CN117777126A - Imidazopyridines as IRAK4 degradants and uses thereof - Google Patents
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- CN117777126A CN117777126A CN202311275384.3A CN202311275384A CN117777126A CN 117777126 A CN117777126 A CN 117777126A CN 202311275384 A CN202311275384 A CN 202311275384A CN 117777126 A CN117777126 A CN 117777126A
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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Abstract
The invention discloses an imidazopyridine compound serving as an IRAK4 degradation agent and application thereof. The IRAK4 degrading compound is an imidazopyridine compound shown as a formula (I), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof. The compound of the invention can be used for treating diseases related to IRAK4, and has good drug prospect.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, in particular to a compound for degrading IRAK4, and more particularly relates to an imidazopyridine compound shown in a formula (I), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or prodrug thereof, a preparation method of the imidazopyridine compound, and application of the imidazopyridine compound in preparation of a medicament for treating IRAK4 related diseases.
Background
IRAK4, interleukin-1 receptor associated kinase 4, is a serine/threonine specific protein kinase with biologically important kinase activity that plays an important role in the kinase immune system. IRAK4 belongs to the IRAK family, and family members also include IRAK1, IRAK2, IRAKM (I-RAK 3), and the like. The human IRAK-4 gene is located in the p11.12 region of the x chromosome and codes for 52kDa protein. IRAK4 proteins, like other family members, contain serine-threonine Kinase Domains (KD) and N-terminally conserved Death Domains (DD), are key molecules in Toll-like receptors (Toll like receptor, TLRs), and interleukin 1 receptors (Intereukin-1, IL-1 Rs) signaling pathways, involved in regulating intracellular signaling cascades and inflammatory responses. TLRs are a family of transmembrane pattern recognition receptors that play a central role in innate immune signaling. The IL-1Rs family initiates immune responses upon stimulation by a variety of IL-1 cytokines. However, conventional small molecule inhibitors are prone to developing resistance, and thus inhibition of IRAK4 kinase activity alone may not be sufficient to produce an effective therapeutic effect.
PROTAC, i.e., protein targeted degradation chimera (Proteolysis targeting chimera), is different from the technology of traditional small molecule inhibitors, which usually need to act on the active site of the target protein to inhibit its activity, but is a bifunctional small molecule, and the PROTAC molecule comprises an E3 ubiquitin ligase ligand and a target Protein (POI) ligand, which are linked by a linker to make the target protein and the E3 ubiquitin ligase meet each other, label the target protein with ubiquitin, and degrade the protein by means of the in vivo "cleaner" ubiquitin-proteasome approach. Therefore, compared with the traditional small molecule inhibitor, the novel drug development by using the PROTAC technology has high advantages and feasibility, and is expected to become a promising novel drug of the next generation.
Disclosure of Invention
The invention aims to provide a PROTAC compound with a novel structure, and particularly relates to the PROTAC compound with an IRAK4 degradation effect. The compound of the invention has good IRAK4 protein degradation activity, and can be used for treating diseases related to IRAK 4.
In a first aspect of the present invention, the present invention provides a compound which is a compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof,
Wherein,
E 1 is-CH 2 -or-C (=o) -;
R 1 is H, halogen, CN, C 1-6 Alkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 4-9 membered heterocycloalkyl, -NHC 1-6 Alkyl, -N (C) 1-6 Alkyl group 2 、-NH-C 4-9 Cycloalkyl, -NH-C 4-9 Heterocycloalkyl (e.g., -NH-4-9 membered heterocycloalkyl) or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 4-9 membered heterocycloalkyl, -NHC 1-6 Alkyl, -N (C) 1-6 Alkyl group 2 、-NH-C 4-9 Cycloalkyl, -NH-C 4-9 Heterocycloalkyl (e.g., -NH-4-9 membered heterocycloalkyl) and 5-10 membered heteroaryl are each optionally substituted with 1 or more R 11 Substitution;
R 2 is H or C 1-6 An alkyl group;
R 3 is H, halogen, CN, C 1-6 Alkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl and 5-10 membered heteroaryl are each optionally substituted with 1 or more R 31 Substitution;
is->
Ring A and ring B are each independently absent, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 A membered aryl or 5-10 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 The membered aryl and the 5-10 membered heteroaryl are each optionally substituted with 1 or more R a Substitution;
L 1 、L 2 and L 3 Are each independently a single bond, -O-, -N (R) 22 )-、-P(O)-、-P(O)O-、-S-、-S(O)-、-S(O) 2 -、-S(O) 2 -N(R 22 )-、C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 1-12 Heteroalkyl wherein, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl and C 1-12 Heteroalkyl groups are each optionally substituted with 1 or more R b Substitution;
ring C is C 6-10 Aryl or 5-10 membered heteroaryl;
the "4-12 membered heterocycloalkyl", "5-10 membered heteroaryl" and "C 1-12 "hetero" of a heteroalkyl "is a heteroatom or heteroatom group; the number of the hetero atoms or hetero atom groups is 1 or more, and each hetero atom or hetero atom group is N, -O-, -N (R) 22 )-、-P(O)-、-P(O)O-、-S-、-S(O)-、-S(O) 2 -、-S(O) 2 -N(R 22 ) -; when the number of the hetero atoms or the hetero atom groups is plural, the hetero atoms or the hetero atom groups are the same or different;
each R is 11 H, C independently 1-6 Alkyl, halogen, OH or CN;
each R is 31 Is defined as case 1 or case 2:
case 1: each R is 31 H, C independently 1-6 Alkyl, halogen, OH, NH 2 Or CN;
case 2: each R is 31 Independently C substituted with 1, 2 or 3 halogens 1-6 An alkyl group;
each R is 22 Independently H or C 1-6 An alkyl group;
each R is a Independently is halogen, =o, OH, NH 2 Or C 1-6 An alkyl group;
each R is b Independently H, =o, halogen, OH, NH 2 Or C 1-6 An alkyl group;
r is 1, 2, 3 or 4.
In an optional embodiment of the invention, the compound of formula (I), a tautomer thereof, a stereoisomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof,
Wherein,
E 1 is-CH 2 -or-C (=o) -;
R 1 is H, halogen, CN, C 1-6 Alkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 4-9 membered heterocycloalkyl, -NHC 1-6 Alkyl, -N (C) 1-6 Alkyl group 2 、-NH-C 4-9 Cycloalkyl, -NH-C 4-9 Heterocycloalkyl (e.g., -NH-4-9 membered heterocycloalkyl) or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 4-9 memberedHeterocyclylalkyl, -NHC 1-6 Alkyl, -N (C) 1-6 Alkyl group 2 、-NH-C 4-9 Cycloalkyl, -NH-4-9 membered heterocycloalkyl and 5-10 membered heteroaryl are each optionally substituted with 1 or more R 11 Substitution;
R 2 is H or C 1-6 An alkyl group;
R 3 is cyclopropyl, each of which is optionally substituted with 1 or more R 31 Substitution;
is->
Ring A and ring B are each independently absent, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 A membered aryl or 5-10 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 The membered aryl and the 5-10 membered heteroaryl are each optionally substituted with 1 or more R a Substitution;
L 1 、L 2 and L 3 Are each independently a single bond, -O-, -N (R) 22 )-、-P(O)-、-P(O)O-、-S-、-S(O)-、-S(O) 2 -、-S(O) 2 -N(R 22 )-、C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 1-12 Heteroalkyl wherein, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl and C 1-12 Heteroalkyl groups are each optionally substituted with 1 or more R b Substitution;
ring C is C 6-10 Aryl or 5-10 membered heteroaryl;
the "4-12 membered heterocycloalkyl", 5-10 membered heteroaryl and "C 1-12 "hetero" of a heteroalkyl "is a heteroatom or heteroatom group; the number of the hetero atoms or hetero atom groups is 1 or more, and each hetero atom or hetero atom group is N, -O-, -N (R) 22 )-、-P(O)-、-P(O)O-、-S-、-S(O)-、-S(O) 2 -、-S(O) 2 -N(R 22 )-;
Each R is 11 H, C independently 1-6 Alkyl, halogen, OH or CN;
each R is 31 H, C independently 1-6 Alkyl, halogen, OH or CN;
each R is 22 Independently H or C 1-6 An alkyl group;
each R is a Independently is halogen, =o, OH, NH 2 Or C 1-6 An alkyl group;
each R is b Independently H, =o, halogen, OH, NH 2 Or C 1-6 An alkyl group;
r is 1, 2, 3 or 4.
In an optional embodiment of the invention, the compound of formula (I), a tautomer thereof, a stereoisomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof,
wherein,
E 1 is-CH 2 -or-C (=o) -;
R 1 is cyclopropyl, optionally substituted with 1 or more R 11 Substitution;
R 2 is H or C 1-6 An alkyl group;
R 3 is H, halogen, CN, C 1-6 Alkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl and 5-10 membered heteroaryl are each optionally substituted with 1 or more R 31 Substitution;
is->
Ring A and ring B are each independently absent, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 A membered aryl or 5-10 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 The membered aryl and the 5-10 membered heteroaryl are each optionally substituted with 1 or more R a Substitution;
L 1 、L 2 and L 3 Are each independently a single bond, -O-, -N (R) 22 )-、-P(O)-、-P(O)O-、-S-、-S(O)-、-S(O) 2 -、-S(O) 2 -N(R 22 )-、C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 1-12 Heteroalkyl wherein, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl and C 1-12 Heteroalkyl groups are each optionally substituted with 1 or more R b Substitution;
ring C is C 6-10 Aryl or 5-10 membered heteroaryl;
the "4-12 membered heterocycloalkyl", 5-10 membered heteroaryl and "C 1-12 "hetero" of a heteroalkyl "is a heteroatom or heteroatom group; the number of the hetero atoms or hetero atom groups is 1 or more, and each hetero atom or hetero atom group is N, -O-, -N (R) 22 )-、-P(O)-、-P(O)O-、-S-、-S(O)-、-S(O) 2 -or-S (O) 2 -N(R 22 )-;
Each R is 11 H, C independently 1-6 Alkyl, halogen, OH or CN;
each R is 31 H, C independently 1-6 Alkyl, halogen, OH, NH 2 Or CN;
each R is 22 Independently H or C 1-6 An alkyl group;
each R is a Independently is halogen, =o, OH, NH 2 Or C 1-6 An alkyl group;
each R is b Independently H, =o, halogen, OH, NH 2 Or C 1-6 An alkyl group;
r is 1, 2, 3 or 4.
In an optional embodiment of the invention, the 4-9 membered heterocycloalkyl, the-NH-C 4-9 Heterocyclic ringThe "hetero" in the alkyl group and the 3-12 membered heterocycloalkyl group is a heteroatom or a heteroatom group; the number of the hetero atoms or hetero atom groups is 1 or more, and each hetero atom or hetero atom group is N, -O-, -N (R) 22 )-、-P(O)-、-P(O)O-、-S-、-S(O)-、-S(O) 2 -or-S (O) 2 -N(R 22 )-;R 22 Is as defined above.
In an alternative embodiment of the invention, the number of heteroatoms or groups of heteroatoms is 1, 2, 3 or 4.
In an optional embodiment of the invention, R 1 In the above, the C 1-6 Alkyl, said-O-C 1-6 C in alkyl 1-6 Alkyl, the-NHC 1-6 C in alkyl 1-6 Alkyl and said-N (C) 1-6 Alkyl group 2 C in (C) 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or isopropyl.
In an optional embodiment of the invention, R 1 In the above, the C 3-6 Cycloalkyl and the-O-C 3-6 C in cycloalkyl 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.
In an optional embodiment of the invention, R 1 Is C 1-6 Alkyl, -O-C 1-6 Alkyl (-O-C) 1-3 Alkyl) or C 3-6 Cycloalkyl group, the C 1-6 Alkyl, -O-C 1-6 Alkyl and C 3-6 Cycloalkyl optionally substituted with one or more R 11 And (3) substitution.
In an optional embodiment of the invention, R 1 Is thatCyclopropyl or methoxy, said +.>Cyclopropyl and methoxy are each optionally substituted with one or more R 11 And (3) substitution.
In an optional embodiment of the invention, R 1 Is C 1-3 Alkyl or cyclopropyl, said C 1-3 Alkyl and cyclopropyl are each optionally substituted with one or more R 11 And (3) substitution.
In an optional embodiment of the invention, R 1 Is thatOr cyclopropyl, said->And cyclopropyl is each optionally substituted with one or more R 11 And (3) substitution.
In an optional embodiment of the invention, R 1 Is cyclopropyl, said cyclopropyl optionally being substituted with one or more R 11 And (3) substitution.
In an optional embodiment of the invention, the substituent R 11 Is 1, 2, 3 or 4.
In an optional embodiment of the invention, each R 11 Independently halogen, OH or CN.
In an optional embodiment of the invention, each R 11 Independently OH.
In an optional embodiment of the invention, R 1 Is thatOr methoxy.
In an optional embodiment of the invention, R 1 Is that
In an optional embodiment of the invention, R 1 Is that
In an optional embodiment of the invention, R 1 Is that
In an optional embodiment of the invention, R 2 H.
In an optional embodiment of the invention, R 3 In the above, the C 1-6 Alkyl and said-O-C 1-6 C in alkyl 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or isopropyl.
In an optional embodiment of the invention, R 3 In the above, the C 3-6 Cycloalkyl and the-O-C 3-6 C in cycloalkyl 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, e.g. cyclopropyl.
In an optional embodiment of the invention, R 3 Is C 1-6 Alkyl or C 3-6 Cycloalkyl group, the C 1-6 Alkyl and C 3-6 Cycloalkyl groups are each optionally substituted with 1 or more R 31 And (3) substitution.
In an optional embodiment of the invention, R 3 is-CH 3 Or cyclopropyl, said-CH 3 And cyclopropyl is each optionally substituted with one or more R 31 And (3) substitution.
In an optional embodiment of the invention, R 3 Is cyclopropyl, said cyclopropyl optionally being substituted with one or more R 31 And (3) substitution.
In an optional embodiment of the invention, the substituent R 31 Is 1, 2, 3 or 4.
In an optional embodiment of the invention, each R 31 Wherein the halogen is F, cl, br or I.
In an optional embodiment of the invention, each R 31 Independently H, halogen, OH or CN.
In an optional embodiment of the invention, each R 31 H, F, cl, br, OH or CN, independently.
In an optional embodiment of the invention, R 31 For C substituted by 1, 2 or 3 halogens 1-6 An alkyl group.
In an optional embodiment of the invention,R 3 Is halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl group, the C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally substituted with 1, 2 or 3R groups, respectively 31 Substituted, R 31 Is halogen or C substituted by 1, 2 or 3 halogens 1-6 An alkyl group. In an optional embodiment of the invention, R 3 F, cl, -CF 3 、(e.g.)> )。
In an optional embodiment of the invention, R 3 is-CF 3 。
In an optional embodiment of the invention, R 3 Is that
In an optional embodiment of the invention, in ring C, the 5-10 membered heteroaryl is a 5-or 6-membered heteroaryl, the heteroatom is N, the number is 1 or 2, preferably pyridinyl (e.g.) Or pyrimidinyl (e.g.)>)。
In an optional embodiment of the present invention,is->
In an optional embodiment of the invention, L 1 、L 2 And L 3 Are each independently a single bond, -O-, -N (R) 22 )-、-S(O)-、-S(O) 2 -、-S(O) 2 -N(R 22 )-、-C 1-6 Alkyl-, -C 2-6 Alkynyl-, -C 1-6 alkyl-O-, -C 1-6 alkyl-N (R) 22 )-、-C 1-6 alkyl-S (O) -, C 1-6 alkyl-S (O) 2 -、-C 1-6 alkyl-S (O) 2 -N(R 22 )-、-S(O) 2 -N(R 22 )-C 1-6 Alkyl-, -C 1-6 alkyl-O-C 1-6 Alkyl-, -C 1-6 alkyl-N (R) 22 )-C 1-6 Alkyl-, -C 1-6 alkyl-S (O) -C 1-6 Alkyl-, -C 1-6 alkyl-S (O) 2 -C 1-6 Alkyl-, -C 1-6 alkyl-S (O) 2 -N(R 22 )-C 1-6 Alkyl-, -O-C 1-6 alkyl-O-, -N (R) 22 )-C 1-6 alkyl-N (R) 22 )-、-S(O)-C 1-6 alkyl-S (O) -, -S (O) 2 -C 1-6 alkyl-S (O) 2 -、-S(O) 2 -N(R 22 )-C 1-6 alkyl-S (O) 2 -N(R 22 ) -, or O-C 1-6 alkyl-N (R) 22 ) -, wherein each of the C 1-6 Alkyl and-C 2-6 Alkynyl-each independently optionally substituted with 1, 2, 3 or 4R b And (3) substitution.
In an optional embodiment of the invention, each R 22 Independently H or C 1-6 An alkyl group.
In an optional embodiment of the invention, each R 22 Independently H or CH 3 。
In an optional embodiment of the invention, each R b Independently halogen, = O, OH or NH 2 。
In an optional embodiment of the invention, L 1 、L 2 And L 3 Are each independently a single bond, -O-, -N (R) 22 )-、-S(O)-、-S(O) 2 -、-S(O) 2 -N(R 22 )-、-(CH 2 ) m -、-C 2 H 2 -、-(CH 2 ) m -C 2 H 2 -、-O-(CH 2 ) m -C 2 H 2 -、-(CH 2 ) n -O-、-(CH 2 ) n -N(R 22 )-、-(CH 2 ) n -S(O)-、-(CH 2 ) n -S(O) 2 -、-(CH 2 ) n -S(O) 2 -N(R 22 )-、-S(O) 2 -N(R 22 )-(CH 2 ) n -、-(CH 2 ) n -O-(CH 2 ) n -、-(CH 2 ) n -N(R 22 )-(CH 2 ) n -、-(CH 2 ) n -S(O)-(CH 2 ) n -、-(CH 2 ) n -S(O) 2 -(CH 2 ) n -、-(CH 2 ) n -S(O) 2 -N(R 22 )-(CH 2 ) n -、-O-(CH 2 ) n -O-、-O-(CH 2 ) n -N(R 22 ) -; wherein each m, n is independently 1, 2, 3 or 4.
In an optional embodiment of the invention, L 1 Is a single bond, -CH 2 -、
In an optional embodiment of the invention, L 2 Is a single bond, -CH 2 -、
In an optional embodiment of the invention, L 3 Is a single bond, -CH 2 -、
In one aspect of the inventionIn optional embodiments, ring A and ring B are each independently absent, C 3-6 Cycloalkyl or 4-8 membered heterocycloalkyl, said C 3-6 Cycloalkyl and 4-8 membered heterocycloalkyl are each optionally substituted with one or more R a And (3) substitution.
In an alternative embodiment of the invention, in ring A and ring B, the C 3-12 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In an optional embodiment of the invention, in ring A and ring B, the 3-12 membered heterocycloalkyl is a 4-12 membered heterocycloalkyl, preferably a 4, 5, 6 or 7 membered monocyclic or bicyclic spiro heterocycloalkyl, the number of heteroatoms being N, 1 or 2, more preferably azetidinyl, piperidinyl, piperazinyl or 2-azaspiro [3.3] heptanyl.
In an optional embodiment of the invention, rings A and B are each independently absent, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl, said C 3-12 Cycloalkyl and 3-12 membered heterocycloalkyl are each optionally substituted with one or more R a And (3) substitution.
In an alternative embodiment of the invention, ring A and ring B are each independently absent, azetidinyl, cyclohexyl, piperidinyl, piperazinyl or 2-azaspiro [3.3 ]]Heptyl, said cyclohexyl, piperidinyl, piperazinyl and 2-azaspiro [3.3 ]]The heptyl groups are each optionally substituted with one or more R a And (3) substitution.
In an optional embodiment of the invention, the substituent R a Is 1, 2, 3 or 4.
In an optional embodiment of the invention, each R a Independently = O, F, cl, br, OH or NH 2 。
In an alternative embodiment of the invention, ring A is absent,
In an alternative embodiment of the invention, ring B is absent,
In an optional embodiment of the present invention,in which, when ring A and ring B are absent, L 1 、L 2 And L 3 Not both single bonds.
In an optional embodiment of the present invention,is->
In an optional embodiment of the present invention,wherein L is 1 Is a single bond or-C 1-6 alkyl-S (O) 2 -; ring A is optionally substituted with 1, 2, or 3R a Substituted 4-8 membered heterocycloalkyl (4-8 membered heterocycloalkyl may be bound to L through a heteroatom) 2 Is connected with each other); l (L) 2 is-C 1-6 Alkyl-, -C 1-6 alkyl-O-C 1-6 alkyl-or-C 1-6 alkyl-S (O) 2 -;L 3 is-O-C 1-6 alkyl-N (R) 22 )-、-O-C 1-6 alkyl-O-or-C 2-6 Alkynyl-.
In an optional embodiment of the present invention,wherein ring A and ring B are each independently C 3-6 Cycloalkyl or 4-8 membered heterocycloalkyl, said C 3-6 Cycloalkyl and 4-8 membered heterocycloalkyl are each independently optionally substituted with 1, 2, or 3R a Substitution; l (L) 2 Is a single bond、-C 1-6 alkyl-or-C 1-6 alkyl-N (R) 22 )-;L 3 Is a single bond, -C 1-6 alkyl-O-, -C 1-6 alkyl-N (R) 22 ) -or-C 2-6 Alkynyl-.
