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HK1186732B - 2-arylimidazo[1,2-b]pyridazine,2-phenylimidazo[1,2-a]pyridine, and 2-phenylimidazo[1,2-a]pyrazine derivatives - Google Patents

2-arylimidazo[1,2-b]pyridazine,2-phenylimidazo[1,2-a]pyridine, and 2-phenylimidazo[1,2-a]pyrazine derivatives Download PDF

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HK1186732B
HK1186732B HK13114185.1A HK13114185A HK1186732B HK 1186732 B HK1186732 B HK 1186732B HK 13114185 A HK13114185 A HK 13114185A HK 1186732 B HK1186732 B HK 1186732B
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Hong Kong
Prior art keywords
pyridazin
imidazo
trifluoromethyl
phenyl
alkyl
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HK13114185.1A
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Chinese (zh)
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HK1186732A1 (en
Inventor
罗伯特．N．阿特金森
安迪．J．奥门
詹姆士．M．斐尔
肯尼司．H．黄
艾蜜莉．D．史密斯
Original Assignee
江苏恒瑞医药股份有限公司
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Priority claimed from PCT/US2011/066837 external-priority patent/WO2012088411A1/en
Publication of HK1186732A1 publication Critical patent/HK1186732A1/en
Publication of HK1186732B publication Critical patent/HK1186732B/en

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Description

2-arylimidazo [1,2-b ] pyridazine, 2-phenylimidazo [1, 2-a ] pyridine, and 2-phenylimidazo [1, 2-a ] pyrazine derivatives
Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims benefit of united states provisional applications having application numbers 61/426, 216, 61/514, 833, and 61/523, 688, filed 12, month 22, 2010, 2011, 8, month 15, each of which is incorporated herein by reference in its entirety.
Technical Field
The present invention relates to compounds, compositions and methods for treating various diseases. In particular, the present invention relates to compounds that antagonize the activity of Smoothened (no corresponding intermediate) proteins, thereby inhibiting the Hedgehog signaling pathway.
Introduction to related Art
The hedgehog (Hh) signaling pathway is an important regulatory pathway for cellular physiological processes. Hedgehog family members play a key role in the developmental processes, cell differentiation and proliferation of vertebrates and invertebrates. Three vertebrate hedgehog genes are known, including sonic hedgehog (Shh), indian hedgehog (Ihh) and desert hedgehog (Dhh). Their translated gene products become secreted proteins through the post-translational modification of autoproteolytic, palmitoylation, and cholesterol attachment. Post-translational modifications control the spatial and temporal distribution of the Hh protein, allowing the protein to function as a morphogen in part. The induction of Hh proteins occurs in embryonic and adult cells, plays a role in regulating morphogenetic patterns, and causes cell differentiation.
The hedgehog signaling pathway involves three Hh ligands (Dhh, Shh or Ihh), twelve transmembrane proteins Patched (no corresponding intermediate) (PTCH1), 7 transmembrane proteins smoothened (smo), and the Gli transcription factor family, among other regulatory proteins. Since the activity of Smoothened is inhibited by the interaction of Patched proteins and Smoothened, Hh signaling pathways are typically in an inactive state without binding to Hh ligands. Binding of Hh ligand to Patched disrupts the interaction of Patched and Smoothened, resulting in Smoothened activation and translocation to the cell membrane. In mammalian systems, Smoothened and other downstream pathway members localize to non-moving cilia as part of the signaling activation process. Activation of Smoothened in turn leads to a series of events that cause the translocation of Gli transcription factors (Gli 1 and Gli2 in particular) into the nucleus where they activate transcription of their target genes. Target genes for Gli transcription factors include Wnts, TGF β, c-Myc, cyclins, and Patched and Gli themselves.
The Hh signaling pathway is tightly regulated under normal conditions and plays an important role in the proper processes of cell proliferation, cell differentiation, and embryonic pattern formation. However, under abnormal conditions, the hedgehog signaling pathway may become abnormal and cause disease. For example, Patched loss-of-function mutations are found in people with Guillain-syndrome, a hereditary syndrome with a high risk of brain and skin cancer. Mutations in Smoothened or Gli protein function are commonly found in glioblastoma and basal cell carcinoma (the most common skin cancer in the united states). Aberrant activation of Hh signaling is also associated with prostate cancer metastasis. Aberrant expression of Patched, Smoothened, sonic hedgehog was also observed in human pancreatic tumors. Importantly, even if the members of the Hh signaling pathway are not directly involved in cancer mutations, activation of the pathway still plays a critical role in the process of tumor cell proliferation; tumor cells establish an active autocrine loop by which they make and respond to Hh ligands to promote tumor cell proliferation.
The effect of cyclopamine on mouse graft tumor models further confirms the role of aberrant Hh signaling pathways in tumors. Cyclopamine, an alkaloid derived from a natural product, was found to be an antagonist of the hedgehog signaling pathway. Cyclopamine slows tumor growth progression or inhibits tumor metastasis in a variety of models of transplantable tumors.
Thus, aberrant hedgehog signaling may lead to or contribute to a range of diseases, including a variety of cancers. The role played by Hh signaling in disease may be due to loss-of-function mutations or gain-of-function mutations in pathway members or abnormal activation of pathways. While small molecule antagonists may inhibit or reverse the effects of aberrant hedgehog signaling. Thus, molecules that antagonize the hedgehog signaling pathway (e.g., modulators of Smoothened activity) are urgently needed and clinically useful.
Brief description of the invention
The present invention provides compounds of formula (I) as shown below, pharmaceutical compositions comprising these compounds and methods of using these compounds or their compositions in the treatment of diseases and/or disorders, such as proliferative diseases and angiogenesis mediated diseases and the like.
In a broader embodiment (embodiment 1), the present invention provides compounds of formula (I):
(I)
and pharmaceutically acceptable salts thereof, wherein
R1Is that
R1-AWherein R is1-AIs hydrogen, halogen, -CN, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, -CO2H、-CO2(C1-C6Alkyl), -S (C)1-C6Alkyl), -SO (C)1-C6Alkyl), -SO2(C1-C6Alkyl), -CONH2、-CONH(C1-C6Alkyl), -CON (C)1-C6Alkyl radical)2、-NHCO(C1-C6Alkyl), -NHCO2(C1-C6Alkyl group), C3-C8Cycloalkyl, aryl, heteroaryl, heterocyclyl, (C)3-C8Cycloalkyl) C1-C6Alkyl, (aryl) C1-C6Alkyl, (heteroaryl) C1-C6Alkyl, (heterocyclyl) C1-C6Alkyl radical, C3-C8Cycloalkoxy, aryloxy, heteroaryloxy, (aryloxy) C1-C6Alkyl, (heteroaryloxy) C1-C6Alkyl, -OR9、-SR9or-NR9R11Wherein R is11Is hydrogen or unsubstituted C1-C6An alkyl group, a carboxyl group,
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group, in addition to the unsubstituted alkyl group, is optionally substituted with one or more R at a substitutable position8Substitution;
wherein R is8Is halogen, -CN, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-NH(C1-C6Alkyl) -OH, -NH (C)1-C6Alkyl group) - (C1-C6Alkoxy), -C1-C6alkoxy-OH, -C1-C6Alkoxy radical- (C1-C6Alkoxy group), C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Halogenoalkoxy, hydroxy (C)1-C6Alkyl group), (C)1-C6Alkoxy) C1-C6Alkyl, amino (C)1-C6Alkyl), -S (C)1-C6Alkyl), -CO2H、-CO2(C1-C6Alkyl), -C (O) (C)1-C6Alkyl), -SO2(C1-C6Alkyl), -SO2NH2、-SO2NH(C1-C6Alkyl), -SO2N(C1-C6Alkyl), -CON (H) OR80Wherein R is80Is hydrogen or a hydroxy protecting group, -CONH2、-CONH(C1-C6Alkyl), -CON (C)1-C6Alkyl radical)2、-NHCO(C1-C6Alkyl), -C (= NH) NH2、-C(=NH)NH-NH2、-C(=NOH)NH2or-NHCO2(C1-C6Alkyl), wherein each alkyl, alkenyl, alkynyl, alkoxy is optionally-CO on a substitutable carbon2(C1-C6) Alkyl OR-CON (H) OR80Substitution;
wherein R is9Is C3-C8Cycloalkyl radical, C3-C8cycloalkyl-C (O) -, aryl-C (O) -, heteroaryl-C (O) -, heterocyclyl-C (O) -, aryl-SO2-, heteroaryl-SO2-、(C3-C8Cycloalkyl) C1-C6Alkyl, (aryl) C1-C6Alkyl, (heteroaryl) C1-C6Alkyl, or (heterocyclyl) C1-C6Alkyl, wherein each cyclic moiety is optionally substituted with one or more halogen, -CN, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy, hydroxy C1-C6Alkyl, H2N(C1-C6Alkyl) -, C1-C6alkyl-NH- (C)1-C6Alkyl radical) -, di- (C)1-C6Alkyl) -N (C)1-C6Alkyl) -, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, -CO2(C1-C6) Alkyl OR-CON (H) OR80Wherein each alkyl, alkenyl, alkynyl, alkoxy is optionally substituted with one R92The substitution is carried out by the following steps,
wherein R is92is-COR94Wherein R is94Is (C)1-C6) Alkoxy, NHOR80or-NR7R96
Wherein R is96Is aryl or heteroaryl, each aryl or heteroaryl being optionally substituted by up to three halogens, -CN, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Halogenoalkoxy, hydroxy (C)1-C6Alkyl group), (C)1-C6Alkoxy) C1-C6Alkyl, amino (C)1-C6Alkyl), or-S (C)1-C6Alkyl) substitution; or
R1Is that
R1-BWherein R is1-BIs RW-Rz-RY-RX-, wherein
RXIs a bond, -O-, -N (R)7)-、-(C1-C3Alkyl) N (R)7) -, or-C (O) -;
wherein R is7Is hydrogen or optionally substituted by C1-C4Alkoxycarbonyl substituted C1-C8An alkyl group;
RYis C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl, each C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with R8Substitution;
rz is a bond, C1-C6Alkylene, -O-, -O (C)1-C4Alkylene) -, - (C)1-C4Alkylene) O-, -N (R)7)-、-(C1-C4Alkylene) N (R)7)-、-N(R7)(C1-C4Alkylene) -, -C (O) - (C)1-C4Alkylene) -, - (C)1-C4Alkylene group C (O) -, -N (R)7)C(O)-、-N(R7)C(O)O-、-C(O)N(R7)-、-C(O)N(R7)(C1-C4Alkylene) -, -N (R)7)C(O)N(R7)-、-OC(O)-、-C(O)O-、-C(O)O(C1-C4Alkylene) -, -OC (O) O-, -OC (O) N (R)7)-、-S(O)2-、-S(O)2(C1-C4Alkylene) -, -S (O)2N(R7)-、-OS(O)2N(R7)-、-N(R7)S(O)2-, or-OS (O)2O-；
RWIs C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl, each C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with R8Substitution;
R2is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C3-C8Cycloalkyl, aryl, heteroaryl, heterocycloalkyl, (C)3-C8Cycloalkyl) C1-C6Alkyl, (aryl) C1-C6Alkyl, (heteroaryl) C1-C6Alkyl, (heterocyclyl) C1-C6Alkyl, (aryloxy) C1-C6Alkyl, or (heteroaryloxy) C1-C6Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R at a substitutable position10Substitution;
wherein R is10Is halogen, -CN, -OH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Halogenoalkoxy, hydroxy (C)1-C6Alkyl group), (C)1-C6Alkoxy) C1-C6Alkyl, amino (C)1-C6Alkyl), -CO2H、-CO2(C1-C6Alkyl), -SO2(C1-C6Alkyl), -CONH2、-CONH(C1-C6Alkyl), -CON (C)1-C6Alkyl radical)2、CON(H)OR80、-NHCO(C1-C6Alkyl), or-NHCO2(C1-C6Alkyl), wherein each alkyl, alkenyl, alkynyl, alkoxy is optionally substituted on substitutable carbons by one R102The substitution is carried out by the following steps,
wherein R is102is-COR104Wherein R is104Is- (C)1-C6) Alkoxy, -NHOR80or-NR7R110、
Wherein R is110Is aryl or heteroaryl, each aryl or heteroaryl being optionally substituted by up to three halogens, -CN, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Halogenoalkoxy, hydroxy (C)1-C6Alkyl group), (C)1-C6Alkoxy) C1-C6Alkyl, amino (C)1-C6Alkyl), or-S (C)1-C6Alkyl) substitution;
R3is hydrogen, halogen, -CN, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C3-C8Cycloalkyl, aryl, heteroaryl, heterocyclyl, (aryl) C1-C6Alkyl, or (heteroaryl) C1-C6An alkyl group;
a is a bond, -O-, -N (R)7)-、-C(O)-、-N(R7)C(O)-、-N(R7)C(O)O-、-C(O)N(R7)-、-N(R7)C(O)N(R7)-、-OC(O)-、-C(O)O-、-OC(O)O-、-OC(O)N(R7)-、-S(O)2-、-S(O)2N(R7)-、-OS(O)2N(R7)-、-N(R7)S(O)2-, or-OS (O)2O-；
X is N or CR4；
R4Is hydrogen, halogen, -CN, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Halogenoalkoxy, hydroxy (C)1-C6Alkyl group), (C)1-C6Alkoxy) C1-C6Alkyl, amino (C)1-C6Alkyl group), C3-C8Cycloalkyl, aryl, heteroaryl, heterocyclyl, (aryl) C1-C6Alkyl, or (heteroaryl) C1-C6An alkyl group;
each Y is independently N or CR5Provided that only one Y is N;
each R5Independently hydrogen, halogen, -CN, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Halogenoalkoxy, hydroxy (C)1-C6Alkyl group), (C)1-C6Alkoxy) C1-C6Alkyl, amino (C)1-C6Alkyl group), C3-C8Cycloalkyl, aryl, heteroaryl, heterocyclyl, (aryl) C1-C6Alkyl, or (heteroaryl) C1-C6Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with one or more R at a substitutable position10Substitution;
each Z is independently N or CR6Provided that only one Z is N; and
each R6Independently hydrogen, halogen, -CN, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Halogenoalkoxy, hydroxy (C)1-C6Alkyl group), (C)1-C6Alkoxy) C1-C6Alkyl, amino (C)1-C6Alkyl group), C3-C8Cycloalkyl, aryl, heteroaryl, heterocyclyl, (aryl) C1-C6Alkyl, or (heteroaryl) C1-C6Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with one or more R at a substitutable position10And (4) substitution.
The invention also provides useful intermediate compounds for the synthesis of compounds of formula (I), wherein some of the intermediate compounds are also comprised in formula (I).
The invention also provides processes for preparing the compounds of the invention and intermediates used in these processes.
The invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, solvent, adjuvant or diluent.
The invention also provides a method of inhibiting hedgehog signaling in vitro and in vivo comprising administering a compound of formula (I).
The invention also provides a method of treating a disease or disorder comprising administering a compound of formula (I). Examples of diseases and disorders include proliferative diseases and angiogenesis-mediated diseases, such as cancer.
The invention further provides kits comprising a compound or a pharmaceutical composition thereof, said kit having instructions for use of said compound or composition.
The invention further provides compounds that can be administered alone or in combination with other drugs or therapies known to be effective in the treatment of disease to enhance the overall therapeutic effect in the treatment of the disease.
Brief Description of Drawings
Figure 1 shows the results of the compound in example 633 tested as an inhibitor of the expression of Gli1 as described in example 705.
Figure 2 shows the results of the compound in example 284 tested as an inhibitor of the expression of Gli1 as described in example 705.
Figure 3 shows the results of the compound of example 284 tested as a tumor growth inhibitor in a human prostate cancer cell PC-3 nude transplant tumor model as described in example 706.
Detailed Description
In another embodiment, embodiment 2, the present invention provides a compound of formula IA
I-A。
The compound of embodiment 3 is the following compound of embodiment 2, wherein:
each R5Independently hydrogen, halogen, -CN, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with one or more R at a substitutable position10Substitution;
wherein R is10Is halogen, -CN, -OH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, -CO2H、-CO2(C1-C6Alkyl), -SO2(C1-C6Alkyl), -CONH2、-CONH(C1-C6Alkyl), -CON (C)1-C6Alkyl radical)2、-CON(H)OH、-NHCO(C1-C6Alkyl), or-NHCO2(C1-C6Alkyl groups);
the compound of embodiment 4 is the following compound of embodiment 3 wherein:
each R5Independently hydrogen, halogen, -CN, -OH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C3-C8Cycloalkyl, or aryl, wherein each alkyl, cycloalkyl, or aryl group is optionally substituted with one or more R at a substitutable position10And (4) substitution.
The compound of embodiment 5 is the following compound of embodiment 4 wherein:
each R5Independently hydrogen, optionally substituted by one or more R10Substituted C1-C6Alkyl radical, C3-C8Cycloalkyl, or aryl.
The compound of embodiment 6 is the following compound of embodiments 2-5, having the general formula I-B:
I-B。
the compound of embodiment 7 is the following compound of embodiment 6: wherein R is5Is hydrogen, C optionally substituted in substitutable positions by one or more halogens1-C6Alkyl radical, C3-C8Cycloalkyl, or aryl.
The compound of embodiment 8 is the following compound of embodiment 7: wherein R is5Is hydrogen.
The compound of embodiment 9 is the following compound of embodiment 7: wherein R is5Is C1-C6An alkyl group.
The compound of embodiment 10 is the following compound of embodiment 9: wherein R is5Is methyl.
The compound of embodiment 11 is the following compound of embodiments 2-10: wherein each Z is CR6。
The compound of embodiment 12 is the following compound of embodiment 11: wherein each R6Independently hydrogen, halogen, -CN, -OH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy, or C1-C6A haloalkoxy group.
The compound of embodiment 13 is the following compound of embodiment 12: wherein each R6Independently is hydrogen, halogen, or C1-C6An alkyl group.
The compound of embodiment 14 is the following compound of embodiment 13: wherein each R6Independently hydrogen.
The compound of embodiment 15 is the following compound of embodiments 2-14: wherein R is3Is hydrogen, halogen, -CN, -OH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, or C3-C8A cycloalkyl group.
The compound of embodiment 16 is the following compound of embodiment 15: wherein R is3Is hydrogen, halogen, -CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, or C3-C8A cycloalkyl group.
The compound of embodiment 17 is the following compound of embodiment 16: wherein R is3Is C1-C6Alkyl radical, C1-C6Haloalkyl, or C1-C6A haloalkoxy group.
In embodiment 18The compounds of (a) are the following in embodiments 1-17: wherein R is3Is C1-C6Alkyl or C1-C6A haloalkyl group.
The compound of embodiment 19 is the following compound of embodiment 18: wherein R is3Is methyl or trifluoromethyl.
The compounds of embodiment 19-a include the following compounds of embodiments 2-26: wherein-A-R2Is C1-C6Alkoxy radical, C1-C6Alkylamido, mono-or di- (C)1-C6) Alkylamino, wherein the alkyl moiety of each is optionally substituted by C1-C6Alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, or N-hydroxyaminocarbonyl.
The compound of embodiment 20 is the following compound of embodiments 2-19: wherein A is a bond, -N (R)7)-、-N(R7)C(O)-、-C(O)N(R7) -, or-S (O)2N(R7)-。
The compound of embodiment 21 is the following compound of embodiment 20: wherein A is-N (R)7)C(O)-。
The compound of embodiment 22 is the following compound of embodiments 2-21: wherein R is2Is hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C8Cycloalkyl, aryl, heteroaryl, (C)3-C8Cycloalkyl) C1-C6Alkyl, (aryl) C1-C6Alkyl, (heteroaryl) C1-C6Alkyl, (aryloxy) C1-C6Alkyl, or (heteroaryloxy) C1-C6Alkyl, wherein each alkyl, cycloalkyl, aryl, or heteroaryl group is optionally substituted with one or more R10And (4) substitution.
The compound of embodiment 23 is the following compound of embodiment 22: wherein R is2Is C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C8Cycloalkyl, aryl, heteroaryl, (C)3-C8Cycloalkyl) C1-C6Alkyl, (aryl) C1-C6Alkyl, or (aryloxy) C1-C6Alkyl, wherein each alkyl, cycloalkyl, or aryl group is optionally substituted with one or more R at substitutable positions10And (4) substitution.
The compound of embodiment 24 is the following compound of embodiment 23: wherein R is2Is C1-C6Alkyl or C1-C6A haloalkyl group.
The compound of embodiment 25 is the following compound of embodiment 24: wherein R is2Is C1-C6An alkyl group.
The compound of embodiment 26 is the following compound of embodiment 25: wherein R is2Is a tert-butyl group.
The compound of embodiment 27 is the following compound of embodiments 2-26: wherein-A-R2is-N (R)7)C(O)(C1-C6Alkyl groups).
The compound of embodiment 28 is the following of embodiments 2-26A compound: wherein-A-R2is-NHC (O) (tert-butyl).
The compound of embodiment 29 is the following compound of embodiments 2-28: wherein R is1Is R1-A。
The compound of embodiment 30 is the following compound of embodiment 29: wherein R is1-AIs hydrogen, halogen, -CN, -OH, -SH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, -CO2H、-CO2(C1-C6Alkyl), -S (C)1-C6Alkyl), -SO (C)1-C6Alkyl), -SO2(C1-C6Alkyl), -CONH2、-CONH(C1-C6Alkyl), -CON (C)1-C6Alkyl radical)2、C3-C8Cycloalkyl, aryl, heteroaryl, heterocyclyl, (C)3-C8Cycloalkyl) C1-C6Alkyl, (aryl) C1-C6Alkyl, (heteroaryl) C1-C6Alkyl, (heterocyclyl) C1-C6Alkyl, -OR9、-SR9or-NHR9Wherein each alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with one or more R8And (4) substitution.
The compound of embodiment 31 is the following compound of embodiment 30: wherein R is1-AIs hydrogen, halogen, -CN, -NH (C)1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C1-C6Alkoxy, -S (C)1-C6Alkyl), -SO (C)1-C6Alkyl), -SO2(C1-C6Alkyl), -CONH2、C3-C8Cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR9or-NHR9Wherein each alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with one or more R8Substitution;
wherein R is8Is halogen, -CN, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Halogenoalkoxy, hydroxy (C)1-C6Alkyl group), (C)1-C6Alkoxy) C1-C6Alkyl, amino (C)1-C6Alkyl), -S (C)1-C6Alkyl), -CO2H、-CO2(C1-C6Alkyl), -C (O) (C)1-C6Alkyl), -SO2(C1-C6Alkyl), -CONH2、-CONH(C1-C6Alkyl), -CON (C)1-C6Alkyl radical)2、-NHCO(C1-C6Alkyl), -C (= NH) NH2、-C(=NOH)NH2or-NHCO2(C1-C6Alkyl), wherein each alkyl, alkenyl, alkynyl, alkoxy is optionally-CO on a substitutable carbon2(C1-C6) Alkyl or-CON (H) OH.
The compound of embodiment 32 is the following compound of embodiment 31: wherein R is1-AIs hydrogen, halogen, -CN, -NH (C)1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C1-C6Alkoxy, -S (C)1-C6Alkyl), -SO (C)1-C6Alkyl), -SO2(C1-C6Alkyl), -CONH2、C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with one or more R at a substitutable position8And (4) substitution.
