Claims for Patent: 9,162,994

Summary for Patent: 9,162,994

Title:	1,2,4-thiazoloidin-3-one derivatives and their use in the treatment of cancer
Abstract:	According to the invention there is provided a compound of formula (I) wherein: A represents C(.dbd.N--W-D) or S; B represents S or C(--NH--W-D); when: A represents C(.dbd.N--W-D) and B represents S then the bond between B and the NH atom is a single bond; or A represents S and B represents C(--NH--W-D) then the bond between B and the NH atom is a double bond; X represents -Q-[CR.sup.xR.sup.y].sub.n--; W represents --[CR.sup.xR.sup.y].sub.m-- or --C(O)--[CR.sup.xR.sup.y].sub.p--; Q represents a bond, --N(R.sup.a)--, --S--, or --O--; A.sub.1 to A.sub.5 respectively represent C(R.sup.1), C(R.sup.2), C(R.sup.3), C(R.sub.4) and C(R.sup.5), or, alternatively, up to two of A.sub.1 to A.sub.5 may independently represent N; D represents phenyl, pyridyl or pyrimidinyl optionally substituted by one or more R.sup.6 groups, which compounds are useful in the treatment of cancer.
Inventor(s):	Westman; Jacob (Blomsberg, SE), Hallett; Allan (Welwyn Garden City, GB), Vagberg; Jan (Sollentuna, SE)
Assignee:	BETAGENON AB (Umea, SE)
Application Number:	13/381,426
Patent Claims:	1. A compound of formula I, ##STR00081## wherein: A represents S; B represents C(--NH--W-D); the bond between B and the NH group is a double bond; X represents --Q-[CR.sup.xR.sup.y].sub.n--; W represents --[CR.sup.xR.sup.y].sub.m-- or --C(O)--[CR.sup.xR.sup.y].sub.p--; Q represents a bond, --N(R.sup.a)--, --S--, or --O--; A.sub.1 to A.sub.5 respectively represent C(R.sup.1), C(R.sup.2), C(R.sup.3), C(R.sup.4) and C(R.sup.5), or, alternatively, up to two of A.sub.1 to A.sub.5 may independently represent N; D represents phenyl, pyridyl or pyrimidinyl optionally substituted by one or more R.sup.6 groups; R.sup.x and R.sup.y, on each occasion when used herein, are independently selected from H, halo, C.sub.1-6 alkyl (optionally substituted by one or more halo atoms), aryl (optionally substituted by one or more halo atoms) or R.sup.x and R.sup.y are linked to form, along with the carbon atom to which they are attached, a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or C.sub.1-6 alkyl (optionally substituted by one or more halo atoms); R.sup.1 to R.sup.5 independently represent H, halo, --R.sup.7, --CF.sub.3, --CN, --NO.sub.2, --C(O)R.sup.7, --C(O)OR.sup.7, --C(O)--N(R.sup.7a)R.sup.7b, --N(R.sup.7a)R.sup.7b, --N(R.sup.7).sub.3.sup.+, --SR.sup.7, --OR.sup.7, --NH(O)R.sup.7, --SO.sub.3R.sup.7, aryl or heteroaryl (which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and R.sup.16), or any two of R.sup.1 to R.sup.5 which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I, an aromatic or non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo, --R.sup.7, --OR.sup.7 and .dbd.O; R.sup.6 independently represents, on each occasion when used herein, cyano, --NO.sub.2, halo, C.sub.1-6 alkyl (which alkyl group is substituted by one or more halo atoms), --OR.sup.8, --N(R.sup.8)C(O)R.sup.8, --NR.sup.9R.sup.10, --SR.sup.11, --Si(R.sup.12).sub.3, --OC(O)R.sup.13, --C(O)OR.sup.13, --C(O)R.sup.14, --C(O)NR.sup.15aR.sup.15b, --S(O).sub.2NR.sup.15cR.sup.15d, aryl or heteroaryl (which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and R.sup.16), or any two R.sup.6 groups which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I, an aromatic or non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo, --R.sup.7, --OR.sup.7 and .dbd.O; R.sup.7, on each occasion when used herein, is selected from H or C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 cycloalkyl, aryl and heteroaryl (wherein the latter four groups are optionally substituted by one or more halo atoms); R.sup.7a and R.sup.7b are independently selected from H, or C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 cycloalkyl, aryl and heteroaryl, or R.sup.7a and R.sup.7b are optionally linked to form, along with the nitrogen atom to which they are attached, an aromatic or non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo, --R.sup.7, --OR.sup.7 and .dbd.O; R.sup.a, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15a, R.sup.15b, R.sup.15c and R.sup.15d, on each occasion where used herein, independently represent H or R.sup.16; R.sup.16 represents, on each occasion when used herein, C.sub.1-6 alkyl optionally substituted by one or more halo atoms; n represents 1 or 2; m represents 0, 1 or 2; and p represents 0, 1 or 2; or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof. 2. A compound as claimed in claim 1, wherein each R.sup.6 independently represents --CN, --CF.sub.3, --OCF.sub.3, --F or --Cl. 3. A compound as claimed in claim 1, wherein at least one of A.sub.1 to A.sub.5 is not (C--H). 4. A compound of formula I as claimed in claim 1, wherein R.sup.x and R.sup.y are independently selected from H, C.sub.1-6 alkyl (optionally substituted by one or more fluoro atoms), aryl (optionally substituted by one or more halo atoms) or R.sup.x and R.sup.y are linked to form, along with the carbon atom to which they are attached, a non-aromatic 3- to 6-membered unsubstituted ring. 5. A compound of formula I as claimed in claim 1, wherein X represents --CH.sub.2--, --CH.sub.2CH.sub.2--, --O--CH.sub.2CH.sub.2--, --N(CH.sub.3)--CH.sub.2CH.sub.2--, --S--CH.sub.2CH.sub.2 --, 1,1-cyclopropyl or --C(H)(4-chlorophenyl)-. 6. A compound of formula I as claimed in claim 1, wherein at least one of R.sup.1 to R.sup.5, when present, represents halo, --R.sup.7, --CF.sub.3, --CN, --C(O)R.sup.7, --C(O)OR.sup.7, --C(O)--N(R.sup.7a)R.sup.7b, --N(R.sup.7).sub.3.sup.+, --SR.sup.7, --OR.sup.7 or --NH(O)R.sup.7, or any two of R.sup.1 to R.sup.5 which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I, an aromatic or non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo, --R.sup.7, --OR.sup.7 and .dbd.O. 7. A compound of formula I as claimed in claim 6, wherein at least one of R.sup.1 to R.sup.5, when present, represents 4H-[1,2,4]-triazolyl, --OR.sup.7, --Cl, --F, --CF.sub.3, --CN or --C(O)--N(R.sup.7a)R.sup.7b. 8. A compound of formula I as claimed in claim 1, wherein R.sup.6 independently represents --C(O)NR.sup.15aR.sup.15b, cyano, --Br, --Cl, --F, C.sub.1-6 alkyl (which alkyl group is substituted by one or more halo atoms), OR.sup.8, --NR.sup.9R.sup.10, SR.sup.11, --C(O)OR.sup.13, --C(O)R.sup.14, --S(O).sub.2NR.sup.15cR.sup.15d, aryl or heteroaryl (which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and R.sup.16), or any two R.sup.6 groups which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I, quinoline, tetrahydroquinoline, isoquinoline or tetrahydroisoquinoline, wherein the additional ring system of the quinoline, tetrahydroquinoline, isoquinoline or tetrahydroisoquinoline moiety is itself optionally substituted by one or more substituents selected from halo, --R.sup.7, --OR.sup.7 and .dbd.O. 9. A compound of formula I as claimed in claim 8, wherein R.sup.6 independently represents C.sub.1-6 alkyl (which alkyl group is substituted by one or more halo atoms), --CN, --OCF.sub.3, --Br, --Cl, --F, --OR.sup.8, --NR.sup.9R.sup.10 or --SR.sup.11. 10. A compound of formula I as claimed in claim 1, wherein n represents 1 or 2; m represents 0 or 1; and/or p represents 0 or 1. 11. A compound of formula I as claimed in claim 1, wherein W represents a direct bond, --CH.sub.2--, --C(O)-- or --C(O)CH.sub.2--. 12. A compound as claimed in claim 10, wherein W represents --C(O)-- or --C(O)CH.sub.2--. 13. A compound as claimed in claim 1, which is selected from the group: xix) 4-fluoro-N-[3-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadi- azol-5-yl]benzamide; xx) 2-(4-fluorophenyl)-N-[3-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-t- hiadiazol-5-yl]acetamide; xxi) 4-chloro-N-[2-[(3,4-difluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]be- nzamide; xxii) 4-chloro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzam- ide; xxiii) 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzam- ide; xxiv) 4-chloro-N-[2-[2-(phenoxy)ethyl]-3-oxo-1,2,4-thiadiazol-5-yl]be- nzamide; xxv) 4-chloro-N-[2-[2-[(4-chlorophenyl)-methyl-amino]ethyl]-3-oxo-1,2,4-thiadi- azol-5-yl]benzamide; xxvi) 4-chloro-N-[2-[2-(4-chlorophenyl)sulfanylethyl]-3-oxo-1,2,4-thiadiazol-5-- yl]benzamide; xxvii) 3,4-dichloro-N-[2-[1-(4-fluorophenyl)cyclopropyl]-3-oxo-1,2,4-thiadiazol-- 5-yl]benzamide; xxviii) 3,4-dichloro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]be- nzamide; xxix) N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]-4-methoxy-benz- amide; xxx) 2,6-dichloro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]be- nzamide; xxxi) 2,4-dichloro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]be- nzamide; xxxii) N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]-4-(trifluorome- thoxy)-benzamide; xxxiii) N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]-3,5-bis(triflu- oromethyl)-benzamide; xxxiv) 3,4-difluoro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]be- nzamide; xxxv) 2-chloro-6-fluoro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-- yl]benzamide; xxxvi) 3,5-difluoro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2;4-thiadiazol-5-yl]be- nzamide; xxxviii) 5-(3,4-dichlorophenylamino)-2-(2-phenoxyethyl)-[1,2,4]thiadiazol-3-one; xlvi) 1,5-(3,4-dichlorophenylamino)-2-(4-methoxybenzyl)-[1,2,4]thiadiazol- -3-one; xlvii) 1,5-(3,4-dichlorophenylamino)-2-(4-chlorobenzyl)-[1,2,4]thiadiazol-3-one; xlviii) 1,5-(3,4-dichlorophenylamino)-2-(3,4-difluorobenzyl)-[1,2,4]thiad- iazol-3-one; xlix) 1,5-(3,4-dichlorophenylamino)-2-(3-fluorobenzyl)-[1,2,4]thiadiazol-3-one; l) 1,5-(3,4-dichlorophenylamino)-2-(benzyl)-[1,2,4]thiadiazol-3-one; li) 5-(3,4-dichlorophenylamino)-2-phenethyl-[1,2,4]thiadiazol-3-one; lii) 2-[2-[(4-chlorophenyl)-methyl-amino]ethyl]-5-[(3,4-dichlorophenyl)amino]-- 1,2,4-thiadiazol-3-one; liii) 2-[2-(4-chlorophenyl)sulfanylethyl]-5-[(3,4-dichlorophenyl)amino]-1,2,4-t- hiadiazol-3-one; liv) 3-[[5-[(4-chlorophenyl)amino]-3-oxo-1,2,4-thiadiazol-2-yl]methyl]-N-methy- l-benzamide; lv) 5-[(6-chloro-3-pyridyl)amino]-2-[(3,4-difluorophenyl)methyl]-1,2,4-thiadi- azol-3-one; lvi) 2-[(3,4-difluorophenyl)methyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4- -thiadiazol-3-one; lvii) 2-[(3,4-difluorophenyl)methyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,- 4-thiadiazol-3-one; lviii) 5-[(4-chlorophenyl)amino]-2-[1-(4-chlorophenyl)cyclopropyl]-1,2,4-thiadia- zol-3-one; lix) 5-[(3,4-dichlorophenyl)methylamino]-2-[(3,4-difluorophenyl)methyl]-1,2,4-- thiadiazol-3-one; lxi) 2-[(4-methoxyphenyl)methyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-th- iadiazol-3-one; lxii) 2-[(4-chlorophenyl)methyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thi- adiazol-3-one; lxiii) 2-[(3-fluorophenyl)methyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thi- adiazol-3-one; lxiv) 2-[phenylethyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thiadiazol-3-o- ne; lxv) 2-[(4-methoxyphenyl)methyl]-5-[[4-(trifluoromethoxy)phenyl]amino]- -1,2,4-thiadiazol-3-one; lxvi) 2-[(4-chlorophenyl)methyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-th- iadiazol-3-one; lxvii) 2-[(3-fluorophenyl)methyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-th- iadiazol-3-one; lxviii) 2-[phenylethyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-thiadiazol-3-- one; and lxix) 4-[[2-[(3,4-difluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]amino]benz- onitrile. 14. A pharmaceutical formulation including a compound as defined in claim 1, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 15. A combination product comprising: (A) a compound of formula I as defined in claim 1, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof; and (B) another therapeutic agent useful in the treatment of cancer, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier. 16. A combination product as claimed in claim 15 which comprises a pharmaceutical formulation including the compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof: another therapeutic agent useful in the treatment of cancer; and a pharmaceutically-acceptable adjuvant, diluent or carrier. 17. A combination product as claimed in claim 15, which comprises a kit of parts comprising components: (a) a pharmaceutical formulation including the compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical formulation including another therapeutic agent useful in the treatment of cancer in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other. 18. A kit of parts as claimed in claim 17, wherein components (A) and (B) are suitable for sequential, separate and/or simultaneous use in the treatment of cancer. 19. A combination product as claimed in claim 15, wherein the other therapeutic agent is selected from: (i) a cytostatic, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (ii) an angiogenesis inhibitor, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (iii) tamoxifen, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (iv) an aromatase inhibitor, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (v) trastuzumab (Herceptin), or another antibody that is useful in the treatment of cancer; (vi) a tyrosine kinase inhibitor, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (vii) a glitazone, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (viii) biguanides, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (ix) a statin, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (x) an inhibitor of activity of the mammalian target of rapamycin (mTOR), or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (xi) an oligomycin, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (xii) AICAR (aminoimidazole carboxamide ribonucleotide), or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (xiii) a peroxisome proliferator-activated receptor (PPAR) agonist, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (xiv) A-769662, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (xv) D942 (5-(3-(4-(2-(4-Fluorophenyl)ethoxy)-phenyl)propyl)furan-2-carboxylic acid), or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (xvi) AM251, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (xvii) a SIRT1 activator, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; and/or (xviii) salidroside, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof. 20. A combination product as claimed in claim 19, wherein the other therapeutic agent is selected from cisplatin, doxorubicin, tamoxifen, anastrozole, letrozole, exemastane, herceptin, imatinib, gefitinib, erlotinib, canertinib, sunitinib, zactima, vatalanib, sorafenib, leflunomide, lapatinib, rosiglitazone, metformin, fluvastatin, simvastatin, rosuvastatin, pravastatin, atorvastatin, lovastatin and rapamycin. 21. A combination product as claimed in claim 20, wherein the other therapeutic agent is selected from cisplatin, doxorubicin, tamoxifen and herceptin. 22. A method of inhibiting cell proliferation, which method comprises the administration of an effective amount of a compound of formula I as defined in claim 1, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof or a pharmaceutical formulation including the compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof ; and another therapeutic agent useful in the treatment of cancer; and a pharmaceutically-acceptable adjuvant, diluent or carrier, to a patient in need of such treatment, wherein the cancer is of the prostate. 23. A method of treatment of cancer, which method comprises the administration of an effective amount of a compound of formula I as defined in claim 1, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof a pharmaceutical formulation including the compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof; and another therapeutic agent useful in the treatment of cancer; and a pharmaceutically-acceptable adjuvant, diluent or carrier, to a patient in need of such treatment, to a patient in need of such treatment, wherein the cancer is of the prostate. 24. A kit of parts comprising: (I) one of components (a) and (b) as defined in claim 17, together with (II) instructions to use that component in conjunction with the other of the two components. 25. A method of making a kit of parts as defined in claim 17, which method comprises bringing a component (a) into association with a component (b), thus rendering the two components suitable for administration in conjunction with each other. 26. A process for the preparation of a compound of formula I as defined in claim 1, (i) for compounds of formula I wherein A represents S, cyclisation of a compound of formula IIa, ##STR00082## wherein A.sub.1 to A.sub.5, X, W and D are as defined in claim 1; (ii) for compounds of formula I wherein A represents S, W represents --[CR.sup.xR.sub.y].sub.m-- and m represents 1 or 2, reaction of a compound of formula III, ##STR00083## wherein A.sub.1 to A.sub.5 and X are as defined in claim 1, with a compound of formula IV, L.sub.2-W.sup.1-D IV wherein L.sub.2 represents a suitable leaving group, W.sup.1 represents --[CR.sup.xR.sup.y].sub.m-- in which m represents 1, and D is as defined in claim 1; (iii) for compounds of formula I wherein A represents S, W represents --[CR.sup.xR.sup.y].sub.m-- and m represents 0, reaction of a compound of formula III as hereinbefore defined with a compound of formula V, L.sub.3-D V wherein L.sub.3 is a suitable leaving group and D is as defined in claim 1; (iv) for compounds of formula I wherein A represents S, W represents --C(O)--[CR.sup.xR.sup.y].sub.p--, reaction of a compound of formula III as hereinbefore defined, with a compound of formula VI, L.sub.4-W.sup.2-D VI wherein L.sub.4 is a suitable leaving group or --OH, W.sup.2 represents --C(O)--[CR.sup.xR.sup.y].sub.p--, and D is as defined in claim 1; (v) for compounds of formula I wherein A represents S, and Q is a bond, --O-- or --S--, reaction of a compound of formula VII, ##STR00084## wherein W and D are as defined in claim 1, with a compound of formula VIII, ##STR00085## wherein A.sub.1 to A.sub.5, n, R.sup.x and R.sup.y are as defined in claim 1, L.sub.5 is a suitable leaving group and Q is a bond, --O-- or --S--; (vi) for compounds of formula I wherein W is --[CR.sup.xR.sup.y].sub.m--, reaction of a compound of formula IX, ##STR00086## wherein L.sub.6 represents a suitable leaving group and A.sub.1 to A.sub.5 and X are as defined in claim 1, with a compound of formula X, H.sub.2N--W-D X wherein W and D are as defined in claim 1; and wherein A.sub.1 to A.sub.5, X, W and D are as defined in claim 1 above. 27. A process for the preparation of a pharmaceutical formulation as defined in claim 14, which process comprises bringing into association the compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, with a pharmaceutically-acceptable adjuvant, diluent or carrier. 28. A process for the preparation of a combination product as defined in claim 15, which process comprises bringing into association the compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, with the other therapeutic agent that is useful in the treatment of cancer.

Details for Patent 9,162,994

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2039-02-26
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2039-02-26
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2039-02-26