In an optional embodiment of the present invention,wherein L is 1 is-C 1-6 alkyl-S (O) 2 -、-C 1-6 alkyl-S (O) 2 -N(R 22 ) -or-C 1-6 alkyl-N (R) 22 )-;L 2 is-C 1-6 alkyl-or-C 1-6 alkyl-O-C 1-6 Alkyl-; l (L) 3 is-O-or-O-C 1-6 alkyl-O-.
In an optional embodiment of the present invention,is->
In an optional embodiment of the present invention,is->
Preferably, R 3 Is halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl group, providedThe C is 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally substituted with 1, 2 or 3R groups, respectively 31 Substituted, each R 31 Independently halogen.
Preferably, R 3 Is halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl group, the C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally substituted with 1, 2 or 3R groups, respectively 31 Substituted, each R 31 Independently C substituted with 1, 2 or 3 halogens 1-6 An alkyl group.
In an optional embodiment of the invention, the compound is a compound of formula (II) or (III), a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof,
wherein R is 1 Andis defined as in the present invention.
Preferably, in formula (II) or (III), R 1 Is C 1-6 Alkyl, said C 1-6 Alkyl is optionally substituted with 1, 2 or 3R 11 And (3) substitution. More preferably, R 1 Is C 1-6 Alkyl, said C 1-6 Alkyl is optionally substituted with 1, 2 or 3R 11 Substituted, R 11 Is OH.
In a preferred embodiment of the present invention, the compound of formula (I) is a compound of formula (IV):
R 3 is C 3-6 Cycloalkyl group, the C 3-6 Cycloalkyl is optionally substituted with 1 or 2R 31 Substitution; each R is 31 Independently C substituted with 1, 2 or 3 halogens 1-6 An alkyl group;
ring a and ring B are each independently 4-8 membered heterocycloalkyl; l (L) 2 is-C 1-6 An alkyl group; l (L) 1 And L 3 Is a single bond.
In a preferred embodiment of the invention, in formula (I),
E 1 is-C (=o) -;
R 1 is C 1-6 Alkyl, -O-C 1-6 Alkyl or C 3-6 Cycloalkyl group, the C 1-6 Alkyl, said-O-C 1-6 Alkyl and said C 3-6 Cycloalkyl groups are optionally substituted with 1, 2 or 3R groups, respectively 11 Substitution;
R 2 Is H;
R 3 is halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl group, the C 1-6 Alkyl and said C 3-6 Cycloalkyl groups are each optionally substituted with 1 or more R 31 Substitution;
is->
Wherein L is 1 Is a single bond or-C 1-6 alkyl-S (O) 2 -; ring A is optionally substituted with 1, 2, or 3R a Substituted 4-8 membered heterocycloalkyl; l (L) 2 is-C 1-6 Alkyl-, -C 1-6 alkyl-O-C 1-6 alkyl-or-S (O) 2 -;L 3 is-O-, -N (R) 22 )-、-O-C 1-6 alkyl-O-, -C 1-6 alkyl-O-C 1-6 alkyl-O-or-C 2-6 Alkynyl-;
wherein ring A and ring B are each independently C 3-6 Cycloalkyl or 4-8 membered heterocycloalkyl, said C 3-6 Cycloalkyl and 4-8 membered heterocycloalkyl are each independently optionally substituted with 1, 2, or 3R a Substitution; l (L) 2 Is a single bond, -C 1-6 alkyl-or-C 1-6 alkyl-N (R) 22 )-;L 3 Is a single bond, -C 1-6 alkyl-O-, -C 1-6 alkyl-N (R) 22 ) -or-C 2-6 Alkynyl-;
wherein L is 1 is-C 1-6 alkyl-S (O) 2 -、-C 1-6 alkyl-S (O) 2 -N(R 22 ) -or-C 1-6 alkyl-N (R) 22 )-;L 2 is-C 1-6 alkyl-or-C 1-6 alkyl-O-C 1-6 Alkyl-; l (L) 1 is-O-or-O-C 1-6 alkyl-O-;
ring C is a 5-10 membered heteroaryl;
each R is 11 Independently halogen;
each R is 31 Is defined as case 1 or case 2:
case 1; each R is 31 Independently halogen;
case 2: each R is 31 Independently C substituted with 1, 2 or 3 halogens 1-6 An alkyl group;
each R is 22 Independently H or C 1-6 An alkyl group;
r is 1 or 2, 3 or 4.
In a preferred embodiment of the invention, the compound has the structure, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, as shown below:
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/>
/>
/>
/>
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In a second aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective dose of the above-described compound, a tautomer thereof, a stereoisomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, and a pharmaceutically acceptable excipient.
In a third aspect of the invention, the invention provides the use of a compound as defined above, a tautomer thereof, a stereoisomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, or a pharmaceutical composition as defined above, in the manufacture of a medicament for the treatment or prophylaxis of a disease associated with IRAK 4.
According to a specific embodiment of the invention, the use of the above-described compounds or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof or the above-described pharmaceutical composition for the manufacture of a medicament for the treatment or prevention of a disease associated with IRAK4, which medicament is useful for the treatment or prevention of cancer, neurodegenerative disorders, viral diseases, autoimmune diseases, inflammatory diseases, genetic disorders, hormone-related diseases, metabolic disorders, diseases associated with organ transplantation, immunodeficiency disorders, destructive bone diseases, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T-cell activation, cardiovascular disorders or CNS disorders.
According to a specific embodiment of the invention, the use of the above-mentioned compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or the above-mentioned pharmaceutical compositions for the preparation of a medicament for the treatment or prophylaxis of diseases associated with IRAK4, the medicament is useful for treating or preventing brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, neuroglioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, cervical or head tumor, epidermodysplasia, psoriasis, prostatic hyperplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, hodgkin's and non-hodgkin's, breast cancer, follicular carcinoma, undifferentiated carcinoma, papilloma, seminoma, melanoma, abcdlbcl, hodgkin's lymphoma, primary cutaneous T cell lymphoma, chronic lymphocytic leukemia, smoking-type multiple myeloma, leukemia, chronic large B cell lymphoma, bcl, chronic leukemia, diffuse-cell lymphoma, lymphomas (lymphomas, lymphomas in the range of lymphomas such as lymphomas between the bezel, lymphomas of the bezel cell lymphoma, lymphomas of the bezel's lymphoma, lymphomas of the spleen, lymphomas of the range of lymphomas, lymphomas of lymphomas, parkinson's disease, amyotrophic lateral sclerosis, huntington's disease, cerebral ischemia or traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, diabetes therapy, metabolic syndrome, obesity, neurodegenerative diseases caused by organ transplantation or graft versus host disease, ocular diseases such as ocular allergy, conjunctivitis, dry eye or vernal conjunctivitis, diseases affecting the nose including allergic rhinitis; an autoimmune blood disorder is described as a condition, such as hemolytic anemia, aplastic anemia, pure erythrocyte anemia and idiopathic thrombocytopenia, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, dermatomyositis, chronic active hepatitis, myasthenia gravis, stefan-Johnson syndrome, idiopathic sprue, font-type immunoinflammatory bowel disease, irritable bowel syndrome, celiac disease, dental root periostitis, chronic active hepatitis, crohn's disease, inflammatory bowel disease, and inflammatory bowel disease pulmonary clear membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine eye disease, grave's disease, sarcoidosis, dry eye, vernal conjunctivitis, interstitial pulmonary fibrosis, psoriasis arthritis, systemic juvenile idiopathic arthritis, nephritis, vasculitis, interstitial cystitis, diverticulitis, glomerulonephritis, chronic granulomatous disease endometriosis, leptospirosis nephropathy, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle atrophy, catabolism, obesity, slow fetal growth, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrosis ectodermal dysplasia, behcet's disease, pigmentary incontinence, paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, anaphylaxis, systemic anaphylaxis, sinusitis, ocular allergy, silica-induced diseases, COPD, lung disease, cystic fibrosis, acid-induced lung injury, pulmonary arterial hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, and, inclusion body myositis, myasthenia gravis, thyroiditis, addison's disease, lichen planus, type 1 diabetes, type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, cystitis, dacryocystitis, dermatitis, dermatomyositis, encephalitis, inflammation of the liver, and inflammation of the liver endocarditis, endometritis, enteritis, enterocolitis, upper ankle inflammation, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, henno-Xu Lanzi plaque disease (Henoch-Schonlein purpura), hepatitis, suppurative sweat gland inflammation, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, liver fibrosis, renal fibrosis, alcoholic fatty liver, non-alcoholic fatty liver, heart fibrosis, psoriasis, crohn's disease, inflammatory bowel disease, ovaritis, orchitis, osteoarthritis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, local pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, arthromeningitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, sclerosing disease, leukoplakia, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, falling leaf pemphigus, paraneoplastic pemphigus, acquired bullous epidermolysis, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, valvulvitis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryptomelane related peri-syndrome or osteoarthritis conditions.
In a fourth aspect of the invention, the invention provides a compound of formula II-1 or II-2:
wherein R is 4 And R is 5 Independently H or-Boc; r is R 1 、R 2 、R 3 、L 1 、L 2 The definitions of r, ring A and ring B are as described above.
The compound shown in the formula II-1 is preferably/>
/>
The compound shown in the formula II-2 is preferably/>
Terminology and definitions
Those skilled in the art will appreciate that, in accordance with the convention used in the art, the present invention describes the structural formula of the group usedAnd->All means that the corresponding group is linked to other fragments, groups in the compound through this site.
Unless otherwise indicated, terms and definitions used in the present application, including the description of the present application and the claims, are as follows.
As will be appreciated by those skilled in the art, in accordance with the conventions used in the art, in the structural formulae of the present application,for depicting chemical bonds, which are points where a moiety or substituent is attached to a core structure or a backbone structure.
Unless otherwise specified, the term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases, unless otherwise specified.
In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. They may serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the invention.
The term "pharmaceutical composition" means, unless otherwise specified, a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
Unless otherwise specified, the term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of the category of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of the pharmaceutical formulation, i.e., by increasing flowability and/or tackiness, making the formulation more suitable for direct compression.
The term "prodrug" refers to a compound of the invention that can be converted to a biologically active compound under physiological conditions or by solvolysis, unless otherwise specified. Prodrugs of the invention are prepared by modifying functional groups in the compounds, which modifications may be removed by conventional procedures or in vivo to give the parent compound. Prodrugs include compounds wherein a hydroxyl group or amino group of a compound of the invention is attached to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl group, free amino group, respectively.
Unless otherwise specified, the term "stereoisomer" refers to an isomer produced by the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers, non-corresponding isomers and conformational isomers.
Depending on the choice of starting materials and methods, the compounds according to the invention may be present in the form of one of the possible isomers or mixtures thereof, for example as pure optical isomers or as isomer mixtures, for example as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefix D and L or R and S are used to denote the absolute configuration of the molecule in terms of chiral center (or chiral centers) in the molecule. The prefixes D and L or (+) and (-) are symbols for designating the rotation of plane polarized light by a compound, where (-) or L represents that the compound is left-handed. The compound prefixed with (+) or D is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are generally referred to as mixtures of enantiomers. The 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process. Many geometric isomers of olefins, c=n double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. When the compounds described herein contain olefinic double bonds, such double bonds include E and Z geometric isomers unless specified otherwise. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may be in cis or trans (cis-or trans-) configuration.
When the bonds to chiral carbons in the formulae of the present invention are depicted in straight lines, it is understood that both the (R) and (S) configurations of the chiral carbons and the enantiomerically pure compounds and mixtures thereof resulting therefrom are included within the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J.chem. Ed.1985, 62:114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by the wedge-shaped key and the dashed key.
Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. The compounds of the invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of the racemic mixture of the compounds may be carried out by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid that is an optically active salified organic acid. Suitable resolving agents for use in the fractional recrystallisation process are, for example, D and L forms of optically active acids such as tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulphonic acids such as β -camphorsulphonic acid. Other resolving agents suitable for the fractional crystallization process include stereoisomerically pure forms of α -methyl-benzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methyl ephedrine, cyclohexylethylamine, 1, 2-diaminocyclohexane, and the like. Resolution of the racemic mixture may also be carried out by eluting on a chromatographic column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High Performance Liquid Chromatography (HPLC) or Supercritical Fluid Chromatography (SFC) may be used. The choice of the particular method and elution conditions, choice of chromatographic column can be selected by one skilled in the art based on the structure of the compound and the results of the assay. Further, any enantiomer or diastereomer of a compound described herein may also be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
Unless otherwise specified, the term "tautomer" refers to a functional group isomer that results from the rapid movement of an atom in a molecule at two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Proton-mobile tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The location of the equilibrium depends on the chemical nature of the molecule. For example, among many aliphatic aldehydes and ketones such as acetaldehyde, the ketone type predominates; whereas, among phenols, the enol form is dominant. The present invention encompasses all tautomeric forms of the compounds.
The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds may be labeled with radioisotopes, such as deuterium 2 H) Tritium% 3 H) Iodine-125% 125 I) Or C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For the purposes of the present oral dosage form, an "effective amount" of one active agent in a composition refers to that amount which is required to achieve the desired effect when used in combination with another active agent in the composition. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.
Unless otherwise specified, the term "active ingredient," "therapeutic agent," "active agent" or "active agent" refers to a chemical entity that is effective in treating a disorder, disease or condition of interest.
Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, including deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =o), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on the aromatic group. When the number of substituents is plural, each substituent is independent and may be the same or different For example "Ring A and Ring B are optionally substituted with 1 or more R a Substituted ", each R a Are independent and can be the same or different.
Unless otherwise specified, the term "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
Unless otherwise specified, when an enumerated linking group does not indicate its linking direction, its linking direction is arbitrary, for example,medium linking group L 2 is-C 1-6 alkyl-N (R) 22 ) -, at this time-C 1-6 alkyl-N (R) 22 ) The ring a and the ring B may be connected in the same direction as the reading order from left to right, or may be connected in the opposite direction to the reading order from left to right.
Unless otherwise specified, the term "C 1-6 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C is 1-6 Alkyl includes C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C 6 And C 5 Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, and the like.
Unless otherwise specified, the term "C 1-3 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C is 1-3 Alkyl includes C 1-2 And C 2-3 Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl(Et), propyl (including n-propyl and isopropyl), and the like.
The term "halo" may be used interchangeably with the term "halo substituted" alone or as part of another substituent.
Unless otherwise specified, or "halogen substituted alkyl" is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogens.
Unless otherwise specified, "C 2-6 Alkenyl "is used to denote a straight-chain or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. The C is 2-6 Alkenyl groups include C 2-4 、C 2-3 、C 4 、C 3 And C 2 Alkenyl groups, and the like; it may be monovalent, divalent or multivalent. C (C) 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentodienyl, hexodienyl, and the like.
Unless otherwise specified, "C 2-6 Alkynyl "is used to denote a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. The C is 2-6 Alkynyl includes C 2-4 、C 2-3 、C 4 、C 3 And C 2 Alkynyl groups, and the like. It may be monovalent, divalent or multivalent. C (C) 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
Unless otherwise specified, the term "C 3-8 Cycloalkyl "means a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, which includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings. The C is 3-8 Cycloalkyl includes C 3-6 、C 3-5 、C 4-8 、C 4-6 、C 4-5 、C 5-8 Or C 5-6 Cycloalkyl groups, and the like; it may be monovalent, divalent or multivalent. C (C) 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cycloHexyl, cycloheptyl, norbornyl, [2.2.2 ]]Bicyclooctane, and the like.
Unless otherwise specified, the term "C 3-6 Cycloalkyl "means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, said C 3-6 Cycloalkyl includes C 3-5 、C 4-5 And C 5-6 Cycloalkyl groups, and the like; it may be monovalent, divalent or multivalent. C (C) 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
Unless otherwise specified, C n-n+m Or C n -C n+m Comprising any one of the specific cases of n to n+m carbons, e.g. C 1-12 Comprises C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 、C 11 And C 12 Also included is any one of the ranges n to n+m, e.g. C 1-12 Comprises C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 And C 9-12 Etc.; similarly, n-membered to n+m-membered means that the number of atoms on the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and any one of n to n+m is also included, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-8-membered ring, 6-10-membered ring, and the like.
The term "heterocycloalkyl" includes monocyclic and bicyclic saturated systems, wherein bicyclic systems include spiro, fused and bridged rings.
Unless otherwise specified, C 4-9 The heterocycloalkyl group may be a 4-9 membered heterocycloalkyl group, the term "4-9 membered heterocycloalkyl" or "3-12 membered heterocycloalkyl" by itself or in combination with other terms, denotes a saturated cyclic group consisting of 4 to 9 or 12 ring atoms, respectively, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be Optionally oxidized (i.e., NO and S (O) p, p being 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings. In addition, in the case of the "4-9 membered heterocycloalkyl" group, the heteroatom may occupy the position of attachment of the heterocycloalkyl group to the remainder of the molecule. For example, 4-9 membered heterocycloalkyl includes, but is not limited to, 4-, 5-, 6-, 7-, 8-, 9-membered. Examples of 4-9 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, etc. The term "aryl" means, unless otherwise specified, a polyunsaturated aromatic hydrocarbon substituent, which may be mono-or polysubstituted, and which may be monovalent, divalent or multivalent, and which may be monocyclic or polycyclic (e.g. 1 to 3 rings; wherein at least one ring is aromatic), fused together or covalently linked.
The term "heteroaryl" refers to an aryl group (or ring) containing one to four heteroatoms. In one exemplary embodiment, the heteroatom is selected from B, N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Heteroaryl groups may be attached to the remainder of the molecule through heteroatoms. Non-limiting examples of aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isoxazolyl, thiazolyl, furanyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyrimidinyl, 2-pyridyl, 2-quinolyl, 5-quinolyl, 2-pyridyl, 5-quinolyl, and 5-quinolyl. The substituents of any of the above aryl and heteroaryl ring systems are selected from the acceptable substituents described below.
In addition, unless explicitly indicated otherwise, the description "… …" as used in the present invention is to be understood in a broad sense as meaning that each individual depicted is independent of the other and may be independently the same or different. In more detail, the expression "… …" independently "may mean that specific options expressed between identical coincidences in different groups do not affect each other, or that specific options expressed between identical symbols in identical groups do not affect each other.
Unless otherwise specified, the term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans.
The term "therapeutically effective amount" refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought by a researcher, veterinarian, medical doctor or other clinician in a tissue, system, animal, individual or human, which includes one or more of the following: (1) prevention of disease: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not experienced or developed a pathology or symptomatology of the disease. (2) inhibition of disease: for example, inhibiting a disease, disorder or condition (i.e., preventing further development of pathology and/or symptoms) in an individual experiencing or presenting with the pathology or symptoms of the disease, disorder or condition. (3) alleviation of disease: for example, alleviating a disease, disorder or condition (i.e., reversing the pathology and/or symptoms) in an individual experiencing or presenting with the pathology or symptoms of the disease, disorder or condition.
The term "treatment" and other similar synonyms as used herein include the following meanings:
(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;
(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;
(iii) Alleviating a disease or condition, i.e., causing the state of the disease or condition to subside; or alternatively
(iv) Alleviating symptoms caused by the disease or condition.
On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the invention has at least one of the following technical effects:
(1) The invention provides a compound for degrading IRAK4, which has novel structure, excellent pharmacokinetic property and good drug effect or drug forming property, and can be used for effectively treating IRAK4 related diseases and symptoms.
(2) The degradation activity of the compound of the invention on IRAK4 protein reaches nM level, and the compound has excellent degradation effect and dose dependency.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Unless otherwise indicated, the compounds of the present invention are structurally defined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is Tetramethylsilane (TMS).
Abbreviations for the present invention are defined as follows:
m: molar concentration, e.g. 1M hydrochloric acid means 1mol/L hydrochloric acid solution
N: equivalent concentration, e.g. 2N hydrochloric acid means 2mol/L hydrochloric acid solution
DMSO: dimethyl sulfoxide
LC-MS: liquid chromatography-mass spectrometry
IC 50 : half inhibition concentration refers to the concentration at which half of the maximum inhibition effect is achieved.
Preparation of intermediate I
N- (6-amino-5-fluoro-4- (2-hydroxypropan-2-yl) pyridin-3-yl) -6- (trifluoromethoxy) pyridine carboxamide (intermediate I)
The synthetic route for intermediate I is shown below:
the first step: synthesis of 2- (5-bromo-2, 3-difluoropyridin-4-yl) propan-2-ol (Compound IB)
Tetrahydrofuran (40 mL) and lithium diisopropylamide (97 mL,2mol/L in THF) were added to a 500mL three-necked flask, cooled to-78deg.C, 5-bromo-2, 3-difluoropyridine (25 g,129mmol, dissolved in 40mL tetrahydrofuran) was slowly added with stirring, the reaction solution was stirred for 2 hours, then anhydrous acetone (22.5 g,387 mmol) was added dropwise, and the temperature was slowly raised to-40deg.C and stirred for 3 hours. Water (100 mL) was added to the reaction solution, the mixture was warmed to room temperature, the organic phase was collected after separation, the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure to give a residue which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =5:1) to give 2- (5-bromo-2, 3-difluoropyridin-4-yl) propan-2-ol (compound IB) (31 g, yield 95%)
And a second step of: synthesis of N- (5, 6-difluoro-4- (2-hydroxypropan-2-yl) pyridin-3-yl) -6- (trifluoromethyl) pyridine carboxamide (Compound IC)
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2- (5-bromo-2, 3-difluoropyridin-4-yl) propan-2-ol (compound IB) (20 g,79 mmol) and 6-trifluoromethylpyridine-2-carboxamide (22.6 g,119 mmol) were placed in toluene (300 mL), potassium phosphate (33.7 g, 1597 mmol), cuI (0.76 g,4 mmol) and 1, 10-phenanthroline (0.86 g,4.76 mmol) were added in this order and heated to 90℃under nitrogen and stirred for 20 hours. The reaction solution was cooled to room temperature, water (300 mL) was added, the solution was separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (100 ml×3), the organic phases were combined, washed successively with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =3:1) to give compound N- (5, 6-difluoro-4- (2-hydroxypropan-2-yl) pyridin-3-yl) -6- (trifluoromethyl) pyridine amide (compound IC) (14 g, yield 49%).
1 H NMR(400MHz,DMSO-d 6 )δ12.66(s,1H),9.10(s,1H),8.49–8.43(m,1H),8.39(t,1H),8.22–8.18(m,1H),6.73(s,1H),1.66(s,3H),1.65(s,3H).
And a third step of: synthesis of N- (6-amino-5-fluoro-4- (2-hydroxypropan-2-yl) pyridin-3-yl) -6- (trifluoromethoxy) pyridine carboxamide (intermediate I)
N- (5, 6-difluoro-4- (2-hydroxypropan-2-yl) pyridin-3-yl) -6- (trifluoromethyl) pyridine carboxamide (8 g,22.14 mmol) was dissolved in DMSO (100 mL), then ammonia (25%, 102 mL) was added and the reaction was stirred at 95℃for 48 hours. The reaction solution was cooled to room temperature, diluted with water (300 mL), extracted with ethyl acetate (100 ml×4), the organic phases were combined, washed with saturated sodium chloride (100 ml×3), concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane: methanol (V/V) =20:1) to give N- (6-amino-5-fluoro-4- (2-hydroxypropan-2-yl) pyridin-3-yl) -6- (trifluoromethoxy) pyridine carboxamide (intermediate I) (4 g, yield 50.4%).
1 H NMR(400MHz,DMSO-d6)δ12.17(s,1H),8.84(d,1H),8.43–8.31(m,2H),8.16–8.10(m,1H),6.34(s,1H),6.05(s,2H),1.64–1.57(m,6H).
LC-MS,M/Z(ESI):359.3[M+H] +
Preparation of intermediate II
N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine amide (intermediate II)
The synthetic route for intermediate II is shown below:
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the first step: synthesis of tert-butyl 4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (trifluoromethyl) pyridinoylamino) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (Compound IIA)
To a solution of tert-butyl 4- (2-bromoacetyl) piperidine-1-carboxylate (1.88 g,6.14 mmol) and N- (6-amino-5-fluoro-4- (2-hydroxypropan-2-yl) pyridin-3-yl) -6- (trifluoromethoxy) pyridine carboxamide (intermediate I) (2.00 g,5.58 mmol) in N-propanol (20.0 mL) was added sodium bicarbonate (520 mg,6.15 mmol) and the reaction stirred at 100deg.C for 10 hours at room temperature. After the reaction, 4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (trifluoromethyl) methylpyridinamido) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (compound IIA) (4.32 g, crude product) was obtained by direct concentration.
LC-MS,M/Z(ESI):566.2[M+H] +
And a second step of: synthesis of N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine amide (intermediate II)
To a solution of tert-butyl 4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (trifluoromethyl) methylpyridoylamino) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (compound IIA) (4.32 g,7.63 mmol) in methylene chloride (30.0 mL) was added trifluoroacetic acid (20.0 mL) and the reaction stirred at 25℃for 1 hour at room temperature. After the reaction, the crude product was directly concentrated, and the crude product was dissolved in water, and the pH was adjusted to 9 with 1N sodium hydroxide solution, and filtered to give N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) picolinamide (intermediate II) (2.24 g, crude product).
LC-MS,M/Z(ESI):466.2[M+H] +
Preparation of intermediate III
N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (1- (piperidin-4-ylmethylene) piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (intermediate III)
The synthetic route is as follows:
the first step: synthesis of tert-butyl 4- ((4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (trifluoromethyl) picolinamido) imidazo [1,2-a ] pyridin-2-yl) piperidin-1-yl) methyl) piperidine-1-carboxylate (Compound IIIB)
To a solution of N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (intermediate II) (500 mg,1.07 mmol) and 1-t-butoxycarbonyl piperidine-4-carbaldehyde (343 mg,1.61 mmol) in dichloromethane (7 mL) at room temperature was added sodium borohydride acetate (683 mg,3.22 mmol), and the reaction was stirred at 25℃for 2 hours. After the completion of the reaction, water (10 mL) was added to dilute the solution, the pH of the solution was adjusted to 10 with an aqueous NaOH solution (1 mol/L), the organic phases were extracted with methylene chloride (10 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl 4- ((4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (trifluoromethyl) picolinamido) imidazo [1,2-a ] pyridin-2-yl) piperidin-1-yl) methyl) piperidine-1-carboxylate (Compound IIIB) (1.01 g, crude product).
LC-MS,M/Z(ESI):663.4[M+H] +
And a second step of: synthesis of N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (1- (piperidin-4-ylmethylene) piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (intermediate III)
To a solution of tert-butyl 4- ((4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (trifluoromethyl) methylpyridinamido) imidazo [1,2-a ] pyridin-2-yl) piperidin-1-yl) methyl) piperidine-1-carboxylate (1.00 g,1.51 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (4.62 g,40.5 mmol) and the reaction stirred at 25℃for 1 hour. After the completion of the reaction, the crude product was concentrated under reduced pressure, the crude product was dissolved in water, the pH was adjusted to 10 with an aqueous NaOH solution (1 mol/L), a large amount of solids were produced, and the solids were collected by filtration, and dried under vacuum to give N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (1- (piperidin-4-methylene) piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (intermediate III) (498 mg, yield 58.3%).
LC-MS,M/Z(ESI):563.3[M+H] +
Preparation of intermediate 1-a
2- (2- ((2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethyl 4-methylbenzenesulfonate (intermediate 1-a)
The synthetic route for intermediate 1-a is shown below:
the first step: synthesis of 2- (2-hydroxyethoxy) ethyl 4-methylbenzenesulfonate
To a solution of p-toluenesulfonyl chloride (9.00 g,47.2 mmol) in tetrahydrofuran (60.0 mL) was slowly added an aqueous solution (30.0 mL) of 2- (2-hydroxyethoxy) ethanol (10.0 g,94.4 mmol) and sodium hydroxide (2.45 g,61.3 mmol) at 0℃and the reaction was stirred at 25℃for 1 hour. After completion of the reaction, water (100 mL) was added thereto for dilution, and ethyl acetate (100 mL. Times.3) was used for extraction. The organic phase was dried and concentrated to give a crude product which was separated by column chromatography (petroleum ether: ethyl acetate (V/V) =5:1 to 1:1) to give 2- (2-hydroxyethoxy) ethyl 4-methylbenzenesulfonate (7.00 g, yield 56.9%).
And a second step of: synthesis of 2- (2, 6-dioxopiperidin-3-yl) -5- (2- (2-hydroxyethoxy) ethoxy) isoindoline-1, 3-dione
To a solution of 2- (2-hydroxyethoxy) ethyl 4-methylbenzenesulfonate (6.83 g,26.2 mmol) and 2- (2, 6-dioxo-3-piperidinyl) -5-hydroxy-isoindoline-1, 3-dione (6.00 g,21.9 mmol) in N, N-dimethylformamide (50.0 mL) was added potassium carbonate (6.05 g,43.7 mmol), and the reaction was stirred at 70℃for 12 hours. After the reaction was completed, the crude product was directly concentrated, and the crude product was filtered through celite (MeOH/DCM (60.0 ml, V/v=1:4), and the filtrate was concentrated under reduced pressure to give the compound 2- (2, 6-dioxopiperidin-3-yl) -5- (2- (2-hydroxyethoxy) ethoxy) isoindoline-1, 3-dione (7.00 g, crude).
And a third step of: synthesis of 2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethyl 4-methylbenzenesulfonate (intermediate 1-a)
To a solution of 2- (2, 6-dioxopiperidin-3-yl) -5- (2- (2-hydroxyethoxy) ethoxy) isoindoline-1, 3-dione (4.70 g,12.9 mmol), 4-dimethylpyridine (158 mg,1.30 mmol), triethylamine (3.02 g,29.8 mmol) in dichloromethane (50.0 mL) was added p-toluenesulfonyl chloride (2.97 g,15.6 mmol) and the reaction stirred at 25℃for 2 hours. After the reaction, the crude product was obtained by direct concentration under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =5:1 to 2:1) to give the compound 2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethyl 4-methylbenzenesulfonate (intermediate 1-a) (2.21 g, yield 32.8%).
LC-MS,M/Z(ESI):517.2[M+H] +
Preparation of intermediate 2-a
2- (2- (2- ((2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethyl 4-methylbenzenesulfonate (intermediate 2-a)
The synthetic route for intermediate 2-a is shown below:
the first step: synthesis of 2- (2, 6-dioxopiperidin-3-yl) -5- (2- (2- (2-hydroxyethoxy) ethoxy) isoindoline-1, 3-dione
To a solution of 2- [2- (2-hydroxyethoxy) ethoxy ] ethyl 4-methylbenzenesulfonate (1.11 g,3.65 mmol) and 2- (2, 6-dioxo-3-piperidyl) -5-hydroxy-isoindoline-1, 3-dione (1.00 g,3.65 mmol) in N, N-dimethylformamide (10.0 mL) was added potassium carbonate (2.02 g,14.6 mmol), and the reaction was stirred at 80℃for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, meOH/DCM (70.0 ml, V/v=1:4) was added to the crude product, the resulting suspension was filtered through celite, and the filtrate was concentrated to give crude 2- (2, 6-dioxopiperidin-3-yl) -5- (2- (2- (2-hydroxyethoxy) ethoxy) isoindoline-1, 3-dione (700 mg, crude).
And a second step of: synthesis of 2- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethyl 4-methylbenzenesulfonate (intermediate 2-a)
To a solution of 2- (2, 6-dioxopiperidin-3-yl) -5- (2- (2- (2-hydroxyethoxy) ethoxy) isoindoline-1, 3-dione (600 mg,1.48 mmol), triethylamine (1.05 g,10.3 mmol) and N, N-lutidine (9.04 mg, 74.0. Mu. Mol) in dichloromethane (7.00 mL) was added p-toluenesulfonyl chloride (564 mg,2.96 mmol) and the reaction stirred at 25℃for 2 hours at room temperature. After the reaction, the crude product is directly concentrated to obtain crude product, and the crude product is separated and purified by a chromatographic column (petroleum ether: ethyl acetate (V/V) =5:1 to 1:1) to obtain compound 2- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethyl 4-methylbenzenesulfonate (intermediate 2-a) (300 mg, crude product).
LC-MS,M/Z(ESI):561.2[M+H] +
Synthesis of intermediate 3-a
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The synthetic route for intermediate 3-a is shown below:
the first step: synthesis of 2- (2, 6-dioxopiperidin-3-yl) -4- ((2- (2-hydroxyethoxy) ethyl) amino) isoindoline-1, 3-dione
Diisopropylethylamine (2.81 g,21.72 mmol) was added to a solution of 2- (2, 6-dioxo-3-piperidyl) -4-fluoro-isoindoline-1, 3-dione (2.00 g,7.24 mmol) and 2- (2-aminoethoxy) ethanol (761 mg,7.24 mmol) in dimethyl sulfoxide (20.0 mL) at room temperature, and the mixture was stirred at 70℃for 12 hours. The reaction was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (10.0 mL. Times.3). The organic phases were combined, washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the compound 2- (2, 6-dioxopiperidin-3-yl) -4- ((2- (2-hydroxyethoxy) ethyl) amino) isoindoline-1, 3-dione (2.00 g, crude).
LC-MS,M/Z(ESI):362.0[M+H] +
And a second step of: synthesis of 2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethyl methane sulphonic acid (intermediate 3-a)
To a solution of 2- (2, 6-dioxopiperidin-3-yl) -4- ((2- (2-hydroxyethoxy) ethyl) amino) isoindoline-1, 3-dione (500 mg,1.38 mmol) in dichloromethane (5.00 mL) was added methylsulfonated methanesulfonyl (313 mg,1.80 mmol) and triethylamine (420 mg,4.15 mmol) at room temperature. The mixture was stirred at room temperature for 12 hours. After completion of the reaction, water (10.0 mL) was added for dilution, followed by extraction with ethyl acetate (10.0 mL. Times.3). The organic phases were combined, washed successively with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (dichloromethane: methanol (V/V) =10:1) to give the compound 2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethylmethanesulfonic acid (321 mg, yield 47.7%).
LC-MS,M/Z(ESI):440.1[M+H] +
Synthesis of intermediate 4-a
2- (4- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperazin-1-yl) acetaldehyde (intermediate 4-a)
The synthetic route for intermediate 4-a is shown below:
the first step: synthesis of tert-butyl 4- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperazine-1-carboxylate
Tert-butylpiperazine-1-carboxylate (806 mg,3.62 mmol) and 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindole-1, 3-dione (1.00 g,3.62 mmol) were dissolved in dimethyl sulfoxide (10.0 mL) at room temperature, triethylamine (733 mg,7.24 mmol) was added, and the reaction stirred at 120℃for 6 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (10.0 mL), and extracted with ethyl acetate (10.0 mL. Times.3). The organic phases were combined, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the compound tert-butyl 4- (2, 6-dioxo-piperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperazine-1-carboxylate (3.50 g, crude).
LC-MS,M/Z(ESI):443.2[M+H] +
And a second step of: synthesis of 2- (2, 6-dioxopiperidin-3-yl) -5- (piperazin-1-yl) isoindoline-1, 3-dione
To a solution of tert-butyl 4- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperazine-1-carboxylate (3.50 g,7.91 mmol) in ethyl acetate (40.0 mL) was added a solution of hydrochloric acid in ethyl acetate (4M, 20.0 mL) and the reaction was stirred at room temperature for 12 hours. After the reaction, the compound 2- (2, 6-dioxopiperidin-3-yl) -5- (piperazin-1-yl) isoindoline-1, 3-dione (2.50 g, crude product) was obtained by direct concentration under reduced pressure.
LC-MS,M/Z(ESI):343.1[M+H] +
And a third step of: synthesis of 5- (4- (2, 2-diethoxyethyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
To a solution of 2- (2, 6-dioxopiperidin-3-yl) -5- (piperazin-1-yl) isoindoline-1, 3-dione (2 g,5.84 mmol) and 2-bromo-1, 1-diethoxy-ethane (1.15 g,5.84 mmol) in N, N-dimethylformamide (20.0 mL) was added N, N-diisopropylethylamine (2.27 g,17.5 mmol), and the reaction was stirred at 100℃for 12 hours. The reaction was cooled to room temperature, diluted with water (20.0 mL) and extracted with ethyl acetate (10.0 mL. Times.3). The organic phases were combined, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was isolated by chromatography (petroleum ether: ethyl acetate (V/V) =10:1 to 1:1) to give 5- (4- (2, 2-diethoxyethyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione as a yellow oil (1.30 g, 41.5% yield).
LC-MS,M/Z(ESI):459.2[M+H] +
Fourth step: synthesis of 2- (4- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperazin-1-yl) acetaldehyde
To a solution of 5- (4- (2, 2-diethoxyethyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (300 mg, 654. Mu. Mol) in water (7.00 mL) at room temperature was added a dioxane solution (4M, 7.00 mL) of hydrochloric acid, and the reaction solution was stirred at 50℃for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (20.0 mL), quenched, and extracted with ethyl acetate (10.0 mL. Times.3). The organic phases were combined, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the compound 2- (4- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperazin-1-yl) acetaldehyde (intermediate 4-a) (200 mg, crude).
LC-MS,M/Z(ESI):385.1[M+H] +
Synthesis of intermediate 6-a
2- ((2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethyl 4-methylbenzenesulfonate (intermediate 6-a)
The synthetic route for intermediate 6-a is shown below:
the first step: synthesis of 2- (2, 6-dioxopiperidin-3-yl) -5- (2-hydroxyethoxy) isoindoline-1, 3-dione
To a solution of 2- (2, 6-dioxo-3-piperidyl) -5-hydroxy-isoindoline-1, 3-dione (1.50 g,5.47 mmol), 2-bromoethanol (751 mg,6.02 mmol) and potassium iodide (328 mg,5.47 mmol) in N, N-dimethylformamide (10.0 mL) was added sodium hydrogencarbonate (919 mg,10.9 mmol), and the reaction was stirred at 100℃for 16 hours at room temperature. After the reaction is finished, the crude product is directly obtained by concentration. The crude product was purified by chromatography (dichloromethane: methanol (V/V) =50:1 to 10:1) to give the compound 2- (2, 6-dioxopiperidin-3-yl) -5- (2-hydroxyethoxy) isoindoline-1, 3-dione (450 mg, yield 23.0%).
And a second step of: synthesis of 2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethyl 4-methylbenzenesulfonate (intermediate 6-a)
To a solution of 2- (2, 6-dioxopiperidin-3-yl) -5- (2-hydroxyethoxy) isoindoline-1, 3-dione (450 mg,1.41 mmol) and triethylamine (428 mg,4.24 mmol) in dichloromethane (6.00 mL) at room temperature was added p-toluenesulfonyl chloride (377 mg,1.98 mmol) and the reaction stirred at 25℃for 2 hours. After the reaction, the mixture was concentrated directly to give a crude product, which was separated by a column chromatography (petroleum ether: ethyl acetate (V/V) =5:1 to 1:1) to give compound 2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethyl 4-methylbenzenesulfonate (intermediate 6-a) (240 mg, yield 35.9%).
LC-MS,M/Z(ESI):473.0[M+H] +
Preparation of intermediate IV
4- (6-bromo-8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (target compound IV)
The synthetic route for target intermediate IV is shown below:
first step 2- (2-amino-5-bromo-3-fluoropyridin-4-yl) propan-2-ol (IVB)
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2- (5-bromo-2, 3-difluoropyridin-4-yl) propan-2-ol (15.0 g,59.5 mmol) was dissolved in 1, 4-dioxane (15 mL), and aqueous ammonia (54.6 g,514mmol,60.0mL,33% purity) was added and stirred at 90℃for 12 hours under nitrogen. After the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure to give a crude product, and purified by column chromatography (petroleum ether: ethyl acetate (V/V) =2:1) to give compound 2- (2-amino-5-bromo-3-fluoropyridin-4-yl) propan-2-ol (IV) (10.0 g, yield 63.2%).
LC-MS,M/Z(ESI):250.9(M+H + )
Second step Synthesis of tert-butyl 4- (6-bromo-8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (IV)
2- (2-amino-5-bromo-3-fluoropyridin-4-yl) propan-2-ol (5.50 g,22.1 mmol) was dissolved in isopropanol (70 mL), replaced with nitrogen three times, N-t-butoxycarbonyl-4- (2-bromoacetyl) piperidine (10.1 g,33.1 mmol) and sodium bicarbonate (1.85 g,22.1 mmol) were added and stirred at 80℃for 12 hours. After the reaction was completed, quenched with water (100 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated to give a crude product, which was separated and purified by column chromatography (petroleum ether: ethyl acetate (V/V) =0:1) to give the compound 4- (6-bromo-8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (intermediate I) (14.0 g, yield 69.4%).
LC-MS,M/Z(ESI):456.1(M+H + )
Preparation of intermediate V
Synthesis of 6-cyclopropyl-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (7)
The synthetic route for intermediate V is shown below:
the first step: synthesis of methyl 6-cyclopropylpyridinium formate (VB)
methyl 6-cyclopropylpicolinate
Cyclopropylboronic acid (29.8 g,277 mmol), methyl 6-bromo-2-picolinate (30.0 g,138 mmol), potassium phosphate (58.9 g,277 mmol) and 1, 1-bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex (5.67 g,6.94 mmol) were placed in toluene (450 mL) and the reaction was reacted at 100℃for 16 hours under danqi1 atmosphere. After the reaction is finished, the reaction liquid is cooled to room temperature, the filtrate is collected by filtration, and the crude product is obtained by decompression and concentration. The crude product was separated by chromatography (petroleum ether: ethyl acetate (V/V) =100:1 to 5:1) to give compound 6-cyclopropylpyridinium formate (2) (7.25 g, yield 29.4%).
LC-MS,M/Z(ESI):178.2(M+H + )
And a second step of: synthesis of 6-cyclopropyl pyridine carboxamide (VC)
To a solution of methyl 6-cyclopropylpyridinium formate (VB) (7.00 g,39.4 mmol) in methanol (25 mL) was added ammonia (25.2 g,271mmol, 30%) at room temperature, and the reaction was stirred at 60℃for 2 hours. After the reaction, the reaction solution was cooled to room temperature, and concentrated under reduced pressure to give 6-cyclopropylpyridine carboxamide (VC) (6.10 g, yield 95.3%).
LC-MS,M/Z(ESI):163.2(M+H + )
And a third step of: synthesis of 6-cyclopropyl-N- (5, 6-difluoro-4- (2-hydroxypropan-2-yl) pyridin-3-yl) pyridinecarboxamide (VD)
To a toluene solution (40 mL) of 6-cyclopropyl-N- (5, 6-difluoro-4- (2-hydroxypropan-2-yl) pyridin-3-yl) pyridine carboxamide (VC) (6.00 g,36.6 mmol) and 2- (5-bromo-2, 3-difluoro-4-pyridinyl) propan-2-ol (9.30 g,36.6 mmol) were added cuprous iodide (352 mg,1.85 mmol), 1, 10-phenanthroline (400 mg,2.22 mmol) and potassium phosphate (15.7 g,73.9 mmol), and the reaction was stirred under nitrogen at 90℃for 12 hours. After the completion of the reaction, the reaction mixture was poured into water (15 mL), extracted with ethyl acetate (15 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was separated by chromatography (petroleum ether: ethyl acetate (V./V) =20:1 to 2:1) to give the compound 6-cyclopropyl-N- (5, 6-difluoro-4- (2-hydroxypropan-2-yl) pyridin-3-yl) pyridine carboxamide (VD) (3.01 g, yield 37.6%).
LC-MS,M/Z(ESI):334.1(M+H + )
Fourth step: synthesis of N- (6-amino-5-fluoro-4- (2-hydroxypropan-2-yl) pyridin-3-yl) -6-cyclopropylpyridine carboxamide (VE)
6-cyclopropyl-N- (5, 6-difluoro-4- (2-hydroxypropan-2-yl) pyridin-3-yl) pyridinecarboxamide (VD) (3.00 g,9.00 mmol), dimethyl sulfoxide (60 mL) and ammonia (19.5 g,156mmol,28% purity) were added to a sealed tube at room temperature, and the reaction was stirred under nitrogen at 120℃for 12 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (60 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated to give a brown oil. It was separated by chromatography (petroleum ether: ethyl acetate (V/V) =50:1 to 0:1) to give the compound N- (6-amino-5-fluoro-4- (2-hydroxypropan-2-yl) pyridin-3-yl) -6-cyclopropylpyridine carboxamide (VE) (2.80 g, 94.1% yield).
LC-MS,M/Z(ESI):331.2(M+H + )
Fifth step: synthesis of tert-butyl 4- (6- (6-cyclopropylpyridinium carboxamido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (VF)
To a solution of N- (6-amino-5-fluoro-4- (2-hydroxypropan-2-yl) pyridin-3-yl) -6-cyclopropylpyridine carboxamide (VE) (200 mg, 605. Mu. Mol) in isopropanol (2 mL) was added tert-butyl 4- (2-bromoacetyl) piperidine-1-carboxylate (185 mg, 605. Mu. Mol) and sodium bicarbonate (50.8 mg, 605. Mu. Mol) at room temperature, and the reaction was stirred under nitrogen at 100℃for 12 hours. After the reaction was completed, water (3 mL) was added to quench, ethyl acetate (15 mL) was extracted, and the organic phase was dried and concentrated to give a crude product, which was purified by beating with petroleum ether (10 mL) at room temperature to give the compound tert-butyl 4- (6- (6-cyclopropylpyridinium-carboxamido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (VF) (110 mg, yield 32.5%).
LC-MS,M/Z(ESI):538.4(M+H+)
Sixth step: synthesis of 6-cyclopropyl-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (V)
To a solution of tert-butyl 4- (6- (6-cyclopropylpyridinium carboxamido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (VF) (110 mg, 204. Mu. Mol) in methylene chloride (1 mL) at 0deg.C under nitrogen was added trifluoroacetic acid (140 mg,1.23 mmol), and the reaction mixture was stirred at 0deg.C for 2 hours. After the completion of the reaction, the reaction mixture was poured into a saturated sodium hydrogencarbonate solution (5 mL), filtered, and the cake was collected and dried to give the compound 6-cyclopropyl-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (VF) (89.0 mg, 99.4% yield).
LC-MS,M/Z(ESI):438.43(M+H + )
Preparation of intermediate VI
Synthesis of 2-cyclopropyl-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyrimidine-4-carboxamide (VI)
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The synthetic route for intermediate VI is shown below:
the first step: synthesis of 2-cyclopropyl-pyrimidine-4-carboxylic acid (VIB)
Methyl 2-chloropyrimidine-4-carboxylate (2.00 g,12.3 mmol), cyclopropylboronic acid (6.71 g,14.7 mmol) was dissolved in toluene (20 mL), and tricyclohexylphosphine (233 mg,1.22 mmol), potassium phosphate (7.80 g,36.8 mmol), palladium acetate (65.0 mg, 289. Mu. Mol) was added thereto, and the reaction solution was stirred under nitrogen atmosphere at 90℃for 12 hours. After the completion of the reaction, water (100 mL) was added to the reaction mixture, the pH was adjusted to 5 with hydrochloric acid (1 mol/L), and extracted with ethyl acetate (60 mL), and the organic phase was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =1:1) to give the compound 2-cyclopropylpyrimidine-4-carboxylic acid (VIB) (1.40 g, yield 21.2%).
LC-MS,M/Z:165.2(M+H + )
And a second step of: synthesis of 2-cyclopropyl-pyrimidine-4-carboxamide (VIC)
2-Cyclopropylpyrimidine-4-carboxylic acid (4.90 g,29.9 mmol) was dissolved in tetrahydrofuran (50 mL), 1-carbonyldiimidazole (14.5 g,89.6 mmol) was added, and stirred at 50℃for 12 hours under nitrogen protection, aqueous ammonia (15.9 g,149mmol,17.4mL,33% purity) was added to the reaction solution, and stirred at 25℃for 2 hours. After completion of the reaction, water (50 mL) was added, and extracted with ethyl acetate (150 mL), and the organic phase was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, concentrated, and concentrated to give a crude product. The crude product was purified by preparative high performance liquid chromatography (column: welch Ultimate XB _c18-40 um, mobile phase: 0.1% nh4hco 3/methanol, gradient: 10-100%,10 min) to give compound 2-cyclopropylpyrimidine-4-carboxamide (VIC) (2.20 mg, yield 45.2%).
LC-MS,M/Z:164.3(M+H + )
And a third step of: synthesis of tert-butyl 4- (6- (2-cyclopropylpyrimidin-4-carbazoyl amido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (VID)
2-Cyclopropylpyrimidine-4-carboxamide (200 mg,1.23 mmol), 4- (6-bromo-8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-carboxylic acid tert-butyl ester (671 mg,1.47 mmol) was dissolved in toluene (2 mL), and cuprous iodide (23.3 mg, 122. Mu. Mol), 1, 10-phenanthroline (44.1 mg, 245. Mu. Mol) and potassium phosphate (780 mg,3.68 mmol) were added thereto and stirred under nitrogen at 90℃for 2 hours. After the completion of the reaction, water (40 mL) was added to the reaction mixture, which was extracted with ethyl acetate (60 mL), and the organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =1:1) to give compound 4- (6- (2-cyclopropylpyrimidin-4-carbazoylamino) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (VID) (140 mg, yield 21.2%).
LC-MS,M/Z:539.1(M+H + )
Fourth step Synthesis of 2-cyclopropyl-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyrimidine-4-carboxamide (VI)
Tert-butyl 4- (6- (2-cyclopropylpyrimidin-4-carbazoyl amido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (120 mg,223 μmo) was dissolved in dichloromethane (2.4 mL) and trifluoroacetic acid (3.68 g,32.3mmol,2.4 mL) was added at 0deg.C and the reaction temperature was kept at 0deg.C with stirring for 1 hour. After the completion of the reaction, the reaction mixture was poured into an aqueous sodium hydrogencarbonate solution (40 mL), extracted with methylene chloride (100 mL), and the organic phase was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound 2-cyclopropyl-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyrimidine-4-carboxamide (VI) (70 mg, yield 71.6%)
LC-MS,M/Z:439.2(M+H + )
Synthesis of intermediate VII
Synthesis of 6-cyclopropyl-5-fluoro-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (VII)
The synthetic route for intermediate VII is shown below:
the first step: synthesis of 6-bromo-5-fluoropyridine carboxamide (VIIB)
To a solution of 6-bromo-5-fluoropicolinic acid (5.00 g,22.7 mmol) in tetrahydrofuran (20 mL) was added carbonyldiimidazole (5.53 g,34.0 mmol) at room temperature and stirred at room temperature for 2 hours. Ammonia water (15.9 g,136mmol,17.5mL,30% purity) was further added, and the reaction was stirred at 25℃for 0.5 hours. After the reaction, the reaction mixture was quenched by pouring it into water (100 mL), directly filtered, and the cake was collected and dried to give Compound 6-bromo-5-fluoropyridine carboxamide (VIIB) (4.50 g,90.4% yield).
LC-MS,M/Z(ESI):219.9(M+H + )
And a second step of: synthesis of 6-cyclopropyl-5-fluoropyridine carboxamide (VIIC)
To a mixed solution of 6-bromo-5-fluoromethylpyridine amide (VIIB) (500 mg,2.28 mmol) and cyclopropylboronic acid (196.10 mg,2.28 mmol) in toluene (5.00 mL) and water (0.5 mL) at room temperature were added cesium carbonate (1.49 g,4.57 mmol) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (167 mg, 228. Mu. Mol), and the reaction solution was stirred at 100℃for 12 hours under nitrogen. After the reaction, the reaction liquid was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography (column: phenomenex luna C18:150:25 mm x 10um; mobile phase a:0.1% hydrochloric acid, b=acetonitrile ]; gradient: 15% -45%,10 min) to obtain compound 6-cyclopropyl-5-fluoropyridine carboxamide (VIIC) (250 mg, yield 60.7%).
LC-MS,M/Z(ESI):181.0(M+H + )
And a third step of: synthesis of tert-butyl 4- (6- (6-cyclopropyl-5-fluoromethylpyridinamido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (VIID)
To a toluene solution (10 mL) of 6-cyclopropyl-5-fluoropyridine carboxamide (VIIC) (250 mg,1.26 mmol) and tert-butyl 4- (6-bromo-8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (intermediate IV) (690 mg,1.51 mmol) were added cuprous iodide (12.0 mg, 63.0. Mu. Mol), 1, 10-phenanthroline (22.7 mg, 126. Mu. Mol) and potassium phosphate (535 mg,2.52 mmol) at room temperature, the reaction mixture was replaced with nitrogen three times, and stirred at 90℃for 12 hours. After the reaction was completed, the reaction solution was poured into water (15 mL), extracted with ethyl acetate (15 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was separated by chromatography column (petroleum ether: ethyl acetate (V/V) =50:1 to 1:1) to give compound 4- (6- (6-cyclopropyl-5-fluoromethylpyridinylamino) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (VIID) (350 mg, yield 35.6%).
LC-MS,M/Z(ESI):556.3(M+H + )
Fourth step: synthesis of 6-cyclopropyl-5-fluoro-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (VII)
To 4- (6- (6-cyclopropyl-5-fluoromethylpyridinamido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (VIID) (100 mg, 174. Mu. Mol) in dichloromethane (5 mL) at 0deg.C was added trifluoroacetic acid (1 mL) and the mixture was stirred at 0deg.C for 1 hour. After the reaction was completed, the reaction solution was poured into a saturated sodium bicarbonate solution (20 mL), filtered, and the cake was collected and dried to give the compound 6-cyclopropyl-5-fluoro-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (VII) (82.0 mg, crude).
LC-MS,M/Z(ESI):456.3(M+H + )
Synthesis of intermediates VIIG-P1 and VIIG-P2
Synthesis of tert-butyl (R & S) -4- (6- (6- (2, 2-difluorocyclopropyl) pyridinecarboxamido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (intermediates VIIIG-P1 and VIIIG-P2)
Is that
Is that
In another configuration different from VIIIG-P1
The synthetic routes for intermediates VIIIG-P1 and VIIIG-P2 are shown below:
the first step: synthesis of tert-butyl 6-bromopyridine-2-carboxylate (VIIIB)
6-bromo-2-pyridinecarboxylic acid (10.0 g,49.5 mmol) was dissolved in tetrahydrofuran (100 mL), 4-dimethylaminopyridine (3.02 g,24.7 mmol) and di-tert-butyl dicarbonate (21.6 g,99.0mmol,22.7 mL) were added, and the mixture was stirred under nitrogen at 25℃for 1 hour. After completion of the reaction, the reaction mixture was poured into water (20 mL) at 0 ℃, extracted with ethyl acetate (50 mL x 3), the combined organic phases dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give the crude product which was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate (V/V) =100:1 to 5:1) to give tert-butyl 6-bromopyridine-2-carboxylate (VIIIB) (11.2 g, yield 87.6%).
And a second step of: synthesis of tert-butyl 6-vinylpyridine-2-carboxylate (VIIIC)
Tert-butyl 6-bromopyridine-2-carboxylate (VIIIB) (11.0 g,42.6 mmol) was dissolved in isopropanol (110 mL), potassium vinyltrifluoroborate (11.4 g,85.2 mmol), 1-bis (diphenylphosphorus) ferrocene palladium chloride (3.12 g,4.26 mmol) and triethylamine (12.9 g,127mmol,17.8 mL) were added and stirred under nitrogen at 90℃for 12 hours. After completion of the reaction, the reaction mixture was poured into water (50 mL), extracted with ethyl acetate (50 ml×3), the combined organic phases dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give the crude product which was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate (V/V) =100:1 to 5:1) to give the compound 6-vinylpyridine-2-carboxylic acid tert-butyl ester (VIIIC) (8.10 g, 92.6% yield).
LC-MS,M/Z(ESI):204.1(M+H + )
And a third step of: synthesis of tert-butyl 6- (2, 2-difluorocyclopropyl) pyridine-2-carboxylate (VIIID)
Tert-butyl 6-vinylpyridine-2-carboxylate (VIIIC) (3.00 g,14.6 mmol) was dissolved in toluene (30 mL), and (bromodifluoromethyl) trimethylsilane (7.42 g,36.5 mmol) and tetrabutylammonium bromide (471 mg,1.46 mmol) were added and stirred under nitrogen at 70℃for 12 hours. After completion of the reaction, the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (15 mL x 3), the combined organic phases dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give the crude product which was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate (V/V) =100:1 to 10:1) to give tert-butyl compound 6- (2, 2-difluorocyclopropyl) pyridine-2-carboxylate (VIIID) (5.00 g, 67.0% yield).
LC-MS,M/Z(ESI):200.0(M-56+H + )
Fourth step: synthesis of 6- (2, 2-difluorocyclopropyl) pyridine-2-carboxylic acid (VIIIE)
Tert-butyl 6- (2, 2-difluorocyclopropyl) pyridine-2-carboxylate (VIIID) (5.00 g,19.6 mmol) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (11.1 g,97.9mmol,7.28 mL) was added under nitrogen, and the reaction was stirred at 25℃for 2 hours. After the completion of the reaction, the reaction mixture was directly spin-dried to give compound 6- (2, 2-difluorocyclopropyl) pyridine-2-carboxylic acid (VIIIE) (3.80 g, 97.4% yield).
LC-MS,M/Z(ESI):200.0(M+H + )
Fifth step: synthesis of 6- (2, 2-difluorocyclopropyl) pyridine-2-carboxamide (VIIIF)
6- (2, 2-Difluorocyclopropyl) pyridine-2-carboxylic acid (VIIIE) (3.70 g,18.5 mmol) was dissolved in tetrahydrofuran (50 mL), 1-carbonyldiimidazole (6.03 g,37.1 mmol) was added, stirring was continued at 25℃for 2 hours under nitrogen protection, and then aqueous ammonia (6.51 g,55.7mmol,7.15mL,30% purity) was added, and stirring was continued at 25℃for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was purified by preparative liquid chromatography (column: welch Ultimate XB-C18-40 μm, mobile phase: a=0.1% ammonia water, b=methanol; gradient: 10% -100%,10 min) to obtain compound 6- (2, 2-difluorocyclopropyl) pyridine-2-carboxamide (VIIIF) (2.00 g, yield 54.3%).
LC-MS,M/Z(ESI):199.2(M+H + )
1 H NMR(400MHz,DMSO-d6)δ8.11(s,1H),7.99-7.85(m,2H),7.70-7.52(m,2H),3.29-3.19(m,1H),2.82-2.65(m,1H),2.08-1.88(m,1H)
Sixth step: synthesis of tert-butyl 4- (6- (6- (2, 2-difluorocyclopropyl) pyridinecarboxamido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (VIIIG)
6- (2, 2-Difluorocyclopropyl) pyridine-2-carboxamide (500 mg,2.52 mmol) was dissolved in toluene (10 mL), 4- (6-bromo-8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 1) (1.73 g,3.78 mmol), potassium phosphate (1.61 g,7.57 mmol), 1, 10-phenanthroline (150 mg, 756. Mu. Mol) and cuprous iodide (144 mg, 756. Mu. Mol) were added and stirred under nitrogen at 95℃for 2 hours. After completion of the reaction, the reaction mixture was poured into water (15 mL), extracted with ethyl acetate (15 mL x 3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give the crude product, which was purified by column chromatography (mobile phase: dichloromethane/ethyl acetate (V/V) =10:1 to 1:1) to give compound 4- (6- (6- (2, 2-difluorocyclopropyl) picolinamido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (VIIIG) (1.30 g, 89.8% yield).
LC-MS,M/Z(ESI):574.3(M+H + )
Seventh step: synthesis of tert-butyl (R or S) -4- (6- (6- (2, 2-difluorocyclopropyl) pyridinecarboxamido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (VIIG-P1)
Synthesis of tert-butyl (S or R) -4- (6- (6- (2, 2-difluorocyclopropyl) pyridinecarboxamido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (VIIG-P2)
(In another configuration different from VIIIG-P1)
Tert-butyl 4- (6- (6- (2, 2-difluorocyclopropyl) pyridinecarboxamido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (intermediate II) (700 mg) was subjected to supercritical fluid chromatography (Column: columbel OD-3 50X 4.6mm I.D.,3 μm; mobile phase A: supercritical fluid carbon dioxide; mobile phase B: isopropanol (0.05% diethylamine), gradient elution: supercritical fluid carbon dioxide containing isopropanol (0.05% diethylamine) in a proportion of from 5% to 40% flow rate: 3mL/min; detector: PDA; column temperature: 35 ℃ C.; column pressure: 100 bar) resolution to give the compound (R or S) -4- (6- (6- (2, 2-difluorocyclopropyl) pyrido [1,2-a ] imidazo [1,2-a ] pyridin-1-yl) piperidine-7- (2-hydroxypropan-1-7) (VII-1 mg) piperidine-m-1-300 mg, retention time = 1.65min,42.8% yield) and tert-butyl (intermediate VIIIG-P2, another configuration corresponding to VIIIG-P1) compound (S or R) -4- (6- (6- (2, 2-difluorocyclopropyl) picolinamido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (300 mg,523 μmol, peak 2, retention time = 1.99min 42.8% yield).
LC-MS,M/Z(ESI):574.3(M+H + )
Synthesis of intermediate VIII-P1
Synthesis of (R or S) -6- (2, 2-difluorocyclopropyl) -N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (VIII-P1)
Is that
The synthetic route for intermediate VIII-P1 is shown below:
(R or S) -4- (6- (6- (2, 2-difluorocyclopropyl) pyridylcarboxamido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (intermediate VIIG-P1) (280 mg, 488. Mu. Mol) was dissolved in methylene chloride (3 mL), replaced with nitrogen three times, and trifluoroacetic acid (2.87 g,25.1 mmol) was added dropwise to the reaction solution at 0℃and stirred at 0℃for 0.5 hours. After the reaction was completed, the reaction was quenched with aqueous sodium bicarbonate (50 mL), extracted with dichloromethane (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the compound (R or S) -6- (2, 2-difluorocyclopropyl) -N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (intermediate VIII-P1) (200 mg, 86.5%) as a product.
LC-MS,M/Z:474.2(M+H + )
Synthesis of intermediate VIII-P2
Synthesis of (S or R) -6- (2, 2-difluorocyclopropyl) -N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) picolinamide (VIII-P2)
Is that
In another configuration different from VIII-P1
The synthetic route for intermediate VIII-P2 is shown below:
(S or R) -4- (6- (6- (2, 2-difluorocyclopropyl) pyridylcarboxamido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (intermediate VIIIG-P2) (300 mg, 523. Mu. Mol) was dissolved in methylene chloride (3 mL), replaced with nitrogen three times, and trifluoroacetic acid (3.07 g,26.9mmol,2 mL) was added dropwise to the reaction solution at 0℃while stirring at 0℃for 0.5 hours. After the reaction was completed, the reaction was quenched with aqueous sodium bicarbonate (50 mL), extracted with dichloromethane (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the compound (S or R) -6- (2, 2-difluorocyclopropyl) -N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) picolinamide (intermediate VIII-P2) (200 mg, yield 74.30%).
LC-MS,M/Z:474.2(M+H + )
Synthesis of intermediate IX
Synthesis of N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (1- (trifluoromethyl) cyclopropyl) pyridine carboxamide (IX)
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The synthetic route for intermediate IX is shown below:
the first step: synthesis of methyl 6- (3, 3-trifluoroprop-1-en-2-yl) picolinate (IXB)
Methyl 6-bromopyridine-2-carboxylate (5.50 g,25.4 mmol) and hexanediol 1- (trifluoromethyl) ethylene borate (7.91 g,35.6 mmol) were dissolved in acetonitrile (100 mL), and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (1.86 g,2.55 mmol) and potassium carbonate (2.00M, 28.0 mL) were added and stirred under nitrogen at 80℃for 1.5 hours. After completion of the reaction, the reaction mixture was poured into water (250 mL), extracted with ethyl acetate (100 ml×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate (V/V) =100:1 to 20:1) to give methyl picolinate (IXB) of compound 6- (3, 3-trifluoroprop-1-en-2-yl) (5.00 g, 84.9% yield).
LC-MS,M/Z(ESI):232.2(M+H + )
1 H NMR(400MHz,CDCl 3 )δ8.10(d,1H),7.89(t,1H),7.67(d,1H),6.73-6.81(m,1H),6.21(d,1H),4.01(s,3H)
And a second step of: synthesis of methyl 6- (1- (trifluoromethyl) cyclopropyl) picolinate (IXC)
Methyl 6- (3, 3-trifluoroprop-1-en-2-yl) picolinate (IXB) (2.50 g,10.8 mmol) and tetrafluoroboroester methyldiphenyl sulfonium (4.67 g,16.2 mmol) were dissolved in tetrahydrofuran (25.0 mL), lithium bis (trimethylsilyl) amide (1.00 m,32.4 mL) was added dropwise at-70 ℃ under nitrogen protection, and the reaction solution was stirred at-70 ℃ for 3 hours. After completion of the reaction, the reaction mixture was added to an aqueous ammonium chloride solution (200 mL) at 0 ℃, extracted with ethyl acetate (100 mL. Times.3), dried, filtered and concentrated to give a crude product, which was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate (V/V) =100:1 to 20:1) to give compound 6- (1- (trifluoromethyl) cyclopropyl) picolinic acid methyl ester (IXC) (1.28 g, yield 48.27%).
LC-MS,M/Z(ESI):246.2(M+H + )
And a third step of: synthesis of 6- (1- (trifluoromethyl) cyclopropyl) pyridine carboxamide (IXD)
Methyl 6- (1- (trifluoromethyl) cyclopropyl) picolinate (IXC) (1.20 g,4.89 mmol) was dissolved in tetrahydrofuran (6.0 mL), aqueous ammonia (12.0 mL) was added at 0deg.C, and the reaction mixture was stirred at 25deg.C under nitrogen for 12 hours. After completion of the reaction, the reaction mixture was concentrated to give compound 6- (1- (trifluoromethyl) cyclopropyl) pyridine carboxamide (IXD) (800 mg, yield 71.0%).
LC-MS,M/Z(ESI):231.0(M+H + )
Fourth step: synthesis of tert-butyl 4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (1- (trifluoromethyl) cyclopropyl) pyridine carboxamide) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (IXE)
6- (1- (trifluoromethyl) cyclopropyl) pyridine carboxamide (IXD) (130 mg, 564. Mu. Mol) was dissolved in toluene (1.30 mL), 4- [ 6-bromo-8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl ] piperidine-1-carboxylic acid tert-butyl ester (309 mg, 677. Mu. Mol), potassium phosphate (319 mg,1.69 mmol), 1, 10-phenanthroline (33.5 mg, 169. Mu. Mol) and cuprous iodide (32.2 mg, 169. Mu. Mol) were added and stirred under nitrogen at 95℃for 1 hour. After completion of the reaction, the reaction mixture was poured into water (15.0 mL), extracted with ethyl acetate (15 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate (V/V) =10:1 to 1:1) to give compound 4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (1- (trifluoromethyl) cyclopropyl) pyridine formylamino) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (IXE) (230 mg, 67.2% yield).
LC-MS,M/Z(ESI):606.3(M+H + )
Fifth step: synthesis of N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (1- (trifluoromethyl) cyclopropyl) pyridine carboxamide (IX)
Tert-butyl 4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (1- (trifluoromethyl) cyclopropyl) pyridine carboxamide) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (IXE) (150 mg, 247. Mu. Mol) was dissolved in dichloromethane (1.5 mL), trifluoroacetic acid (1.00 mL) was added at 0deg.C, and the reaction solution was stirred at 0deg.C for 3 hours. After completion of the reaction, the reaction solution was poured into sodium hydrogencarbonate (15.0 mL) at 0 ℃, ph=7 was adjusted, and the filter cake was collected by filtration, and dried to give the compound N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (1- (trifluoromethyl) cyclopropyl) pyridine carboxamide (IX) (100 mg, yield 79.8%).
LC-MS,M/Z(ESI):506.2(M+H + )
Preparation of intermediates XF-P1 and XF-P2
Synthesis of trans-4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (2- (trifluoromethyl) cyclopropyl) pyridinoylamino) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (XF-P1)
Synthesis of tert-butyl cis-4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (2- (trifluoromethyl) cyclopropyl) pyridinoylamino) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (XF-P2)
The synthetic routes for intermediates XF-P1 and XF-P2 are shown below
First step, 2-trifluoroethane-1-diazonium synthesis (XB)
2, 2-trifluoroethylamine hydrochloride (15.0 g,110 mmol) was dissolved in methyl t-butyl ether (50 mL) and water (20 mL), a solution of sodium nitrite (8.40 g,122 mmol) in water (20.0 mL) was added at 0℃and the reaction solution was stirred under nitrogen atmosphere at 25℃for 3 hours. After the reaction was completed, the aqueous phase and the organic phase were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the compound 2, 2-trifluoroethane-1-diazonium (XB) (12 g, crude product).
Second step, synthesis of 4, 5-tetramethyl-2- (2- (trifluoromethyl) cyclopropyl) -1,3, 2-dioxaborolan (5_1)
4, 5-tetramethyl-2-vinyl-1, 3, 2-dioxaborolan (10.0 g,64.9 mmol) and palladium acetate (1.46 g,6.49 mmol) were dissolved in methyl tert-butyl ether (20 mL), replaced with nitrogen three times, and 2, 2-trifluoroethane-1-diazonium (10.9 g,97.4 mmol) was added dropwise to the reaction mixture, and the reaction temperature was kept at 25℃and stirred for 12 hours. After the reaction, the mixture was filtered, and the organic phase was concentrated to give a crude product, which was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate (V/V) =20/1) to give compound 4, 5-tetramethyl-2- (2- (trifluoromethyl) cyclopropyl) -1,3, 2-dioxaborolan (XC) (9.20 g, yield 60.0%).
1 H NMR(400MHz,CDCl 3 )δ1.78-1.65(m,1H),1.23(s,12H),1.04-0.98(m,1H),0.89-0.79(m,1H),0.39-0.26(m,1H)
Third step, synthesis of methyl 6- (2- (trifluoromethyl) cyclopropyl) picolinate (XD)
Methyl 6-bromopyridine carboxylate (6.0 g,27.8 mmol) and 4, 5-tetramethyl-2- (2- (trifluoromethyl) cyclopropyl) -1,3, 2-dioxaborolan (7.87 g,33.3 mmol) were dissolved in dioxane (50 mL), nitrogen was replaced three times, cesium carbonate (27.2 g,83.3 mmol) and diphenylphosphine palladium dichloride (1.95 g,2.78 mmol) were added, and stirred at 100℃for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the organic phase was concentrated to give a yellow oil, which was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate (V/V) =10/1) to give methyl 6- (2- (trifluoromethyl) cyclopropyl) picolinate (XD) (3.40 g, yield 49.9%).
LC-MS,M/Z(ESI):246.0(M+H + )
Fourth step, synthesis of 6- (2- (trifluoromethyl) cyclopropyl) pyridine carboxamide (XE)
Methyl 6- (2- (trifluoromethyl) cyclopropyl) picolinate (3.80 g,15.5 mmol) was dissolved in tetrahydrofuran (19 mL), aqueous ammonia (34.6 g,326mmol,38mL,33% purity) was added at 0deg.C, and the reaction stirred at 25deg.C for 12 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to give compound 6- (2- (trifluoromethyl) cyclopropyl) pyridine carboxamide (XE) (3.10 g, yield 86.9%).
1 H NMR(400MHz,CDCl 3 )δ8.06(d,1H),7.79(t,1H),7.62(d,1H),7.45(d,1H),5.71(s,1H),2.54-2.44(m,1H),2.34-2.19(m,1H),1.52-1.40(m,2H)
Fifth step Synthesis of tert-butyl 4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (2- (trifluoromethyl) cyclopropyl) pyridinoylamino) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (XF)
6- (2- (trifluoromethyl) cyclopropyl) pyridine carboxamide (300 mg,1.30 mmol), 4- (6-bromo-8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (773 mg,1.69 mmol) was dissolved in toluene (6 mL), cuprous iodide (49.6 mg, 261. Mu. Mol), 1, 10-phenanthroline (70.5 mg, 391. Mu. Mol) and potassium phosphate (830 mg,3.91 mmol) were added and stirred at 100℃for 2 hours under nitrogen. After the completion of the reaction, the reaction solution was cooled to room temperature, water (40 mL) was added, and extracted with ethyl acetate (60 mL), and the organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =5:1) to give tert-butyl 4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (2- (trifluoromethyl) cyclopropyl) pyridinylamino) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (XF) (500 mg, yield 62.9%).
LC-MS,M/Z(ESI):606.3(M+H + )
Sixth step Synthesis of trans-4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (2- (trifluoromethyl) cyclopropyl) pyridinoylamino) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (XF-P1)
Synthesis of tert-butyl cis-4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (2- (trifluoromethyl) cyclopropyl) pyridinoylamino) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (XF-P2)
4- (8-fluoro-7- (2-hydroxy-propan-2-yl) -6- (6- (2- (trifluoromethyl) cyclopropyl) pyridin-amido) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (XF) (500 mg, 826. Mu. Mol) is subjected to supercritical fluid chromatographic separation (column: DAICEL CHIRALCEL OD-250 mm. Times.50 mm,10um; mobile phase A: supercritical fluid carbon dioxide; mobile phase B: ethanol (0.1% ammonia), gradient elution: supercritical fluid carbon dioxide containing 0.1% ammonia of ethanol in a proportion of from 5% to 40%); flow rate: 3mL/min; a detector: a PDA; column temperature: 35 ℃; column pressure: 100 bar) to give tert-butyl trans-4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (2- (trifluoromethyl) cyclopropyl) pyridinoylamino) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (XF-P1) (200 mg, 40.0% yield, peak 1, retention time = 1.706 min) and tert-butyl cis-4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (2- (trifluoromethyl) cyclopropyl) pyridinoylamino) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylate (XF-P2) (200 mg, 40.9% yield, peak 2, retention time = 1.80 min).
XF-P1: 1 H NMR(400MHz,CDCl 3 )δ12.18(br s,1H),9.36(s,1H),8.05(d,J=7.6Hz,1H),7.82(t,J
=7.7Hz,1H),7.48(d,J=7.8Hz,1H),7.21(d,J=2.9Hz,1H),4.05(br d,J=11.8Hz,2H),2.86-2.68(m,
2H),2.67-2.41(m,3H),1.97-1.81(m,8H),1.75-1.67(m,1H),1.61(br d,J=3.5Hz,1H),1.56-1.47(m,3H),1.45(s,9H)
LC-MS,M/Z(ESI):606.3(M+H + )
XF-P2: 1 H NMR(400MHz,CDCl 3 )δ=12.19(br s,1H),9.35(s,1H),8.05(d,J=7.3Hz,1H),7.81(t,
J=7.7Hz,1H),7.48(d,J=7.4Hz,1H),7.21(d,J=3.0Hz,1H),4.04(br d,J=11.9Hz,2H),2.83-2.67(m,2H),2.65-2.41(m,3H),1.94(br s,2H),1.90-1.83(m,6H),1.61(br d,J=4.4Hz,1H),1.55-1.47(m,3H),1.45(s,9H),1.26-1.23(m,1H)
LC-MS,M/Z(ESI):606.3(M+H + )
Preparation of intermediate X-P1
Synthesis of trans-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (-2- (trifluoromethyl) cyclopropyl) pyridine carboxamide (X-P1)
Intermediate X-P1The synthetic route of (2) is as follows:
the compound trans-4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (2- (trifluoromethyl) cyclopropyl) pyridinamido) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (XF-P1) (200 mg, 330. Mu. Mol) was dissolved in dichloromethane (3 mL), replaced with nitrogen three times, trifluoroacetic acid (3.07 g,26.9 mmol) was added dropwise to the reaction solution at 0℃and the reaction temperature was kept at 0℃with stirring for 2 hours. After the completion of the reaction, the reaction mixture was poured into an aqueous sodium hydrogencarbonate solution (50 mL), filtered, and the cake was dried to give the compound trans-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (-2- (trifluoromethyl) cyclopropyl) pyridine carboxamide (X-P1) (170 mg, crude product).
LC-MS,M/Z(ESI):506.2(M+H + )
Preparation of intermediate X-P2
Synthesis of cis-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- ((1S, 2S) -2- (trifluoromethyl) cyclopropyl) pyridine carboxamide (X-P2)
The synthetic route for intermediate X-P2 is shown below:
cis-4- (8-fluoro-7- (2-hydroxypropan-2-yl) -6- (6- (2- (trifluoromethyl) cyclopropyl) pyridinamido) imidazo [1,2-a ] pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (XF-P2) (200 mg, 330. Mu. Mol) was dissolved in dichloromethane (3 mL), replaced with nitrogen three times, trifluoroacetic acid (3.07 g,26.9 mmol) was added dropwise to the reaction solution at 0℃and the reaction temperature was kept at 0℃under stirring for 2 hours. After the completion of the reaction, the reaction mixture was poured into an aqueous sodium hydrogencarbonate solution (50 mL), filtered, and the cake was dried to give the compound cis-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (-2- (trifluoromethyl) cyclopropyl) pyridine carboxamide (X-P2) (170 mg, crude product).
LC-MS,M/Z(ESI):506.2(M+H + )
Preparation of intermediate XI
Synthesis of 6-cyclopropyl-N- (8-fluoro-2- ((1 r,4 r) -4- (hydroxymethyl) cyclohexyl) -7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (XI)
The synthetic route for intermediate XI is shown below:
the first step: synthesis of methyl (1 r,4 r) -4- (chlorocarbonyl) cyclohexane-1-carboxylate (XIB)
(1 r,4 r) -4- (methyl-cyclohexan-1-carboxylic acid (10.0 g,53.7 mmol) was dissolved in methylene chloride (100 mL), N-dimethylformamide (393 mg,5.37mmol, 413. Mu.L) was added, oxalyl chloride (15.0 g,118 mmol) was added dropwise to the reaction solution at 25℃under nitrogen protection, and stirring was carried out at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated directly to give methyl (1 r,4 r) -4- (chlorocarbonyl) cyclohexane-1-carboxylate (XIB) (10.0 g, yield 90.9%).
And a second step of: synthesis of methyl (1 r,4 r) -4- (2-diazoacetyl) cyclohexane-1-carboxylate (XIC)
To a solution of methyl (1 r,4 r) -4- (chlorocarbonyl) cyclohexane-1-carboxylate (10.0 g,48.9 mmol) in tetrahydrofuran (50 mL) and acetonitrile (50 mL) at room temperature was added dropwise trimethylsilyl diazomethane (2.00M in n-hexane, 29.3 mL) at 0deg.C, and the reaction was warmed to 25deg.C and stirred for 2 hours. After the reaction, it was concentrated under reduced pressure to give methyl (1 r,4 r) -4- (2-diazoacetyl) cyclohexane-1-carboxylate (10 g, crude product).
And a third step of: synthesis of methyl (1 r,4 r) -4- (2-bromoacetyl) cyclohexane-1-carboxylate (XID)
Hydrobromic acid (10.0 g,49.5mmol,6.72mL,40% purity) was added dropwise to methyl (1 r,4 r) -4- (chlorocarbonyl) cyclohexane-1-carboxylate (10.0 g,48.9 mmol) in tetrahydrofuran (50 mL) and acetonitrile (50 mL) at 0℃and the reaction mixture was stirred at 0℃for 0.5 hours. After the completion of the reaction, aqueous sodium hydrogencarbonate (500 mL) was added, and extracted with ethyl acetate (300 mL), and the organic phase was washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =2:1) to give methyl (1 r,4 r) -4- (2-bromoacetyl) cyclohexane-1-carboxylate (XID) (2.00 g, yield 19.9%).
1 H NMR(400MHz,CDCl 3 )δ4.16(s,2H),3.67(s,3H),2.70-2.61(m,1H),2.32-2.25(m,1H),2.09(d,2H),1.99(d,2H),1.50–1.35(m,4H)
Fourth step (1 r,4 r) -4- (6- (6-cyclopropylpyridinium carboxamido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) cyclohexane-1-carboxylic acid methyl ester (XIE)
N- (6-amino-5-fluoro-4- (2-hydroxypropan-2-yl) pyridin-3-yl) -6-cyclopropylmethyl pyridine amide (2.40 g,7.26 mmol) and methyl (1 r,4 r) -4- (2-bromoacetyl) cyclohexane-1-carboxylate (2.87 g,10.9 mmol) were dissolved in isopropanol (24 mL), sodium bicarbonate (610 mg,7.26 mmol) was added and the reaction was warmed to 80℃and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (100 mL) was added, and the filter cake was collected by filtration, and dried to give the compound (1 r,4 r) -4- (6- (6-cyclopropylpyridinium carboxamido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) cyclohexane-1-carboxylic acid methyl ester (XIE) (3.50 g, crude product).
LC-MS,M/Z:495.1(M+H + )
1 H NMR(400MHz,CDCl 3 )δ12.14(s,1H),9.38(s,1H),7.97(d,1H),7.72(t,1H),7.44-7.35(m,1H),7.23(d,1H),3.72-3.65(m,3H),3.38(s,1H),2.74-2.62(m,1H),2.36-2.24(m,1H),2.16(d,2H),2.12-2.07(m,1H),2.05-1.97(m,2H),1.86(d,6H),1.51-1.36(m,4H),1.32-1.26(m,2H),1.12-1.00(m,2H)。
Fifth step Synthesis of 6-cyclopropyl-N- (8-fluoro-2- ((1 r,4 r) -4- (hydroxymethyl) cyclohexyl) -7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (XI)
Methyl (1 r,4 r) -4- (6- (6-cyclopropylpyridinium carboxamido) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-2-yl) cyclohexane-1-carboxylate (3.40 g,6.87 mmol) was dissolved in tetrahydrofuran (34 mL), and lithium aluminum hydride solution (2.5M, 5.50 mL) was added dropwise at 0deg.C under nitrogen and stirred for 0.5 hours. After the reaction, add sodium sulfate decahydrate (1.40 g) at 0deg.C to quench the reaction, filter, concentrate the organic phase to obtain crude product, purify by preparative high performance liquid chromatography (column Welch Ultimate XB-SiOH 250 x 70 x 10um; solvent: A=n-hexane (0.1% NH 3H 2O), B=ethanol; gradient: 15% -55%,15 min) to obtain compound 6-cyclopropyl-N- (8-fluoro-2- ((1 r,4 r) -4- (hydroxymethyl) cyclohexyl) -7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (XI) (1.51 g, yield 39.4%).
LC-MS,M/Z:467.1(M+H + )
1 H NMR(400MHz,DMSO-d6)δ12.40(s,1H),9.47(s,1H),7.94-7.80(m,3H),7.64-7.57(m,1H),6.54(s,1H),4.40(t,1H),3.26(t,2H),2.65-2.54(m,1H),2.25-2.17(m,1H),2.06(d,2H),1.84(d,2H),1.70(d,6H),1.48-1.34(m,3H),1.25-1.18(m,2H),1.08-0.97(m,4H)。
Preparation of intermediate 7-a
Synthesis of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (7-a)
The synthetic route for intermediate 7-a is shown below:
the first step: synthesis of 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (hydroxymethyl) piperidin-1-yl) isoindoline-1, 3-dione
2- (2, 6-dioxo-piperidin-3-yl) -5-fluoro-isoindole-1, 3-dione (6.00 g,21.7 mmol) and 4-piperidinemethanol (2.75 g,23.8 mmol) were dissolved in N, N-dimethylformamide (30 mL), then N, N-diisopropylethylamine (2.81 g,21.72 mmol) was added and stirred at 80℃for 12 hours under nitrogen. After completion of the reaction, the reaction mixture was poured into ice water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phase dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate (V/V) =50:1/1:1) to give the compound 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (hydroxymethyl) piperidin-1-yl) isoindoline-1, 3-dione (6.10 g, 75.6% yield).
LC-MS,M/Z(ESI):372.1(M+H + )
And a second step of: synthesis of 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (hydroxymethyl) piperidin-1-yl) isoindoline-1, 3-dione (7-a)
2- (2, 6-Dioxopiperidin-3-yl) -5- (4- (hydroxymethyl) piperidin-1-yl) isoindoline-1, 3-dione (1.00 g,2.69 mmol) was dissolved in dichloromethane (20 mL) and dess-Martin oxidant (1.48 g,3.50 mmol) was added and stirred at 25℃for 1 hour under nitrogen. After completion of the reaction, the reaction mixture was poured into sodium sulfite solution (100 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give crude product, which was purified by column chromatography (mobile phase: dichloromethane/ethyl acetate (V/V) =5:1 to 1:1) to give the compound 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (hydroxymethyl) piperidin-1-yl) isoindoline-1, 3-dione (7-a) (200 mg,541 μmol,20.1% yield).
LC-MS,M/Z(ESI):370.1(M+H + )
Preparation of intermediate 8-a
Synthesis of 2- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) acetaldehyde (8-a)
The synthetic route for intermediate 8-a is shown below:
the first step: synthesis of 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (2-hydroxyethyl) piperidin-1-yl) isoindoline-1, 3-dione
To 2- (2, 6-dioxo-3-piperidyl) -5-fluoro-1, 3-isoindoline dione (2.80 g,10.1 mmol) in N, N-dimethylformamide (28 mL) was added 4-piperidineethanol (1.57 g,12.1 mmol) and N, N-diisopropylethylamine (2.62 g,20.2mmol,3.53 mL) at room temperature. The reaction solution was stirred at 90℃for 12 hours. After the reaction was completed, the reaction mixture was slowly poured into water (20 mL) to quench, ethyl acetate (15 ml×3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was separated by chromatography column (petroleum ether: ethyl acetate (V/V) =50:1 to 0:1) to give the compound 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (2-hydroxyethyl) piperidin-1-yl) isoindoline-1, 3-dione (1.20 g, yield 20.4%).
LC-MS,M/Z(ESI):386.2(M+H+)
And a second step of: synthesis of 2- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) acetaldehyde (8-a)
To a solution of 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (2-hydroxyethyl) piperidin-1-yl) isoindoline-1, 3-dione (1.00 g,2.59 mmol) in methylene chloride (30 mL) at 0deg.C was added dess-martin oxidant (1.10 g,2.59 mmol), and after stirring for 0.5 hours, the reaction solution was slowly raised to 25deg.C and stirred for 1 hour. After the reaction, the reaction mixture was slowly poured into an aqueous sodium thiosulfate solution (20 mL) to quench, extracted with ethyl acetate (15 ml×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. Isolation by chromatography (petroleum ether: ethyl acetate (V/V) =50:1 to 0:1) afforded compound 2- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) acetaldehyde (8-a) (561 mg, 56.3% yield).
LC-MS,M/Z(ESI):384.5(M+H + )
Intermediate 9-a
Synthesis of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) azetidine-3-carbaldehyde (9-a)
First step Synthesis of 2- (2, 6-Dioxopiperidin-3-yl) -5- (3- (hydroxymethyl) azetidin-1-yl) dihydro-isoindole-1, 3-dione
2- (2, 6-Dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (2.00 g,7.24 mmol) was dissolved in N, N-dimethylformamide (40 mL), and triethylamine (3.66 g,36.2mmol,5.04 mL) and (azetidin-3-yl) methanolic hydrochloride (1.07 g,8.69 mmol) were added and the reaction stirred at 85℃for 1 hour. After completion of the reaction, water (100 mL) was added to quench the reaction, the mixture was extracted with methylene chloride (150 mL), and the organic phase was washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the compound 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (hydroxymethyl) azetidin-1-yl) isoindoline-1, 3-dione (700 mg, yield 28.1%).
LC-MS,M/Z(ESI):344.1(M+H + )
Second step Synthesis of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) azetidine-3-carbaldehyde (9-a)
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- (hydroxymethyl) azetidin-1-yl) isoindoline-1, 3-dione (700 mg,2.04 mmol) was dissolved in dichloromethane (14 mL), and dessert-martin oxidant (1.04 g,2.45 mmol) was added and stirred at 25℃for 2 hours. After completion of the reaction, quenched with water (40 mL), extracted with dichloromethane (20.0 mL), and the organic phase was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =0/1) to give compound 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) azetidine-3-carbaldehyde (300 mg, yield 43.1%).
LC-MS,M/Z(ESI):342.1(M+H + ).
Example 1: preparation of target Compound 1
Synthesis of N- (2- (1- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (Compound 1)
The synthetic route for target compound 1 is shown below:
the first step: synthesis of N- (2- (1- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (Compound 1)
To a solution of 2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethyl 4-methylbenzenesulfonate (intermediate 1-a) (887 mg,1.72 mmol), N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (intermediate II) (400 mg, 858. Mu. Mol), potassium iodide (428 mg,2.58 mmol) in acetonitrile (7.00 ml) was added diisopropylethylamine (55mg, 4.30 mmol) and the reaction was stirred at 80℃for 3 hours. After the reaction, concentrating to obtain a crude product, separating the crude product by a chromatographic plate (dichloromethane: methanol (V/V) =5:1), and purifying by preparative high performance liquid chromatography (column: column: phenomenex Synergi C: 150 x 25mm x 10 μm; mobile phase: water (0.225% formic acid) -acetonitrile; B%:14% -44%,9 min) to obtain N- (2- (1- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-yl) oxo) ethoxy) ethyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropane-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (compound 1).
LC-MS,M/Z(ESI):810.4[M+H] +
1 H NMR(400MHz,CDCl 3 )δ12.69(s,1H),9.61(s,1H),9.33(s,1H),8.56(d,1H),8.15(t,1H),7.86(d,1H),7.81(d,1H),7.50–7.37(m,2H),7.27–7.25(m,1H),5.06–4.95(m,1H),4.39–4.29(m,2H),3.89(b,4H),3.39–3.26(m,2H),2.77(br s,6H),2.53–2.42(m,2H),2.12–2.08(m,6H),1.87(d,6H)。
Example 2: preparation of target Compound 2
Synthesis of N- (2- (1- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (Compound 2)
The synthetic route for target compound 2 is shown below:
the first step: synthesis of N- (2- (1- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (Compound 2)
To a solution of 2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethyl 4-methylbenzenesulfonate (intermediate 2-a) (240 mg, 429. Mu. Mol), N- [ 8-fluoro-7- (1-hydroxy-1-methyl-ethyl) -2- (4-piperidinyl) imidazo [1,2-a ] pyridin-6-yl ] -6- (trifluoromethyl) pyridine-2-carboxamide (intermediate II) (400 mg, 859. Mu. Mol), potassium iodide (428 mg,2.58 mmol) in acetonitrile (5.00 mL) was added diisopropylethylamine (333 mg,2.58 mmol) and the reaction stirred at 80℃for 4 hours. After the reaction, directly concentrating to obtain a crude product, separating the crude product by a thin-layer chromatography silica gel plate (dichloromethane: methanol (V/V) =5:1), and purifying by preparative high performance liquid chromatography (column: column: phenomenex Synergi C18:150X125 mm×10μm; mobile phase: water (0.225% formic acid) -acetonitrile; (acetonitrile): 14% -44%,9 min) to obtain N- (2- (1- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-yl) oxo-ethoxy) ethyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropane-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (compound 2).
LC-MS,M/Z(ESI):840.3[M+H] +
1 H NMR(400MHz,CDCl 3 )δ12.6(s,1H),9.54(s,1H),8.86(s,1H),8.49(d,1H),8.14(t,1H),7.87(d,1H),7.77(d,1H),7.44(d,1H),7.39(d,1H),7.24(d,1H),5.04–4.94(m,1H),4.34–4.27(m,2H),4.08–3.99(m,2H),3.95–3.87(m,2H),3.77–3.68(m,5H),3.66–3.58(m,2H),3.26–3.20(m,2H),3.15–3.00(m,3H),2.93–2.73(m,4H),2.29–2.24(m,3H),1.88(d,6H),1.29–1.21(m,1H)。
Example 3: preparation of target Compound 3
Synthesis of N- (2- (1- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (Compound 3)
The synthetic route for target compound 3 is shown below:
the first step: synthesis of N- (2- (1- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (Compound 3)
To a solution of 2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethylmethanesulfonic acid (intermediate 3-a) (307 mg, 698. Mu. Mol) and N- [ 8-fluoro-7- (1-hydroxy-1-methyl-ethyl) -2- (4-piperidinyl) imidazo [1,2-a ] pyridin-6-yl ] -6- (trifluoromethyl) pyridine-2-carboxamide (intermediate II) (578mg, 838. Mu. Mol) in N, N-dimethylformamide (5.00 mL) was added potassium carbonate (383 mg,2.79 mmol) at room temperature. The mixture was stirred at 70℃for 12 hours. After the completion of the reaction, the reaction mixture was quenched by addition of water (10.0 mL) at room temperature, followed by extraction with ethyl acetate (10.0 mL. Times.3). The organic layer was washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product is separated by chromatography plates (dichloromethane: methanol (V/V) =5:1), and purified by preparative high performance liquid chromatography (chromatographic column: phenomenex luna C: 150 x 40mm x 15 μm; mobile phase: [ water (FA) -ACN ]; B (ACN)%: 16% -46%,9 min) to give N- (2- (1- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (compound 3).
LC-MS,M/Z(ESI):809.2[M+H] +
1 H NMR(400MHz,DMSO-d 6 )δ12.65(s,1H),11.11(br s,1H),9.48(s,1H),8.48–8.35(m,2H),8.22–8.17(m,1H),7.87(d,1H),7.60(dd,1H),7.17(d,1H),7.05(d,1H),6.63(br t,1H),5.05(dd,1H),3.62(dt,5H),3.53–3.44(m,4H),2.99(d,2H),2.93–2.78(m,1H),2.63–2.55(m,3H),2.20(t,2H),2.05–1.90(m,3H),1.76–1.59(m,8H)。
Example 4: preparation of target Compound 4
Synthesis of N- (2- (1- (2- (4- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperazin-1-yl) ethyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (Compound 4)
The synthetic route for target compound 4 is shown below:
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the first step: synthesis of N- (2- (1- (2- (4- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperazin-1-yl) ethyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (Compound 4)
To a solution of 2- (4- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperazin-1-yl) acetaldehyde (intermediate 4-a) (150 mg, 390. Mu. Mol) and N- [ 8-fluoro-7- (1-hydroxy-1-methyl-ethyl) -2- (4-piperidinyl) imidazo [1,2-a ] pyridin-6-yl ] -6- (trifluoromethyl) pyridine-2-carboxamide (182 mg, 390. Mu. Mol) (tetrahydrofuran (40.0 mL) of intermediate II) and N, N-diisopropylethylamine (8.00 mL) was added potassium acetate (76.6 mg, 780. Mu. Mol) at room temperature, then the mixture was stirred at room temperature for half an hour, and sodium borohydride acetate (165 mg, 780. Mu. Mol) was added thereto, and then the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (20.0 mL), quenched, and then extracted with ethyl acetate (10.0 ml×3). The organic phases were combined, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was separated by chromatography (ethyl acetate: methanol (V/V) =5:1) and purified by high performance liquid chromatography (column: phenomenex Luna C: 150 x 25mm x 10 μm; mobile phase: [ water (FA) -ACN ], B%:11% -41%,9 min) to give N- (2- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperazin-1-yl) ethyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (compound 4).
LC-MS,M/Z(ESI):834.5[M+H] +
1 H NMR(400MHz,CDCl 3 )δ12.68(br s,1H),9.50(s,1H),8.49(s,1H),8.45(d,1H),8.13(t,1H),7.87(d,1H),7.69(d,1H),7.39–7.44(m,1H),7.32(d,1H),7.06(d,1H),4.94(dd,1H),3.52–3.31(m,6H),2.90–3.03(m,4H),2.75–2.89(m,5H),2.63–2.72(m,6H),2.30–2.02(m,3H),1.86(d,6H),1.31-1.18(m,2H)。
Example 5: preparation of target Compound 5
N- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) ethoxy) ethyl) sulfonyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (Compound 5)
The synthetic route for target compound 5 is shown below:
the first step: synthesis of 2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethylcarbamic imidothioate (Compound 5-1)
A solution of 2- [2- [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxo-isoindolin-5-yl ] oxoethoxy ] ethyl 4-methylbenzenesulfonate (intermediate 1-a) (1.20 g,2.32 mmol) in ethanol (25.0 mL) was added to thiourea (212 mg,2.79 mmol) at room temperature, and the reaction stirred at 90℃for 12 hours. After the reaction, the mixture was concentrated directly to give 2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethylcarbamate (compound 5-1).
LC-MS,M/Z(ESI):421.1[M+H] +
And a second step of: synthesis of 2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethane-1-sulfonyl chloride (Compound 5-2)
N-chlorosuccinimide (1.43 g,10.7 mmol) was added in portions to a solution of 2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethylcarbamate (compound 5-1) (1.00 g,2.38 mmol) in acetonitrile (15.0 mL) of dilute hydrochloric acid (1M, 2.38 mL) at 0℃and the reaction stirred at 25℃for 1 hour. After the reaction is finished, acetonitrile is directly removed by concentration, water is added for dilution, and ethyl acetate extraction is carried out. The organic phase is dried and concentrated to obtain 2- (2- ((2- (2, 6-dioxopiperidine-3-yl)) material
1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethane-1-sulfonyl chloride (compound 5-2).
LC-MS,M/Z(ESI):445.1[M+H] +
And a third step of: synthesis of N- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethyl) sulfonyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (Compound 5)
To a solution of N- [ 8-fluoro-7- (1-hydroxy-1-methyl-ethyl) -2- (4-piperidinyl) imidazo [1,2-a ] pyridin-6-yl ] -6- (trifluoromethyl) pyridine-2-carboxamide (intermediate II) (200 mg, 429. Mu. Mol), triethylamine (434 mg,4.30 mmol) and N, N-lutidine (5.25 mg, 42.9. Mu. Mol) in dichloromethane (6.00 mL) was added 2- [2- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindolin-5-yl ] oxoethoxy ] ethanesulfonyl chloride (compound 5-2) (573 mg,1.29 mmol) and the reaction was stirred at 25℃for 3 hours. After completion of the reaction, water (10 mL) was added thereto for dilution, and ethyl acetate (10 mL. Times.3) was used for extraction. The organic phase was washed with saturated sodium bicarbonate solution (10 ml×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give crude product. The crude product was separated by chromatography (dichloromethane: methanol=10:1) and purified by preparative high performance liquid chromatography (column: phenomenex Synergi C, 150, 25mm, 10 μm; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; B%:30% -60%,9 min) to give N- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethoxy) ethyl) sulfonyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridinecarboxamide (compound 5).
LC-MS,M/Z(ESI):874.4[M+H] +
1 H NMR(400MHz,CDCl 3 )δ12.73(s,1H),9.65(s,1H),9.43(s,1H),8.55(d,1H),8.16(t,1H),7.87(d,1H),7.78(d,1H),7.40(d,1H),7.36(d,1H),7.24(dd,1H),4.99(dd,1H),4.29(t,2H),3.99–3.82(m,6H),3.27(t,2H),3.01–2.75(m,5H),2.69–2.58(m,2H),2.22–2.02(m,2H),1.92–1.79(m,9H)。
Example 6: preparation of target Compound 6
N- (2- (1- ((1- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxo) ethyl) piperidin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (Compound 6)
The synthetic route for target compound 6 is shown below:
to a solution of N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (1- (piperidin-4-ylmethyl) piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (intermediate III) (200 mg, 355. Mu. Mol), diisopropylethylamine (459 mg,3.55 mmol) in acetonitrile (4.00 mL) was added 2- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindolin-5-yl ] oxoethyl 4-methylbenzenesulfonate (intermediate 6-a) (168 mg, 355. Mu. Mol) and the reaction was stirred at 80℃for 3 hours at room temperature. The reaction liquid is cooled to room temperature, reduced pressure concentration is carried out to obtain crude products, and the crude products are sequentially subjected to chromatographic plate separation (dichloromethane/methanol (V/V) =8:1), high performance liquid chromatography purification (chromatographic column: phenomenex Synergi C, 150, 25mm, 10 mu m; mobile phase: water (0.225% formic acid) -acetonitrile ]; B (acetonitrile)%: 5% -35%,9 min) is carried out, thus obtaining N- (2- (1- ((1- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-yl) oxo) ethyl) piperidin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (compound 6).
LC-MS,M/Z(ESI):863.4[M+H] +
1 H NMR(400MHz,CDCl 3 )δ12.65(s,1H),9.50(s,1H),8.46(d,1H),8.30(s,1H),8.14(t,1H),7.87(d,1H),7.79(d,1H),7.41(d,1H),7.36(d,1H),7.26–7.19(m,1H),5.01–4.92(m,1H),4.29(t,2H),3.32–3.29(m,2H),3.19–3.11(m,2H),3.01–2.76(m,6H),2.62–2.57(m,2H),2.55–2.45(m,2H),2.38–2.26(m,5H),2.08–1.99(m,4H),1.88(d,8H),1.52–1.39(m,2H)。
Example 7: preparation of target Compound 7
Synthesis of N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (Compound 7)
The synthetic route for target compound 7 is shown below:
to a solution of 2- (2, 6-dioxo-3-piperidyl) -5-fluoro-isoindoline-1, 3-dione (73.6 mg, 266. Mu. Mol) and diisopropylethylamine (114 mg, 888. Mu. Mol) in dimethyl sulfoxide (1.50 mL) at room temperature was added N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (1- (piperidin-4-ylmethyl) piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (intermediate III) (100 mg, 177. Mu. Mol), and the reaction solution was stirred at 100℃for 3 hours. After the reaction, directly concentrating to obtain a crude product, separating the crude product by a chromatographic plate (dichloromethane: methanol (V/V) =7:1), and purifying by a preparative high performance liquid chromatography (chromatographic column: phenomenex Synergi C: 150 x 25mm x 10 μm; mobile phase: water (0.225% formic acid) -acetonitrile ]; B (acetonitrile)%: 16% -46%,9 min), thereby obtaining N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropane-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine carboxamide (compound 7).
LC-MS,M/Z(ESI):819.5[M+H] +
1 H NMR(400MHz,CDCl 3 )δ12.63(s,1H),9.52(s,1H),8.57(d,1H),8.14(t,1H),8.03(s,1H),7.88(d,1H),7.68(t,1H),7.41(d,1H),7.28(d,1H),7.05(d,1H),5.00(s,1H),3.97(d,2H),3.18(s,2H),3.05–2.77(m,6H),2.57–2.40(m,4H),2.30–2.11(m,4H),2.06–1.96(m,5H),1.89(d,6H),1.40–1.31(m,2H)。
Example 8: preparation of target Compound 8
Synthesis of 6-cyclopropyl-N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (Compound 8)
The synthetic route for target compound 8 is shown below:
to a solution of 1- (2, 6-dioxo-piperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 7-a) (16.8 mg, 45.7. Mu. Mol) in methylene chloride (2 mL) at room temperature was added 6-cyclopropyl-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (intermediate V) (20.0 mg, 45.7. Mu. Mol), and the reaction solution was stirred at 25℃for 1 hour, followed by sodium borohydride acetate (19.3 mg, 91.4. Mu. Mol) and the reaction solution was stirred at 25℃for 0.5 hours. After the reaction, water (3 mL) was added to quench, dichloromethane (15 mL) was added to extract, the organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by preparative high performance liquid chromatography (column: waters Xbridge BEH C: 150 x 25mm x 5 μm, solvent a = 0.1% aqueous ammonia, B = acetonitrile; gradient: 56% -86%,10 min) to obtain compound 6-cyclopropyl-N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropane-2-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (compound 8).
LC-MS,M/Z(ESI):791.4(M+H + )
1 H NMR(400MHz,DMSO-d6)δ11.1(s,1H),8.45(s,1H),7.87-7.89(m,2H),7.78-7.77(m,1H),7.65-7.63(m,1H),7.39-7.37(m,1H),7.31-7.30(m,1H),7.24 -7.23(m,1H),5.03-5.08(m,1H),4.04(d,1H),2.99-2.97(m,2H),2.95-2.92(m,3H),2.59-2.57(m,2H),2.18-2.16(m,3H),2.01-1.94(m,6H),1.81-1.82(m,1H),1.78(s,7H),1.70-1.69(m,3H),1.23-1.21(m,2H),1.01-1.00(m,2H),0.98-0.97(m,4H)
Example 9: preparation of target Compound 9
Synthesis of 6-cyclopropyl-N- (2- (1- (2- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) ethyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (Compound 9)
The synthetic route for target compound 9 is shown below:
6-cyclopropyl-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (intermediate V) (50 mg, 114. Mu. Mol) and 2- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) acetaldehyde (8-a) (52.5 mg, 138. Mu. Mol) were dissolved in dichloromethane (1 mL) and sodium borohydride acetate (48.5 mg, 228. Mu. Mol) was added and stirred at room temperature for 1 hour. After completion of the reaction, water (5 mL) was added, the mixture was extracted with ethyl acetate (15 mL), the organic phase was washed with saturated brine (5 mL), then dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, which was purified by preparative high performance liquid chromatography (column: phenomenex luna C18:25 mm x 10 μm; mobile phase: solvent A=0.1% formic acid, B=acetonitrile; gradient: 25% -55%,7 min) to give the compound 6-cyclopropyl-N- (2- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) ethyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (compound 9)
LC-MS,M/Z(ESI):805.5(M+H + )
1 H NMR(400MHz,CDCl 3 -d6)δ12.09(s,1H),9.35(s,1H),7.91-7.89(m,2H),7.65–7.58(m,2H),
7.32-7.30(m,1H),6.98-6.97(m,1H),4.90-4.86(m,1H),3.86(d,2H),3.41–3.40(m,1H),2.90-2.65(m,9H),2.41-2.36(m,2H),2.04-2.01(m,6H),1.78-1.75(m,4H),1.52-1.48(m,5H),1.24-1.15(m,8H),0.97-0.96(m,3H)
Example 10: preparation of target Compound 10
Synthesis of 6- (2, 2-difluorocyclopropyl) -N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-dihydro-isoindol-5-ylpiperidin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (Compound 10)
The synthetic route for the target compound 10 is shown below:
6- (2, 2-Difluorocyclopropyl) -N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (VIII) (80.0 mg, 168. Mu. Mol) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-isoindol-5-yl) piperidine-4-carbaldehyde (7-a) (62.4 mg, 168. Mu. Mol) were dissolved in tetrahydrofuran (2 mL), stirred at 25℃for 11 hours, sodium triacetoxyborohydride (71.6 mg, 337. Mu. Mol) was added and stirred at 25℃for 1 hour. After completion of the reaction, the reaction mixture was poured into sodium bicarbonate (15 mL), ph=7 was adjusted, extracted with ethyl acetate (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative high performance liquid chromatography (column: phenomenex luna C, 150 x 25mm x 10 μm; mobile phase: solvent a=water+0.1% formic acid, b=acetonitrile; gradient: 22% -52%,9 min) to give compound 6- (2, 2-difluorocyclopropyl) -N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-isoindol-5-yl piperidin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (compound 10).
Example 11: preparation of target Compound 11
Synthesis of 2-cyclopropyl-N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) pyrimidine-4-carboxamide (Compound 11)
The synthetic route of target compound 12 is shown below:
2-cyclopropyl-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyrimidine-4-carboxamide (intermediate V) (60.0 mg, 137. Mu. Mol), 1- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 7-a) (75.8 mg, 20. Mu. Mol) was dissolved in dichloromethane (2 mL), stirred at 25℃for 12 hours, sodium borohydride acetate (72.5 mg, 342. Mu. Mol) was added and stirring was continued for 0.5 hours. After the completion of the reaction, water (40 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (60 mL), and the organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative high performance liquid chromatography (column: _ Phenomenex Luna C18 18150×25mm, solvent: a=0.1% hydrochloric acid, b=acetonitrile; gradient: 10% -40%,10 min) to give the compound 2-cyclopropyl-N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) piperidin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) pyrimidine-4-carboxamide (compound 11).
LC-MS,M/Z:792.4(M+H + )
1 H NMR(400MHz,DMSO-d6)δ12.35(s,1H),9.48(s,1H),8.85(d,1H),8.20-7.99(m,1H),7.89(d,1H),7.68(d,1H),7.36(d,1H),7.28(d,1H),7.10-7.01(m,1H),5.06-4.83(m,1H),3.96(d,2H),3.12(d,2H),3.04-2.94(m,2H),2.90-2.83(m,2H),2.80-2.71(m,1H),2.43-2.35(m,3H),2.28(t,2H),2.18-2.11(m,4H),2.05-2.02(m,2H),1.97-1.91(m,4H),1.89(d,6H),1.42-1.31(m,2H),1.31-1.25(m,2H),1.21-1.14(m,2H)
Example 12: preparation of Compound 12
Synthesis of 6-cyclopropyl-N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-isoindol-5-yl) azetidin-3-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide
The synthetic route for compound 12 is shown below:
6-cyclopropyl-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (intermediate V) (120 mg, 274. Mu. Mol) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) azetidine-3-carbaldehyde (intermediate 9-a) (140 mg, 411. Mu. Mol) were dissolved in tetrahydrofuran (2.4 mL), sodium borohydride acetate (116 mg, 548. Mu. Mol) was added and stirred at room temperature for 2 hours. After completion of the reaction, water (40 mL) was added, the organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate (V/V) =0/1) to give the compound which was subjected to supercritical fluid chromatography (column (S, S) Whelk-O150 x 4.6mm i.d.,3.5 μm; mobile phase a: [ supercritical fluid carbon dioxide ]; mobile phase B: isopropanol (0.05% diethylamine), gradient elution: supercritical fluid carbon dioxide containing isopropanol (0.05% diethylamine) in a ratio of from 5% to 50%, flow rate: 3mL/min; detector: PDA; column temperature: 35 ℃ c; column pressure: 100 bar) to give the compound 6-cyclopropyl-N- (2- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxodihydro-indol-5-azetidine-3-5-hydroxy-1- (2, 3-dioxo-3-imidazolyl) -1-hydroxy-imidazol-3-yl) 1-hydroxy-1- (2, 3-hydroxypyridine) a-3-yl) 1-hydroxypyridine-1-2-hydroxy-1-hydroxypyridine-3-carbazide) amide)
1 H NMR(400MHz,CDCl 3 )δ(s,1H),9.50(s,1H),8.01(d,2H),7.75(t,1H),7.66(d,1H),7.41(d,1H),7.38-7.29(m,2H),6.79(d,1H),6.58-6.49(m,1H),5.00-4.90(m,1H),4.34-4.04(m,2H),4.00(s,2H),3.24-2.66(m,8H),2.55-2.43(m,1H),2.27-2.03(m,5H),1.89(d,6H),1.27-1.24(m,2H),1.22(d,3H),1.11-1.01(m,2H)。
Example 13: preparation of target Compound 13
Synthesis of 6-cyclopropyl-N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -5-fluoropyridine carboxamide (Compound 13)
The synthetic route for target compound 13 is shown below:
to a solution of 6-cyclopropyl-5-fluoro-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (50 mg, 109.77. Mu. Mol) (intermediate VII) in dichloromethane (5 mL) at room temperature was added 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 7-a) (48.65 mg, 131.72. Mu. Mol) and stirred at room temperature for 11 hours, followed by sodium borohydride acetate (46.53 mg, 219.54. Mu. Mol) and the reaction solution was stirred at 25℃for 0.5 hours. After the reaction, water (3 mL) was added to quench, dichloromethane (15 mL) was used to extract, and the organic phase was concentrated to give a crude product, which was purified by preparative high performance liquid chromatography (column: welch Xtimate C18 x 25mm x 5 μm, solvent a=0.1% formic acid, b=acetonitrile; gradient: 18% -48%,10 min) to give the compound 6-cyclopropyl-N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropane-2-yl) imidazo [1,2-a ] pyridin-6-yl) -5-fluoropyridine carboxamide (compound 13).
LC-MS,M/Z(ESI):809.4(M+H + )
1 H NMR(400MHz,DMSO-d6)δ12.31(s,1H),11.06(s,1H),9.45(s,1H),8.02-7.92(m,1H),7.90-7.77(m,2H),7.65(d,1H),7.31(d,1H),7.26-7.16(m,1H),6.60(s,1H),5.13-5.00(m,1H),4.13-3.95(m,2H),3.06-2.81(m,5H),2.70-2.59(m,2H),2.58-2.54(m,1H),2.41-2.31(m,2H),2.17(d,2H),2.09-1.92(m,5H),1.91-1.77(m,3H),1.70(d,6H),1.67-1.61(m,1H),1.31(s,2H),1.21-1.02(m,4H)
Example 14: preparation of target Compound 14
6- ((R) -2, 2-Difluorocyclopropyl) -N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (target compound 14)
The synthetic route for target compound 14 is shown below:
(R) -6- (2, 2-Difluorocyclopropyl) -N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (VIII-P1) (70.0 mg, 148. Mu. Mol), 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) azetidine-3-carbaldehyde (75.7 mg, 222. Mu. Mol) was dissolved in dichloromethane (2 mL) and stirred at 25℃for 12 hours. Sodium borohydride acetate (78.3 mg, 370. Mu. Mol) was added to the reaction solution, and the reaction solution was stirred at 25℃for 0.5 hours. The reaction was quenched with water (40 mL), extracted with ethyl acetate (20 mL x 3), the organic phases combined, washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by preparative high performance liquid chromatography (column 3_Phenomenex Luna C18 150*25mm*5 μm; solvent: a=0.1% hydrochloric acid, b=acetonitrile; gradient: 13% -43%,10 min) to give compound 6- ((R) -2, 2-difluorocyclopropyl) -N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (compound 14).
LC-MS,M/Z(ESI):799.4(M+H + )
1 H NMR(400MHz,CDCl 3 )δ12.31(s,1H),9.46(s,1H),8.19-8.12(m,1H),7.88(t,1H),7.65(d,1H),7.48(d,1H),7.31(d,1H),6.80(d,1H),6.58-6.42(m,1H),5.07-4.81(m,1H),4.16(t,2H),3.82-3.60(m,2H),3.16-3.02(m,1H),2.99-2.80(m,6H),2.79-2.65(m,4H),2.18-2.02(m,5H),1.90(d,3H),1.83(d,3H),1.77-1.71(m,2H),1.26(s,3H)
Example 15: preparation of target Compound 15
6- ((S) -2, 2-Difluorocyclopropyl) -N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (target compound 15)
(Another configuration that is different from compound 14)
The synthetic route for target compound 15 is shown below:
(S) -6- (2, 2-Difluorocyclopropyl) -N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (70.0 mg, 148. Mu. Mol), 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) azetidine-3-carbaldehyde (75.7 mg, 222. Mu. Mol) was dissolved in dichloromethane (2 mL) and stirred at 25℃for 12 hours. Sodium borohydride acetate (78.3 mg, 370. Mu. Mol) was added to the reaction solution, and the reaction solution was stirred at 25℃for 0.5 hours. The reaction was quenched with water (40.0 mL), extracted with ethyl acetate (20 mL x 3), the organic phases combined, washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by preparative hplc (column Phenomenex Luna C, 150 x 25mm x 5um; solvent: a=0.1% hydrochloric acid, b=acetonitrile; gradient: 13% -43%,10 min) to give compound 6- ((S) -2, 2-difluorocyclopropyl) -N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) pyridine carboxamide (compound 15).
LC-MS,M/Z(ESI):799.4(M+H + )
1 H NMR(400MHz,CDCl 3 )δ12.32(s,1H),9.47(s,1H),8.16(d,1H),7.87(t,1H),7.65(d,1H),7.48(d,1H),7.32(d,1H),6.80(d,1H),6.55-6.45(m,1H),5.00-4.88(m,1H),4.17(t,2H),3.73(t,2H),3.17-3.04(m,1H),3.04-2.81(m,6H),2.81-2.67(m,4H),2.27-2.04(m,5H),1.89(d,3H),1.84(d,3H),1.80(s,2H),1.26(s,3H)
Examples: preparation of target Compound 16
Synthesis of N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (1- (trifluoromethyl) cyclopropyl) pyridine carboxamide (Compound 16)
The synthetic route for target compound 16 is shown below:
n- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (1- (trifluoromethyl) cyclopropyl) pyridine carboxamide (IX) (50.0 mg, 98.9. Mu. Mol) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) piperidine-4-carbaldehyde (43.8 mg, 118. Mu. Mol) were dissolved in tetrahydrofuran (1.00 mL), sodium acetate (24.3 mg, 296. Mu. Mol) was added, and sodium triacetoxyborohydride (62.8 mg, 296. Mu. Mol) was added and the reaction mixture was stirred at 25℃for 1 hour. After the reaction was completed, the reaction solution was poured into sodium bicarbonate (15.0 mL), pH was adjusted to 7, extracted with dichloromethane (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated directly to give a crude product, which was purified by high performance liquid chromatography (column Phenomenex luna C18250 x 50mm x 15um; mobile phase: solvent a=water+0.1% formic acid, b=acetonitrile; gradient: 22% -52%,9 min) to give compound N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (1- (trifluoromethyl) cyclopropyl) pyridine carboxamide (compound 16).
LC-MS,M/Z(ESI):859.4(M+H + )
1 H NMR(400MHz,DMSO-d 6 )δ12.38(s,1H),11.07(s,1H),9.47(s,1H),8.08-8.20(m,2H),7.89(d,1H),7.81-7.87(m,1H),7.65(d,1H),7.30(s,1H)7.23(d,1H),6.66(s,1H),5.06(dd,1H),3.98-4.11(m,2H),2.86-3.03(m,6H),2.63-2.71(m,2H),2.32(d,1H),2.17(d,2H),1.93-2.06(m,5H),1.78-1.88(m,3H),1.75(s,2H),1.70(d,6H),1.61-1.66(m,1H),1.49-1.55(m,2H),1.16(d,2H)
Example 17-1: preparation of target Compound 17A
trans-N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (2- (trifluoromethyl) cyclopropyl) pyridine carboxamide (target compound 17A)
The synthetic route for target compound 17A is shown below:
trans-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (-2- (trifluoromethyl) cyclopropyl) pyridine carboxamide (X-P1) (70.0 mg,138 μmol), 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (76.7 mg,208 μmol) was dissolved in dichloromethane (2 mL) and the reaction was stirred at 25 ° for 12 hours. Sodium borohydride acetate (73.4 mg, 346. Mu. Mol) was added to the reaction solution, and stirring was continued at 25℃for 0.5 hours. After the reaction, the reaction mixture was added to water (40 mL), extracted with ethyl acetate (60 mL), and the organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by preparative high performance liquid chromatography (column Phenomenex Luna C, 150 x 25mm x 5 μm; solvent: a=0.1% hydrochloric acid, b=acetonitrile; gradient: 15% -45%,10 min) to give the compound trans-N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (2- (trifluoromethyl) cyclopropyl) pyridine carboxamide (17A).
LC-MS,M/Z(ESI):859.4(M+H + )
1 H NMR(400MHz,DMSO-d 6 )δ12.51(s,1H),11.06(s,1H),9.50(s,1H),8.05-7.97(m,2H),7.89(d,1H),7.85-7.78(m,1H),7.65(d,1H),7.31(d,1H),7.27-7.19(m,1H),6.77(s,1H),5.11-5.02(m,1H),4.10-3.99(m,2H),3.04-2.88(m,4H),2.86-2.77(m,2H),2.65-2.59(m,1H),2.52(s,4H),2.22-2.14(m,2H),2.07-1.96(m,4H),1.95(d,1H),1.88-1.77(m,3H),1.71(s,6H),1.68-1.61(m,1H),1.59-1.52(m,1H),1.51-1.43(m,1H),1.23-1.11(m,2H)
Example 17-2: preparation of target Compound 17B
cis-N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (2- (trifluoromethyl) cyclopropyl) pyridine carboxamide (target compound 17B)
cis-N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- ((1 s,2 s) -2- (trifluoromethyl) cyclopropyl) pyridine carboxamide (X-P2) (70.0 mg,138 μmol), 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (76.7 mg,208 μmol) was dissolved in dichloromethane (2 mL) and stirred at 25 ℃ for 12 hours. Sodium borohydride acetate (73.4 mg, 346. Mu. Mol) was added to the reaction solution, stirred at 25℃for 0.5 hour, the reaction solution was added to water (40 mL), extracted with ethyl acetate (60 mL), the organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by preparative high performance liquid chromatography (column Phenomenex Luna C18 150X 5. Mu.m; solvent: A=0.1% hydrochloric acid, B=acetonitrile; gradient: 15% -45%,10 min) to give the compound cis-N- (2- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -8-fluoro-7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (2- (trifluoromethyl) cyclopropyl) pyridine carboxamide (target compound 17B).
LC-MS,M/Z:859.4(M+H + )
1 H NMR(400MHz,DMSO-d 6 )δ12.51(s,1H),11.07(s,1H),9.50(s,1H),8.04-7.97(m,2H),7.89(d,1H),7.84-7.79(m,1H),7.65(d,1H),7.31(s,1H),7.27-7.20(m,1H),6.77(s,1H),5.18-4.96(m,1H),4.05(d,2H),3.02-2.97(m,1H),2.96-2.87(m,3H),2.86-2.77(m,2H),2.60(d,1H),2.58-2.55(m,2H),2.47(d,2H),2.18(d,2H),2.08-1.97(m,4H),1.96-1.93(m,1H),1.88-1.77(m,3H),1.71(s,6H),1.68-1.62(m,1H),1.59-1.52(m,1H),1.51-1.44(m,1H),1.23-1.10(m,2H).
Biological testing
Experimental example 1: effect of Compounds on HEK293 cell IRAK4 protein
Experimental method
1) And (5) culturing the cells. The culture medium for cell culture is DMEM culture medium containing inactivated 10% fetal bovine serum, 100U/ml penicillin and 100 μg/ml streptomycin, HEK293-IRAK4-Hibit cells are cultured in an incubator with 5% CO2 at 37 ℃, and the cell confluency rate reaches 80-90% for passage, and then the cells are separated into bottles for passage. Cells in the logarithmic growth phase were plated, HEK293-IRAK4-Hibit cells were plated in 96-well plates, 100ul of medium, 20000-3000 cells per well, and cultured overnight.
2) The compound was diluted. The compound was dissolved in DMSO to a concentration of 10mM. The compounds were then diluted in a gradient with DMSO to concentrations of 2000. Mu.M, 500. Mu.M, 125. Mu.M, 32.25. Mu.M, 7.81. Mu.M, 1.95. Mu.M, 0.49. Mu.M, 0.12. Mu.M, and 0.031. Mu.M, respectively.
3) Adding medicine. 1. Mu.L of the diluted compound was added to 1ml of complete medium, and 100. Mu.L of the mixture was added to a 96-well plate at working concentrations of 1000nM, 250n M, 62.5n M, 15.6n M, 3.91n M, 0.98n M, 0.24n M, 0.061nM, 0.015nM and 0nM.
4) And (5) activity detection. The detection was carried out by 24 hours of drug treatment according to Promega company HiBiT Lytic Detection System.
5) DC50 calculation. The comparative IRAK4 (%) = (Lumninence experiment-Lumninence blank)/(Lumninence dmso-Lumninence blank) was calculated using a fitting according to log (inhibitor) vs.
Experimental results the compounds of the invention as shown in table 1 degrade IRAK4 protein results data.
TABLE 1 results data on degradation of IRAK4 protein by the compounds of the invention
Conclusion of experiment:
the degradation activity of the compound of the invention on IRAK4 protein reaches nM level, and the compound has excellent degradation effect and dose dependency.
Experimental example 2: determination of the Effect of Compounds on IL-1 beta-induced Activity of HEK293-NF-kB-Luciferase cell reporter Gene
HEK293-NF-kB-Luciferase cells were cultured in DMEM medium containing inactivated 10% fetal bovine serum, 100U/ml penicillin and 100. Mu.g/ml streptomycin at 37℃in an incubator of 5% CO2, and passaged and split-bottle after reaching a cell density of 80-90%. Cells in the logarithmic phase were plated in 96-well plates at 30000. After overnight incubation, the cells were treated with different drug concentrations for 18 hours. IL-1. Beta. Was added to give a final concentration of 1ng/ml and treated for 4 hours. Detection was performed using One-Lite Luciferase Assay System from Vazyme.
Conclusion of experiment: the compound can obviously inhibit the activation of IL-1 beta induced NF-kB signal channels, and the inhibition function is positively correlated with the dosage.
EXAMPLE 3 determination of the Effect of Compounds on LPS-induced inflammatory factor content of THP1 cells
THP1 cells were cultured in RPMI-1640 medium containing inactivated 10% foetal calf serum, 100U/ml penicillin and 100. Mu.g/ml streptomycin in an incubator at 37℃with 5% CO2 to a cell density of 1X 10. Sup.6, passaged and split-flask. Tumor cells in the logarithmic growth phase were plated in 96-well plates at 40000. After overnight incubation, the cells were treated with different drug concentrations for 18 hours. LPS was added to a final concentration of 2ng/ml and treated for 4 hours. Cell supernatants were taken and assayed for TNF content by ELISA.
Conclusion of experiment: in the LPS stimulated THP1 cell model, the compound can significantly inhibit the production of TNF, and the inhibition function is positively correlated with the dosage.
Example 4: determination of Compounds stability to liver microsomes
The stability of human liver microsomes of the compounds of the present invention was determined according to the following experimental method. The hepatic microsome stability test of the compound was tested using in vitro co-incubation of the compound with human hepatic microsomes. Test compounds were first formulated as a 10mM stock solution in DMSO solvent, followed by dilution of the compounds to 0.5mM using acetonitrile. Liver microsomes (Corning) were diluted with PBS to a microsome/buffer solution, and 0.5mM of the compound was diluted with the solution to a working solution having a compound concentration of 1.5. Mu.M and a liver microsome concentration of 0.75mg/ml. The reaction was started by taking a deep well plate, adding 30. Mu.L of working solution per well, then adding 15. Mu.L of pre-warmed 6mM NADPH solution, and incubating at 37 ℃. At 0, 5, 15, 30, 45 minutes of incubation, the reaction was terminated by adding 135 μl acetonitrile to the corresponding wells. After the reaction was terminated with acetonitrile at the last 45 min time point, the deep-well plate was vortexed for 10 minutes (600 rpm/min) and then centrifuged for 15 minutes. Taking supernatant after centrifugation, adding purified water in a ratio of 1:1, performing LC-MS/MS detection to obtain a ratio of the peak area of the compound to the internal standard peak area at each time point, comparing the ratio of the peak area of the compound at 5, 15, 30 and 45 minutes with the ratio of the peak area at 0 minute, calculating the residual percentage of the compound at each time point, and calculating T1/2 by using Graphpad 5 software.
Conclusion of experiment: the compound of the invention has good liver microsome stability.
Example 5: determination of PK Properties of Compounds in mice
3 male ICR mice were used at a dose of 10mg/kg, the route of administration was gastric lavage, vehicle 5% DMSO+10% Solutol+85% Saline, overnight fast, and blood collection time points were 5, 15, 30 minutes and 1, 2, 4, 6, 8, 24 hours before and after administration. Blood samples 6800g were centrifuged at 2-8deg.C for 6 minutes, and plasma was collected and stored at-80deg.C. 10. Mu.L of plasma at each time point was taken, 200. Mu.L of methanol containing 100ng/mL of internal standard was added, and after vortexing and mixing, 18000g was centrifuged for 7 minutes at 2-8 ℃. 200 μl was transferred to a 96-well sample plate for quantitative LC-MS/MS analysis. The principal pharmacokinetic parameters were analyzed using the WinNonlin 7.0 software non-compartmental model. Experimental results the PK parameter results for the compounds of the invention are shown in Table 2
Conclusion of experiment: in a mouse model, the compounds of the invention have good pharmacokinetic properties.
Table 2: PK parameters of Compounds
Cmax(ng/mL) | Tmax(hr) | AUC0-t(h*ng/mL) | T1/2(hr) | |
Compound 10 | 144.00 | 4.00 | 2184.92 | 7.28 |
Claims (11)
1. A compound of formula (I), a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof,
E 1 is-CH 2 -or-C (=o) -;
R 1 Is H, halogen, CN, C 1-6 Alkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 4-9 membered heterocycloalkyl, -NHC 1-6 Alkyl, -N (C) 1-6 Alkyl group 2 、-NH-C 4-9 Cycloalkyl, -NH-C 4-9 Heterocycloalkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 4-9 membered heterocycloalkyl, -NHC 1-6 Alkyl, -N (C) 1-6 Alkyl group 2 、-NH-C 4-9 Cycloalkyl, -NH-C 4-9 Heterocycloalkyl and 5-10 membered heteroaryl are each optionally substituted with 1 or more R 11 Substitution;
R 2 is H or C 1-6 An alkyl group;
R 3 is H, halogen, CN, C 1-6 Alkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl and 5-10 membered heteroaryl are each optionally substituted with 1 or more R 31 Substitution;
is->
Ring A and ring B are each independently absent, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, and,C 6-10 A membered aryl or 5-10 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 The membered aryl and the 5-10 membered heteroaryl are each optionally substituted with 1 or more R a Substitution;
L 1 、L 2 and L 3 Are each independently a single bond, -O-, -N (R) 22 )-、-P(O)-、-P(O)O-、-S-、-S(O)-、-S(O) 2 -、-S(O) 2 -N(R 22 )-、C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 1-12 Heteroalkyl wherein, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl and C 1-12 Heteroalkyl groups are each optionally substituted with 1 or more R b Substitution;
Ring C is C 6-10 Aryl or 5-10 membered heteroaryl;
the "4-12 membered heterocycloalkyl", "5-10 membered heteroaryl" and "C 1-12 "hetero" of a heteroalkyl "is a heteroatom or heteroatom group; the number of the hetero atoms or hetero atom groups is 1 or more, and each hetero atom or hetero atom group is N, -O-, -N (R) 22 )-、-P(O)-、-P(O)O-、-S-、-S(O)-、-S(O) 2 -、-S(O) 2 -N(R 22 ) -; when the number of the hetero atoms or the hetero atom groups is plural, the hetero atoms or the hetero atom groups are the same or different;
each R is 11 H, C independently 1-6 Alkyl, halogen, OH or CN;
each R is 31 Is defined as case 1 or case 2:
case 1: each R is 31 H, C independently 1-6 Alkyl, halogen, OH, NH 2 Or CN;
case 2: each R is 31 Independently C substituted with 1, 2 or 3 halogens 1-6 An alkyl group;
each R is 22 Independently H or C 1-6 An alkyl group;
each R is a Independently is halogen, =o, OH, NH 2 Or C 1-6 An alkyl group;
each R is b Independently H, =o, halogen, OH, NH 2 Or C 1-6 An alkyl group;
r is 1, 2, 3 or 4.
2. The compound of formula (I), tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein the 4-9 membered heterocycloalkyl, the-NH-C 4-9 The "hetero" in the heterocycloalkyl group and the 3-12 membered heterocycloalkyl group is a heteroatom or a heteroatom group; the number of the hetero atoms or hetero atom groups is 1 or more, and each hetero atom or hetero atom group is N, -O-, -N (R) 22 )-、-P(O)-、-P(O)O-、-S-、-S(O)-、-S(O) 2 -or-S (O) 2 -N(R 22 )-;R 22 The definition of claim 1, preferably, the number of heteroatoms or hetero-radicals is 1, 2, 3 or 4;
and/or R 1 In the above, the above-mentioned-NH-C 4-9 Heterocycloalkyl is-NH-4-9 membered heterocycloalkyl;
and/or R 1 In the above, the C 1-6 Alkyl, said-O-C 1-6 C in alkyl 1-6 Alkyl, the-NHC 1-6 C in alkyl 1-6 Alkyl and said-N (C) 1-6 Alkyl group 2 C in (C) 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or isopropyl;
and/or R 1 In the above, the C 3-6 Cycloalkyl and the-O-C 3-6 C in cycloalkyl 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl;
and/or R 3 In the above, the C 1-6 Alkyl and said-O-C 1-6 C in alkyl 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or isopropyl;
and/or R 3 In the above, the C 3-6 Cycloalkyl and the-O-C 3-6 C in cycloalkyl 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentylA group or cyclohexyl, preferably cyclopropyl;
and/or R 3 Is C 1-6 Alkyl or C 3-6 Cycloalkyl group, the C 1-6 Alkyl and C 3-6 Cycloalkyl groups are each optionally substituted with 1 or more R 31 Substitution;
and/or each R 31 Wherein the halogen is F, cl, br or I;
and/or in ring C, the 5-10 membered heteroaryl is a 5-or 6-membered heteroaryl, the heteroatom is N, the number is 1 or 2, preferably pyridinyl;
the pyridyl group is preferablyThe pyrimidinyl radical is preferably +.>
And/or, in ring A and ring B, the C 3-12 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
and/or in ring A and ring B, the 3-12 membered heterocycloalkyl is 4-12 membered heterocycloalkyl, preferably 4-, 5-, 6-or 7-membered monocyclic or bicyclic spiro-heterocycloalkyl, the heteroatom is N, the number is 1 or 2, more preferably azetidinyl, piperidinyl, piperazinyl or 2-azaspiro [3.3] heptanyl.
3. The compound of claim 1, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein the number of heteroatoms or groups of heteroatoms is 1, 2, 3 or 4;
and/or R 1 Is C 1-6 Alkyl, -O-C 1-6 Alkyl or C 3-6 Cycloalkyl group, the C 1-6 Alkyl, -O-C 1-6 Alkyl and C 3-6 Cycloalkyl optionally substituted with one or more R 11 Substitution;
and/or substituent R 11 Is 1, 2, 3 or 4;
and/or each R 11 Independently halogen, OH or CN, preferably OH;
and/or R 2 Is H;
and/or R 3 Is halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, preferably C 1-6 Alkyl or C 3-6 Cycloalkyl; the C is 1-6 Alkyl and C 3-6 Cycloalkyl groups are each optionally substituted with 1 or more R 31 Instead of the above-mentioned,
and/or substituent R 31 Is 1, 2, 3 or 4;
and/or each R 31 Independently H, halogen, OH, CN or C substituted with 1, 2 or 3 halogens 1-6 An alkyl group; preferably H, halogen, OH or CN;
and/or each R 22 Independently H or C 1-6 An alkyl group;
and/or each R b Independently halogen, = O, OH or NH 2 ;
And/or, ring A and ring B are each independently absent, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl, said C 3-12 Cycloalkyl and 3-12 membered heterocycloalkyl are each optionally substituted with one or more R a Substitution;
and/or substituent R a Is 1, 2, 3 or 4;
and/or each R a Independently = O, F, cl, br, OH or NH 2 ;
And/or L 1 、L 2 And L 3 Are each independently a single bond, -O-, -N (R) 22 )-、-S(O)-、-S(O) 2 -、-S(O) 2 -N(R 22 )-、-(CH 2 ) m -、-C 2 H 2 -、-(CH 2 ) m -C 2 H 2 -、-O-(CH 2 ) m -C 2 H 2 -、-(CH 2 ) n -O-、-(CH 2 ) n -N(R 22 )-、-(CH 2 ) n -S(O)-、-(CH 2 ) n -S(O) 2 -、-(CH 2 ) n -S(O) 2 -N(R 22 )-、-S(O) 2 -N(R 22 )-(CH 2 ) n -、-(CH 2 ) n -O-(CH 2 ) n -、-(CH 2 ) n -N(R 22 )-(CH 2 ) n -、-(CH 2 ) n -S(O)-(CH 2 ) n -、-(CH 2 ) n -S(O) 2 -(CH 2 ) n -、-(CH 2 ) n -S(O) 2 -N(R 22 )-(CH 2 ) n -、-O-(CH 2 ) n -O-、-O-(CH 2 ) n -N(R 22 ) -; wherein each m, n is independently 1, 2, 3 or 4.
4. A compound according to claim 3, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein R 1 Is C 1-3 Alkyl, cyclopropyl or-O-C 1-3 Alkyl, preferablyCyclopropyl or methoxy, more preferably +.>Or cyclopropyl, most preferably cyclopropyl, said C 1-3 Alkyl,/->And cyclopropyl is each optionally substituted with one or more R 11 Substitution;
and/or R 3 is-CH 3 Or cyclopropyl, preferably cyclopropyl, said-CH 3 And cyclopropyl is each optionally substituted with one or more R 31 Instead of the above-mentioned,
and/or each R 31 H, F, cl, br, OH or CN independently;
and/or each R 22 Independently H or CH;
and/or, ring A and ring B are each independently absent, azetidinyl, cyclohexyl,piperidinyl, piperazinyl or 2-azaspiro [3.3 ]]Heptyl, said cyclohexyl, piperidinyl, piperazinyl and 2-azaspiro [3.3 ]]The heptyl groups are each optionally substituted with one or more R a Substitution;
and/or L 1 Is a single bond, -CH 2 -、
And/or L 2 Is a single bond, -CH 2 -、
And/or L 3 Is a single bond, -CH 2 -、
5. The compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 4, wherein R 1 Is thatOr methoxy; preferably +.>
And/or R 3 F, cl, -CF 3 、 Preferably CF 3 ;
And/or ring A is absent,
And/or ring B is absent,
6. The compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1,is->
And/or the number of the groups of groups,is->
Preferably:wherein L is 1 Is a single bond or-C 1-6 alkyl-S (O) 2 -; ring A is optionally substituted with 1, 2, or 3R a Substituted 4-8 membered heterocycloalkyl; l (L) 2 is-C 1-6 Alkyl-, -C 1-6 alkyl-O-C 1-6 alkyl-or-C 1-6 alkyl-S (O) 2 -;L 3 is-O-C 1-6 alkyl-N (R) 22 )-、-O-C 1-6 alkyl-O-or-C 2-6 Alkynyl-;
wherein ring A and ring B are each independently C 3-6 Cycloalkyl or 4-8 membered heterocycloalkyl, said C 3-6 Cycloalkyl and 4-8 membered heterocycloalkyl are each independently optionally substituted with 1, 2, or 3R a Substitution; l (L) 2 Is a single bond, -C 1-6 alkyl-or-C 1-6 alkyl-N (R) 22 )-;L 3 Is a single bond, -C 1-6 alkyl-O-, -C 1-6 alkyl-N (R) 22 ) -or-C 2-6 Alkynyl-;
wherein L is 1 is-C 1-6 alkyl-S (O) 2 -、-C 1-6 alkyl-S (O) 2 -N(R 22 ) -or-C 1-6 alkyl-N (R) 22 )-;L 2 is-C 1-6 alkyl-or-C 1-6 alkyl-O-C 1-6 Alkyl-; l (L) 3 is-O-or-O-C 1-6 alkyl-O-;
more preferably, the process is carried out,is->
And/or the number of the groups of groups,is->
Preferably, R 3 Is halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl group, the C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally substituted with 1, 2 or 3R groups, respectively 31 Substituted, each R 31 Independently halogen or C substituted by 1, 2 or 3 halogen 1-6 An alkyl group.
7. A compound according to any one of claims 1-6, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, characterized in that it is any one of the following schemes:
scheme 1:
the compound shown in the formula (I), a tautomer thereof, a stereoisomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof,
wherein,
E 1 is-CH 2 -or-C (=o) -;
R 1 is cyclopropyl, optionally substituted with 1 or more R 11 Substitution;
R 2 is H or C 1-6 An alkyl group;
R 3 is H, halogen, CN, C 1-6 Alkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl and 5-10 membered heteroaryl are each optionally substituted with 1 or more R 31 Substitution;
is->
Ring A and ring B are each independently absent, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 A membered aryl or 5-10 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 The membered aryl and the 5-10 membered heteroaryl are each optionally substituted with 1 or more R a Substitution;
L 1 、L 2 and L 3 Are each independently a single bond, -O-, -N (R) 22 )-、-P(O)-、-P(O)O-、-S-、-S(O)-、-S(O) 2 -、-S(O) 2 -N(R 22 )-、C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 1-12 Heteroalkyl wherein, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl and C 1-12 Heteroalkyl groups are each optionally substituted with 1 or more R b Substitution;
ring C is C 6-10 Aryl or 5-10 membered heteroaryl;
the "4-12 membered heterocycloalkyl", 5-10 membered heteroaryl and "C 1-12 "hetero" of a heteroalkyl "is a heteroatom or heteroatom group; the number of the hetero atoms or hetero atom groups is 1 or more, and each hetero atom or hetero atom group is N, -O-, -N (R) 22 )-、-P(O)-、-P(O)O-、-S-、-S(O)-、-S(O) 2 -or-S (O) 2 -N(R 22 )-;
Each R is 11 H, C independently 1-6 Alkyl, halogen, OH or CN;
each R is 31 H, C independently 1-6 Alkyl, halogen, OH, NH 2 Or CN;
each R is 22 Independently H or C 1-6 An alkyl group;
each R is a Independently is halogen, =o, OH, NH 2 Or C 1-6 An alkyl group;
each R is b Independently H, =o, halogen, OH, NH 2 Or C 1-6 An alkyl group;
r is 1, 2, 3 or 4;
scheme 2:
the compound is a compound shown in a formula (II) or (III), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof,
wherein R is 1 Andis as defined in any one of claims 1 to 6;
preferably, in formula (II) or (III), R 1 Is C 1-6 Alkyl, said C 1-6 Alkyl is optionally substituted with 1 or 2 or 3R 11 Substitution; more preferably, R 1 Is C 1-6 Alkyl, said C 1-6 Alkyl is optionally substituted with 1 or 2 or 3R 11 Substituted, R 11 OH;
scheme 3:
the compound shown in the formula (I) is a compound shown in the formula (IV):
R 3 is C 3-6 Cycloalkyl group, the C 3-6 Cycloalkyl is optionally substituted with 1 or 2R 31 Substitution; each R is 31 Independently C substituted with 1, 2 or 3 halogens 1-6 An alkyl group;
ring a and ring B are each independently 4-8 membered heterocycloalkyl; l (L) 2 is-C 1-6 An alkyl group; l (L) 1 And L 3 Is a single bond;
scheme 4:
in the formula (I) of the present invention,
E 1 is-C (=o) -;
R 1 is C 1-6 Alkyl, -O-C 1-6 Alkyl or C 3-6 Cycloalkyl group, the C 1-6 Alkyl, said-O-C 1-6 Alkyl and said C 3-6 Cycloalkyl groups are optionally substituted with 1, 2 or 3R groups, respectively 11 Substitution;
R 2 is H;
R 3 is halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl group, the C 1-6 Alkyl and said C 3-6 Cycloalkyl groups are each optionally substituted with 1 or more R 31 Substitution;
is->
Wherein L is 1 Is a single bond or-C 1-6 alkyl-S (O) 2 -; ring A is optionally substituted with 1, 2, or 3R a Substituted 4-8 membered heterocycloalkyl; l (L) 2 is-C 1-6 Alkyl-, -C 1-6 alkyl-O-C 1-6 alkyl-or-SO) 2 -;L 3 is-O-, -N (R) 22 )-、-O-C 1-6 alkyl-O-, -C 1-6 alkyl-O-C 1-6 alkyl-O-or-C 2-6 Alkynyl-;
wherein ring A and ring B are each independently C 3-6 Cycloalkyl or 4-8 membered heterocycloalkyl, said C 3-6 Cycloalkyl and 4-8 membered heterocycloalkyl are each independently optionally substituted with 1, 2, or 3R a Substitution; l (L) 2 Is a single bond, -C 1-6 alkyl-or-C 1-6 alkyl-N (R) 22 )-;L 3 Is a single bond, -C 1-6 alkyl-O-, -C 1-6 alkyl-N (R) 22 ) -or-C 2-6 Alkynyl-;
wherein L is 1 is-C 1-6 alkyl-S (O) 2 -、-C 1-6 alkyl-S (O) 2 -N(R 22 ) -or-C 1-6 alkyl-N (R) 22 )-;L 2 is-C 1-6 alkyl-or-C 1-6 alkyl-O-C 1-6 Alkyl-; l (L) 1 is-O-or-O-C 1-6 alkyl-O-;
ring C is a 5-10 membered heteroaryl;
each R is 11 Independently halogen;
each R is 31 Is defined as case 1 or case 2:
case 1; each R is 31 Independently halogen;
case 2: each R is 31 Independently C substituted with 1, 2 or 3 halogens 1-6 An alkyl group;
each R is 22 Independently H or C 1-6 An alkyl group;
r is 1 or 2, 3 or 4.
8. The compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein the compound has the structure, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:
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9. a pharmaceutical composition, characterized in that it comprises a therapeutically effective dose of a compound according to any one of claims 1-8, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient.
10. Use of a compound according to any one of claims 1-8, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 9, for the preparation of a medicament for the treatment or prophylaxis of a disease associated with IRAK 4;
the medicament is preferably for use in the treatment or prophylaxis of cancer, neurodegenerative disorders, viral diseases, autoimmune diseases, inflammatory diseases, genetic disorders, hormone-related diseases, metabolic disorders, diseases associated with organ transplantation, immunodeficiency disorders, destructive bone diseases, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular disorders or CNS disorder diseases;
the medicament is preferably useful for the treatment or prophylaxis of brain, kidney, liver, adrenal, bladder, breast, stomach, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervical, testis, genitourinary tract, esophagus, larynx, skin, bone, thyroid, sarcoma, neuroblastoma, multiple myeloma, gastrointestinal, neck or head tumor, hyperproliferation of the epidermis, psoriasis, prostatic hyperplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, hodgkin and non-hodgkin's, breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, abcdlbcl, hodgkin's lymphoma, primary skin T cell lymphoma chronic lymphocytic leukemia, smoky indolent multiple myeloma, leukemia, diffuse large B-cell lymphoma DLBCL, chronic lymphocytic leukemia CLL, chronic lymphocytic lymphoma, primary exudative lymphoma, burkitt's lymphoma leukemia, acute lymphocytic leukemia, B-cell pre-lymphocytic leukemia, lymphoplasmacytic lymphoma, waldenstein's macroglobulinemia spleen edge zone lymphoma, multiple myeloma, or plasmacytoma or intravascular large B-cell lymphoma, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, huntington's disease, cerebral ischemia or traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, diabetes treatment, metabolic syndrome, obesity, neurodegenerative diseases caused by organ transplantation or graft-versus-host disease, ocular diseases such as ocular allergy, conjunctivitis, dry eye or vernal conjunctivitis, diseases affecting the nose, including allergic rhinitis; an autoimmune blood disorder is described as a condition, such as hemolytic anemia, aplastic anemia, pure erythrocyte anemia and idiopathic thrombocytopenia, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, dermatomyositis, chronic active hepatitis, myasthenia gravis, stefan-Johnson syndrome, idiopathic sprue, font-type immunoinflammatory bowel disease, irritable bowel syndrome, celiac disease, dental root periostitis, chronic active hepatitis, crohn's disease, inflammatory bowel disease, and inflammatory bowel disease pulmonary clear membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine eye disease, gray Lei Fushi disease, sarcoidosis, dry eye, vernal conjunctivitis, interstitial pulmonary fibrosis, psoriasis arthritis, systemic juvenile idiopathic arthritis, nephritis, vasculitis, interstitial cystitis, diverticulitis, glomerulonephritis, chronic granulomatous disease, endometriosis, leptospirosis nephropathy, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle atrophy, catabolism, obesity, slow fetal growth, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrosis ectodermal dysplasia, behcet's disease, pigmentary incontinence, paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, anaphylaxis, systemic allergic reactions, sinusitis, ocular allergies, silica-induced diseases, COPD, lung disease, cystic fibrosis, acid-induced lung injury, pulmonary arterial hypertension, polyneuropathy, cataract, muscle inflammation in combination with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, addison's disease, lichen planus, type 1 diabetes, type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, cystitis, dacryocystitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epiankle, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, henno-Xu Lanzi maculosis, hepatitis, suppurative sweat gland inflammation, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, liver fibrosis, renal fibrosis, alcoholic fatty liver, nonalcoholic fatty liver, heart fibrosis, psoriasis, inflammation of the heart Crohn's disease, inflammatory bowel disease, oophoritis, orchitis, osteomyelitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, regional pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, arthritic, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, sclerosing disease, white spot disease, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, leaf-type pemphigus, paraneoplastic pemphigus, acquired bullous epidermolysis, acute and chronic gout, chronic arthritis, psoriasis, rheumatoid arthritis, juvenile rheumatoid arthritis, gouty arthritis, cryptothermal proteins are associated with their syndromes or osteoarthritis disorders.
11. A compound of formula II-1 or II-2:
wherein R is 4 And R is 5 Independently H or-Boc; r is R 1 、R 2 、R 3 、L 1 、L 2 Definition of r, ring A and Ring BAll as claimed in any one of claims 1 to 8;
the compound shown in the formula II-1 is preferably
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The compound shown in the formula II-2 is preferably />
Applications Claiming Priority (2)
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