The compound of embodiment 33 is the following compound of embodiment 32: wherein R is1-AIs hydrogen, halogen, -CN, -NH (C)1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C1-C6Alkoxy, -S (C)1-C6Alkyl), -SO (C)1-C6Alkyl), -SO2(C1-C6Alkyl), or-CONH2Wherein each alkyl group is optionally substituted with one or more R8And (4) substitution.
The compound of embodiment 34 is the following compound of embodiment 33: wherein R is1-AIs hydrogen, halogen, -NH (C)1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C1-C6Alkoxy, -S (C)1-C6Alkyl), -SO (C)1-C6Alkyl), or-SO2(C1-C6Alkyl) wherein each alkyl group is optionally substituted with one or more R8And (4) substitution.
The compound of embodiment 35 is the following compound of embodiment 34: wherein R is1-Ais-NH (C)1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical、C1-C6Alkoxy, -S (C)1-C6Alkyl), or-SO2(C1-C6Alkyl) wherein each alkyl group is optionally substituted with one or more R8And (4) substitution.
The compound of embodiment 36 is the following compound of embodiment 34: wherein R is1-AIs hydrogen, halogen, C1-C6Alkyl, or C1-C6Alkoxy, wherein each alkyl group is optionally substituted with one or more R8Substitution;
wherein R is8Is halogen, -CN, -OH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Alkoxy, -C (= NH) NH2、-C(=NOH)NH2Or C1-C6A haloalkoxy group.
The compound of embodiment 37 is the following compound of embodiment 36: wherein R is1-AIs optionally substituted by one or more R8Substituted C1-C6An alkoxy group.
The compound of embodiment 38 is the following compound of embodiment 36: wherein R is1-AIs a halogen.
The compound of embodiment 39 is the following compound of embodiment 32: wherein R is1-AIs C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with one or more R at a substitutable position8And (4) substitution.
The compounds of embodiment 39-a include the following compounds of embodiment 39: wherein R is1-AIs substituted by one or two R8Substituted piperidinyl, wherein one R is8Is cyano, halogen, -SO2NH2、-CONH2、-C(=NOH)NH2、-C(=NH)NH2、C1-C3Alkoxycarbonyl substituted C of2-C4Alkenyl, or C1-C6A haloalkyl group of (a).
The compounds of embodiment 39-B include the following compounds of embodiment 39: wherein R is1-AIs substituted by one or two R8Substituted piperidinyl, wherein one R is8Is cyano, halogen, -SO2NH2、-CONH2、-C(=NOH)NH2、-C(=NH)NH2、C1-C3Alkoxycarbonyl or N-hydroxyaminocarbonyl substituted C2-C4Alkenyl, or trifluoromethyl.
The compound of embodiment 40 is the following compound of embodiment 39: wherein R is1-AIs aryl or heteroaryl, wherein each aryl or heteroaryl group is optionally substituted by one or more R8And (4) substitution.
The compound of embodiment 41 is the following compound of embodiment 40: wherein R is1-AIs optionally substituted by one or more R8A substituted aryl group;
wherein R is8Is halogen, -CN, -OH, -SO2NH2、-CO2H、-CONH2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-C(=NOH)NH2、-C(=NH)NH2、C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C3Alkoxycarbonyl substituted C2-C4Alkenyl, or C1-C6A haloalkoxy group.
The compound of embodiment 42 is the following compound of embodiment 40: wherein R is1-AIs optionally substituted by one or more R8Substituted heteroaryl;
wherein R is8Is halogen, -CN, -OH, -SO2NH2、-CO2H、-CONH2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-C(=NOH)NH2、-C(=NH)NH2、C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C3Alkoxycarbonyl or N-hydroxyaminocarbonyl substituted C2-C4Alkenyl, or C1-C6A haloalkoxy group.
The compounds of embodiment 42-a include the following compounds of embodiment 40: wherein R is1-AIs phenyl or pyridyl, wherein each phenyl and pyridyl is substituted by one or two R8Is substituted in which one R is8Is C1-C6Alkoxy radical, C1-C6Alkylamido, or mono-or di- (C)1-C6) Alkylamido, and wherein the alkyl moiety of each is optionally substituted by C1-C6Alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl or N-hydroxyaminocarbonyl.
The compounds of embodiment 42-B include the following compounds of embodiment 40: wherein R is1-AIs one or two R8Substituted phenyl, in which one R is8Is cyano, halogen, -SO2NH2、-CONH2、-C(=NOH)NH2、-C(=NH)NH2、C1-C3Alkoxycarbonyl or N-hydroxyaminocarbonyl substituted C2-C4Alkenyl, or C1-C2A haloalkyl group of (a).
The compounds of embodiment 42-C include the following compounds of embodiment 40: wherein R is1-AIs one or two R8Substituted pyridyl wherein one R is8Is cyano, halogen, -SO2NH2、-CONH2、-C(=NOH)NH2、-C(=NH)NH2、C1-C3Alkoxycarbonyl or N-hydroxyaminocarbonyl substituted C2-C4Alkenyl, or C1-C2A haloalkyl group of (a). The compounds of embodiment 42-D include the following compounds of embodiment 40: wherein R is1-AIs phenyl or pyridyl, wherein each phenyl and pyridyl is substituted by one or two R8In which one R is substituted8Is C1-C3Alkoxy radical, C1-C3Alkylamido, or mono-or di- (C)1-C3) Alkylamido, and wherein the alkyl moiety of each is optionally substituted by C1-C3Alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl or N-hydroxyaminocarbonyl.
The compound of embodiment 43 is the following compound of embodiments 2-26: wherein R is1-Ais-OR9or-NHR9；
Wherein R is9Is C3-C8Cycloalkyl, aryl, heteroaryl, heterocyclyl, (C)3-C8Cycloalkyl) C1-C6Alkyl, (aryl) C1-C6Alkyl, (heteroaryl) C1-C6Alkyl, or (heterocyclyl) C1-C6Alkyl, wherein each radical is optionally substituted in one or more halogen, -CN, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, -CO2(C1-C6) Alkyl or-CON (H) OH.
The compound of embodiment 44 is the following compound of embodiments 2-28: wherein R is1Is R1-B。
The compound of embodiment 45 is the following compound of embodiment 44: wherein R is1is-RX-RY-Rz-RWWherein
RXIs a bond-O-, -N (R)7) -, or-C (O) -;
wherein R is7Is hydrogen or C1-C6An alkyl group;
RYis C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein each C is3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with R8Substitution;
rz is a bond, C1-C6Alkylene, -O-, -O (C)1-C4Alkylene) -, - (C)1-C4Alkenyl) O-, -N (R)7)-、-(C1-C4Alkylene) N (R)7)-、-N(R7)(C1-C4Alkylene) -, -C (O) - (C)1-C4Alkylene) -, - (C)1-C4Alkylene group C (O) -, -N (R)7)C(O)-、-N(R7)C(O)O-、-C(O)N(R7) -, or-C (O) N (R)7)(C1-C4Alkylene) -; and
RWis C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl, each C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with R8And (4) substitution.
The compound of embodiment 46 is the following compound of embodiment 45: wherein R is1is-RX-RY-Rz-RWWherein
RXIs a bond, -O-, -N (R)7) -, or-C (O) -;
wherein R is7Is hydrogen or C1-C6An alkyl group;
RYis C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl, each C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with R8Substitution;
rz is a bond, C1-C6Alkylene, -C (O) - (C)1-C4Alkylene) -, or-C (O) N (R)7) -; and
RWis C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl, each C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with R8And (4) substitution.
The compound of embodiment 47 is the following compound of embodiment 45: wherein R is1is-RX-RY-Rz-RWWherein
RXIs a bond, -O-, -N (R)7) -, or-C (O) -;
wherein R is7Is hydrogen or C1-C6An alkyl group;
RYis aryl, heteroaryl, or heterocyclyl, each aryl, heteroaryl, or heterocyclyl optionally substituted with R8Substitution; rz is a bond, C1-C6Alkylene, -O-, -O (C)1-C4Alkylene) -, - (C)1-C4Alkylene) O-, -N (R)7)-、-(C1-C4Alkylene) N (R)7)-、-N(R7)(C1-C4Alkylene) -, -C (O) - (C)1-C4Alkylene) -, - (C)1-C4Alkylene group C (O) -, -N (R)7)C(O)-、-N(R7)C(O)O-、-C(O)N(R7) -, or-C (O) N (R)7)(C1-C4Alkylene) -; and
RWis C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl, each C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with R8And (4) substitution.
The compound of embodiment 48 is the following compound of embodiment 47: wherein R is1is-RX-RY-Rz-RWWherein
RXIs a bond, -O-, -N (R)7) -, or-C (O) -;
wherein R is7Is hydrogen or C1-C6An alkyl group;
RYis heteroaryl or heterocyclyl, each heteroaryl or heterocyclyl being optionally substituted by R8Substitution;
rz is a bond, C1-C6Alkylene, -O-, -O (C)1-C4Alkylene) -, - (C)1-C4Alkylene) O-, -N (R)7)-、-(C1-C4Alkylene) N (R)7)-、-N(R7)(C1-C4Alkylene) -, -C (O) - (C)1-C4Alkylene) -, - (C)1-C4Alkylene group C (O) -, -N (R)7) C (O) -, or-C (O) N (R)7)-；
RWIs C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl, each C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with R8And (4) substitution.
The compound of embodiment 49 is the following compound of embodiments 44-48: wherein R isYIs piperidinyl, piperazinyl, or pyridyl, each piperidinyl, piperazinyl, or pyridyl optionally substituted with R8And (4) substitution.
The compound of embodiment 50 is the following compound of any of embodiments 44-49: wherein R isWIs phenyl, piperidinyl, piperazinyl, morpholinyl, or pyridinyl, each of which is optionally substituted with R8And (4) substitution.
A compound of embodiment 51 is the following compound of any of embodiments 44-50: wherein-A-R2Is hydrogen.
Compounds of embodiment 52 the following compounds of any of embodiments 44-51: wherein R is3Is hydrogen or halogen.
The compound of embodiment 53 is the following compound of embodiment 52: wherein R is3Is hydrogen.
A compound of embodiment 54 is the compound of embodiment 1 wherein the compound has the formula shown in any one of I-C, I-D, or I-E:
I-CI-D
I-E。
the compound of embodiment 55 is the following compound of embodiment 54: wherein each R5Independently hydrogen, halogen, optionally substituted by one or more R10Substituted C1-C6Alkyl radical, C3-C8Cycloalkyl, or aryl;
wherein R is10Is halogen, -CN, -OH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, -CO2H、-CO2(C1-C6Alkyl), -SO2(C1-C6Alkyl), -CONH2、-CONH(C1-C6Alkyl), -CON (C)1-C6Alkyl radical)2、-CON(H)OH、-NHCO(C1-C6Alkyl), or-NHCO2(C1-C6Alkyl groups).
The compound of embodiment 56 is the following compound of embodiment 55: wherein each R5Independently is hydrogen, halogen, or C1-C6An alkyl group.
The compound of embodiment 57 is the following compound of embodiment 56: wherein each R5Independently hydrogen.
A compound of embodiment 58 is the following compound of any of embodiments 54-57: wherein R is4Is hydrogen, halogen, or C1-C6An alkyl group.
The compound of embodiment 59 is the following compound of embodiment 58: wherein R is4Is hydrogen.
The compound of embodiment 60 is the following compound of embodiments 54-59: wherein each Z is CR6。
The compound of embodiment 61 is the following compound of embodiment 60: wherein each R6Independently hydrogen, halogen, -CN, -OH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy, or C1-C6A haloalkoxy group.
The compound of embodiment 62 is the following compound of embodiment 61: wherein each R6Independently is hydrogen, halogen, or C1-C6An alkyl group.
The compound of embodiment 63 is the following compound of embodiment 62: wherein each R6Independently hydrogen.
The compound of embodiment 64 is the following compound of any of embodiments 54-63: wherein R is3Is hydrogen, halogen, -CN, -OH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, or C3-C8A cycloalkyl group.
The compound of embodiment 65 is the following compound of embodiment 64: wherein R is3Is hydrogen, halogen, -CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, or C3-C8A cycloalkyl group.
The compound of embodiment 66 is the following compound of embodiment 65: wherein R is3Is C1-C6Alkyl radical, C1-C6Haloalkyl, or C1-C6A haloalkoxy group.
The compound of embodiment 67 is the following compound of embodiment 66: wherein R is3Is C1-C6Alkyl or C1-C6A haloalkyl group.
The compound of embodiment 68 is the following compound of embodiment 67: wherein R is3Is methyl or trifluoromethyl.
A compound of embodiment 69 is any of embodiments 54-68The following compounds: wherein A is a bond, -N (R)7)-、-N(R7)C(O)-、-C(O)N(R7) -, or-S (O)2N(R7)-。
The compound of embodiment 70 is the following compound of embodiment 69: wherein A is-N (R)7)C(O)-。
The compound of embodiment 71 is the following compound of embodiments 54-70: wherein R is2Is C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C8Cycloalkyl, aryl, heteroaryl, (C)3-C8Cycloalkyl) C1-C6Alkyl, (aryl) C1-C6Alkyl, or (aryloxy) C1-C6Alkyl, wherein each alkyl, cycloalkyl, or aryl group is optionally substituted with one or more R at substitutable positions10And (4) substitution.
The compound of embodiment 71 is the following compound of embodiment 72: wherein R is2Is C1-C6Alkyl or C1-C6A haloalkyl group.
The compound of embodiment 73 is the following compound of embodiment 72: wherein R is2Is C1-C6An alkyl group.
The compound of embodiment 74 is the following compound of embodiment 73: wherein R is2Is a tert-butyl group.
The compound of embodiment 75 is the following compound of any of embodiments 54-74: wherein-A-R2is-N (R)7)C(O)(C1-C6Alkyl groups).
A compound of embodiment 76 is a compound of any of embodiments 54-74: wherein in the compound-A-R2is-NHC (O) (tert-butyl).
A compound of embodiment 77 is the following compound of any of embodiments 54-76: wherein R is1Is hydrogen, halogen, -NH (C)1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C1-C6Alkoxy, -S (C)1-C6Alkyl), or-SO2(C1-C6Alkyl) wherein each alkyl group is optionally substituted with one or more R8Substitution;
wherein R is8Is halogen, -CN, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Halogenoalkoxy, hydroxy (C)1-C6Alkyl group), (C)1-C6Alkoxy) C1-C6Alkyl, amino (C)1-C6Alkyl), -S (C)1-C6Alkyl), -CO2H、-CO2(C1-C6Alkyl), -C (O) (C)1-C6Alkyl), -SO2(C1-C6Alkyl), -CONH2、-CONH(C1-C6Alkyl), -CON (C)1-C6Alkyl radical)2、-CON(H)OH、-NHCO(C1-C6Alkyl), -C (= NH) NH2、-C(=NOH)NH2or-NHCO2(C1-C6Alkyl), wherein each alkyl, alkenyl, alkynyl, alkoxy is optionally-CO on a substitutable carbon2(C1-C6) Alkyl or-CONH (OH).
The compound of embodiment 78 is the following compound of any of embodiments 54-76: wherein R is1Is C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with one or more R at a substitutable position8Substitution;
wherein R is8Is halogen, -CN, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-NH(C1-C6Alkyl) -OH, -NH (C)1-C6Alkyl group) - (C1-C6Alkoxy), -C1-C6alkoxy-OH, -C1-C6Alkoxy radical- (C1-C6Alkoxy group), C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Halogenoalkoxy, hydroxy (C)1-C6Alkyl group), (C)1-C6Alkoxy) C1-C6Alkyl, amino (C)1-C6Alkyl), -S (C)1-C6Alkyl), -CO2H、-CO2(C1-C6Alkyl), -C (O) (C)1-C6Alkyl), -SO2(C1-C6Alkyl), -CONH2、-CONH(C1-C6Alkyl), -CON (C)1-C6Alkyl radical)2、-CON(H)OH、-NHCO(C1-C6Alkyl), -C (= NOH) NH2、-C(=NH)NH2or-NHCO2(C1-C6Alkyl) in which each alkyl, alkenyl, alkyneThe radicals, alkoxy being optionally substituted on carbon by-CO2(C1-C6) Alkyl or-CONH (OH).
The compound of embodiment 79 is the following compound of embodiment 78: wherein R is1Is aryl or heteroaryl, wherein each aryl or heteroaryl group is optionally substituted by one or more R8And (4) substitution.
The compound of embodiment 80 is the following compound of embodiment 79: wherein R is1Is aryl, optionally substituted by one or more R8Substitution;
wherein R is8Is halogen, -CN, -OH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Alkoxy, -C (= NOH) NH2、-C(=NH)NH2Or C1-C6A haloalkoxy group.
A compound of embodiment 81 is the following compound of any of embodiments 54-76: wherein R is1is-OR9or-NHR9；
Wherein R is9Is C3-C8Cycloalkyl, aryl, heteroaryl, heterocyclyl, (C)3-C8Cycloalkyl) C1-C6Alkyl, (aryl) C1-C6Alkyl, (heteroaryl) C1-C6Alkyl, or (heterocyclyl) C1-C6Alkyl radical, each of which is C3-C8Cycloalkyl, aryl, heteroaryl, heterocyclyl, (C)3-C8Cycloalkyl) C1-C6Alkyl, (aryl) C1-C6Alkyl, (heteroaryl) C1-C6Alkyl, or (heterocyclyl) C1-C6Alkyl is optionally substituted by one or more halogens, -CN, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, -CO2(C1-C6) Alkyl or-CONH (OH).
A compound of embodiment 82 is a compound of any of embodiments 54-76: wherein R is1is-RX-RY-Rz-RWWherein
RXIs a bond, -O-, -N (R)7) -, or-C (O) -;
wherein R is7Is hydrogen or C1-C6An alkyl group;
RYis C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl, each C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with R8Substitution;
rz is a bond, C1-C6Alkylene, -O-, -O (C)1-C4Alkylene) -, - (C)1-C4Alkylene) O-, -N (R)7)-、-(C1-C4Alkylene) N (R)7)-、-N(R7)(C1-C4Alkylene) -, -C (O) - (C)1-C4Alkylene) -, - (C)1-C4Alkylene group C (O) -, -N (R)7)C(O)-、-N(R7)C(O)O-、-C(O)N(R7) -, or
-C(O)N(R7)(C1-C4Alkylene) -; and
RWis C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl, each C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with R8And (4) substitution.
The compound of embodiment 83 is the following compound of embodiments 2-26: wherein R is1-AIs NR9R11Wherein
R9Is C3-C8cycloalkyl-C (O) -, aryl-C (O) -, heteroaryl-C (O) -, heterocycle-C (O) -, aryl-SO2-, or heteroaryl-SO2-, each of which is C3-C8cycloalkyl-C (O) -, aryl-C (O) -, heteroaryl-C (O) -, heterocycle-C (O) -, aryl-SO2-, or heteroaryl-SO2Optionally substituted by one or more halogens, -CN, -OH, -SH, -NO at substitutable positions2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Haloalkoxy, -CO2(C1-C6) Alkyl, -SO2NH2、-CONH2、-C(=NOH)NH2、-C(=NH)NH2Optionally C1-C3Alkoxycarbonyl substituted C2-C6Alkenyl, or-CON (H) OH.
The compound of embodiment 84 is the following compound of embodiments 2-26: wherein R is1-AIs NHR9Wherein
R9Is C5-C6heterocyclyl-C (O) -, pyridinoyl, benzoyl, phenylsulfonyl, where each C is5-C6heterocyclyl-C (O) -, pyridinoyl, benzoylThe radical, phenylsulfonyl, is optionally substituted by one or more halogens, -CN, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Haloalkoxy, -CO2(C1-C6) Alkyl, -SO2NH2、-CONH2、-C(=NOH)NH2、-C(=NH)NH2Optionally C1-C3Alkoxycarbonyl substituted C2-C6Alkenyl, or-CON (H) OH.
The compound of embodiment 85 is the following compound of embodiments 2-26: wherein R is1-AIs NHR9Wherein R is9Is benzoyl optionally substituted at a substitutable position with one or more groups selected from: halogen, -CN, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Haloalkoxy, -CO2(C1-C6) Alkyl, -SO2NH2、-CONH2、-C(=NOH)NH2、-C(=NH)NH2Optionally C1-C3Alkoxycarbonyl substituted C2-C6Alkenyl, or-CON (H) OH.
The compound of embodiment 86 is the following compound of embodiments 2-26: wherein R is1-AIs NHR9And R9Is benzoyl optionally substituted at a substitutable position with one or more groups selected from: halogen, -CN, -NH2、-NH(C1-C6Alkyl radical)、-N(C1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Haloalkoxy, -CO2(C1-C6) Alkyl, -SO2NH2、-CONH2、-C(=NOH)NH2、-C(=NH)NH2Optionally C1-C3Alkoxycarbonyl substituted C2-C6Alkenyl, or-CON (H) OH.
A compound of embodiment 87 is a compound of any of embodiments 39-43 or 83-86: wherein A is-CONH-and R2Is that
C1-C6Alkyl or
Optionally substituted by 1 or 2R10Substituted C1-C6An alkyl group;
wherein R is10Is halogen, -CN, -OH, -NO2、-NH2、-NH(C1-C3Alkyl), -N (C)1-C3Alkyl radical)2、C1-C3Alkyl radical, C2-C4Alkenyl radical, C2-C3Alkynyl, C1-C3Alkoxy radical, C1-C2Haloalkyl, C1-C3Alkoxy, hydroxy (C)1-C3Alkyl group), (C)1-C3Alkoxy) C1-C3Alkyl, amino (C)1-C3Alkyl), -CO2H、-CO2(C1-C3Alkyl), -SO2(C1-C3Alkyl), -CONH2、-CONH(C1-C3Alkyl), -CON (C)1-C3Alkyl radical)2、-CON(H)OH、-NHCO(C1-C3Alkyl), or-NHCO2(C1-C6Alkyl groups).
The invention also provides a pharmaceutical composition comprising a compound of any of embodiments 1-82 and a pharmaceutically acceptable carrier, solvent, adjuvant or diluent.
The invention also provides a method of inhibiting hedgehog pathway signaling in a sample comprising contacting one or more compounds according to any one of embodiments 1-82 with the sample. More specifically, the present invention provides a method of treating cancer comprising administering to a subject in need of such treatment an effective amount of one or more compounds according to any one of embodiments 1-82. Specific cancers include basal cell carcinoma, lung cancer, breast cancer, pancreatic cancer, and prostate cancer.
The invention also provides methods of inhibiting angiogenesis. The method comprises administering to a subject in need of such treatment an effective amount of one or more compounds according to any one of embodiments 1-82.
Therapeutic applications
The methods, compounds, pharmaceutical compositions of the present invention relate to inhibiting the activation of the hedgehog signaling pathway. Activation of this Hh signaling pathway may occur dependent on the Hh ligand or independent of the Hh ligand. The methods, compounds, and pharmaceutical compositions of the invention may be used in vitro or in vivo to modulate or inhibit cell proliferation and/or cell differentiation, examples of such uses being the inhibition of the growth of hyperproliferative cells, the inhibition of tissue formation from stem cells.
In certain embodiments, the compounds and pharmaceutical compositions described herein are capable of inhibiting aberrant or proliferative states resulting from a Patched loss-of-function phenotype, a Smoothened gain-of-function phenotype, a Gli gain-of-function phenotype, and an Hh ligand overexpression phenotype. In certain embodiments, the compounds and pharmaceutical compositions described herein are capable of inhibiting hedgehog signaling in normal or neoplastic cells or tissues that do not contain mutations that activate the hedgehog pathway.
One aspect of the invention relates to the use of the compounds or pharmaceutical compositions described herein to inhibit or attenuate the activity of the hedgehog signaling pathway in a sample in vitro or in vivo. The sample may take many forms. Examples of samples for use herein include, but are not limited to, hedgehog pathway members in recombinant cell systems, purified samples, partially purified samples, cultured cells, cell extracts, biopsy cells and extracts thereof, bodily fluids (e.g., blood, serum, urine, stool, saliva, semen, tears) and extracts thereof. For example, a method of the invention may involve contacting a Smoothened antagonist with a cell in vitro or in vivo.
In certain embodiments, the compounds and pharmaceutical compositions of the present invention are antagonists that inhibit activation of hedgehog signaling by binding to Smoothened. In certain embodiments, in addition to the inhibition of Smoothened, proteins in the hedgehog signaling pathway downstream of Smoothened (e.g., Gli) in cells can be inhibited, either in vivo or in vitro. For example, Gli protein synthesis, expression, regulatory status, steady state, location in the cell, and/or Gli protein activity may be inhibited.
Another embodiment of the invention is the administration of a compound or pharmaceutical composition described in the invention to a patient to treat the patient. The patient being treated may be diseased, exhibit a diseased state, or be at risk of developing a disease or disease recurrence. The treatment may result in the patient recovering (cure, remedy or heal). Alternatively, treatment of a patient can prevent, ameliorate, attenuate, alleviate or ameliorate a disease. Alternatively, treatment of a patient may affect or alter disease symptoms or predisposition to disease. The diseases that can be treated are those in which the progression of the disease is inhibited by inhibition of the hedgehog signaling pathway. For example, inhibition of the hedgehog signaling pathway can directly kill or inhibit diseased cells or tissues. Or inhibition of the hedgehog signaling pathway can result in stabilization of the protein, which in turn kills or inhibits the diseased cells or tissue. Alternatively, inhibition of the hedgehog signaling pathway may inhibit the function of other proteins to activate diseased cells or tissues.
Related diseases that may be treated by administering a compound or pharmaceutical composition described herein to a patient include, but are not limited to: proliferative diseases, especially cancer; skin diseases such as atopic dermatitis and psoriasis; bone overgrowth disorders such as acromegaly and megacephaly; and vascular proliferative disorders. In addition, the methods, compounds, and compositions provided herein have therapeutic and cosmetic applications, including modulating bone and cartilage formation and repair, modulating neural tissue, and modulating hematopoietic function. The compounds of the invention are also useful in the treatment of liver fibrosis. The applicable diseases also include any diseases whose activity can be modulated by inhibition of the hedgehog signaling pathway. Diseases that may be applicable also include those whose presence, maintenance, or progression is mediated by a Patched loss-of-function phenotype, a Smoothened gain-of-function phenotype, a Gli gain-of-function phenotype, and an Hh ligand overexpression phenotype.
The compounds or pharmaceutical compositions described in the present invention are particularly useful for the treatment of cancer. Cancer, as defined herein, is a disease that manifests as uncontrolled or unregulated cell proliferation, abnormal cell differentiation, an abnormal ability to invade surrounding tissues, and an inappropriate ability to establish new growth at an ectopic site. Cancer as defined herein includes primary and metastatic cancers. Cancers that can be treated include solid tumors and blood-type tumors, and tumors can occur anywhere in the body, including skin, tissues, organs, bone, cartilage, blood, and blood vessels. The cancer treatable may be adult or childhood cancer.
In some embodiments, the compounds or pharmaceutical compositions described herein are used to treat a patient who is suffering from cancer or is at risk of cancer recurrence. Non-limiting examples of cancers that can be treated by the compounds or compositions described herein include acute lymphocytic leukemia, acute myelogenous leukemia, adrenocortical cancer, aids-related cancer, anal cancer, appendiceal cancer, astrocytoma, atypical teratoid/rhabdoid tumor, basal cell carcinoma, biliary tract cancer, bladder cancer, breast cancer, bronchial tumor, burkitt's lymphoma, carcinoid tumor, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disease, colon cancer, rectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, ewing sarcoma family tumor, extracranial germ cell tumor, extragonadal germ cell tumor, gallbladder cancer, gastric (stomach) cancer, colon cancer, rectal cancer, cervical cancer, bladder cancer, Gastrointestinal stromal tumor (GIST), gestational trophoblastic tumor, glioma (adult), glioma (childhood brain stem), hairy cell leukemia, head and neck cancer, heart cancer, hepatocyte (liver) cancer, hodgkin lymphoma, hypopharynx cancer, intraocular melanoma, islet cell tumor, kaposi's cavity sarcoma, kidney (renal cell) cancer, langerhans' cell histiocytosis, laryngeal cancer, lip and oral cavity cancer, liver cancer, medulloblastoma, melanoma, merkel cell carcinoma, mesothelioma, primary occult metastatic squamous neck cancer, oral cavity cancer (mouthcancer), multiple endocrine adenoma syndrome, multiple myeloma, mycosis fungoides, myelodysplastic/myeloproliferative tumors, nasal cavity and sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer, oral cavity cancer (oralcer), Oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer, papilloma, parathyroid cancer, penile cancer, throat cancer (pharyngealcancer), pineal parenchymal tumor, pineal cytoma, pituitary tumor, pleuropulmonary blastoma, primary Central Nervous System (CNS) lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland tumors, sezary syndrome, small cell lung cancer, small bowel cancer, soft tissue sarcoma, squamous cell carcinoma, gastric (stomach) cancer, primitive neuroectodermal tumors, testicular cancer, throat cancer (throatancer), thymoma and thymus cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, urinary tract cancer, uterine sarcoma, vaginal cancer, vulval cancer, Waldenstrom's macroglobulinemia, and wilms' tumor.
In some embodiments, the compounds or compositions described herein are used to treat a patient suffering from or at risk of recurrence of a cancer selected from the group consisting of basal cell carcinoma, breast cancer, large bowel cancer, stomach cancer, glioblastoma, hematological cancer, liver cancer, lung cancer, medulloblastoma, melanoma, ovarian cancer, pancreatic cancer, and prostate cancer.
In some embodiments and certain diseases, the Smoothened antagonists described in this invention are used to treat the disease in combination with other therapeutic agents that have been approved or recognized by the appropriate regulatory authorities as being suitable for treating the disease. The Smoothened antagonists of the present invention can be administered with other therapeutic agents in separate or compounded dosage forms. When the Smoothened antagonist of the present invention and the other agent are administered separately, they may be administered simultaneously, or the Smoothened antagonist may be administered first, or the other agent may be administered first.
Pharmaceutical composition
In another aspect, the invention provides a composition comprising one or more compounds of formula (I) as described herein and a suitable carrier, excipient or diluent. The specific nature of the carrier, excipient or diluent will depend on the actual requirements of the composition and may vary within suitable or acceptable ranges for veterinary or human use. The composition may optionally include one or more additional compounds.
For the treatment or prevention of diseases, the compounds described herein may be administered alone, as a mixture of one or more compounds, or in combination or association with other agents useful in the treatment and/or association with such diseases. The compounds may also be administered in combination or association with agents for the treatment of other diseases such as steroids, membrane stabilizers, 5LO inhibitors, inhibitors of leukotriene synthesis and receptors, inhibitors of IgE isotyping or IgE synthesis, inhibitors of IgG isotyping or IgG synthesis, beta-agonists, trypsin inhibitors, aspirin, COX inhibitors, methotrexate, anti-tumor necrosis factor drugs, retuxin (no corresponding intermediate), PD4 inhibitors, p38 inhibitors, PDE4 inhibitors and antihistamines, to name but a few. The compounds may be administered as the compound itself or as a composition containing the compound.
Pharmaceutical compositions containing the compounds may be manufactured by means of conventional mixing, dissolving, granulating, sugar-coating, emulsifying, encapsulating, entrapping and lyophilizing processes. They may also be prepared in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or adjuvants which facilitate processing of the compounds into preparations which can be used pharmaceutically.
As previously mentioned, the pharmaceutical compositions may be prepared from a prototype of the compound, or in the form of a hydrate, solvate, N-oxide or pharmaceutically acceptable salt of the compound. In general, these salts are more soluble in aqueous solution than the corresponding free acids and bases, but it is also possible to form salts having a lower solubility than the corresponding free acids and bases.
The pharmaceutical compositions may be in a form suitable for administration by any means, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, and the like, or in a form suitable for inhalation or intraperitoneal administration.
For topical administration, the compounds may be formulated as solutions, gels, ointments, creams, suspensions, and the like, as are well known in the art. Systemic formulations include those designed for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, oromucosal or pulmonary administration.
Injectable formulations which may be employed include sterile suspensions, solutions, or emulsions of the active compounds in aqueous or oily vehicles. The composition may also contain formulating agents such as suspending, stabilizing and/or dispersing agents. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, and may contain an added preservative. Injectable dosage forms may also be provided in powder form for reconstitution with a suitable vehicle before use, including, but not limited to, sterile pyrogen-free water, buffers, glucose solutions and the like. For this purpose, the active compound may be dried by any known technique, such as freeze-drying, and reconstituted prior to use.
For mucosal administration, penetrants appropriate to the barrier to be permeated are used in the medicament. Such penetrants are known in the art.
For oral administration, the pharmaceutical compositions may be in the form of tablets, dragees, capsules prepared by conventional methods and containing pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or dibasic calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may also be coated by methods known in the art, for example with sugar coatings, film coatings or enteric coatings.
Liquid preparations for oral use can be, for example, elixirs, solutions, syrups or suspensions, or can be presented as a dry product for constitution with water or other suitable vehicle before use. Liquid preparations may be prepared in a conventional manner using pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (such as lecithin or gum arabic); non-aqueous carrier (such as almond oil, oily ester, alcohol, cremophore)TMOr fractionated vegetable oils); and preservatives (e.g., methyl or propyl parabens or sorbic acid). The formulation may also contain suitable buffer salts, preservatives, flavours, colours and sweeteners.
Formulations for oral administration are suitably prepared according to known methods to provide controlled release of the compound.
For buccal administration, the compositions may be in the form of conventional tablets or lozenges.
For rectal and vaginal administration, the compounds may be presented as solutions (retention enemas), suppositories or ointments containing conventional suppository carriers such as cocoa butter or other glycerides.
For nasal administration or administration by inhalation or insufflation, the compounds may be presented as a pressurized pack spray or nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbon, carbon dioxide or other suitable gas. If a pressurized aerosol is used, a valve can be designed to dose the dosage unit of the drug. Capsules and cartridges (e.g., of gelatin) for use in inhalers and insufflators may be formulated containing a powdered mixture of the compound and a suitable powder base such as lactose or starch.
For ophthalmic administration, the compounds may be formulated as solutions, emulsions, suspensions, and the like suitable for ophthalmic administration. A variety of suitable carriers for administering the compounds to the eye are well known in the art.
For extended delivery, the compounds can be formulated as depot (depot) formulations for drug implantation or intramuscular administration. The compounds may be prepared using suitable polymeric or hydrophobic materials (e.g. emulsions in acceptable oils) or ion exchange resins, or as sparingly soluble derivatives (e.g. sparingly soluble salts). Alternatively, transdermal delivery systems for percutaneous absorption, which are formed as adhesive wafers or patches for slow release of the compounds, may also be used. In this manner, a permeation enhancer may be used to facilitate transdermal permeation of the compound.
Alternatively, other drug delivery systems may be employed. Liposomes and emulsions are examples of well known delivery vehicles for delivering compounds. Certain organic solvents, such as dimethyl sulfoxide (DMSO), although more toxic, may also be used.
If desired, the pharmaceutical composition may be presented in a sachet or dispenser which may contain one or more unit doses of the compound. For example, the pouch may contain a metal or plastic film, such as a blister pack. The pouch or dispenser may carry instructions for use.
The compounds and compositions thereof described herein are generally employed in an amount effective to achieve the desired effect, e.g., in an amount effective to treat or prevent a particular disease. By therapeutically beneficial is meant eradication or amelioration of the disease to be treated and/or eradication or amelioration of one or more symptoms associated with the disease to be treated such that the patient's experience or condition is improved, although the patient is still ill. Therapeutic benefit also typically includes halting or slowing disease progression, whether or not the disease is ameliorated.
The dosage of a compound administered depends on a variety of factors including, for example, the indication being treated, the mode of administration, whether the desired effect is prophylactic or therapeutic, the severity of the indication being treated and the age and weight of the patient, the conversion and efficiency of the particular compound to a pharmaceutically active compound under the chosen route of administration, and the bioavailability.
Determination of an effective dose for a particular use or mode of administration of a compound is well within the ability of those skilled in the art. The effective dose can be estimated preliminarily from the results of in vitro activity and metabolic tests. For example, when the compound is administered to an animal, it may be prepared in an initial dose such that the concentration of the active metabolite of the compound in the plasma is equal to or greater than the IC of the particular compound as determined in an in vitro assay50. The dose calculated to achieve such plasma concentrations is determined by consideration of the bioavailability of the desired route of administration of the particular compound, and is well within the capabilities of those skilled in the art. Initial doses of the compounds can also be estimated based on in vivo assays, such as animal models. Animal models that can be used to test the efficacy of active metabolites in the treatment or prevention of the various aforementioned diseases are well known in the art. Animal models suitable for testing bioavailability and/or metabolism of a compound into active metabolites are also well known in the art. One of ordinary skill can routinely use this information to determine the dosage of a particular compound suitable for administration to a human.
The dosage range will generally be from about 0.0001 mg/kg/day, 0.001 mg/kg/day or 0.01 mg/kg/day to about 100 mg/kg/day, although higher or lower may be possible depending on, among other factors, the activity of the active metabolic compound, the bioavailability, the pharmacokinetic and other pharmacokinetic properties of the compound, the mode of administration and the various other factors discussed above. The dosage and time between administrations can be adjusted individually to achieve a blood concentration of the compound and/or the active metabolic compound sufficient to support a therapeutic or prophylactic effect. For example, the compound may be administered once a week, several times a week (e.g., every other day), once a day or several times a day, depending on, among other factors, the mode of administration, the particular indication being treated, and the judgment of the clinician. In the case of topical administration or selective ingestion, such as topical application, the effective local concentration of the compound and/or active metabolic compound may be independent of the blood level. One skilled in the art will be able to optimize the dosage administered without undue experimentation.
Definition of
The following terms and expressions are used herein with the indicated meanings.
As used herein, the term "a single transverse line," - ", or double transverse line," = "may be preceded and/or followed to indicate the order of attachment of the chemical bond between the indicated substituent and its parent; the single horizontal line represents a single bond and the double horizontal line represents a double bond. Without a single or double cross-bar, it is understood that a single bond is formed between the substituent and its parent; further, unless the horizontal lines indicate otherwise, the order in which the substituents are read is from left to right. E.g. C1-C6Alkoxycarbonyloxy and-OC (O) C1-C6Alkyl groups represent the same functional groups; similarly, arylalkyl and-alkylaryl also represent the same functional groups.
The term "alkenyl" as used herein, unless otherwise specified, refers to straight or branched chain hydrocarbons containing from 2 to 10 carbon atoms and at least one carbon-carbon double bond. Representative examples of alkenyl groups include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, and 3, 7-dimethylocta-2, 6-dienyl.
As defined herein, the term "alkoxy" as used herein, means a connection between the alkyl group and the parent molecule through an oxygen atom. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, and hexoxy.
The term "alkyl" as used herein, unless otherwise specified, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2-dimethylpentyl, 2, 3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. When an "alkyl" group is a linking group between two other moieties, then it may also be straight or branched; examples include, but are not limited to-CH2-，-CH2CH2-，-CH2CH2CHC(CH3)-，-CH2CH(CH2CH3)CH2-。
The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, e.g., - (CH)2)n-, where n is a positive integer, preferably from one to six, from one to four, from one to three, from one to two or from two to three. Substituted alkylene chain means that on a polymethylene group, one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those of the substitutable aliphatic groups described below. The alkylene chain may also be substituted at one or more positions with an aliphatic group or a substituted aliphatic group.
The term "alkynyl" as used herein denotes a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
The term "aryl" as used herein denotes an aromatic hydrocarbon ring system comprising at least one aromatic ring, e.g., phenyl (i.e., monocyclic aryl); or a bicyclic ring system containing at least one aromatic hydrocarbon ring (e.g., phenyl); or an aromatic bicyclic ring in which the aromatic portion of the ring system contains only carbon atoms. Preferably, the aryl group has a 6-14 membered ring, more preferably a 6-10 membered ring. Examples of aryl groups include, for example, phenyl, naphthyl, anthracenyl, azulenyl 1,2, 3, 4-tetrahydronaphthyl, indenyl, 2, 3-dihydroindenyl and biphenyl. Preferably, the bicyclic aryl is azulenyl, naphthyl, or phenyl fused with a monocyclic cycloalkyl, monocyclic cycloalkenyl, or monocyclic heterocyclyl. More preferred aryl groups are phenyl and naphthyl. More preferred aryl is phenyl. The bicyclic aryl is attached to the parent molecule through any carbon atom of an aromatic portion of the ring system (e.g., the phenyl portion of the bicyclic system, or any carbon atom on the naphthyl or azulene group). The fused monocyclic cycloalkyl or monocyclic heterocyclyl moieties on the bicyclic aryl are optionally substituted with one or two oxygen and/or sulfur groups. Representative examples of bicyclic aryl groups include, but are not limited to, azulenyl, naphthyl, indan-1-yl, indan-2-yl, indan-3-yl, indan-4-yl, 2, 3-indolin-5-yl, 2, 3-indolin-6-yl, 2, 3-indolin-7-yl, inden-1-yl, inden-2-yl, inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen-1-yl, 5, 6, 7, 8-tetrahydronaphthalen-1-yl, dihydronaphthalen-1-yl, and the like, 5, 6, 7, 8-tetrahydronaphthalen-2-yl, 2, 3-dihydrobenzofuran-4-yl, 2, 3-dihydrobenzofuran-5-yl, 2, 3-dihydrobenzofuran-6-yl, 2, 3-dihydrobenzofuran-7-yl, benzo [ d ] [1, 3] dioxolan-4-yl, benzo [ d ] [1, 3] dioxolan-5-yl, 2H-benzopyran-2-on-6-yl, 2H-benzopyran-2-on-7-yl, 2H-benzopyran-2-on-8-yl, isoindol-1, 3-diketo-4-yl, isoindol-1, 3-diketo-5-yl, inden-1-keto-4-yl, inden-1-keto-5-yl, inden-1-keto-6-yl, inden-1-keto-7-yl, 2, 3-dihydrobenzo [ b ] [1, 4] dioxan-5-yl, 2, 3-dihydrobenzo [ b ] [1, 4] dioxan-6-yl, 2H-benzo [ b ] [1, 4] oxazine 3(4H) -on-5-yl, 2H-benzo [ b ] [1, 4] oxazine 3(4H) -on-6-yl, 2H-benzo [ b ] [1, 4] oxazine 3(4H) -on-7-yl, 2H-benzo [ b ] [1, 4] oxazin-3 (4H) -on-8-yl, benzo [ d ] oxazin-2 (3H) -on-5-yl, benzo [ d ] oxazin-2 (3H) -on-6-yl, benzo [ d ] oxazin-2 (3H) -on-7-yl, benzo [ d ] oxazin-2 (3H) -on-8-yl, quinazolin-4 (3H) -on-5-yl, quinazolin-4 (3H) -on-6-yl, quinazolin-4 (3H) -on-7-yl, quinazolin-4 (3H) -on-8-yl, quinazolin-2 (1H) -on-5-yl, and pharmaceutically acceptable salts thereof, Quinazolin-2 (1H) -on-6-yl, quinazolin-2 (1H) -on-7-yl, quinazolin-2 (1H) -on-8-yl, benzo [ d ] thiazol-2 (3H) -on-4-yl, benzo [ d ] thiazol-2 (3H) -on-5-yl, benzo [ d ] thiazol-2 (3H) -on-6-yl, and benzo [ d ] thiazol-2 (3H) -on-7-yl. In some embodiments, bicyclic aryl is (i) naphthyl; or (ii) benzene fused with a five or six membered monocycloalkyl, five or six membered monocyclocycloalkenyl, five or six membered monocyclic heterocyclyl wherein the fused cycloalkyl, cycloalkenyl and heterocyclyl groups are optionally substituted by one or two independent oxygen or sulfur groups.
The aryl groups of the present invention may be substituted with various groups as exemplified herein. That is, any carbon atom in the aromatic ring system which may be substituted may be further bonded to a variety of ring substituents, e.g., halogen, OH, NO2、CN、NH2、C1-C8Alkyl radical, C1-C8Alkoxy, NH (C)1-C8Alkyl), NH (C)1-C8Alkyl) (C1-C8Alkyl group), C3-C10Cycloalkyl group, (C)3-C10Cycloalkyl) alkyl, (C)3-C10Cycloalkyl) alkoxy, C2-C9Heterocycloalkyl radical, C1-C8Alkenyl radical, C1-C8Alkynyl, halogen (C)1-C8) Alkyl, halogen (C)1-C8) Alkoxy, oxo, amino (C)1-C8) Alkyl, mono-and di (C)1-C8Alkyl) amino (C)1-C8) Alkyl radical, C1-C8Acyl radical, C1-C8Acyloxy, C1-C8Sulfonyl radical, C1-C8Thio, C1-C8Sulfonamide, C1-C8An aminosulfonyl group.
An "aralkyl" or "arylalkyl" group comprises an aryl group as defined herein andand alkyl groups connected by covalent bonds. Both aryl and alkyl groups may be independently optionally substituted. Preferably, the aralkyl group is aryl (C)1-C6) Alkyl groups including, but not limited to, benzyl, phenethyl, and naphthylmethyl. Herein, "aralkyl" and "arylalkyl" are interchangeable.
The terms "cyano" and "nitrile" as used herein denote a-CN group.
The term "cycloalkyl" as used herein denotes a monocyclic or bicyclic cycloalkyl ring system. Monocyclic ring systems are understood to mean cyclic hydrocarbon radicals having from 3 to 8 carbon atoms, which radicals may be saturated or unsaturated, but which are not aromatic. In certain embodiments, the cycloalkyl group is fully saturated. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems refer to bridged monocyclic or fused bicyclic rings. Bridged monocycles comprise monocyclic cycloalkyl groups in which two non-adjacent carbon atoms of the monocycle are connected by an alkylene bridge containing one to three additional carbon atoms (i.e., the form of the bridging group: - (CH)2)w-, where w is 1,2 or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo [3.1.1]Heptane, bicyclo [2.2.1]Heptane, bicyclo [2.2.2]Octane, bicyclo [3.2.2]Nonane, bicyclo [3.3.1]Nonanes and bicyclo [4.2.1]Nonane. Fused bicyclic cycloalkyl ring systems include monocyclic cycloalkyl fused to phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocyclyl or monocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl can be attached to the parent molecule through any carbon atom on the monocyclic cycloalkyl. The cycloalkyl group may be optionally substituted with one or two groups independently oxygen or sulfur. In some embodiments, fused bicyclic cycloalkyl refers to a five or six membered monocyclic cycloalkyl fused to a benzene ring, a five or six membered monocyclic cycloalkyl, a five or six membered monocyclic cycloalkenyl, a five or six membered monocyclic heterocyclyl, or a five or six membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted with one or two groups independently oxygen or sulfur.
