory compounds based on pyrazolo pyrimidine |
| CN102372717B (en) * | 2010-08-20 | 2014-06-18 | 和记黄埔医药（上海）有限公司 | Pyrrolopyrimidine compound and use thereof |
| WO2014025486A1 (en) * | 2012-08-06 | 2014-02-13 | Acea Biosciences Inc. | Novel pyrrolopyrimidine compounds as inhibitors of protein kinases |
-
2017
- 2017-09-03 CN CN201710783074.0A patent/CN109422751B/en active Active
-
2018
- 2018-09-02 WO PCT/CN2018/103708 patent/WO2019042443A1/en active Application Filing
- 2018-09-02 CN CN201880004075.3A patent/CN109963853B/en active Active
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1767533A1 (en) * | 2000-12-27 | 2007-03-28 | Celgene Corporation | N-{(2-(2,6-dioxo(3-piperidyl)-1,3-dioxo-2,3-dihydro-1H-isoindolin-4-yl)methyl}cyclopropylcarboxamide as TNF inhibitor |
| CN103119045A (en) * | 2010-08-20 | 2013-05-22 | 和记黄埔医药（上海）有限公司 | Pyrrolopyrimidine compounds and uses thereof |
| CN103502249A (en) * | 2011-05-17 | 2014-01-08 | 普林斯匹亚生物制药公司 | Azaindole derivatives as tyrosine kinase inhibitors |
| CN104736569A (en) * | 2012-01-12 | 2015-06-24 | 耶鲁大学 | Compounds & methods for the enhanced degradation of targeted proteins & other polypeptides by an e3 ubiquitin ligase |
| CN104853754A (en) * | 2012-11-20 | 2015-08-19 | 普林斯匹亚生物制药公司 | Azaindole derivatives as jak3 inhibitors |
| CN106458993A (en) * | 2014-04-14 | 2017-02-22 | 阿尔维纳斯股份有限公司 | Imide-based modulators of proteolysis and associated methods of use |
| CN105712998A (en) * | 2014-12-05 | 2016-06-29 | 上海润诺生物科技有限公司 | Azaindole derivatives, preparation method and applications thereof in medicine |
| WO2017176958A1 (en) * | 2016-04-06 | 2017-10-12 | The Regents Of The University Of Michigan | Monofunctional intermediates for ligand-dependent target protein degradation |
| WO2017180417A1 (en) * | 2016-04-12 | 2017-10-19 | The Regents Of The University Of Michigan | Bet protein degraders |
| WO2018119441A1 (en) * | 2016-12-23 | 2018-06-28 | Arvinas, Inc. | Egfr proteolysis targeting chimeric molecules and associated methods of use |
| CN109422751A (en) * | 2017-09-03 | 2019-03-05 | 上海美志医药科技有限公司 | One kind has the degradation active compound of tyrosine protein kinase JAK3 |
Non-Patent Citations (2)
| Title |
|---|
| BAI LONGCHUAN等: "Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer", 《CANCER RESEARCH》 * |
| ZHOU BING等: "Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression", 《J. MED. CHEM.》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109422751A (en) | 2019-03-05 |
| CN109422751B (en) | 2022-04-22 |
| CN109963853B (en) | 2022-04-22 |
| WO2019042443A1 (en) | 2019-03-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109422752A (en) | One kind has inhibition and the active compound of bruton's tyrosine protein kinase B tk of degrading | |
| CN109963844B (en) | Compound for inhibiting and degrading tyrosine protein kinase ALK | |
| CN109952304A (en) | One kind inhibits and the compound for the CDK that degrades | |
| CN110317192A (en) | One kind has the compound of degradation estrogen receptor activity | |
| WO2018175311A1 (en) | Crystalline forms of 4-(1-(1,1-di(pyridin-2-yl)ethyl)-6-(3,5-dimethylisoxazol-4-yl)-1h- pyrrolo[3,2-b]pyridin-3-yl)benzoic acid that inhibits bromodomain | |
| ES2929526T3 (en) | (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl) acid L-arginine crystal salt acetic acid for use in disorders associated with the S1P1 receptor | |
| RU2434851C1 (en) | Cyclic n,n'-diarylthioureas or n,n'-diarylureas - antagonists of androgen receptors, anti-cancer medication, method of obtaining and application | |
| JP2021503443A (en) | Antagonist of muscarinic acetylcholine receptor M4 | |
| JP2021513519A (en) | Muscarinic acetylcholine receptor M4 antagonist | |
| JP2020530451A (en) | Antagonist of muscarinic acetylcholine receptor M4 | |
| CN111662294A (en) | Compound with activity of degrading Btk | |
| CN109963853A (en) | One kind has the degradation active compound of tyrosine protein kinase JAK3 | |
| JP5726301B2 (en) | New antihistamine | |
| CN109937203A (en) | One kind has inhibition and the active compound of tyrosine protein kinase JAK1 or JAK2 of degrading | |
| CN109516990B (en) | Pyrimidotriazole compounds, preparation method and application thereof | |
| CN111499619B (en) | Medicine for treating hepatic fibrosis and preparation method thereof | |
| KR101812128B1 (en) | 3-Isoxazol-3-yl)-pyrazolo[3,4-d]pyrimidine-4-amine derivatives as protein kinase inhibitors | |
| WO2023160672A1 (en) | Compounds and compositions for treating conditions associated with lpa receptor activity | |
| JP2022029880A (en) | Crystall form of 3-[8-[6-(1,2,4-triazol-1-yl)pyridin-3-yl]oxyoctyl]oxetane-3-carboxylic acid and method for producing the same | |
| CN116120327A (en) | Beta-elemene 13, 14-position symmetrical disubstituted derivative and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |