JPWO2021007160A5 - - Google Patents

Description

Clause C24. said support is polysaccharide hydrogel, alginate, agarose, cellulose, hyaluronic acid, chitosan, chitin, chondroitin sulfate, heparan sulfate, heparin, gelatin, collagen, polymer matrix, metal, ceramic, or plastic, and The method of any of clauses C1-C23, each of which may be optionally modified.
This specification includes the disclosure of the following inventions.
[1]
A compound of formula (I), or a pharmaceutically acceptable salt thereof
(In the formula,
each occurrence of R ^1a is independently selected from the group consisting of C _1-4 alkyl, hydrogen, and C _1-4 haloalkyl;
R ^1b at each occurrence is C(O)N(R ^1c )—C _1-6 alkylene-CO ₂ H, C(O)OH, C(O)N(R ^1c )CHR ^1e CO ₂ H, C(O)N(R ^1c )—C _1-6 alkylene-C(O)OC _1-4 alkyl, C(O)OC _1-4 alkyl, C(O)N(R ^1c )CHR ^1e C(O ) independently selected from the group consisting of OC _1-4 alkyl, hydrogen, C _1-4 alkyl, and C _1-4 haloalkyl;
each occurrence of R ^lc is independently hydrogen or C _1-4 alkyl;
each occurrence of R ^1e is independently —C _1-4 alkylene-CO ₂ H, —C _1-4 alkylene-CONH ₂ , or —C _1-4 alkylene-OH;
D is independently at each occurrence a cyclic dinucleotide;
L ¹ is independently a linker at each occurrence;
m is independently 1, 2, or 3 at each occurrence;
p is independently 0, 1, or 2 at each occurrence).
[2]
A compound according to [1] of formula (IA), or a pharmaceutically acceptable salt thereof
.
[3]
The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof, wherein R ^1a is hydrogen.
[4]
The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof, wherein R ^1a is C _1-4 alkyl.
[5]
The compound of [1] or [2], or a pharmaceutically acceptable salt thereof, wherein R ^1a is CH ₃ .
[6]
The compound according to any one of [1] to [5], or a pharmaceutically acceptable salt thereof, wherein R 1b is hydrogen ^.
[7]
The compound according to any one of [1] to [5], wherein R ^1b is C(O)N(R ^1c )—C _1-6 alkylene- CO ₂ H, or a pharmaceutically acceptable the salt.
[8]
The compound of [7], or a pharmaceutically acceptable salt thereof, wherein R ^1b is C(O)N(R ^1c )CH ₂ CO ₂ H.
[9]
The compound according to any one of [1] to [5] or [7] to [8], or a pharmaceutically acceptable salt thereof, wherein R 1c is hydrogen ^.
[10]
The compound according to any one of [1] to [5], or a pharmaceutically acceptable salt thereof, wherein R 1b is C(O) OH ^.
[11]
D is independently
(wherein Y is a nucleobase and X is O or S)
The compound according to any one of [1] to [10], or a pharmaceutically acceptable salt thereof.
[12]
teeth,
is;
The compound according to any one of [1] to [11], or a pharmaceutically acceptable salt thereof, wherein D' is a cyclic dinucleotide payload moiety.
[13]
the cyclic dinucleotide payload portion comprising:
The compound according to [12], or a pharmaceutically acceptable salt thereof.
[14]
the cyclic dinucleotide payload portion comprising:
The compound according to [12], or a pharmaceutically acceptable salt thereof.
[15]
the following:

The compound according to [1], or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
[16]
A pharmaceutical composition comprising the compound according to any one of [1] to [15], or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[17]
A compound according to any one of [1] to [15], or a pharmaceutically acceptable salt thereof, for use in treating cancer or for use in enhancing or inducing an immune response, or A pharmaceutical combination comprising the pharmaceutical composition of [16] and a therapeutic support composition, wherein the therapeutic support composition comprises a biocompatible support and the formula
(In the formula,
R ²⁰ is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, CF 3 , CF 2 -R', _NO 2 _, OR _' , SR', C(=O)R', C(=S)R', OC(=O)R''', SC(=O)R''', OC(=S)R''', SC (=S)R''', S(=O)R', S(=O) _2R ''', S(=O) _2NR'R '', C(=O)OR', C(=O)SR', C(=S)OR', C(=S)SR', C(=O)NR'R'', C(=S)NR'R'',NR'R'',NR'C(=O)R'',NR'C(=S)R'',NR'C(=O)OR'',NR'C(=S)OR'',NR'C(=O)SR'',NR'C(=S)SR'',OC(=O)NR'R'',SC(=O)NR'R'', OC(=S )R'R''', SC(=S)R'R'', NR'C(=O)NR''R'', and NR'C(=S)NR''R'' selected from;
R′ and R″ at each occurrence are independently selected from hydrogen, aryl and alkyl; R′″ at each occurrence is independently selected from aryl and alkyl;
R ³⁰ is halogen, cyano, nitro, hydroxy, alkyl, haloalkyl; alkenyl, alkynyl, alkoxy; haloalkoxy; heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl;
R ^a , R ^31a and R ^31b are each independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;
t is 0, 1, 2, 3, or 4)
A pharmaceutical combination comprising a tetrazine-containing group of
[18]
The pharmaceutical combination of [17], wherein the tetrazine-containing group is linked or directly attached to a hyaluronic acid biocompatible support.
[19]
The therapeutic support composition comprises formula (II)
(where ^G2 is
is;
R ²² is a linker of 1-100 linking atoms)
A pharmaceutical combination according to [17], comprising a substituted hyaluronic acid unit of
[20]
G2 is ^_
The pharmaceutical combination according to [19], wherein
[21]
G2 is ^_
is;
A pharmaceutical combination according to [19], wherein R ²⁰ is hydrogen or C _1-4 alkyl.
[22]
A pharmaceutical combination according to any one of [17] to [21], wherein said use is for the treatment or prevention of cancer.
[23]
A pharmaceutical combination according to [22], wherein the cancer is melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioma, lung cancer, soft tissue cancer, soft tissue sarcoma, osteosarcoma, or pancreatic cancer.
[24]
The pharmaceutical combination of [22] or [23], wherein said cancer is a solid tumor.
[25]
The pharmaceutical combination of [22] or [23], wherein said cancer is soft tissue sarcoma.
[26]
The pharmaceutical combination of [25], wherein said soft tissue sarcoma is fibrosarcoma, rhabdomyosarcoma, or Ewing's sarcoma.
[27]
A pharmaceutical combination according to any one of [17] to [21], wherein said use is for enhancing or eliciting an immune response.
[28]
The pharmaceutical combination of [27], wherein said immune response is an increase in one or more of leukocytes, lymphocytes, monocytes and eosinophils.
[29]
The following: anticancer drugs, immune checkpoint inhibitors, or compounds of formula (IB), or pharmaceutically acceptable salts thereof
(In the formula, D ¹ is independently an anticancer drug payload, a microbial immunosuppressive drug payload, an anti-restenosis drug payload, an antibiotic payload, an antifungal drug payload, an antiviral drug
a payload selected from an anti-inflammatory/anti-arthritic drug payload, a corticosteroid drug payload, and an ^{immunosuppressive drug payload} ; 11], as defined in any one of
The pharmaceutical combination of any one of [17]-[28], further comprising another additional therapeutic agent selected from the group consisting of:
[30]
p is 0; m is 1; -L ¹ - is
The pharmaceutical combination according to [29], wherein
[31]
The pharmaceutical combination of [29] or [30], wherein the anticancer drug is doxorubicin.
[32]
A kit comprising the compound according to any one of [1] to [15], or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to [16], and instructions for its use .
[33]
The kit of [32], further comprising the therapeutic support composition of any one of [19]-[23].
[34]
The kit of [32] or [33], further comprising the compound of formula (IB) of any one of [29] to [31].

Claims (18)

compounds of formula (II-A) or (III-A)
(In the formula,
R. ^1A is C _{1 to 4} alkyl, C _{1 to 4} haloalkyl, and C _{1 to 4} independently selected from the group consisting of alkoxy;
R. ^1B is replaced by G ¹ , OH, -NR ^1c -C _{1 to 4} Alkylene-G ¹ , -NR ^1c -C _{1 to 4} Alkylene-N(R ^1d ) ₂ , -N(R ^1c ) CHR ^1e CO ₂ H, -N(R ^1c )-C _{1 to 6} Alkylene-CO ₂ H, -N(R ^1f )-C _2-4 Alkylene-(N(C _{1 to 4} Alkylene-CO ₂ H)-C _2-4 alkylene) _n -N(C _{1 to 4} Alkylene-CO ₂ H) ₂ , -N(R ^1c ) CHR ^1e C(O)OC _{1 to 6} alkyl, —N(R ^1c )-C _{1 to 6} Alkylene-C(O)OC _{1 to 6} alkyl, and —N(R ^1f )-C _2-4 Alkylene-(N(C _{1 to 4} Alkylene-C(O)OC _{1 to 6} alkyl)-C _2-4 alkylene) _n -N(C _{1 to 4} Alkylene-C(O)OC _{1 to 6} alkyl) ₂ independently selected from the group consisting of;
R. ^1c and R ^1d is independently hydrogen or C _{1 to 4} is alkyl;
R. ^1e is independently -C _{1 to 4} Alkylene-CO ₂ H, -C _{1 to 4} Alkylene-CONH ₂ , or -C _{1 to 4} is alkylene-OH;
R. ^1f is independently hydrogen, C _{1 to 6} alkyl, or -C _{1 to 4} Alkylene-CO ₂ is H;
D. ¹ is, independently at each occurrence, an anticancer drug payload;
L. ¹ is independently a linker on each occurrence;
L. ² is -C(O)- and C _{1 to 3} independently selected from the group consisting of alkylene;
G. ¹ is independently optionally substituted heterocyclyl at each occurrence;
m is 1, 2, or 3;
n is independently 0, 1, 2, or 3 at each occurrence; and
p is independently 0, 1, or 2 at each occurrence)
or a pharmaceutically acceptable salt thereof, for use in a method of enhancing or inducing an immune response, or a disease or disorder such as cancer, infection, tissue injury, stenosis, ischemia, revascularization, to a method of treating or preventing myocardial infarction, arrhythmia, vascular occlusion, inflammation, autoimmune disorders, graft rejection, macular degeneration, rheumatoid arthritis, osteoarthritis, periprosthetic infection, and pigmented villonodular synovitis A pharmaceutical composition for use comprising:
The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (II-A) or (III-A), or a pharmaceutically acceptable salt thereof, a therapeutic support composition, and a therapeutically effective amount of with one or more immunomodulatory agents or pharmaceutically acceptable salts thereof of
The therapeutic support composition comprises a support and the formula
(In the formula,
R. ²⁰ is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, CF ₃ , CF ₂ -R', NO ₂ , OR', SR', C(=O)R', C(=S)R', OC(=O)R''', SC(=O)R''', OC(=S)R' '', SC (=S) R''', S (=O) R', S (=O) ₂ R''', S (=O) ₂ NR'R'', C(=O)OR', C(=O)SR', C(=S)OR', C(=S)SR', C(=O ) NR'R'', C(=S)NR'R'', NR'R'', NR'C(=O)R'', NR'C(=S)R'', NR'C( =O)OR'', NR'C(=S)OR'', NR'C(=O)SR'', NR'C(=S)SR'', OC(=O)NR'R'' , SC(=O)NR'R'', OC(=S)R'R''', SC(=S)R'R'', NR'C(=O)NR''R'', and NR'C(=S)NR''R''; R' and R'' at each occurrence are independently selected from hydrogen, aryl and alkyl; , at each occurrence independently selected from aryl and alkyl; ³⁰ is halogen, cyano, nitro, hydroxy, alkyl, haloalkyl; alkenyl, alkynyl, alkoxy; haloalkoxy; heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; ^a , R ^31a and R ^31b are each independently hydrogen, C ₁ ～C ₆ alkyl, or C ₁ ～C ₆ is haloalkyl; and
t is 0, 1, 3, or 4)
wherein the tetrazine-containing group is linked to or directly attached to a support,
pharmaceutical composition. 2. A pharmaceutical composition according to claim 1 for use in a method of enhancing or inducing an immune response. 2. A pharmaceutical composition according to claim 1 for use in a method of treating or preventing cancer. 4. The pharmaceutical composition according to any one of claims 1-3, wherein the immunomodulatory agent is a toll-like receptor (TLR) agonist. a) a compound of formula (II-A) or (III-A), or a pharmaceutically acceptable salt or composition thereof, according to claim 1;
b) one or more immunomodulatory agents, or pharmaceutically acceptable salts or compositions thereof;
c) instructions for use;
kit containing. a) a therapeutic support composition of claim 1;
b) one or more immunomodulatory agents, or pharmaceutically acceptable salts or compositions thereof;
c) instructions for use;
kit containing. a) a compound of formula (II-A) or (III-A) according to claim 1, or a pharmaceutically acceptable salt thereof;
b) one or more immunomodulatory agents, or pharmaceutically acceptable salts thereof;
c) a pharmaceutically acceptable carrier;
A pharmaceutical composition comprising a) a therapeutic support composition of claim 1;
b) one or more immunomodulatory agents, or pharmaceutically acceptable salts thereof;
c) a pharmaceutically acceptable carrier;
A pharmaceutical composition comprising compounds of formula (II-A) or (III-A)
(In the formula,
R. ^1A is C _{1 to 4} alkyl, C _{1 to 4} haloalkyl, and C _{1 to 4} independently selected from the group consisting of alkoxy;
R. ^1B is replaced by G ¹ , OH, -NR ^1c -C _{1 to 4} Alkylene-G ¹ , -NR ^1c -C _{1 to 4} Alkylene-N(R ^1d ) ₂ , -N(R ^1c ) CHR ^1e CO ₂ H, -N(R ^1c )-C _{1 to 6} Alkylene-CO ₂ H, -N(R ^1f )-C _2-4 Alkylene-(N(C _{1 to 4} Alkylene-CO ₂ H)-C _2-4 alkylene) _n -N(C _{1 to 4} Alkylene-CO ₂ H) ₂ , -N(R ^1c ) CHR ^1e C(O)OC _{1 to 6} alkyl, —N(R ^1c )-C _{1 to 6} Alkylene-C(O)OC _{1 to 6} alkyl, and —N(R ^1f )-C _2-4 Alkylene-(N(C _{1 to 4} Alkylene-C(O)OC _{1 to 6} alkyl)-C _2-4 alkylene) _n -N(C _{1 to 4} Alkylene-C(O)OC _{1 to 6} alkyl) ₂ independently selected from the group consisting of;
R. ^1c and R ^1d is independently hydrogen or C _{1 to 4} is alkyl;
R. ^1e is -C _{1 to 4} Alkylene-CO ₂ H, -C _{1 to 4} Alkylene-CONH ₂ , or -C _{1 to 4} is alkylene-OH;
R. ^1f is hydrogen, C _{1 to 6} alkyl, or -C _{1 to 4} Alkylene-CO ₂ is H;
D. ¹ is, independently on each occurrence, the payload;
L. ¹ is a linker;
L. ² is -C(O)- and C _{1 to 3} selected from the group consisting of alkylene;
G. ¹ is optionally substituted heterocyclyl;
m is 1, 2, or 3;
n is 0, 1, 2, or 3; and
p is 0, 1, or 2)
or a pharmaceutically acceptable salt thereof for use in a method of inhibiting growth of a second tumor, or enhancing or inducing an immune response in a second tumor, comprising
The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (II-A) or (III-A), or a pharmaceutically acceptable salt thereof, and a therapeutic support composition including
The therapeutic support composition comprises a support and the formula
(In the formula,
R. ²⁰ is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, CF ₃ , CF ₂ -R', NO ₂ , OR', SR', C(=O)R', C(=S)R', OC(=O)R''', SC(=O)R''', OC(=S)R' '', SC (=S) R''', S (=O) R', S (=O) ₂ R''', S (=O) ₂ NR'R'', C(=O)OR', C(=O)SR', C(=S)OR', C(=S)SR', C(=O ) NR'R'', C(=S)NR'R'', NR'R'', NR'C(=O)R'', NR'C(=S)R'', NR'C( =O)OR'', NR'C(=S)OR'', NR'C(=O)SR'', NR'C(=S)SR'', OC(=O)NR'R'' , SC(=O)NR'R'', OC(=S)R'R''', SC(=S)R'R'', NR'C(=O)NR''R'', and NR'C(=S)NR''R''; R' and R'' at each occurrence are independently selected from hydrogen, aryl and alkyl; , at each occurrence independently selected from aryl and alkyl; ³⁰ is halogen, cyano, nitro, hydroxy, alkyl, haloalkyl; alkenyl, alkynyl, alkoxy; haloalkoxy; heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; ^a , R ^31a and R ^31b are each independently hydrogen, C ₁ ～C ₆ alkyl, or C ₁ ～C ₆ is haloalkyl; and
t is 0, 1, 3, or 4)
wherein the tetrazine-containing group is linked to or directly attached to a support. compounds of formula (II-A) or (III-A)
(In the formula,
R. ^1A is C _{1 to 4} alkyl, C _{1 to 4} haloalkyl, and C _{1 to 4} selected from the group consisting of alkoxy;
R. ^1B is G ¹ , OH, -NR ^1c -C _{1 to 4} Alkylene-G ¹ , -NR ^1c -C _{1 to 4} Alkylene-N(R ^1d ) ₂ , -N(R ^1c ) CHR ^1e CO ₂ H, -N(R ^1c )-C _{1 to 6} Alkylene-CO ₂ H, -N(R ^1f )-C _2-4 Alkylene-(N(C _{1 to 4} Alkylene-CO ₂ H)-C _2-4 alkylene) _n -N(C _{1 to 4} Alkylene-CO ₂ H) ₂ , -N(R ^1c ) CHR ^1e C(O)OC _{1 to 6} alkyl, —N(R ^1c )-C _{1 to 6} Alkylene-C(O)OC _{1 to 6} alkyl, and —N(R ^1f )-C _2-4 Alkylene-(N(C _{1 to 4} Alkylene-C(O)OC _{1 to 6} alkyl)-C _2-4 alkylene) _n -N(C _{1 to 4} Alkylene-C(O)OC _{1 to 6} alkyl) ₂ selected from the group consisting of;
R. ^1c and R ^1d is independently hydrogen or C _{1 to 4} is alkyl;
R. ^1e is -C _{1 to 4} Alkylene-CO ₂ H, -C _{1 to 4} Alkylene-CONH ₂ , or -C _{1 to 4} is alkylene-OH;
R. ^1f is hydrogen, C _{1 to 6} alkyl, or -C _{1 to 4} Alkylene-CO ₂ is H;
D. ¹ is, independently on each occurrence, the payload;
L. ¹ is a linker;
L. ² is -C(O)- and C _{1 to 3} selected from the group consisting of alkylene;
G. ¹ is optionally substituted heterocyclyl;
m is 1, 2, or 3;
n is 0, 1, 2, or 3; and
p is 0, 1, or 2)
or a pharmaceutically acceptable salt thereof for use in a method of inhibiting tumor metastasis, comprising:
The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (II-A) or (III-A), or a pharmaceutically acceptable salt thereof, and a therapeutic support composition including
The therapeutic support composition comprises a support and the formula
(In the formula,
R. ²⁰ is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, CF ₃ , CF ₂ -R', NO ₂ , OR', SR', C(=O)R', C(=S)R', OC(=O)R''', SC(=O)R''', OC(=S)R' '', SC (=S) R''', S (=O) R', S (=O) ₂ R''', S (=O) ₂ NR'R'', C(=O)OR', C(=O)SR', C(=S)OR', C(=S)SR', C(=O ) NR'R'', C(=S)NR'R'', NR'R'', NR'C(=O)R'', NR'C(=S)R'', NR'C( =O)OR'', NR'C(=S)OR'', NR'C(=O)SR'', NR'C(=S)SR'', OC(=O)NR'R'' , SC(=O)NR'R'', OC(=S)R'R''', SC(=S)R'R'', NR'C(=O)NR''R'', and NR'C(=S)NR''R''; R' and R'' at each occurrence are independently selected from hydrogen, aryl and alkyl; , at each occurrence independently selected from aryl and alkyl; ³⁰ is halogen, cyano, nitro, hydroxy, alkyl, haloalkyl; alkenyl, alkynyl, alkoxy; haloalkoxy; heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; ^a , R ^31a and R ^31b are each independently hydrogen, C ₁ ～C ₆ alkyl, or C ₁ ～C ₆ is haloalkyl; and
t is 0, 1, 3, or 4)
wherein the tetrazine-containing group is linked to or directly attached to a support. 11. The pharmaceutical composition of claim 10, wherein said method further comprises administering to said subject a therapeutically effective amount of one or more immunomodulatory agents. one or more immunomodulatory agents are immune checkpoint inhibitors, toll-like receptor (TLR) agonists, interferon gene stimulating factor (STING) agonists, cytokines, cytokine inhibitors, cytokine receptor agonists, cytokine receptor antagonists , a chemokine, a chemokine inhibitor, a chemokine receptor agonist, or a chemokine receptor antagonist. A compound of formula (I), or a pharmaceutically acceptable salt thereof
(In the formula,
each occurrence of R ^1a is independently selected from the group consisting of C _1-4 alkyl, hydrogen, and C _1-4 haloalkyl;
R ^1b at each occurrence is C(O)N(R ^1c )—C _1-6 alkylene-CO ₂ H, C(O)OH, C(O)N(R ^1c )CHR ^1e CO ₂ H, C(O)N(R ^1c )—C _1-6 alkylene-C(O)OC _1-4 alkyl, C(O)OC _1-4 alkyl, C(O)N(R ^1c )CHR ^1e C(O ) independently selected from the group consisting of OC _1-4 alkyl, hydrogen, C _1-4 alkyl, and C _1-4 haloalkyl;
each occurrence of R ^lc is independently hydrogen or C _1-4 alkyl;
each occurrence of R ^1e is independently —C _1-4 alkylene-CO ₂ H, —C _1-4 alkylene-CONH ₂ , or —C _1-4 alkylene-OH;
D is, at each occurrence, independently a payload selected from the group consisting of toll-like receptor (TLR) agonists and interferon gene stimulating factor (STING) agonists ;
L ¹ is independently a linker at each occurrence;
m is independently 1, 2, or 3 at each occurrence; and p is independently 0, 1, or 2 at each occurrence). 14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein each occurrence of D is independently a cyclic oligodinucleotide . the following:
14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of: A pharmaceutical composition comprising a compound according to any one of claims 13 to 15 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A compound according to any one of claims 13 to 15, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer or in a method of enhancing or inducing an immune response A pharmaceutical composition comprising, in a subject in need thereof, a therapeutically effective amount of a compound of any one of claims 13 to 15, or a pharmaceutically acceptable salt thereof, a therapeutic support composition, wherein the therapeutic support composition comprises a biocompatible support and the formula
(In the formula,
R ²⁰ is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, CF ₃ , CF ₂ -R', NO ₂ , OR', SR', C(=O)R', C(=S)R', OC(=O)R''', SC(=O)R''', OC(=S)R''', SC (=S)R''', S(=O)R', S(=O) _2R ''', S( ₌ O)2NR'R'', C(=O)OR', C(=O)SR', C(=S)OR', C(=S)SR', C(=O)NR'R'', C(=S)NR'R'',NR'R'',NR'C(=O)R'',NR'C(=S)R'',NR'C(=O)OR'',NR'C(=S)OR'',NR'C(=O)SR'',NR'C(=S)SR'',OC(=O)NR'R'',SC(=O)NR'R'', OC(=S )R'R''', SC(=S)R'R'', NR'C(=O)NR''R'', and NR'C(=S)NR''R'' selected from;
R′ and R″ at each occurrence are independently selected from hydrogen, aryl and alkyl; R′″ at each occurrence is independently selected from aryl and alkyl;
R ³⁰ is halogen, cyano, nitro, hydroxy, alkyl, haloalkyl; alkenyl, alkynyl, alkoxy; haloalkoxy; heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl;
R ^a , R ^31a and R ^31b are each independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; and t is 0, 1, 2, 3, or 4 )
and a tetrazine-containing group of 18. A pharmaceutical composition according to claim 17 for use in a method of treating or preventing cancer.