The term "halogen" as used herein refers to chlorine, bromine, iodine or fluorine.
The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" refer to an alkyl, alkenyl or alkoxy group, optionally substituted with one or more halogen atoms.
The term "heteroaryl" as used herein refers to a monocyclic heteroaryl or bicyclic ring system containing at least one heteroaromatic ring. Preferred heteroaryl groups have 5 to 14 ring atoms of which 1 to 4 are heteroatoms selected from oxygen, nitrogen, sulphur and the remaining ring atoms are carbon. More preferred heteroaryl groups have 5 to 10 ring atoms of which 1 to 4 are heteroatoms selected from oxygen, nitrogen, sulphur and the remaining ring atoms are carbon. Examples of heteroaryl groups include, for example, phenyl, naphthyl, anthracenyl, azulenyl 1,2, 3, 4-tetrahydronaphthyl, indenyl, 2, 3-indanyl and biphenyl. More preferred heteroaryl groups are monocyclic heteroaryl groups of five or six members. The five-membered ring consists of two double bonds and one, two, three or four nitrogen atoms and optionally one oxygen or sulfur atom. The six-membered ring consists of three double bonds and one, two, three or four nitrogen atoms. The five or six membered heteroaryl group is attached to the parent molecule through any carbon or nitrogen atom within it. Representative examples of monocyclic heteroaryl groups include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. Bicyclic heteroaryls consist of a monocyclic heteroaryl fused to a phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heteroalkyl, or monocyclic heteroaryl. The fused cycloalkyl or heterocyclyl moiety in a bicyclic heteroaryl group is optionally substituted with one or two groups independently oxygen or sulfur. When the bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl, or heterocycle, the bicyclic heteroaryl group is attached to the parent molecule through any carbon or nitrogen atom on the monocyclic heteroaryl portion of the bicyclic ring system. When the bicyclic heteroaryl is monocyclic fused to a phenyl ring, then the bicyclic heteroaryl group is attached to the parent molecule through any carbon or nitrogen atom of the bicyclic ring system. Representative examples of bicyclic heteroaryls include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzooxadiazolyl, benzothiadiazolyl, benzothiazolyl, phthalazinyl, 5, 6-dihydroquinolin-2-yl, 5, 6-dihydroisoquinolin-1-yl, furopyridinyl, indazolyl, indolyl, isoquinolyl, naphthyridinyl, quinolinyl, purinyl, 5, 6, 7, 8-tetrahydroquinolin-2-yl, 5, 6, 7, 8-tetrahydroquinolin-3-yl, 5, 6, 7, 8-tetrahydroquinolin-4-yl, 5, 6, 7, 8-tetrahydroisoquinolin-1-yl, thienopyridinyl, 4, 5, 6, 7-tetrahydrobenzo [ c ] [1,2, 5 oxadiazolyl and 6, 7-dihydrobenzo [ c ] [1,2, 5] oxadiazol-4 (5H) -yl. In certain embodiments, the fused bicyclic heteroaryl is a five or six membered monocyclic heteroaryl ring fused to a benzene ring, a five or six membered monocyclic cycloalkyl, a five or six membered monocyclic cycloalkenyl, a five or six membered monocyclic heterocyclyl or a five or six membered monocyclic heteroaryl, wherein the fused cycloalkyl, cycloalkenyl and heterocyclic groups are optionally substituted with one or two groups independently oxygen or sulfur.
The heteroaryl groups of the present invention may be substituted with various groups as exemplified herein. That is, any carbon atom in the heteroaromatic ring system that can be substituted may be further bonded to various ring substituents, e.g., halogen, OH, NO2、CN、NH2、C1-C8Alkyl radical, C1-C8Alkoxy, NH (C)1-C8Alkyl), NH (C)1-C8Alkyl) (C1-C8Alkyl group), C3-C10Cycloalkyl group, (C)3-C10Cycloalkyl) alkyl, (C)3-C10Cycloalkyl) alkoxy, C2-C9Heterocycloalkyl radical, C1-C8Alkenyl radical, C1-C8Alkynyl, halogen (C)1-C8) Alkyl, halogen (C)1-C8) Alkoxy, oxo, amino (C)1-C8) Alkyl, mono-and di (C)1-C8Alkyl) amino (C)1-C8) Alkyl radical, C1-C8Acyl radical, C1-C8Acyloxy, C1-C8Sulfonyl radical, C1-C8Thio, C1-C8Sulfonamide, C1-C8An aminosulfonyl group.
The terms "heterocyclyl" and "heterocycloalkyl" are used interchangeably herein to mean a monocyclic heterocycle or a bicyclic heterocycle. The heterocycloalkylaryl groups of the present invention contain 3 to 14 ring atoms, of which 1 to 4 ring atoms are heteroatoms selected from oxygen, nitrogen, sulfur, and the remaining ring atoms are carbon. Preferred heterocycloalkyl groups contain 5 to 10 ring atoms, of which 1 to 4 are heteroatoms selected from oxygen, nitrogen, sulfur and the remaining ring atoms are carbon. That is, monocyclic heterocycle refers to a 3-, 4-, 5-, 6-, or 7-membered ring, which contains at least one heteroatom independently selected from oxygen, nitrogen, and sulfur, and which may be saturated or unsaturated, but which cannot be aromatic. The three-or four-membered ring contains a heteroatom selected from oxygen, nitrogen, sulfur. The five-membered ring may contain zero or one double bond and one, two or three heteroatoms selected from oxygen, nitrogen, sulfur. The six-or seven-membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from oxygen, nitrogen, sulphur. The monocyclic heterocycle may be attached to the parent molecule through any carbon atom or any nitrogen atom on the monocyclic heterocycle. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1, 3-dioxacyclohexyl, 1, 3-dioxolanyl, 1, 3-dithiocyclopentyl, 1, 3-dithiocyclohexyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1-dioxothiomorpholinyl (thiomorpholinyl), thiopyranyl and trithiadinyl. A bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. The bicyclic heterocycle is attached to the parent molecule through any carbon atom or any nitrogen atom on the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocycles include, but are not limited to, 2, 3-dihydrobenzofuran-2-yl, 2, 3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2, 3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. The heterocyclic group is optionally substituted with one or two groups independently oxygen or sulfur. In certain embodiments, bicyclic heterocyclyl refers to a five or six membered monocyclic heterocyclic ring fused to a benzene ring, a five or six membered monocyclic cycloalkyl, a five or six membered monocyclic cycloalkenyl, a five or six membered monocyclic heterocyclic group, or a five or six membered monocyclic heteroaryl, wherein the bicyclic heterocyclic group is optionally substituted with one or two groups independently oxygen or sulfur.
The term "hydroxyl protecting group" refers to a group that prevents or blocks the hydroxyl group from participating in further reactions until the protecting group is removed. Examples of the hydroxyl-protecting group include acetyl, allyl, benzoyl, benzyl, β -methoxyethoxymethyl, methoxymethyl, dimethoxytrityl [ bis- (4-methoxyphenyl) phenylmethyl ], methoxytriphenyl [ (4-methoxyphenyl) diphenylmethyl ], p-methoxybenzyl ether, methylthiomethyl, pivaloyl, tetrahydropyranyl, triphenylmethyl, silyl groups (e.g., trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyloxymethyl and triisopropylsilyl). Other examples include alkyl groups such as methyl and t-butyl, and other ethers such as ethoxyethyl.
The term "nitro" as used herein means-NO2A group.
The term "oxo" as used herein denotes the = O group.
The term "saturated" as used herein means that the chemical structure referred to does not contain any multiple carbon-carbon bonds. For example, saturated cycloalkyl groups as defined herein include cyclohexyl, cyclopropyl and the like.
The term "substituted" as used herein means that the hydrogen groups of the specified moiety are replaced by a specified substituent, provided that the substitution results in a stable or chemically feasible compound. When the term "substitutable" is used to describe a designated atom, it is meant that attached to the atom is a hydrogen radical, which can be replaced by a suitable substituent.
The phrase "one or more substituents" as used herein refers to a number of substituents from one to the maximum possible depending on the number of available bonding sites, provided that the stability and chemical feasibility of the above-described situation are met. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position, and these substituents may be the same or different. The term "independently selected" as used herein means that in a compound, the same or different values may be selected for a given variable in multiple instances.
Aryl (including aryl moieties in aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaryl moieties in heteroaralkyl and heteroaralkoxy and the like) may contain one or more substituents. Examples of suitable substituents for the unsaturated carbon atom of the aryl or heteroaryl group include halogen, -NO2、-CN、-R′、-C(R′)=C(R′)2、-C≡C-R′、-OR′、-SR′″、-S(O)R′″、-SO2R′″、-SO2N(R″)2、-N(R″)2、-NR″C(O)R′、-NR″C(O)N(R″)2、-NR″CO2R′″、-O-CO2R″、-OC(O)N(R″)2、-C-C(O)R′、-CO2R′、-C(O)-C(O)R′、-C(O)R′、-C(O)N(R″)2、-C(=NR″)-N(R″)2、-C(=NR″)-OR′、-N(R″)-N(R″)2、-N(R″)C(-NR″)-N(R″)2、-NR″SO2R′″、-NR″SO2N(R″)、-P(O)(R′)2、-P(O)(R′)2-O-P (O) -OR ' and-P (O) (NR ') -N (R ')2Which isWherein R '"is an optionally substituted aliphatic or aromatic group, and R' and R" are as defined above, or are two adjacent substituents which together with the atoms in between form a five-to six-membered unsaturated or partially unsaturated ring having 0-3 ring atoms selected from nitrogen, oxygen or sulfur.
The non-aromatic heterocyclic ring may be substituted with one or more substituents. Examples of suitable substituents for saturated carbon atoms on aliphatic or non-aromatic heterocyclic rings include, but are not limited to, those listed above as suitable for unsaturated carbon atoms on aryl or heteroaryl groups, also = O, = S, = C (R')2、=N-N(R″)2、=N-OR′、=N-NHC(O)R′、=N-NHCO2R′″、=N-NHSO2R '", or = N-R', wherein each R ', R", and R' "is as defined above. For clarity, the term "substituted aliphatic" refers to an aliphatic group that contains at least one substituent that is not aliphatic.
Suitable substituents for the substitutable nitrogen atom of the heteroaryl or heterocycle include-R ', -N (R')2、-C(O)R′、-CO2R′、-C(O)-C(O)R′、-C(O)CH2C(O)R′、-SO2R′、-SO2N(R′)2、-C(=S)N(R′)2、-C(=NH)-N(R′)2and-NR' SO2R'; wherein each R' is the same as defined above.
The term "thio" as used herein means an = S group.
The term "unsaturated" as used herein means that the chemical structure referred to contains at least one multiple carbon-carbon bond, but is not aromatic. For example, unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like.
It will be apparent to those skilled in the art that certain compounds of the present invention may exist as tautomers and that tautomeric forms of such compounds are within the scope of the invention. Unless otherwise indicated, the chemical structures described hereinIt is also meant to include all stereochemical forms of the structure; for example, the R and S configuration of each asymmetric center. Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds of the invention are also within the scope of the invention. For example, wherein R3aA compound of formula (I) which is hydroxy, with R3aThe carbon atoms to which they are attached will have either the R or S configuration. Both stereoisomers of R and S, as well as all mixtures thereof, are within the scope of the present invention.
"pharmaceutically acceptable" refers 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; or those compounds, materials, compositions and/or dosage forms that have been approved by the U.S. food and drug administration for use in humans and domestic animals.
"pharmaceutically acceptable salts" refers to acid and base addition salts.
By "therapeutically effective amount" is meant an amount of a compound that, when administered to a subject, is sufficient to effectively treat the diseases or disorders described herein. The amount of the compound required to constitute a "therapeutically effective amount" depends on the compound itself, the disorder and its severity, and the age of the subject being treated, but can also be determined by one of ordinary skill in the art by routine means.
"modulation" refers to the treatment, prevention, inhibition, enhancement, or induction of a function, condition, or disorder. For example, it is believed that the compounds of the present invention are capable of modulating arteriosclerosis by stimulating cholesterol efflux from arteriosclerotic lesions in humans.
As used herein, "treatment" includes treatment of a subject, preferably a human, for a disease or disorder described herein, and includes:
i. inhibiting the disease or disorder, that is, inhibiting its development;
relieving the disease or disorder, that is, causing regression of the disorder;
slowing the progression of the disease; and/or
inhibiting, reducing, ameliorating, or slowing the progression of one or more symptoms of a disease or disorder.
By "subject" is meant herein a warm-blooded animal, such as a mammal, preferably a human or a human child, which has or may have one or more of the diseases described herein.
“EC50"refers to the dose, concentration, or amount of a dose-dependent effect that produces 50% of the maximum expression of the particular effect that a particular test compound induces, elicits, or potentiates.
“IC50"refers to the amount, concentration or dose of a particular test compound that produces 50% of the maximal inhibitory effect in the assay to be tested for that effect.
Preparation method
The compounds of the present invention may be prepared by known chemical reactions and procedures. Some representative methods for synthesizing the compounds of the present invention are shown below. It is well known that the nature of the substituents required for the desired target compound often determines the preferred method of synthesis. All variable groups of these methods are as described in the general description, unless specifically defined below.
General procedure
Representative synthetic procedures for preparing the compounds of the present invention are set forth in the following schemes. Unless otherwise specified, R1、R2、R3、R5-R12X and Y are as defined in the above-listed formula (I).
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 6
Examples
The preparation and use of the compounds of the present invention are further illustrated by the following examples, which should not be construed as limiting the scope or particular procedure and spirit of the compounds of the present invention. Unless otherwise indicated, column chromatography used silica gel as the stationary phase in all cases.
The preparation of the compounds of the present invention may be further illustrated by the following embodiments, which should not be construed as limiting the scope or particular procedure of the invention and the spirit of the compounds. Unless otherwise stated, column chromatography used silica gel as the stationary phase in all cases.
Compound identification and purity confirmation were performed by liquid chromatography/UV spectroscopy/mass spectrometry using Waters MicromassZQTMDetector and Waters2695 separation module and Waters2487Duall absorbance detector (Waters corporation, Milford, MA). The wavelength used by the diode array detector is 254nm, and the mass spectrum adopts an electrospray positive ionization mode. Samples were stored at room temperature in an autosampler and approximately 5. mu.L of the sample was injected onto an Ascentis ExpressC18 column (30mmx3mm, 2.7 μm) (Supelco Analytical, Bellefonte, Pa.) and the column temperature was maintained at 40 ℃. The sample was eluted at a flow rate of 1 mL/min, and the mobile phase system consisted of solvent A (water containing 0.1% formic acid) and solvent B (acetonitrile containing 0.1% formic acid), initially washed with a 90% A gradient for 0.3 min, followed by a linear gradient of 10% B to 90% B for 3.6 min, followed by a 90% B gradient for 0.4 min. The column took 0.4 minutes to equilibrate before returning to the starting state before the next run. In the example indicated in some embodiments, the overall run time for the long-consuming process is 10 minutes. The polarization weight and retention time (tR), relative uv absorption area of the compound was used to determine purity and structure. In addition, nuclear magnetic resonance spectroscopy is used to characterize key intermediates and compounds. Optionally, the R of the compound on silica gel TLC plate was measuredfThe value is obtained.
It will be appreciated by those skilled in the art that if the starting materials and reaction conditions are varied, the order of the reactions and the additional steps for synthesizing the compounds encompassed by the present invention will also vary, as shown in the examples below. Many conventional references are available which provide known chemical synthesis methods useful for the synthesis of these disclosed compounds (see, e.g., Smithhand March, March's sadvanced organic chemistry: Reactions, mechanics, and Structure, FifthIndition, Wiley-Interscience, 2001; or Vogel, ATextook of practical organic chemistry, Including Qualitationary organic analysis, Fourthreedition, NewYork: Longman, 1978).
The starting materials are commercially available or may be prepared using well-established literature methods. The reaction is carried out in a suitable solvent which is suitable for the reagents and starting materials used in the experiment and the conversion effected. It will be clear to those skilled in the art of organic synthesis that the functional groups of the molecule should be consistent with the transformations originally envisaged. To obtain the compounds contemplated by the present invention, it is sometimes necessary to make decisions to modify the order of synthetic steps or to select a particular process scheme that is better than the others.
In some cases, protection of certain reactive functionalities is necessary to achieve some of the transformations described above. In general, those skilled in the art of organic synthesis will know which protecting groups are required and the reaction conditions for attaching and removing these protecting groups. For a skilled practitioner, it will be appreciated that there are many options for protecting groups, and the authoritative reference book is: McOmie, "protective group organic chemistry", plenum Press, London dNewYork1973, int. W.GreeneandP.G.M.Wuts, "protective group organic Synthesis", Thirdedition, Wiley, New York1999, in "the peptides"; volume3(editors: E.GrossandJ.Meienhofer), academy Press, LondonandNewYork1981, in "Methodenderorganschel Chemie", Houben-Weyl, 4.sup.the description, Vol.15/l, Georg Thieme Verlag, Stuttgart1974, inh. The protecting group may be removed at a later appropriate stage using known methods.
The compound names in this document are named using chemdrawUltraVersion10.0 or Version12.0, which are commercially available from Cambridge Soft.
Example 1
2-bromo-1- (4-methyl-3-nitrophenyl) ethanone
To a stirred solution of 4-methyl-3-nitrobenzoyl chloride (Sigma-Aldrich, 2.0g, 10mmol) in dichloromethane (50mL) was added trimethylsilyl diazomethane (2.0M in hexanes, 40 mmol). After stirring at room temperature for 2 hours, it was cooled to 0 ℃ and a hydrogen bromide/acetic acid solution (6.33mL, 33% acetic acid hydrogen bromide solution, 35mmol) was added dropwise with nitrogen evolution. After the addition was complete, stirring at 0 ℃ for 5 minutes, concentration, and purification by silica gel chromatography (dichloromethane) gave the title compound (2.42g, light yellow solid) in yield: 93 percent. Rf0.61 (dichloromethane).
Example 2
6-methoxy-2- (4-methyl-3-nitrophenyl) imidazo [1,2-b]Pyridazine
6-Methoxypyridazin-3-amine (Apolloscientific, 0.750g, 5.99mmol) and 2-bromo-1- (4-methyl-3-nitrophenyl) ethanone (1.54g, 5.99mmol) were dissolved in 20mL of acetonitrile with stirring and heated at 80 ℃ with stirring for 16 hours. The reaction mixture was concentrated to dryness and purified by chromatography (hexane-ethyl acetate) to give the title compound (1.45g, light yellow solid), yield: 85 percent. Rf0.45(1:1 ethyl acetate: hexane); LCMS (M/z) =285.4[ M + H]+，tR=7.47 min. (run for 10 minutes).
Example 3
5- (6-methoxyimidazo [1,2-b ]]Pyridazin-2-yl) -2-methylaniline
Mixing 6-methoxy-2- (4-methyl-3-nitrophenyl) imidazo [1, 2-b)]Pyridazine (0.5g, 1.75mmol) was dissolved in 20mL ethanol and 5mL water containing acetic acid (10.5mmol) with stirring, iron powder (0.491g, 8.79mmol) was added, the mixture was heated at 80 ℃ for 4 hours, cooled, concentrated under reduced pressure, then 100mL saturated aqueous sodium bicarbonate was added, the mixture was extracted with ethyl acetate (3 × 50mL), the organic phases were combined, dried over sodium sulfate, filtered and concentrated to dryness, the crude product was purified by chromatography (hexane-ethyl acetate) to give the title compound (0.328g, light yellow solid) in 73% yield Rf0.21 (ethyl acetate); LCMS (M/z) =255.5[ M + H]+，tR=4.89 minutes (run 10 minutes).
Example 4
N- (5- (6-methoxyimidazo [1,2-b ]]Pyridazin-2-yl) -2-methylphenyl) pivaloyl amides
Reacting 5- (6-methoxy imidazo [1,2-b ]]Pyridazin-2-yl) -2-methylaniline (0.050g, 0.206mmol) was dissolved with stirring in 5mL of acetonitrile containing pyridine (0.618mmol), and trimethylacetyl chloride (0.206mmol) was added. Stirred at room temperature for 4 hours, concentrated to dryness, and then chromatographed (hexane-ethyl acetate) to give the titled compoundCompound (0.060g, white solid), yield: 86 percent. Rf0.57 (ethyl acetate); LCMS (M/z) =339.4[ M + H]+，tR=6.37 minutes (run 10 minutes).
Example 5
N- (4-fluorobenzyl) -5- (6-methoxyimidazo [1, 2-b)]Pyridazin-2-yl) -2-methylaniline
In an 8mL vial, 5- (6-methoxyimidazo [2,1-f ] in acetonitrile (0.5mL) is added]Pyridazin-2-yl) -2-methylaniline (20.3mg, 0.08mmol), potassium carbonate (13mg) and 4-fluorobenzyl bromide (19mg, 0.1 mmol). The mixture was stirred for 30 minutes and filtered, and the filtrate was added to 10mL of water to precipitate a solid, which was filtered to give the title compound (10mg, 34% yield) (the same compound as in example 102). LCMSM/z =363.3[ M + H]+，tR=2.57 min.
Example 6
3-chloro-6-methoxy-2- (4-methyl-3-nitrophenyl) imidazo [1,2-b]Pyridazine
Mixing 6-methoxy-2- (4-methyl-3-nitrophenyl) imidazo [1, 2-b)]Pyridazine (0.250g, 0.879mmol) was dissolved in 20mL acetonitrile with stirring, N-chlorosuccinimide (0.879mmol) was added and the mixture was heated at 60 ℃ for 8 hours, then 50mL water and 50mL saturated aqueous sodium bicarbonate solution were added to dilute the reaction mixture, the precipitate formed was collected by filtration, the solid was washed with water (3 × 25mL) and dried in vacuo to give the title compound (0).277g, yellow solid), yield: 98 percent. Rf0.60(1:1 ethyl acetate: hexane); LCMS (M/z) =319.3, 321.2[ M + H]+，tR=3.02 minutes.
Example 7
5- (3-chloro-6-methoxyimidazo [1, 2-b)]Pyridazin-2-yl) -2-methylaniline
3-chloro-6-methoxy-2- (4-methyl-3-nitrophenyl) imidazo [1,2-b]Pyridazine (0.25g, 0.784mmol) was dissolved with stirring in a solution of 50mL ethanol and 10mL water containing acetic acid (4.70mmol), iron powder (0.218g, 3.92mmol) was added, the reaction mixture was heated at 80 ℃ for 2 hours, cooled, concentrated under reduced pressure, and 100mL saturated aqueous sodium bicarbonate was added, the mixture was extracted with ethyl acetate (3 × 50mL), the organic phases were combined, dried over sodium sulfate, filtered and concentrated to dryness, the crude product was purified by chromatography (hexane-ethyl acetate) to give the title compound (0.201g, yellow solid) in 89% yield Rf0.32 (ethyl acetate); LCMS (M/z) =289.4, 291.2[ M + H [)]+，tR=2.21 minutes.
Example 8
N- (5- (3-chloro-6-methoxyimidazo [1, 2-b)]Pyridazin-2-yl) -2-methylphenyl) pivaloyl amides
Reacting 5- (3-chloro-6-methoxyimidazo [1,2-b ]]Pyridazin-2-yl) -2-methylaniline (0.025g, 0.0867mmol) was dissolved in 1mL of acetonitrile containing pyridine (0.261mmol) with stirring, and trimethylethanamine was addedAcid chloride (0.0867 mmol). The mixture was stirred at room temperature for 4 hours, then concentrated to dryness and purified by chromatography (hexane-ethyl acetate) to give the title compound (0.030g, white solid) in yield: 93 percent. LCMS (M/z) =373.4, 375.3[ M + H [ ]]+，tR=2.74 minutes. (same as the compound in example 109)
Example 9
3-bromo-6-methoxy-2- (4-methyl-3-nitrophenyl) imidazo [1,2-b]Pyridazine
Mixing 6-methoxy-2- (4-methyl-3-nitrophenyl) imidazo [1, 2-b)]Pyridazine (0.250g, 0.879mmol) was dissolved in 20mL acetonitrile with stirring, N-bromosuccinimide (0.879mmol) was added and the mixture was heated at 60 ℃ for 8 hours, 50mL water and 50mL saturated aqueous sodium bicarbonate were added to dilute the reaction mixture, the precipitate formed was typically collected by filtration, the solid was washed with water (3 × 25mL) and dried in vacuo to give the title compound (0.300g, yellow solid) in 94% yield Rf0.51(1:1 ethyl acetate: hexane); LCMS (M/z) =363.2, 365.2[ M + H]+，tR=3.02 minutes.
Example 10
3- (4-fluorophenyl) -6-methoxy-2- (4-methyl-3-nitrophenyl) imidazo [1,2-b]Pyridazine
3-bromo-6-methoxy-2- (4-methyl-3-nitrophenyl) imidazo [1,2-b]Pyridazine (0.100g, 0.275mmol), 4-fluorophenylboronic acid (0.412mmol)Sodium carbonate (0.825mmol) was dissolved with 6mL isopropanol and 2mL water with stirring, nitrogen was bubbled through (5 min), bis (triphenylphosphine) palladium dichloride (0.0275g) was added, the reaction mixture was heated at 80 ℃ for 6h, cooled, diluted with 50mL saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 × 25mL), the organic phases were combined, dried over sodium sulfate, filtered and concentrated to dryness, the crude product was purified by chromatography (hexane-ethyl acetate) to give the title compound (0.092g, yellow solid) in 88% yield Rf0.47(1:1 ethyl acetate: hexane); LCMS (M/z) =379.4[ M + H]+，tR=3.07 min.
Example 11
5- (3- (4-fluorophenyl) -6-methoxyimidazo [1, 2-b)]Pyridazin-2-yl) -2-methylaniline
Reacting 3- (4-fluorophenyl) -6-methoxy-2- (4-methyl-3-nitrophenyl) imidazo [1,2-b]Pyridazine (0.075g, 0.0198mmol) was dissolved with stirring in 6mL of ethanol and 2mL of water containing acetic acid (1.18mmol), iron powder (0.055g, 0.991mmol) was added, the reaction mixture was heated at 80 ℃ for 2 hours, cooled, concentrated under reduced pressure, and 50mL of saturated aqueous sodium bicarbonate solution was added, the mixture was extracted with ethyl acetate (3 × 20mL), the organic phases were combined, dried over sodium sulfate, filtered and concentrated to dryness, the crude product was purified by chromatography (hexane-ethyl acetate) to give the title compound (0.065g, yellow solid) in 95% yield Rf0.36(95:5 dichloromethane: methanol); LCMS (M/z) =349.4[ M + H]+，tR=2.31 minutes.
Example 12
N- (5- (3- (4-fluorophenyl) -6-methoxyimidazo [1, 2-b)]Pyridazin-2-yl) -2-methylphenyl) pivaloyl Amines as pesticides
Reacting 5- (3- (4-fluorophenyl) -6-methoxyimidazo [1, 2-b)]Pyridazin-2-yl) -2-methylaniline (0.025g, 0.072mmol) was dissolved with stirring in 1mL of acetonitrile containing pyridine (0.215mmol) and trimethylacetyl chloride (0.072mmol) was added. The mixture was stirred at room temperature for 4 hours, then concentrated to dryness and purified by chromatography (hexane-ethyl acetate) to give the title compound (0.028g, yellow solid) in yield: 90 percent. Rf0.28(1:1 ethyl acetate: hexane); LCMS (M/z) =433.5[ M + H]+，tR=2.74 minutes. (same as the compound in example 114)
Example 13
5- (3-bromo-6-methoxyimidazo [1, 2-b)]Pyridazin-2-yl) -2-methylaniline
3-bromo-6-methoxy-2- (4-methyl-3-nitrophenyl) imidazo [1,2-b]Pyridazine (0.190g, 0.523mmol) was dissolved with stirring in 15mL ethanol and 5mL water containing acetic acid (3.13mmol), iron powder (0.146g, 2.61mmol) was added, the reaction mixture was heated at 80 ℃ for 2 hours, cooled, concentrated under reduced pressure, and 50mL saturated aqueous sodium bicarbonate was added, the mixture was extracted with ethyl acetate (3 × 25mL), the organic phases were combined, dried over sodium sulfate, filtered and concentrated to dryness the crude product was purified by chromatography (using a hexane to ethyl acetate gradient) to give the title compound (0.170g, off-white solid) in 89% yield Rf0.18(1:1 ethyl acetate: hexane); LCMS (M/z) =333.2, 335.2[ M + H]+，tR=2.22 minutes.
Example 14
N- (5- (3-bromo-6-methoxyimidazo [1, 2-b)]Pyridazin-2-yl) -2-methylphenyl) pivaloyl amides
Reacting 5- (3-bromo-6-methoxyimidazo [1,2-b ]]Pyridazin-2-yl) -2-methylaniline (0.165g, 0.495mmol) was dissolved in 25mL of acetonitrile containing pyridine (1.48mmol) and trimethylacetyl chloride (0.495mmol) was added. The mixture was stirred at room temperature for 4 hours, then concentrated to dryness and purified by chromatography (hexane-ethyl acetate) to give the title compound (0.200g, white solid), yield: 97 percent. Rf0.41(1:1 ethyl acetate: hexane); LCMS (M/z) =417.3, 419.3[ M + H [)]+，tR=2.76 min.
Example 15
N- (5- (6-methoxy-3-methylimidazo [1,2-b ]]Pyridazin-2-yl) -2-methylphenyl) pivaloyl amides
Mixing N- (5- (3-bromo-6-methoxyimidazo [1,2-b ]]Pyridazin-2-yl) -2-methylphenyl) pivaloamide (0.050g, 0.119mmol), methylboronic acid (0.357mmol), potassium phosphate (0.714mmol) and 2- (dicyclohexylphosphine) -2', 6' -dimethoxybiphenyl (0.0238mmol) were dissolved in a mixture of 4mL of toluene and 0.4mL of water, nitrogen was passed over (5 min), and palladium acetate (0.0119mmol) was added. The reaction mixture was heated at 100 ℃ for 14 hours, then cooled and concentrated to dryness. The crude product was purified by chromatography (hexanes-ethyl acetate) to give the title compound (2.4mg, white solid), yield: 6 percent. Rf0.64 (ethyl acetate); LCMS (m/z) =353.4[M+H]+，tR=2.15 min. (same as the compound in example 121)
Example 16
2-bromo-1- [ 3-nitro-4- (trifluoromethyl) phenyl]Ethanones
3-Nitro-4- (trifluoromethyl) benzoic acid (Matrixscientific, 2.35g, 10mmol) was dissolved in thionyl chloride (22mL, 300 mmol). The solution was stirred with heating at 95 ℃ for 16 h, then cooled, concentrated, and dichloromethane (51mL) and trimethylsilyldiazomethane (20mL, 2M in hexanes, 40mmol) were added and stirred at room temperature for 2 h. The mixture was cooled to 0 deg.C and hydrogen bromide/acetic acid (6.33mL, 33% hydrogen bromide in acetic acid) was added dropwise with nitrogen evolution. After the addition was complete, the mixture was stirred at 0 ℃ for 5 minutes, then concentrated and purified by silica gel chromatography (dichloromethane) to give the title compound (2.59g, 83% yield). LCMSM/z =313.5[ M + H%]+，tR=2.65 minutes.
Example 17
6-chloro-2- [ 3-nitro-4- (trifluoromethyl) phenyl]Imidazo [2, 1-f)]Pyridazine
6-chloro-3-aminopyridazine (0.842g, 0.0065mol) and 2-bromo-1- [ 3-nitro-4- (trifluoromethyl) phenyl]Ethanone (2.03g, 0.65mmol) was dissolved in 37.34mL of acetonitrile with stirring and heated at 90 ℃ for 48 hours. The reaction mixture was concentrated and purified by silica gel chromatography (dichloromethane to ethyl acetate) to give the title compoundMaterial (1.62g, 73% yield). LCMSM/z =343.3[ M + H]+，tR=3.15 min.
Example 18
5- (6-chloroimidazo [2, 1-f)]Pyridazin-2-yl) -2- (trifluoromethyl) anilines
Iron powder (0.489g) was added to 6-chloro-2- [ 3-nitro-4- (trifluoromethyl) phenyl]Imidazo [2, 1-f)]Pyridazine (0.600g, 1.75mmol), acetic acid (0.802mL) and ethanol/water (10mL, 4:1) in a mixture the mixture was heated at 80 ℃ for 2 hours then cooled, concentrated, 50mL saturated aqueous sodium bicarbonate was added and extracted with ethyl acetate (2 × 50mL) the organic phase was dried and concentrated to give 530mg of the title compound without further purification lcmm/z =313.4[ M + H ]. the title compound was isolated as a solid]+，tR=2.82 minutes.
Example 19
N- (5- (6-chloroimidazo [1,2-b ]]Pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamides
Reacting 5- (6-chloroimidazo [2,1-f ]]Pyridazin-2-yl) -2- (trifluoromethyl) aniline (0.531g, 1.7mmol), acetonitrile (14mL) and pyridine (0.275mL) were added to a 40mL vial. To the stirred mixture was added trimethylacetyl chloride (0.419mL, 3.4mmol) and the mixture was heated at 80 ℃ for 20 minutes. The reaction mixture was concentrated, 25mL of ethyl acetate was added, and the mixture was washed once with hydrochloric acid (15mL, 1M) and once with sodium hydroxide solution (15mL, 1M), respectively. The organic phase is dried, concentrated and passed over silica gelPurification by chromatography (0-100% ethyl acetate in hexanes) gave the title compound (630mg, 93% yield). LCMS (M/z) =397.4, 399.3[ M + H]+，tR=2.87 minutes. (same as the compound in example 126)
Example 20
N- [5- (6-cyclopentyl-imidazo [2,1-f ]]Pyridazin-2-yl) -2- (trifluoromethyl) phenyl]-2, 2-dimethyl-propane Amides of carboxylic acids
A vial was charged with N- [5- (6-chloroimidazo [2,1-f ]]Pyridazin-2-yl) -2- (trifluoromethyl) phenyl]-2, 2-dimethyl-propionamide (0.032g, 0.08mmol), cyclopentyl zinc bromide (0.12mL, 2M in tetrahydrofuran, 0.24mmol), [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (6mg, 0.01mmol) and tetrahydrofuran (0.32 mL). The reaction flask was purged with nitrogen and heated in a microwave at 150 ℃ for 2 hours. To the mixture was added saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (hexane to ethyl acetate) to give the title compound 3.5mg, yield: 11 percent. LCMSM/z =431.5[ M + H%]+，tR=3.21 minutes. (same as the compound in example 316)
Example 21
2, 2-dimethyl-N- [5- (6-methylaminoimidazo [2, 1-f)]Pyridazin-2-yl) -2- (trifluoromethyl) phenyl]C3 Amides of carboxylic acids
Mixing N- [5- (6-chloroimidazo [2,1-f ]]Pyridazin-2-yl) -2- (trifluoromethyl) phenyl]-2, 2-dimethyl-propionamide (0.032g, 0.08mmol), tetrahydrofuran (0.649mL) and methylamine (0.08mL, 2M in tetrahydrofuran, 0.16mmol) were added to an 8mL vial. The mixture was heated and stirred at 80 ℃ for 16 hours. The mixture was concentrated on celite and purified by silica gel chromatography (0-100% ethyl acetate in dichloromethane) to give the title compound 11mg, yield: 35 percent. LCMSM/z =392.5[ M + H ]]+，tR=2.36 min. (same as the compound in example 137)
Example 22
2, 2-dimethyl-N- [5- [6- (4-methyl-1-piperidinyl) imidazo [2,1-f]Pyridazin-2-yl radicals]-2- (trifluoromethyl) Radical) phenyl]Propionamide
DMF (1mL), 4-methylpiperidine (0.030g), cesium carbonate (0.130g) and N- [5- (6-chloroimidazo [2, 1-f)]Pyridazin-2-yl) -2- (trifluoromethyl) phenyl]-2, 2-dimethyl-propionamide (0.0396g, 0.1mmol) was added to an 8mL vial the mixture was stirred at 120 ℃ for 16 hours, then diluted with 5mL of water and extracted with ether (3mL × 2) the organic phase was dried and concentrated with celite, purified by silica gel chromatography (0-100% ethyl acetate in hexane) to give the title compound 0.020g, yield: 43%. LCMSm/z =460.6[ M + H2 ]]+，tR=3.14 minutes. (same as the compound in example 233)
Example 23
N- [5- [6- (4, 4-difluoro-1-piperidinyl) imidazo [2, 1-f)]Pyridazin-2-yl radicals]-2- (trifluoromethyl) phenyl]- 2, 2-dimethyl-propionamide
DMF (1mL), 4-difluoropiperidine hydrochloride (0.048g), cesium carbonate (0.200g) and N- [5- (6-chloroimidazo [2, 1-f)]Pyridazin-2-yl) -2- (trifluoromethyl) phenyl]-2, 2-dimethyl-propionamide (0.0396g, 0.1mmol) was added to an 8mL vial the mixture was stirred at 120 ℃ for 16 hours, then diluted with 5mL of water and extracted with ether (3mL × 2) the organic phase was dried, concentrated with celite, purified by silica gel chromatography (0-100% ethyl acetate in hexane) to give the title compound 0.015g, yield: 31%, (lcmm sm/z =482.56[ M + H2 ])]+，tR=2.89 minutes. (same as the Compound in example 235)
Example 24
N- [5- [6- [ (cis) -2, 6-dimethylmorpholin-4-yl)]Imidazo [2, 1-f)]Pyridazin-2-yl radicals]-2- (trifluoromethyl) Radical) phenyl]-2, 2-dimethyl-propionamide
DMF (1mL), cis-2, 6-dimethylmorpholine (0.034g), cesium carbonate (0.130g) and N- [5- (6-chloroimidazo [2, 1-f)]Pyridazin-2-yl) -2- (trifluoromethyl) phenyl]-2, 2-dimethyl-propionamide (0.0396g, 0.1mmol) was added to an 8mL vial the mixture was stirred at 120 ℃ for 16 hours, then diluted with 5mL of water and extracted with ether (3mL × 2) the organic phase was dried, concentrated with celite, purified by silica gel chromatography (0-100% ethyl acetate in hexane) to give the title compound 0.027g, yield: 57%. lcmm/z =476.6[ M + H2 ]]+，tR=2.77 minutes. (same as the Compound in example 250)
Example 25
2, 2-dimethyl-N- [5- [6- (6-methyl-2-pyridyl) imidazo [2, 1-f)]Pyridazin-2-yl radicals]-2- (trifluoromethyl) Radical) phenyl]Propionamide
Mixing N-tert-butyl-5- (6-chloroimidazo [2,1-f ]]Pyridazin-2-yl) -2- (trifluoromethyl) benzamide (0.025g, 0.063mmol), 6-methyl-2-pyridylzinc bromide (Sigma-Aldrich, 0.26mL, 0.5M in tetrahydrofuran, 0.13mmol), bis (triphenylphosphine) palladium (II) dichloride (0.0044g, 0.0063mmol) and tetrahydrofuran (0.26mL) were added to an 8mL vial. The reaction vessel was purged with nitrogen, and the mixture was stirred at 60 ℃ for 16 hours. The mixture was concentrated, ethyl acetate and dichloromethane (1:1) were added, filtered and purified over silica gel (0-100% ethyl acetate in dichloromethane) to give the title compound 22mg, yield: 78 percent. LCMSM/z =454.6[ M + H%]+，tR=3.34 minutes. (same as the compound in example 149)
Example 26
2, 2-dimethyl-N- [5- [6- (5-methyl-2-pyridyl) imidazo [2, 1-f)]Pyridazin-2-yl radicals]-2- (trifluoromethyl) Radical) phenyl]Propionamide
Mixing N-tert-butyl-5- (6-chloroimidazo [2,1-f ]]Pyridazin-2-yl) -2- (trifluoromethyl) benzamide (0.025g, 0.063mmol), 5-methyl-2-pyridylzinc bromide (Sigma-Aldrich, 0.26mL,0.13mmol, 0.5M in tetrahydrofuran), bis (triphenylphosphine) palladium (II) dichloride (0.0044g, 0.0063mmol) and tetrahydrofuran (0.26mL) were added to an 8mL vial. The reaction vessel is purged with nitrogen, andand the mixture was stirred at 60 ℃ for 16 hours. The mixture was concentrated, ethyl acetate and dichloromethane (1:1) were added, filtered and purified over silica gel (0-100% ethyl acetate in dichloromethane) to give the title compound 20mg, yield: 74 percent. LCMSM/z =454.6[ M + H%]+，tR=3.32 minutes. (same as the Compound in example 150)
Example 27
2, 2-dimethyl-N- [5- [6- (4-methyl-2-pyridyl) imidazo [2, 1-f)]Pyridazin-2-yl radicals]-2- (trifluoromethyl) Radical) phenyl]Propionamide
Mixing N-tert-butyl-5- (6-chloroimidazo [2,1-f ]]Pyridazin-2-yl) -2- (trifluoromethyl) benzamide (0.025g, 0.063mmol), 4-methyl-2-pyridylzinc bromide (0.26mL, 0.13mmol, 0.5M in tetrahydrofuran), bis (triphenylphosphine) palladium (II) dichloride (0.0044g, 0.0063mmol) and tetrahydrofuran (0.26mL) were added to an 8mL vial. The reaction vessel was purged with nitrogen, and the mixture was stirred at 60 ℃ for 16 hours. The mixture was concentrated, ethyl acetate and dichloromethane (1:1) were added, filtered and purified over silica gel (0-100% ethyl acetate in dichloromethane) to give the title compound 18mg, yield: 67%. LCMSM/z =454.6[ M + H%]+，tR=3.32 minutes. (same as the compound in example 151)
Example 28
2, 2-dimethyl-N- [5- [6- (3-methyl-2-pyridyl) imidazo [2, 1-f)]Pyridazin-2-yl radicals]-2- (trifluoromethyl) Radical) phenyl]Propionamide
Mixing N-tert-butyl-5- (6-chloroimidazo [2,1-f ]]Pyridazin-2-yl) -2- (trifluoromethyl) benzamide (0.025g, 0.063mmol), 3-methyl-2-pyridylzinc bromide (0.26mL, 0.13mmol, 0.5M in tetrahydrofuran), bis (triphenylphosphine) palladium (II) dichloride (0.0044g, 0.0063mmol) and tetrahydrofuran (0.26mL) were added to an 8mL vial. The reaction vessel was purged with nitrogen, and the mixture was stirred at 60 ℃ for 16 hours. The mixture was concentrated, ethyl acetate and dichloromethane (1:1) were added, filtered and purified over silica gel (0-100% ethyl acetate in dichloromethane) to give the title compound 19mg, yield: 70 percent. LCMSM/z =454.6[ M + H%]+，tR=3.06 min. (same as the compound in example 152)
Example 29
N- [5- (6-cyanoimidazo [2, 1-f)]Pyridazin-2-yl) -2- (trifluoromethyl) phenyl]-2, 2-dimethyl-propionyl Amines as pesticides
Mixing N- [5- (6-chloroimidazo [2,1-f ]]Pyridazin-2-yl) -2- (trifluoromethyl) phenyl]-2, 2-dimethyl-propionamide (0.059g, 0.15mmol), copper cyanide (0.035g, 0.3mmol) and 4-methylmorpholine (0.43mL) were added to an 8mL vial. The mixture was stirred in a microwave at 215 ℃ for 4 hours, then cooled, diluted with ether and saturated aqueous sodium bicarbonate solution and the two-phase mixture was filtered. The organic phase was separated off and the aqueous phase was extracted twice more with diethyl ether. The organic phases were combined, dried, concentrated, and purified by preparative thin-layer chromatography (1:1 hexane: ethyl acetate) to give the title compound 15mg, yield: 26 percent. LCMSM/z =388.5[ M + H%]+，tR=2.56 minutes. (same compound as in example 173)
Example 30
2- [3- (2, 2-dimethylpropionylamino) -4- (trifluoromethyl) phenyl]Imidazo [2, 1-f)]Pyridazine-6-carboxamides
Reacting N- [5- (6-cyano-imidazo [2,1-f ]]Pyridazin-2-yl) -2- (trifluoromethyl) phenyl]-2, 2-dimethyl-propionamide (0.019g, 0.05mmol), ethanol-dimethyl sulfoxide (1.2mL, 5:1), sodium hydroxide solution (0.1mL, 1M) and hydrogen peroxide (0.1mL, 30%) were added to an 8mL vial the mixture was stirred at room temperature for 2 hours, diluted with 4mL of water, extracted with ethyl acetate (2 ×) and dichloromethane (1 ×) the organic phase was dried, concentrated with celite and purified over silica gel (0-100% ethyl acetate in dichloromethane) to give the title compound 12mg, yield 60%, [ lcm/z =406.5[ M + H =406.]+，tR=2.12 minutes. (same as the Compound in example 180)
Example 31
6-chloro-2- [ 3-nitro-4- (trifluoromethyl) phenyl]Imidazo [1, 2-a ]]Pyridine compound
2-amino-5-chloropyridine (0.064g, 0.5mmol) and 2-bromo-1- [ 3-nitro-4- (trifluoromethyl) phenyl]A solution of ethanone (0.156g, 0.5mmol) in 3mL of acetonitrile was stirred at 100 ℃ for 18 h. The mixture was concentrated and purified on silica gel (0 to 100% ethyl acetate in dichloromethane) to give the title compound 165mg, yield: 97 percent. LCMSM/z =342.3[ M + H]+，tR=2.86 minutes.
Example 32
6-chloro-2- [ 3-amino-4- (trifluoromethyl) phenyl]Imidazo [1, 2-a ]]Pyridine compound
Iron powder (0.140g) was added to 6-chloro-2- [ 3-nitro-4- (trifluoromethyl) phenyl]Imidazo [1, 2-a ]]Pyridine (0.171g), acetic acid (0.230mL), and ethanol-water (2mL, 4: 1). The mixture was stirred at 80 ℃ for 2 hours, then cooled, concentrated, added with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate and dichloromethane. The organic phase was dried and concentrated to give the title compound 150mg, yield: 96% without further purification. LCMS (M/z) =312.4[ M + H]+，tR=1.96 minutes.
Example 33
N- [5- (6-chloroimidazo [1, 2-a ]]Pyridin-2-yl) -2- (trifluoromethyl) phenyl]-2, 2-dimethyl-propionamide
Reacting 5- (6-chloroimidazo [1, 2-a ]]Pyridin-2-yl) -2- (trifluoromethyl) aniline (0.156g, 0.5mmol), acetonitrile (4.12mL) and pyridine (0.081mL) were added to a 20mL vial. To the mixture was added trimethylacetyl chloride (0.123mL, 1mmol) and stirred at 80 ℃ for 20 minutes. The solution was concentrated, 10mL of ethyl acetate was added, and washed once with each of hydrochloric acid (10mL, 1M) and sodium hydroxide solution (10mL, 1M) in that order. The organic phase was dried, concentrated and purified on silica gel (0-100% ethyl acetate in hexane) to give the title compound 106mg, yield: 54 percent. LCMS (M/z) =396.4[ M + H]+，tR=2.54 minutes. (andthe compound of example 81 is the same)
Example 34
6-bromo-2- [ 3-nitro-4- (trifluoromethyl) phenyl]Imidazo [1, 2-a ]]Pyridine compound
2-amino-5-bromopyridine (0.259g, 1.5mmol) and 2-bromo-1- [ 3-nitro-4- (trifluoromethyl) phenyl]A solution of ethanone (0.468g, 1.5mmol) in 3mL acetonitrile was heated at 100 ℃ for 18 h. The mixture was concentrated to give 618mg of the title compound without further purification. LCMSM/z =388.3[ M + H%]+，tR=2.94 minutes.
Example 35
6-bromo-2- [ 3-amino-4- (trifluoromethyl) phenyl]Imidazo [1, 2-a ]]Pyridine compound
Iron powder (0.447g) was added to 6-bromo-2- [ 3-nitro-4- (trifluoromethyl) phenyl]Imidazo [1, 2-a ]]Pyridine (0.618g), acetic acid (0.733mL), and ethanol-water (10mL, 4: 1). The mixture was stirred at 80 ℃ for 2 hours, then concentrated, then saturated aqueous sodium bicarbonate solution was added and extracted with ethyl acetate and dichloromethane. The organic phase was dried and concentrated to give the title compound 463mg without further purification. LCMS (M/z) =356.4[ M + H]+，tR=2.04 min.
Example 36
N- [5- (6-bromoimidazo [1, 2-a ]]Pyridin-2-yl) -2- (trifluoromethyl) phenyl]-2, 2-dimethylpropionamide
To a 20mL bottle was added 5- (6-bromoimidazo [1, 2-a ]]Pyridin-2-yl) -2- (trifluoromethyl) aniline (0.463g, 0.0013mol), acetonitrile (7mL) and pyridine (0.210 mL). To the mixture was added trimethylacetyl chloride (0.320mL, 2.6mmol), and stirred at 80 ℃ for 20 minutes. The solution was concentrated, ethyl acetate (10mL) was added, and washed once with HCl (10mL, 1M) and NaOH (10mL, 1M), respectively, in that order. The organic phase was dried, concentrated and purified on silica gel (0-100% ethyl acetate in hexane) to give the title compound (212mg, 37% yield). LCMSM/z =440.4[ M + H%]+，tR=2.67 minutes.
Example 37
N- [5- [6- (2-fluorophenyl) imidazo [1, 2-a)]Pyridin-2-yl) -2- (trifluoromethyl) phenyl]-2, 2-dimethyl Cyclopropyl amides
To an 8mL bottle was added N- [5- (6-bromoimidazo [1, 2-a ]]Pyridin-2-yl) -2- (trifluoromethyl) phenyl]-2, 2-Dimethylpropionamide (0.044g, 0.11mmol), 2-fluorophenylboronic acid (Combi-Blocks, 28mg, 0.2mmol), Na2CO3(0.032g, 0.3mmol), bis (triphenylphosphine) palladium (II) dichloride (7mg, 0.01mmol) and isopropanol-water (1mL, 3: 1). The reaction mixture was stirred at 80 ℃ for 16 h, then cooled, concentrated, added ethyl acetate and dichloromethane (1:1), filtered, concentrated with celite, and purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to give the title compound (25.4mg, 55% yield). LCMSM/z =456.5[ M + H ]]+，tR=2.69 minutes. (Compounds of the same type as in example 83)
Example 38
N- [5- [6- [ 2-fluoro-5- (trifluoromethyl) phenyl]Imidazo [1, 2-a ]]Pyridin-2-yl) -2- (trifluoromethyl) benzene Base of]-2, 2-dimethylpropionamide
To an 8mL bottle was added N- [5- (6-bromoimidazo [1, 2-a ]]Pyridin-2-yl) -2- (trifluoromethyl) phenyl]-2, 2-Dimethylpropionamide (0.044g, 0.11mmol), 2-fluoro-5- (trifluoromethyl) phenylboronic acid (Combi-Blocks, 42mg, 0.2mmol), Na2CO3(0.032g, 0.3mmol), bis (triphenylphosphine) palladium (II) dichloride (7mg, 0.01mmol) and isopropanol-water (1mL, 3: 1). The mixture was stirred at 80 ℃ for 16 h, then cooled, concentrated, added with ethyl acetate and dichloromethane (1:1), filtered, concentrated with celite, and purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to give the title compound (29.9mg, 57% yield). LCMSM/z =524.5[ M + H%]+，tR=3.09 minutes. (Compounds of the same type as in example 84)
Example 39
6-chloro-3-methyl-2-phenylimidazo [1,2-b ]]Pyridazine
6-chloropyridazin-3-amine (1.00g, 7.71mmol) and 2-bromo-1-phenyl-1-propanone (Sigma-Aldrich, 1.54g, 7.71mmol) were dissolved with stirring in 50mL acetonitrile and heated at 80 ℃ for 16 h. The mixture was concentrated to dryness and purified by chromatography (hexane-ethyl acetate)Ester) to afford the title compound (1.52g, 81% yield) as a tan solid. Rf0.52(1:1 ethyl acetate: hexane); LCMS (M/z) =244.2, 246.3[ M + H]+，tR=2.61 minutes.
Example 40
6- (4- (4-fluorophenylmethyl) piperazin-1-yl) -3-methyl-2-phenylimidazo [1,2-b]Pyridazine
6-chloro-3-methyl-2-phenylimidazo [1,2-b ]]Pyridazine (1.00g, 4.35mmol) and 1- (4-fluorophenylmethyl) piperazine (Sigma-Aldrich, 1.54g, 4.35mmol) were dissolved in acetonitrile (50mL) containing triethylamine (13.0mmol) and heated with a microwave at 180 ℃ for 5 hours. The reaction mixture was concentrated to dryness and then purified by chromatography (hexanes-ethyl acetate) to afford the title compound (0.82g, 81% yield) as an off-white solid. Rf0.30 (ethyl acetate); LCMS (M/z) =402.4[ M + H]+，tR=1.74 minutes. (Compounds of the same type as in example 134)
EXAMPLE 41
2-bromo-1- [ 3-bromo-4- (trifluoromethyl) phenyl]Ethanones
A mixture of 3-amino-4- (trifluoromethyl) benzoic acid (matrix scientific, 2.05g, 10mmol) with aqueous hydrobromic acid (48% aq., 20mL) and water (67mL) was cooled to 0 deg.C and sodium nitrite (0.828g) was added portionwise over 15 minutes with stirring. After stirring the solution for an additional 30 minutes, the mixture was added dropwise to a solution of CuBr (2.5g) in aqueous hydrobromic acid (48% aqueous solution, 40mL) and water (100mL)In solution. The mixture was stirred at 75 ℃ for 2 hours, then at room temperature for 16 hours, the pH of the mixture was raised to above 10 with 20% NaOH, and then filtered through celite. The resulting filtrate was acidified with 6M hydrochloric acid to pH1 and extracted with dichloromethane (3 × 100 mL). The organic phases are combined and Na2SO4Drying, filtration and concentration gave 3-bromo-4- (trifluoromethyl) benzoic acid (2.30g, 85.5% yield). LCMSM/z =269.1, 271.1[ M + H [ ]]+。
The crude acid (2.0g, 7.43mmol) was combined with thionyl chloride (25mL) and refluxed for 16 h. The mixture was concentrated under reduced pressure to give a yellow oil, which was dissolved in 50mL of dichloromethane and trimethylsilyl diazomethane (18.5mL, 2M in hexanes) was added. Stir at room temperature for 4 hours, cool to 0 deg.C, and slowly add HBr/HOAc (5.25mL, 33% HBr in acetic acid) with gas evolution. After addition was complete and stirring at 0 ℃ for 20 minutes, then concentration under reduced pressure gave the title compound (2.48g, 96%) as an orange-yellow oil without further purification.
Example 42
2- [ 3-bromo-4- (trifluoromethyl) phenyl]-6-chloroimidazo [1,2-b]Pyridazine
5-Chloropyridazin-2-amine (0.928g, 7.1mmol) and 2-bromo-1- [ 3-bromo-4- (trifluoromethyl) phenyl]Ethanone (2.48g, 7.1mmol) was dissolved in 100mL acetonitrile with stirring and heated at 80 ℃ for 18 h. The mixture was concentrated over celite and purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to give the title compound (1.63g, 61% yield). LCMSm/z =376.1, 378.1[ M + H]+，tR=3.19 minutes. (Compound as in example 203)
Example 43
2- [ 3-bromo-4- (trifluoromethyl) phenyl]-6-ethoxyimidazo [1,2-b]Pyridazine
2- [ 3-bromo-4- (trifluoromethyl) phenyl]-6-chloroimidazo [1,2-b]Pyridazine (1.5g, 3.98mmol) was mixed with THF (50mL), and sodium ethoxide (21% in ethanol, 2.97mL) was added. The mixture was stirred at 50 ℃ for 4h, then the THF solution was concentrated over celite and purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to give the title compound (1.36g, 88.8% yield). LCMS (M/z) =386.3, 388.3[ M + H]+，tR=3.34 minutes. (Compounds of the same type as in example 204)
Example 44
5- (6-ethoxyimidazo [2, 1-f)]Pyridazin-2-yl) -2- (trifluoromethyl) benzonitrile
2- [ 3-bromo-4- (trifluoromethyl) phenyl]-6-ethoxyimidazo [2,1-f]Pyridazine (0.050g, 0.129mmol) and CuCN (0.058g) were added to 4-methylmorpholine (2.0mL), and microwave-heated at 220 ℃ for 10 minutes. The mixture was diluted with methanol (10mL) and the solids were filtered off. The crude solution was distilled to remove methanol. Water (50mL) was added and the insoluble solid was collected. The crude product was purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to afford the title compound (0.03g, 71% yield). LCMSM/z =333.3[ M + H]+。
Example 45
5- (6-ethoxyimidazo [2, 1-f)]Pyridazin-2-yl) -2- (trifluoromethyl) benzoic acid
Mixing 5- (6-ethoxy imidazo [2,1-f ]]A mixture of pyridazin-2-yl) -2- (trifluoromethyl) benzonitrile (0.030g) and NaOH (2mL, 10N) was refluxed for 48 hours. The reaction mixture was cooled and extracted with diethyl ether (2 × 2 mL). The pH was lowered to 1 and extracted with ethyl acetate (2x3 mL). The organic phase was collected, dried and concentrated to give the title compound (0.03g, 99% yield). LCMSM/z =352.3[ M + H%]+。
Example 46
N-tert-butyl-5- (6-ethoxyimidazo [1, 2-b)]Pyridazin-2-yl) -2- (trifluoromethyl) benzamides
To an 8mL vial was added acetonitrile (0.5mL), 5- (6-ethoxyimidazo [2, 1-f)]Pyridazin-2-yl) -2- (trifluoromethyl) benzoic acid (0.035g, 0.0001mol), tert-butylamine (0.016mL), triethylamine (0.055mL), and (benzotriazol-1-oxy) tris (dimethylamino) phosphonium hexafluorophosphate (0.088 g). The mixture was stirred and heated at 80 ℃ for 16 h, cooled, concentrated on celite, and purified on silica gel (0-100% ethyl acetate in hexanes) to give the title compound (0.011g, 28% yield). LCMSM/z =407.5[ M + H%]+，tR=2.74 minutes. (Compounds of the same type as in example 211)
Example 47
5- (6-ethoxy)Imidazo [1,2-b ]]Pyridazin-2-yl) -2- (trifluoromethyl) benzene-1-sulfonyl chloride
Mixing 5- (6-ethoxy imidazo [1,2-b ]]Pyridazin-2-yl) -2- (trifluoromethyl) aniline (1.00g, 3.10mmol) was mixed with concentrated hydrochloric acid (6mL) with stirring, a solution of sodium nitrite (3.41mmol) in water (3mL) was added dropwise at-10 deg.C, and the reaction mixture was stirred for 30 minutes at-10 deg.C. The mixture was then added in small portions to SO containing CuCl (1.55mmol) at 0 deg.C2AcOH (. about.0.2 g/mL, 50mL) solution. The reaction was allowed to cool to room temperature and stirred for an additional hour. The mixture was poured into ice water (400mL) and the precipitate was collected by filtration, washed with ice water (3 × 25mL) and dried in vacuo to give the title compound 1.02g (81%) as a green solid. The product was not further purified.
Example 48
N-cyclopropyl-5- (6-ethoxyimidazo [1,2-b ]]Pyridazin-2-yl) -2- (trifluoromethyl) benzenesulfonamides
Cyclopropylamine (0.025mL, 0.369mmol) was dissolved in acetonitrile (1mL) and 5- (6-ethoxyimidazo [1,2-b ] was added]Pyridazin-2-yl) -2- (trifluoromethyl) benzene-1-sulfonyl chloride (0.123 mmol). The mixture was stirred at 60 ℃ for 12 hours. The mixture was concentrated to dryness and then purified by chromatography eluting with a gradient (hexanes to ethyl acetate) to afford the title compound 0.035g (67%) as a white solid. LCMS (M/z) =427.4[ M + H%]+，tR=2.76 min. (Compounds of the same type as in example 212)
Example 49
6-ethoxy-2- (3- (pyridin-2-yl) -4- (trifluoromethyl) phenyl) imidazo [1,2-b]Pyridazine
To 2- (3-bromo-4- (trifluoromethyl) phenyl) -6-ethoxyimidazo [1,2-b]Pyridazine (0.025g, 0.0647mmol) in THF (0.647mL) containing pyridin-2-ylzinc (II) bromide (0.323mmol) and Pd (dppf) Cl was added2(0.0194 mmol). Heating the mixture at 60 deg.C for 12 hr, cooling, and adding saturated NaHCO3Aqueous solution (1mL) was quenched and extracted with dichloromethane (3 × 3 mL). The organic phases were combined and concentrated to dryness. The crude product was purified by preparative thin layer chromatography eluting with dichloromethane: ethyl acetate: methanol (1:1:0.1) to afford the title compound 0.0022g (9%) as a white solid. Rf0.35(1:1 ethyl acetate: hexane); LCMS (M/z) =385.4[ M + H [)]+，tR=2.69 minutes. (Compounds of the same type as in example 218)
Example 50
1- (4-methyl-3-nitrophenyl) -1-propanone
Fuming nitric acid (100mL) was added dropwise to 1-p-tolyl-1-propanone (Sigma-Aldrich, 121mmol) at 0 ℃ while maintaining the reaction temperature below 10 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour and poured into excess ice water. The mixture was left in the refrigerator overnight, and the precipitate was collected by filtration, washed with ice water, and dissolved in dichloromethane. With saturated NaHCO3The organic solution was washed with aqueous solution (100mL), the organic phase was collected, Na2SO4Dried, filtered and concentrated to dryness. The crude product was purified by chromatography (hexanes-ethyl acetate) to afford the title compound (14.8g, 63%) as a pale yellow solid: rf0.5(1:4 ethyl acetate: hexane).
Example 51
2-bromo-1- (4-methyl-3-nitrophenyl) -1-propanone
1- (4-methyl-3-nitrophenyl) -1-propanone (6.6g, 34.1mmol) was dissolved in dichloromethane (200mL) and liquid bromine (34.1mmol) was added dropwise over 20 minutes. The reaction was stirred at room temperature for 4 hours and then saturated NaHCO was used3Washed with aqueous solution (100mL), and the organic phase, Na, was collected2SO4Dry, filter and concentrate to dryness to give the title compound 9.0g (97%) as an orange oil: rf0.53(1:1 dichloromethane: hexane).
Example 52
6-chloro-3-methyl-2- (4-methyl-3-nitrophenyl) imidazo [1,2-b]Pyridazine
6-chloropyridazin-3-amine (2.38g, 18.3mmol) and 2-bromo-1- (4-methyl-3-nitrophenyl) -1-propanone (5.0g, 18.3mmol) were dissolved in acetonitrile (100mL) with stirring and heated at 80 ℃ for 16 h. The mixture was concentrated to dryness and then purified by silica gel chromatography (hexanes-ethyl acetate) to afford the title compound (3.2g, 57%) as a pale yellow solid: rf0.30 (dichloromethane); LCMS (M/z) =303.3, 305.2[ M + H]+，tR=2.84 minutes.
Example 53
5- (6-chloro-3-methylimidazo [1,2-b ]]Pyridazin-2-yl) -2-methylaniline
Mixing 6-chloro-3-methyl-2- (4-methyl-3-nitrophenyl) imidazo [1,2-b]Pyridazine (2.00g, 6.60mmol) was dissolved in ethanol (100mL) and water (25mL) containing acetic acid (39.6mmol), and iron (1.84g,33.0mmol) was added. The mixture was heated at 80 ℃ for 6 hours, then cooled, concentrated under reduced pressure, and saturated NaHCO was added3Aqueous solution (100 mL). The mixture was extracted with ethyl acetate (3 × 50 mL). Collecting the organic phase, Na2SO4Dried, filtered and concentrated to dryness. The crude product was purified by chromatography (hexanes-ethyl acetate) to afford the title compound (1.45g,80%) as a yellow solid: rf0.52 (ethyl acetate); LCMS (M/z) =273.3,275.3[ M + H]+，tR=1.79 min.
Example 54
N- (5- (6-chloro-3-methylimidazo [1,2-b ]]Pyridazin-2-yl) -2-methylphenyl) pivaloyl amides
Reacting 5- (6-chloro-3-methylimidazo [1,2-b ]]Pyridazin-2-yl) -2-methylaniline (1.40g,5.13mmol) was dissolved in acetonitrile (100mL) and pyridine (15.3mmol) and trimethylacetyl chloride (5.38mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness and then purified by chromatography (hexane to ethyl acetate gradient elution) to afford the title compound (1.25g,68%) as a yellow solid: rf0.24(1:1 ethyl acetate: hexane); LCMS (M/z) =357.4[ M + H]+，tR=2.51 minutes. (Compound analogous to example 311)
Example 55
N- (5- (6- (2-fluorophenyl) -3-methylimidazo [1, 2-b)]Pyridazin-2-yl) -2-methylphenyl) pivaloyl amides
Mixing N- (5- (6-chloro-3-methylimidazo [1,2-b ]]Pyridazin-2-yl) -2-methylphenyl) pivaloamide (0.100g,0.280mmol), 4-fluorophenylboronic acid (0.420mmol), Na2CO3(0.840mmol), isopropanol (9mL) and water (3mL), N2Displacement for 5 min, PdCl is added2(PPh3)2(0.0280). Heating the mixture at 80 deg.C for 12 hr to obtain saturated NaHCO3Aqueous solution (50mL) diluted and extracted with ethyl acetate (3 × 25 mL). Collecting the organic phase, Na2SO4Dried, filtered and concentrated to dryness. The crude product was purified by chromatography (hexane to ethyl acetate gradient elution) to afford the title compound (0.073g,62%) as a yellow solid: rf0.29(1:1 ethyl acetate: hexane); LCMS (M/z) =417.5[ M + H]+，tR=2.71 minutes. (Compounds of the same type as in example 312)
Example 56
6- (2-fluorophenyl) pyridazin-3-amines
6-chloropyridazin-3-amine (3.00g, 23.1mmol), 4-fluorophenylboronic acid (34.7mmol), Na2CO3(69.3mmol), isopropanol (150mL) and water (50mL), N2Displacement for 5 min, PdCl is added2(PPh3)2(1.15 mmol). Heating the mixture at 80 deg.C for 12 hr, concentrating under reduced pressure, adding saturated NaHCO3Aqueous solution (100mL) and extracted with ethyl acetate (3 × 100 mL). Collecting the organic phase, Na2SO4Dried, filtered and concentrated to dryness. Purifying the crude product by chromatography, and subjecting to gradient chromatographyEluent dichloromethane to 70% dichloromethane ethyl acetate methanol (1:1:0.1) to give the title compound (3.82g, 87%) as a white solid: rf0.37(1:1:0.1 dichloromethane: ethyl acetate: methanol); LCMS (M/z) =190.2[ M + H]+，tR=0.44 min.
Example 57
2- (4-bromo-3-nitrophenyl) -6- (2-fluorophenyl) imidazo [1,2-b]Pyridazine
6- (2-fluorophenyl) pyridazin-3-amine (2.22g, 11.7mmol) and 2-bromo-1- (4-bromo-3-nitrophenyl) ethanone (3.78g, 11.7mmol) were dissolved in acetonitrile (100mL) with stirring and heated at 80 ℃ for 12 hours. The mixture was concentrated to dryness and then purified by chromatography (dichloromethane) to afford the title compound (1.83g, 37%) as a yellow solid: rf0.46 (dichloromethane); LCMS (M/z) =413.3, 415.3[ M + H]+，tR=3.19 minutes.
Example 58
6- (2-fluorophenyl) -2- (3-nitro-4- ((trimethylsilyl) ethynyl) phenyl) imidazo [1,2-b]Pyridazine
2- (4-bromo-3-nitrophenyl) -6- (2-fluorophenyl) imidazo [1,2-b]Pyridazine (0.500g, 1.21mmol), ethynyltrimethylsilane (2.42mmol), PdCl2(PPh3)2(0.0242mmol) was dissolved in THF (50mL) containing triethylamine (6.05mmol) and CuI (0.0242mmol) was added. Will N2The displacement was carried out for 5 minutes, followed by heating at 60 ℃ for 12 hours. Will be mixed withThe compound was filtered, then washed with ethyl acetate, the filtrates combined and concentrated under reduced pressure, and the crude product was purified by chromatography (dichloromethane) to afford the title compound (0.425g, 81%) as a yellow solid: rf0.56 (dichloromethane); LCMS (M/z) =431.4[ M + H]+，tR=3.86 minutes.
Example 59
2- (4- (ethynyl) -3-nitrophenyl) -6- (2-fluorophenyl) imidazo [1,2-b]Pyridazine
Reacting 6- (2-fluorophenyl) -2- (3-nitro-4- ((trimethylsilyl) ethynyl) phenyl) imidazo [1,2-b]Pyridazine (0.250g, 0.58mmol) was dissolved in acetonitrile (100mL) with stirring, and a catalytic amount of cerium carbonate (0.101mmol) in water (0.031mL) was added and heated at 60 ℃ for 4 hours. The mixture was concentrated to dryness and then purified by chromatography (dichloromethane) to afford the title compound (0.170g, 82%) as a yellow solid: rf0.40 (dichloromethane); LCMS (M/z) =359.4[ M + H]+，tR=3.02 minutes.
Example 60
2-ethynyl-5- (6- (2-fluorophenyl) imidazo [1, 2-b)]Pyridazin-2-yl) anilines
Reacting 2- (4- (ethynyl) -3-nitrophenyl) -6- (2-fluorophenyl) imidazo [1,2-b]Pyridazine (0.050g, 0.139mmol) was dissolved in ethanol (3mL) and water (1mL) containing acetic acid (0.834mmol), and iron (0.038g, 0.695mmol) was added. The mixture was stirred and heated at 80 ℃ for 2 hours, then concentrated under reduced pressure, and addedSaturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The organic phase was collected, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by chromatography eluting with a gradient of hexane to ethyl acetate to afford the title compound (0.033g, 73%) as a yellow solid: rf0.30(1:1 ethyl acetate: hexane); LCMS (M/z) =329.4[ M + H]+，tR=2.65 minutes. (same as the compound in example 320)
Example 61
N- (2-ethynyl-5- (6- (2-fluorophenyl) imidazo [1, 2-b)]Pyridazin-2-yl) phenyl) pivaloamides
2-ethynyl-5- (6- (2-fluorophenyl) imidazo [1, 2-b)]Pyridazin-2-yl) aniline (0.030g, 0.0913mmol) was dissolved in acetonitrile (1mL) containing pyridine (0.273mmol), and trimethylacetyl chloride (0.0958mmol) was added. The mixture was stirred at room temperature for 4 hours, then concentrated to dryness, and the residue was purified by silica gel chromatography (hexanes-ethyl acetate) to afford the title compound (0.029g, 78%) as a yellow solid: rf0.58(1:1 ethyl acetate: hexane); LCMS (M/z) =413.5[ M + H]+，tR=3.19 minutes. (Compounds of the same type as in example 321)
Example 62
2- (5-bromo-3-nitropyridin-2-yl) malonic acid diethyl ester
NaH (3.36g, 60% mineral oil, 84.2mmol) was mixed with DMF (60mL) and diethyl malonate (84.2mmol) was added dropwise at 0 ℃.The mixture was allowed to cool to room temperature for 20 minutes and then cooled to 0 ℃. A solution of 5-bromo-2-chloro-3-nitropyridine (Combi-Blocks, 42.1mmol) in DMF (20mL) was added slowly and the reaction was allowed to stand at room temperature and heated at 40 ℃ for 3 hours. The reaction was quenched with aqueous acetic acid (1M, 100mL) and extracted with dichloromethane (3x200 mL). The organic phase was collected, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by chromatography (dichloromethane) to afford the title compound (12.8g, 84%) as an oil: rf0.65 (dichloromethane); LCMS (M/z) =361.3, 363.3[ M + H]+，tR=2.59 minutes.
Example 63
5-bromo-2-methyl-3-nitropyridine
Diethyl 2- (5-bromo-3-nitropyridin-2-yl) malonate (12.5g, 34.6mmol) was mixed with HCl (7N in water, 200mL) with stirring and heated to reflux for 18 h. The mixture was cooled to room temperature and extracted with dichloromethane (3 × 200 mL). Collecting the organic phase, Na2SO4Dried, filtered and concentrated to dryness. The crude product was purified by chromatography (dichloromethane) to afford the title compound (5.8g, 84%) as a yellow solid: rf0.67 (dichloromethane); LCMS (M/z) =217.1, 219.1[ M + H]+，tR=2.01 minutes.
Example 64
2-methyl-3-nitro-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine
5-bromo-2-methyl-3-nitropyridine (0.50g, 0.230mmol), bis (pinacol) diboron (2.30mmol), potassium acetate (4.60mmol) were mixed and dissolved in 1, 4-dioxane (5mL), Pd (dppf) was added2Cl2(0.0194 mmol). The mixture was heated at 100 ℃ for 90 minutes with microwave, cooled, concentrated to dryness, and the crude product was purified by chromatography (hexane-ethyl acetate) to give 0.402g (66%) of the title compound as a yellow solid: LCMS (M/z) (boronic acid) =183.2[ M + H]+，tR=0.69 min.
Example 65
Methyl 2- (3- (2-fluorophenyl) -6-iminopyridazin-1 (6H) -yl) acetate hydrobromide salt
6- (2-fluorophenyl) pyridazin-3-amine (0.500g, 2.64mmol) and methyl 2-bromoacetate (2.90mmol) were dissolved in acetonitrile (15mL) with stirring and heated at 80 ℃ for 4 hours. The mixture was cooled to 0 ℃ and the insolubles were collected by filtration and washed with cold acetonitrile (2x10mL) to give the title compound (0.693g, 76%) as a white solid. LCMS (M/z) =262.3[ M + H]+，tR=0.47 min.
Example 66
2-chloro-6- (2-fluorophenyl) imidazo [1,2-b]Pyridazine
Methyl 2- (3- (2-fluorophenyl) -6-iminopyridazin-1 (6H) -yl) acetate hydrobromide (0.5g, 1.46mmol) was dissolved in chlorobenzene (20mL) and POCl was added3(7.30 mmol). Heating the reaction mixture at 120 deg.C for 4 hr, cooling, and reducing pressureConcentrated to dryness and saturated NaHCO was added3Aqueous solution (25 mL). Extract with dichloromethane (3 × 20 mL). Collecting the organic phase, Na2SO4Dried, filtered and concentrated to dryness. The crude product was purified by silica gel chromatography (hexanes-ethyl acetate) to afford the title compound (0.309g, 85%) as a white solid: rf0.39(1:4 ethyl acetate: hexane); LCMS (M/z) =248.2, 250.2[ M + H [)]+，tR=2.51 minutes.
Example 67
6- (2-fluorophenyl) -2- (6-methyl-5-nitropyridin-3-yl) imidazo [1,2-b]Pyridazine
2-chloro-6- (2-fluorophenyl) imidazo [1,2-b]Pyridazine (0.100g, 0.403mmol), 2-methyl-3-nitro-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.605mmol), Na2CO3(2.01mmol) was mixed with isopropanol (3.75mL) and water (1.25mL), N2Displacement for 5 min, PdCl is added2(PPh3)2(0.043 mmol). Heating the mixture at 80 deg.C for 12 hr, cooling, concentrating under reduced pressure, and adding saturated NaHCO3Aqueous solution (20mL) and extracted with ethyl acetate (3 × 20 mL). Collecting the organic phase, Na2SO4Dried, filtered and concentrated to dryness. The crude product was purified by chromatography (hexanes-ethyl acetate) to afford the title compound (0.016g, 11%) as a white solid: rf0.38(1:1 ethyl acetate: hexane); LCMS (M/z) =350.3[ M + H]+，tR=2.71 minutes.
Example 68
N- (5- (6- (2-fluorophenyl) imidazo [1, 2-b)]Pyridazin-2-yl) -2-methylpyridin-3-yl) pivaloamides
Reacting 6- (2-fluorophenyl) -2- (6-methyl-5-nitropyridin-3-yl) imidazo [1,2-b]Pyridazine (0.016g, 0.0458mmol) was dissolved in ethanol (3mL) and water (1mL) containing acetic acid (0.274mmol), and iron (0.013g, 0.229mmol) was added. The mixture was heated at 80 ℃ for 2 hours. The mixture was concentrated under reduced pressure and saturated NaHCO was added3Aqueous solution (10 mL). The mixture was extracted with ethyl acetate (20 mL). The organic phase was collected and concentrated to dryness. The crude amine was dissolved in pyridine (0.137mmol) in acetonitrile (3 mL). To the solution was added trimethylacetyl chloride (0.0503 mmol). The mixture was stirred at room temperature for 4 hours, concentrated to dryness and then purified by silica gel chromatography eluting with a gradient of dichloromethane to dichloromethane: ethyl acetate: methanol (1:1:0.1) to afford the title compound (0.008g, 44%) as a pale yellow solid: rf0.34(1:1:0.1 dichloromethane: ethyl acetate: methanol); LCMSM/z =404.4[ M + H%]+，tR=2.11 minutes. (Compounds of the same type as in example 390)
Example 69
2-bromo-1- (4-methyl-3-nitrophenyl) ethanone
1- (4-methyl-3-nitrophenyl) ethanone (Sigma-Aldrich, 25.08g, 0.14mol) was dissolved in dichloromethane (269mL) and cooled to 0 ℃. To this solution was added liquid bromine (7.17mL, 0.14mol) with stirring at 0 ℃. The reaction mixture was slowly warmed to room temperature and stirred for a total of 90 minutes. Ice water (500mL) was added, the organic phase was collected and the aqueous phase was extracted with dichloromethane (2 × 250 mL). The organic phases were combined, washed with water and Na2SO4Dried and concentrated to give the title compound (36.1g, 99% yield). LCMSM/z=258.3，260.2[M+H]+，tR=2.39 minutes.
Example 70
6-chloro-2- (4-methyl-3-nitrophenyl) imidazo [2,1-f]Pyridazine
6-chloropyridazin-3-amine (18.4g, 0.14mol) and 2-bromo-1- (4-methyl-3-nitrophenyl) ethanone (36.13g, 0.14mol) were dissolved in acetonitrile (219mL) with stirring and heated at reflux for 18 hours. The mixture was diluted with water (500mL), stirred at room temperature for 1 hour, and the solid was collected by filtration to give the title compound (35.65g, 88% yield). LCMSM/z =289.4[ M + H%]+，tR=2.65 minutes.
Example 71
5- (6-chloroimidazo [2, 1-f)]Pyridazin-2-yl) -2-methylaniline
Mixing 6-chloro-2- (4-methyl-3-nitrophenyl) imidazo [2, 1-f)]Pyridazine (1.15g, 0.004mol) was mixed with ethanol-acetic acid (120mL, 2:1) and iron (1.34g) was added. The mixture was stirred at 80 ℃ for 2 hours, cooled to room temperature, filtered through celite, washed with ethyl acetate, and concentrated. The residual oil was dissolved in ethyl acetate (500mL) and saturated NaHCO was used3The aqueous solution (200mL) was washed once. The organic phase was dried and concentrated to give the title compound (0.85g, 82%) without further purification. LCMSM/z =259.4[ M + H ]]+，tR=1.64 minutes.
Example 72
N- [5- (6-chloroimidazo [2, 1-f)]Pyridazin-2-yl radicals]-2-methylphenyl radical]-2, 2-dimethylpropionamide
Adding 5- (6-chloroimidazo [2,1-f ] into a 40mL bottle]Pyridazin-2-yl) -2-methylaniline (0.85g, 3.28mmol), acetonitrile (14mL) and pyridine (0.450 mL). To the mixture was added trimethylacetyl chloride (0.628mL, 0.0051mol), and the mixture was stirred at 80 ℃ for 20 minutes. The mixture was concentrated, dissolved in ethyl acetate (35mL), and washed once with each of HCl (20mL, 1M) and NaOH (20mL, 1M) in that order. The organic phase was dried, concentrated, and purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to afford the title compound (1.05g, 94%). LCMSM/z =343.5[ M + H%]+，tR=2.39 minutes. (Compounds of the same type as in example 118)
Example 73
2, 2-dimethyl-N- [ 2-methyl-5- [6- [2- (trifluoromethyl) -3-pyridine]Imidazo [2, 1-f)]Pyridazine-2- Base of]Phenyl radical]Propionamide
To an 8mL bottle was added N- [5- (6-chloroimidazo [2,1-f ]]Pyridazin-2-yl radicals]-2-methylphenyl radical]-2, 2-dimethylpropionamide (0.034g, 0.0001mol), [2- (trifluoromethyl) -3-pyridine]Boric acid (Combi-Blocks, 0.038g), bis (triphenylphosphine) palladium (II) dichloride (0.007g), Na2CO3(0.032g), and isopropanol-water (1mL, 3: 1). The mixture was heated at 80 ℃ for 16 hours. The mixture was concentrated, dissolved in ethyl acetate and dichloromethane (1:1), filtered, concentrated over celite, and purified by silica gel chromatography (0-100% ethyl acetate in hexane) to give the title compound (0.015g, 33% yield). LCMSM/z =454.6[ M + H%]+，tR=2.52 minutes. (Compounds of the same type as in example 284)
Example 74
2, 2-dimethyl-N- [ 2-methyl-5- [6- (3-methylaminotetrahydropyrrole-1-yl) imidazo [2,1-f]Pyridazine-2- Base of]Phenyl radical]Propionamide
To a microwaveable vial was added butanol (0.183mL), diisopropylethylamine (0.122mL, 0.7mmol), N-methyltetrahydropyrrole-3-amine (0.050g, 0.5mmol), and N- [5- (6-chloroimidazo [2,1-f ]]Pyridazin-2-yl radicals]-2-methylphenyl radical]-2, 2-dimethylpropionamide (0.0397g, 0.1 mmol). The vial was sealed and microwave heated at 180 ℃ for 30 minutes. The mixture was concentrated, dissolved in DMSO, and purified by reverse phase preparative HPLC (gradient elution 15% B:85% a to 100% B, where solvent a =95% water, 5% acetonitrile and 0.1% trifluoroacetic acid; solvent B =90% acetonitrile, 10% water and 0.1% trifluoroacetic acid) to give the title compound (0.006g, 15% yield). LCMSM/z =407.6[ M + H%]+，tR=1.32 minutes. (Compounds of the same type as in example 360)
Example 75
[4- (trifluoromethyl) -3-pyridine]Boric acid
3-bromo-4- (trifluoromethyl) pyridine (matrix scientific, 1g, 0.022mol) and triisopropyl borate (1.25mL) were dissolved in anhydrous THF (9mL), N-butyllithium (2.5M hexyllithium) was added under a nitrogen atmosphere at 78 deg.CAlkane solution, 2 mL). The reaction mixture was stirred at-78 ℃ for 3.5 hours and then gradually warmed to room temperature. The reaction was quenched by addition of water (9 mL). The organic solvent was distilled off under reduced pressure. The resulting aqueous phase was treated with NaOH (10N) to pH10, washed with diethyl ether (1x8mL), and the aqueous phase was acidified with acetic acid to pH 5. The solution was extracted with ethyl acetate (1 × 25mL) and the organic phase was distilled to dryness to afford the title compound (0.150g, 15% yield). LCMSM/z =192.2[ M + H%]+，tR=0.36 min.
Example 76
2, 2-dimethyl-N- [ 2-methyl-5- [6- [4- (trifluoromethyl) -3-pyridine]Imidazo [2, 1-f)]Pyridazine-2- Base of]Phenyl radical]Propionamide
To an 8mL bottle was added N- [5- (6-chloroimidazo [2,1-f ]]Pyridazin-2-yl radicals]-2-methylphenyl radical]-2, 2-dimethylpropionamide (0.034g, 0.1mmol), [4- (trifluoromethyl) -3-pyridine]Boric acid (0.038g), bis (triphenylphosphine) palladium (II) dichloride (7mg), Na2CO3(0.032g), and isopropanol-water (1mL, 3: 1). The mixture was heated at 80 ℃ for 16 h, cooled, concentrated, dissolved in ethyl acetate and dichloromethane (1:1), filtered, concentrated with celite, and purified by silica gel chromatography (10-100% ethyl acetate in hexanes) to give the title compound (0.011g, 25% yield). LCMSM/z =454.5[ M + H%]+，tR=2.47 min. (Compounds of the same type as in example 364)
Example 77
6-chloro-2- [ 3-nitro-4- (trifluoromethyl)Radical) phenyl]Imidazo [1, 2-a ]]Pyrazine esters
5-chloropyrazin-2-amine (0.336g, 2.6mmol) and 2-bromo-1- [ 3-nitro-4- (trifluoromethyl) phenyl]Ethanone (0.811g, 2.6mmol) was dissolved in acetonitrile (15mL) and stirred at 100 ℃ for 18 h. The mixture was concentrated to give the title compound (890mg) without further purification. LCMSM/z =343.3[ M + H]+，tR=2.65 minutes.
Example 78
5- (6-chloroimidazo [1, 2-a ]]Pyrazin-2-yl) -2- (trifluoromethyl) aniline
To 6-chloro-2- [ 3-nitro-4- (trifluoromethyl) phenyl]Imidazo [1, 2-a ]]To a mixture of pyrazine (0.891g), acetic acid (1.19mL), and ethanol-water (10mL, 4:1) was added iron (0.726 g). Stirring the mixture at 80 deg.C for 2 hr, cooling, concentrating, dissolving in saturated NaHCO3Aqueous solution, and extracted with ethyl acetate and dichloromethane. The organic phase was dried and concentrated to give the title compound (813mg) without further purification. LCMSM/z =313.4[ M + H ]]+，tR=2.29 min.
Example 79
N- [5- (6-chloroimidazo [1, 2-a ]]Pyrazin-2-yl) -2- (trifluoromethyl) phenyl]-2, 2-dimethylpropionamide
To a 20mL bottle was added 5- (6-chloroimidazo [1, 2-a ]]Pyrazin-2-yl) -2- (trifluoromethyl) aniline (0.813g, 2.6mmol), acetonitrile (14mL) and pyridine (0.42 mL)0 mL). To the mixture was added trimethylacetyl chloride (0.640mL, 5.2mmol), and stirred at 80 ℃ for 20 minutes. The acetonitrile solution was concentrated over celite and purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to give the title compound (256mg, 25% yield). LCMSM/z =397.5[ M + H%]+，tR=2.62 minutes. (Compounds of the same type as in example 85)
Example 80
N- [5- [6- (2-fluorophenyl) imidazo [1, 2-a)]Pyrazin-2-yl radicals]-2- (trifluoromethyl) phenyl]-2, 2-dimethyl Cyclopropyl amides
To an 8mL bottle was added N- [5- (6-chloroimidazo [1, 2-a ]]Pyrazin-2-yl radicals]-2- (trifluoromethyl) phenyl]-2, 2-Dimethylpropionamide (0.0516g, 0.13mmol), 2-fluorophenylboronic acid (Combi-Blocks, 32mg, 0.26mmol), Na2CO3(0.0413g, 0.39mmol), bis (triphenylphosphine) palladium (II) dichloride (0.009g, 0.01mmol), and isopropanol-water (1mL, 3: 1). The mixture was stirred at 70 ℃ for 16 hours. The reaction mixture was concentrated, dissolved in ethyl acetate and dichloromethane (1:1), and subjected to preparative thin layer chromatography (1:1 hexane: ethyl acetate) to give the title compound (6mg, 10% yield). LCMSM/z =457.5[ M + H ]]+，tR=3.06 min. (Compounds of the same type as in example 86)
The following compounds are prepared essentially according to the procedures and examples described above, with only the starting materials adjusted as necessary to give the desired product.
Example 484
2- (4-methyl-3-pivaloylamidophenyl) imidazo [1,2-b]Pyridazine-6-boronic acid
Mixing N- [5- (6-chloroimidazo [2,1-f ]]Pyridazin-2-yl) -2-methyl-phenyl]-2, 2-dimethyl-propionamide (15.43g0.045mol), bis (pinacol) diboron (17.14g, 0.0675mol), potassium acetate (8.833g, 0.09mol), [1, 1' -bis (diphenylphosphino) ferrocene]A suspension of palladium (II) dichloride (2.305g, 3.15mmol) in dioxane (153mL) was heated at 90 ℃ for 16 h. The reaction mixture was cooled, concentrated, and aqueous sodium hydroxide (150mL, 3M) was added. The mixture was stirred for 1 hour, then extracted with ethyl acetate (300 mL). The organic phase was washed with sodium hydroxide solution (150mL, 3M). The aqueous phases were combined, extracted twice with ether and the pH of the aqueous phase was adjusted to 5 with aqueous hydrochloric acid (6M) with formation of a solid. The heterogeneous solution was cooled in a refrigerator for 2 hours and filtered to give the desired product as a solid (8.56 g). The resulting aqueous solution was extracted with ethyl acetate, combined with the previous organic phase and filtered through celite. The combined organic phases were dried, concentrated and dissolved in aqueous hydrochloric acid (0.5M). The solid product formed was collected by filtration and combined with the solid from the previous filtration to give a total of 10.16g of the expected title compound. LCMS (M/z) =353.5[ M + H [)]+，tR=2.04 min.
Example 485
N- (5- (6- (4-cyano-2- (trifluoromethyl) phenyl) imidazo [1, 2-b)]Pyridazin-2-yl) -2-methylphenyl Pivaloyl amides
To a 200mL round bottom flask was added 2- (4-methyl-3-pivaloylamidophenyl) imidazo [1,2-b]Pyridazin-6-ylboronic acid (11.4g, 0.0325mol), 4-bromo-3- (trifluoromethyl) benzonitrile (10.16g, 0.04mol), potassium carbonate (8.98g, 0.065mol), palladium acetate (0.510g, 2.28mmol), 2-dicyclohexylphosphine-2 ', 6' -dimethoxy-1, 1' -diphenyl (1.868g, 4.55mmol) and isopropanol-water (3:1, 80 mL). The mixture was purged with nitrogen and heated at 90 ℃ for 5 hours. The mixture was then cooled and filtered through celite, concentrated, and purified by silica gel chromatography (0-100% ethyl acetate in dichloromethane). The desired fractions were combined and quadra silmp (mercaptopropyl bound silica gel, 20g) was added and stirred for 24 hours to scavenge the palladium, filtered and concentrated to give the title compound (7.5 g). LCMS (M/z) =478.6[ M + H]+，tR=2.97 min.
Example 486
N- (5- (6- (4- (N' -hydroxycarbamimidoyl) -2- (trifluoromethyl) phenyl) imidazo [1, 2-5 b)]Pyridazin-2-yl) - 2-methylphenyl) pivaloyl amide
To a 500mL round bottom flask was added N- (5- (6- (4-cyano-2- (trifluoromethyl) phenyl) imidazo [1, 2-b)]Pyridazin-2-yl) -2-methylphenyl) pivaloamide (7.496g, 0.0157mol), hydroxylamine hydrochloride (6.55g, 0.0942mol), triethylamine (15.32mL, 0.1099mol), ethanol (82.5mL), and the resulting mixture was stirred at 80 ℃ for 2 hours. Concentrating the mixture with diatomaceous earth, and purifying by silica gel chromatography (eluent: 0-100% of 10:1 ethyl acetate: methanol in dichloro-ethanol)Methane solution). The solid material obtained (greater than 20g) was isolated containing triethylamine and the hydroxylamine salt, which remained present after attempted recrystallization from isopropanol. The solid product was then added to saturated NaHCO with stirring3The aqueous solution and ethyl acetate. The solid suspension was collected by filtration. The liquid fraction was extracted with ethyl acetate and the organic phases, Na, were combined2SO4Drying and concentrating to obtain another solid product. The solid products were combined, dried overnight on a lyophilizer and recrystallized from hot isopropanol to give the title compound (6.56 g). LCMS (M/z) =511.6[ M + H]+，tR=2.49 minutes.
Example 487
N- (5- (6- (4-carbamimidoyl-2- (trifluoromethyl) phenyl) imidazo [1, 2-b)]Pyridazin-2-yl) -2-methylbenzenes Yl) pivaloyl amide
To a 20mL bottle was added N- (5- (6- (4-cyano-2- (trifluoromethyl) phenyl) imidazo [1, 2-b)]Pyridazin-2-yl) -2-methyl l phenyl) pivaloamide (0.052g, 0.11mmol), and a solution of hydrochloric acid in methanol (3N, 3mL) was added. The mixture was stirred at 65 ℃ for 60 hours. The reaction mixture was concentrated, dissolved in ammonia in methanol (7M, 1mL) and stirred for an additional 18 hours at 65 ℃. The mixture was concentrated, dissolved in DMSO and purified by Gilson reverse phase high performance liquid chromatography to give the title compound (0.016g, 29% yield). LCMS (M/z) =495.5[ M + H =]+，tR=2.15 min.
Example 488
N- (2-methyl-5- (6- (3, 4, 5-trimethoxybenzylamino) imidazo [1, 2-b)]Pyridazin-2-yl) phenyl) perylene Pentamides
Under the protection of nitrogen, N- [5- (6-chloroimidazo [2, 1-f)]Pyridazin-2-yl) -2-methyl-phenyl]-2, 2-dimethyl-propionamide (1.0285g, 3mmol), 2-di-tert-butylphosphine-2 ', 4 ', 6' -triisopropylbiphenyl (0.255g, 0.6mmol), sodium tert-butoxide (0.577g, 6mmol), and bis (dibenzylideneacetone) palladium (0) (0.172g, 0.3mmol) were added to a 40mL bottle. Toluene (16mL) and 3, 4, 5-trimethoxybenzylamine (1.54mL, 9mmol) were added and the mixture was heated at 100 ℃ for 1 hour. The reaction mixture was filtered through celite, washed with dichloromethane: ethyl acetate: methanol =1:1:0.1 and concentrated through celite, and purified by silica gel chromatography (0-100%1:1:0.1 dichloromethane: ethyl acetate: methanol) to give the title compound (0.604 g). LCMS (M/z) =504.6[ M + H]+，tR=2.31 minutes.
Example 489
N- [5- (6-aminoimidazo [2, 1-f)]Pyridazin-2-yl) -2-methyl-phenyl]-2, 2-dimethyl-propionamide
Mixing N- (2-methyl-5- (6- (3, 4, 5-trimethoxy benzylamine) imidazo [1, 2-b)]Pyridazin-2-yl) phenyl) pivaloamide (0.604g, 1.2mmol) and trifluoroacetic acid (5mL) were added to a 40mL flask, and the mixture was stirred at 50 ℃ for 16 hours. The reaction mixture was concentrated, dissolved in acetonitrile and added water. The mixture was concentrated to form a solid from the aqueous solution. The mixture was frozen and water was removed by a lyophilizer to give the title compound (0.350 g). LCMS (M/z) =324.5[ M + H]+，tR=1.96 minutes.
Practice ofExample 490
3-bromo-N- [2- [3- (2, 2-dimethylpropionylamino) -4-methyl-phenyl]Imidazo [2, 1-f)]Pyridazin-6-yl radicals] Benzamide derivatives
Into an 8mL flask was added N- [5- (6-aminoimidazo [2,1-f ]]Pyridazin-2-yl) -2-methyl-phenyl]-2, 2-dimethyl-propionamide (0.097g, 0.3mmol), 3-bromobenzoyl chloride (0.059mL, 0.45mmol), pyridine (0.073mL), and acetonitrile (1.0mL), the mixture was stirred at room temperature for 16 hours, concentrated with celite and purified by silica gel chromatography (0-100%1:0.1 ethyl acetate: methanol in dichloromethane) to give the title compound (0.065 g). LCMS (M/z) =506.4, 508.4[ M + H]+，tR=2.96 minutes.
Example 491
3- [3- [ [2- [3- (2, 2-dimethylpropionylamino) -4-methyl-phenyl ] -methyl-propionic acid methyl ester]Imidazo [2, 1-f)]Pyridazin-6-yl radicals] Carbamoyl radical]Phenyl radical]-2-propenoic acid ethyl ester
3-bromo-N- [2- [3- (2, 2-dimethylpropionylamino) -4-methyl-phenyl]Imidazo [2, 1-f)]Pyridazin-6-yl radicals]Benzamide (0.126g, 0.25mmol), ethyl acrylate (0.272mL, 2.5mmol), palladium (II) acetate (2.8mg, 0.01mmol), tri (o-tolyl) phosphine (0.0152g, 0.05mmol), and DMF (1.45mL) were mixed and DIPEA (0.174mL, 1mmol) was added. Introducing nitrogen, sealing, and heating at 110 deg.C for 18 hr. The mixture was cooled and saturated NaHCO was added3Solution (50mL), extracted with ethyl acetate (× 3). The organic phases were combined, washed with water and NaHCO3Washing with solution, washing with saline, drying, concentrating, and purifying by silica gel chromatography (0-100% ethyl acetate)Hexane solution of ester) to give the title compound (0.040 g). LCMS (M/z) =526.6[ M + H]+，tR=2.92 minutes.
Example 492
3- [3- [ [2- [3- (2, 2-dimethylpropionylamino) -4-methyl-phenyl ] -methyl-propionic acid methyl ester]Imidazo [2, 1-f)]Pyridazin-6-yl radicals] Carbamoyl radical]Phenyl radical]-2-propenoic acid
To a 20mL bottle was added 3- [3- [ [2- [3- (2, 2-dimethylacrylamide) -4-methyl-phenyl ] -ethyl methacrylate]Imidazo [2, 1-f)]Pyridazin-6-yl radicals]Carbamoyl radical]Phenyl radical]-a solution of ethyl 2-acrylate (0.042g, 0.08mmol) and tetrahydrofuran-methanol (1mL, 1: 1). To the mixture was added an aqueous sodium hydroxide solution (1mL, 1M), followed by stirring at 50 ℃ for 1 hour. The mixture was concentrated to remove the organic solvent, and extracted once with ethyl acetate. Aqueous hydrochloric acid (1M) was added to reduce the pH to 2, and the resulting solid was filtered to give the title compound (0.025g) without further purification. LCMS (M/z) =498.5[ M + H]+，tR=2.47 min.
Example 493
N- [2- [3- (2, 2-dimethylpropionylamino) -4-methyl-phenyl]Imidazo [2, 1-f)]Pyridazin-6-yl radicals]-3- [3- (hydroxyamino) -3-oxo-1-propenyl group]Benzamide derivatives
To a 20mL vial was added acetonitrile (0.4mL), 3- [3- [ [2- [3- (2, 2-dimethylpropionylamino) -4-methyl-phenyl ] -acetic acid]Imidazo [2, 1-f)]Pyridazin-6-yl radicals]Carbamoyl radical]Phenyl radical]-2-COlefinic acid (0.025g, 0.05mmol), O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (0.0088g, 0.08mmol), triethylamine (0.021mL, 0.15mmol) and (benzotriazole-1-oxo) tris (dimethylamino) phosphonium hexafluorophosphate (0.033g, 0.08 mmol). The mixture was stirred at room temperature for 2 hours, concentrated and dissolved in saturated Na2CO3Aqueous (2mL) and extracted with ethyl acetate and dichloromethane. Mixing the organic phases, drying and concentrating to obtain crude N- [2- [3- (2, 2-dimethylpropionylamino) -4-methyl-phenyl]Imidazo [2, 1-f)]Pyridazin-6-yl radicals]-3- [ 3-oxo-3- (tetrahydropyran-2-yloxyamino) -1-propenyl]A benzamide. The crude product was dissolved in a mixed aqueous solution of hydrochloric acid (1mL, 1M) and methanol (1mL) and stirred at 50 ℃ for 1 hour. The mixture was concentrated, dissolved in DMSO (1mL), and purified by reverse phase Gilson high performance liquid preparative chromatography to give the title compound (0.015 g). LCMS (M/z) =513.5[ M + H]+，tR=2.31 minutes.
Example 494
2- (4-methyl-3-nitro-phenyl) -6- [2- (trifluoromethyl) -3-pyridinyl]Imidazo [2, 1-f)]Pyridazine
To a 500mL flask was added 6-chloro-2- (4-methyl-3-nitro-phenyl) imidazo [2,1-f]Pyridazine (10.104g, 0.035mol), 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) pyridine (journal of organic chemistry, 2011, 76, 1062) (13.38g, 0.049mol), potassium acetate (6.869g, 0.07mol), bis (dibenzylideneacetone) palladium (0) (2.01g, 3.5mmol), 2-dicyclohexylphosphine-2 ', 4 ', 6' -triisopropylbiphenyl (3.34g, 0.007mol), butanol (112mL) and water (20 mL). The reaction mixture was heated at 90 ℃ for 4 hours. The reaction solution was filtered through celite and washed with ethyl acetate. The liquid layers were combined, concentrated over celite, and purified by silica gel chromatography (0-75% ethyl acetate in dichloromethane) to afford the title compound (7.98g, 60% yield). L isCMS(m/z)=400.4[M+H]+，tR=2.76 min.
Example 495
2-methyl-5- [6- [2- (trifluoromethyl) l) -3-pyridinyl]Imidazo [2, 1-f)]Pyridazin-2-yl radicals]Aniline
At 60 ℃,2- (4-methyl-3-nitro-phenyl) -6- [2- (trifluoromethyl) -3-pyridyl]Imidazo [2, 1-f)]A solution of pyridazine (7.986g, 0.02mol) in ethanol-acetic acid (48mL, 1:1) was added slowly to a solution of iron powder (6.702g, 0.12mol) in ethanol-acetic acid (60mL, 2: 1). The mixture was stirred at 70 ℃ for 60 minutes, cooled to room temperature, filtered through celite, washed with ethyl acetate and concentrated. The oily residue was dissolved in ethyl acetate (500mL) and saturated NaHCO was used3The aqueous solution (200mL) was washed twice. The organic phase was dried and concentrated to give the title compound (7.3g, solid). LCMS (M/z) =370.5[ M + H]+，tR=1.85 min.
Example 496
3-bromo-N- [ 2-methyl-5- [6- [2- (trifluoromethyl) -3-pyridinyl]Imidazo [2, 1-f)]Pyridazin-2-yl radicals]Benzene and its derivatives Base of]Benzamide derivatives
To a 20mL bottle was added 2-methyl-5- [6- [2- (trifluoromethyl) -3-pyridinyl]Imidazo [2, 1-f)]Pyridazin-2-yl radicals]Aniline (0.444g, 1.2mmol), 3-bromobenzoyl chloride (0.378mL, 1.8mol), pyridine (0.292mL, 3.6mmol), acetonitrile (4mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture is subjected toCelite concentration and silica gel chromatography (0-100% ethyl acetate in dichloromethane) afforded the title compound (530 mg). LCMS (M/z) =552.3 and 554.3[ M + H [ ]]+，tR=3.04 min.
Embodiment 497
3- [3- [ [ 2-methyl-5- [6- [2- (trifluoromethyl) -3-pyridinyl)]Imidazo [2, 1-f)]Pyridazin-2-yl radicals]Benzene and its derivatives Base of]Carbamoyl radical]Phenyl radical]-2-propenoic acid ethyl ester
To 3-bromo-N- [ 2-methyl-5- [6- [2- (trifluoromethyl) -3-pyridinyl]Imidazo [2, 1-f)]Pyridazin-2-yl radicals]Phenyl radical]To a mixture of benzamide (0.442g, 0.8mmol), ethyl acrylate (0.872mL, 8mmol), palladium (II) acetate (9mg, 0.04mmol), tris (o-tolyl) phosphine (0.049g, 0.16mmol) in DMF (4.6mL) and HMPA (0.4mL) was added DIPEA (0.557mL, 3.2 mmol). The mixture was purged with nitrogen, then sealed, and heated at 100 ℃ for 15 hours. The reaction was incomplete and stirring was continued for 24 hours at 100 ℃. The mixture was poured into saturated NaHCO3Aqueous solution, and extracted with ethyl acetate (2 ×). The organic phases were combined, dried and concentrated to give the title compound (485mg, solid) without further purification. LCMS (M/z) =572.5[ M + H]+，tR=3.14 minutes.
Example 498
3- [3- [ [ 2-methyl-5- [6- [2- (trifluoromethyl) -3-pyridinyl)]Imidazo [2, 1-f)]Pyridazin-2-yl radicals]Benzene and its derivatives Base of]Carbamoyl radical]Phenyl radical]-2-propenoic acid
Into a 40mL flask was added 3- [3- [ [ 2-methyl-5- [6- [6- (trifluoromethyl) -2-pyridinyl)]Imidazo [2, 1-f)]Pyridazin-2-yl radicals]Phenyl radical]Carbamoyl radical]Phenyl radical]Ethyl 2-acrylate (0.486g, 0.85mmol), tetrahydrofuran-methanol mixture (3mL, 1:1), and aqueous sodium hydroxide solution (2mL, 1M). The mixture was stirred at 50 ℃ for 1 hour, cooled, concentrated and water (2mL) was added. Aqueous hydrochloric acid (1M) was added to lower the pH to 2, and the resulting solid was filtered to give the title compound (435 mg). LCMS (M/z) =544.5[ M + H]+，tR=2.69 minutes.
Example 499
To a 4mL vial was added acetonitrile (0.78mL), 3- [3- [ [ 2-methyl-5- [6- [6- (trifluoromethyl) -2-pyridinyl)]Imidazo [2, 1-f)]Pyridazin-2-yl radicals]Phenyl radical]Carbamoyl radical]Phenyl radical]-2-propenoic acid (0.0544g, 0.1mmol), benzene-1, 2-diamine (0.016g, 0.15mmol), triethylamine (0.042mL, 0.3mmol), and (benzotriazole-1-oxo) tris (dimethylamino) phosphonium hexafluorophosphate (0.066g, 0.15 mmol). The mixture was stirred at room temperature for 2h, concentrated, dissolved in DMSO (1.5mL), and purified by Gilson high performance liquid preparative chromatography (reverse phase) to give the title compound (18 mg). LCMS (M/z) =634.6[ M + H]+，tR=2.77 minutes.
The following compounds are prepared essentially according to the procedures and examples described above, with only the starting materials adjusted as necessary to give the desired product.
Example 627
2-bromo-1- (4-ethyl-3-nitrophenyl) ethanone
A solution of 1- (4-methyl-3-nitro-phenyl) ethanone (AMGENINC.; MEMORHARACEUTICAL SCORPORATION WO2007/103260A1) (18.0g, 0.093mol) in dichloromethane (130mL) was cooled to 0 ℃. To this solution was added bromine water (5.3mL, 0.0103mol) and stirred at 0 ℃. The reaction mixture was allowed to slowly reactWarm to room temperature and stir for a total of 90 minutes. Ice water (500mL) was added, the organic phase collected and the aqueous phase extracted with dichloromethane (2 × 250 mL). The combined organic phases were washed with water and Na2SO4Drying and concentration gave the title compound (25.0g, 99% yield).
Example 628
6-chloro-2- (4-ethyl-3-nitrophenyl) imidazo [1,2-b]Pyridazine
A solution of 6-chloropyridazin-3-amine (4.76g, 0.037mol) and 2-bromo-1- (4-ethyl-3-nitrophenyl) ethanone (10.0g, 0.037mol) in acetonitrile (100mL) was heated to reflux for 18 h. The reaction mixture was diluted with water (500mL), stirred at room temperature for 1 hour, and the solid was collected by filtration to give the title compound (6.9g, 62% yield). LCMSM/z =303.3, 305.4[ M + H ]]+，tR=2.90 minutes.
Example 629
5- (6-chloroimidazo [1,2-b ]]Pyridazin-2-yl) -2-ethylanilines
Iron powder (4.61g, 0.0825mol) was added to 6-chloro-2- (4-ethyl-3-nitrophenyl) imidazo [1,2-b ] at 80 ℃]Pyridazine (5.0g, 0.0165mol) EtOH-H containing acetic acid (5.66mL, 0.099mol)2O (150mL, 4:1) mixture. The mixture was stirred at 80 ℃ for 4 hours. The reaction mixture was cooled to room temperature, filtered through celite, washed with ethyl acetate and concentrated. The oily residue was dissolved in ethyl acetate (200mL), andsaturated NaHCO at 100mL3And washing twice. The compound was concentrated with celite and purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to give the title compound (4.02g, 89%). LCMSM/z =273.3,275.3[ M + H]+，tR=1.93 minutes.
Example 630
N- (5- (6-chloroimidazo [1,2-b ]]Pyridazin-2-yl) -2-ethylphenyl) pivaloyl amide
Reacting 5- (6-chloroimidazo [1,2-b ]]Pyridazin-2-yl) -2-ethylaniline (4.00g, 0.0146mol), acetonitrile (120mL) and pyridine (3.54mL, 0.0438mol) were charged to the flask. The mixture was stirred and trimethylacetyl chloride (1.98mL, 0.0161mol) was added and the mixture was stirred at room temperature for 16 hours. Upon completion of the reaction, the mixture was diluted with water (500mL), stirred for 1 hour, and the solid was collected and washed with water (3X50 mL). The crude product was purified by silica gel chromatography (0-50% ethyl acetate in dichloromethane) to give the title compound (4.8g, 92%). LCMSM/z =357.5, 359.4[ M + H [ ]]+，tR=2.57 min.
Example 631
3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) pyridine
3-bromo-2- (trifluoromethyl) pyridine (Oakwood products, 11.3g, 0.05mol), bis (valeryl) diboron (12.7g, 0.05mol), potassium acetate (9.8g, 0.1mol), [1, 1' -bis (biphenylphosphine) ferrocene]A mixture of palladium (II) dichloride (2.56g, 0.0035mol) was suspended in 1, 4-dioxane (106mL) in a round bottom flask. The flask was heated at reflux for 2 hours. The reaction was concentrated with celite and purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to give the title compound (9.2g, 67%). LCMSM/z =274.4[ M + H%]+，tR=2.64 minutes.
Example 632
2-ethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1, 2-b)]Pyridazin-2-yl) anilines
Mixing N- (5- (6-chloroimidazo [1,2-b ]]Pyridazin-2-yl) -2-ethylphenyl) pivaloamide (2.45g, 0.00686mol), 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) pyridine (2.34g, 0.00857mol), K2CO3(2.37g, 0.0171mol), palladium (II) acetate (0.154g, 0.686mmol), 2-dicyclohexylphosphine-2 ', 6' -dimethoxybiphenyl (0.563g, 0.00137mol), isopropanol: water (150mL, 3:1) was added to the 250mL flask. The mixture was stirred and heated to 60 ℃ for 6 hours. The mixture was concentrated to dryness, the crude product was recovered via ethyl acetate (100mL), washed with water (50mL), the organic phase was recovered and concentrated via celite, and purified by silica gel chromatography (0-75% ethyl acetate in dichloromethane). The intermediate was taken up in ethanol (100mL) and concentrated HCl (90mL) was added. The reaction mixture was heated under reflux for 18 hours. The reaction was concentrated, taken up in ethyl acetate (100mL), and taken up in 100mL saturated NaHCO3And (6) washing. The compound was concentrated with celite and purified by silica gel chromatography (0-100% ethyl acetate in dichloromethane) to give the title compound (1.98g, 75% over two steps). LCMSM/z =384.4, 385.4[ M + H [ ]]+，tR=2.59 minutes.
Example 633
N- (2-ethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1, 2-b)]Pyridazin-2-yl) phenyl) -1- Methylcyclopropylcarboxamides
2-ethyl-5- (6- (2- (trifluoromethyl) pyridine-3-yl) imidazo [1, 2-b)]Pyridazin-2-yl) aniline (0.500g, 0.0013mol), acetonitrile (5mL) and pyridine (0.315mL) were added to the flask. The mixture was stirred and 1-methylcyclopropanecarbonyl chloride (0.169g, 0.00143mol) was added, and the mixture was stirred at room temperature for 4 hours. Upon completion of the reaction, the mixture was concentrated on silica gel and purified by silica gel chromatography (0-80% ethyl acetate in dichloromethane) to give the title compound (0.400g, 66%). LCMSM/z =466.5, 467.5[ M + H [ ]]+，tR=2.99 min.1H-NMR(500MHz，DMSO-d6):9.01(s，1H)，8.93(d，J=4.9Hz，1H)，8.92(s，1H)，8.27(m，2H)，7.91(m，2H)，7.43(d，J=9.3Hz，1H)，7.35(d，J=7.8Hz，1H)，2.59(q，J=7.6，2H)，1.44(s，3H)，1.15(t，J=7.6Hz，3H)，1.11(dd，J=6.4，3.4Hz，2H)，0.65(dd，J=6.4，3.4Hz，2H)。
The following compounds are prepared essentially according to the procedures and examples described above, with only the starting materials adjusted as necessary to give the desired product.
In vitro biological evaluation
Example 704
Hedgehog conditioned medium was obtained by transfecting 293H cells with the full length gene encoding human sonic hedgehog (hShh) inserted into the pCMV6 expression vector, which contains a neomycin selectable marker and expresses the target protein with a C-terminal FLAG affinity tag. Conditioned media from hedgehog expressing clones were then screened using G418-containing media and tested to test their ability to activate hedgehog-responsive GLi-luciferase reports in ShhLightII cell lines derived from the university of John Hopkins (TaipaleJ et al. efficiency society catalysis in smoothened patched and patched beredebyycypopamine. Nature406:1005-1009, 2000).
C3H10T1/2 cells were transfected with a pCMV expression vector containing the full-length gene sequence encoding the human Smoothened receptor. The pooled cells, designated 10T1/2/Smo #3, were cultured in G418-selected medium and then activated with 10-20% hShh conditioned medium. The activity of alkaline phosphatase (ALP) in 10T1/2/Smo #3 was increased approximately 5-10 fold over untransfected parent C3H10T1/2 cells, as determined by conversion of the free acid of 4-methylumbelliferone phosphate to a fluorescent product.
Screening of test compound libraries with hShh and 500nM of SAG (Smoothened receptor agonist) activated 10T1/2/Smo #3 cells and ShhLightII reporter cells,to test the ability of the compounds to block activation of the hedgehog signaling pathway. At the same time, use(Promega, Madison Wis.) survival assay cell viability was determined. Those compounds that inhibit the hedgehog signaling pathway by more than 50% activity without loss in cell viability are defined as active compounds).
Compounds were then further evaluated for their specificity for Smoothened binding using a competitive fluorescence binding assay (against 5-10nM of Cyclopamine-BODIPY and 293H cells overexpressing human Smoothened). To further test for non-specific biological activity, compounds were screened in the Wnt3 a-activated TCF/LCF reporter assay and the CMV-driven luciferase constant reporter assay.
Data for some representative compounds of the invention are set forth below. Measurement of these compounds by ALP activity on 10T1/2/Smo #3 cells and by luciferase activity on ShhLigntII reporter cells for hedgehog signaling pathway activation, see Table 1 below. In Table 1, + + + represents an IC50 value of less than 0.3. mu.M, + + represents an IC50 value of between 0.3 and 3. mu.M, + represents an IC50 value of between 3 and 30. mu.M.
TABLE 1
Additional data for the compounds of the invention are shown in table 2 below. Inhibitory Activity of these Compounds on hedgehog Signaling pathway activation by IC50The values (μ M) show that these compounds have their inhibitory activity on hedgehog signaling pathway activation on shligntii reporter cells measured by ALP activity on 10T1/2/Smo #3 cells or by luciferase activity (hShh activation).
TABLE 2
In vivo biological evaluation
Example 705
Pharmacokinetic model of mouse skin. The activity of some compounds of the invention as inhibitors of Gli1 expression was determined using the experimental method of Lucas et al (bioorgmedchemlett.2010, 20(12), 3618-22) as follows. 5-8 week old female NOD-Scid mice were shaved on one side of the posterior rib. Four days after shaving, mice were anesthetized and regrown hair was removed with a depilatory wax strip. After 5 days, mice were orally administered compound or solvent control. At 6 hours post-dose, animals were sacrificed and the waxed portions of skin were excised and stored in RNAlater solution at 4 ℃. Homogenizing the skin sample in Lysis buffer; purifying RNA. RNA was converted to cDNA using reverse transcriptase prior to quantification and analyzed by real-time PCR. Gli1 expression was normalized to GAPDH expression using a standard curve method. Fig. 1 and 2 show that the compounds of the invention inhibit activation of the hedgehog signaling pathway, thereby being able to inhibit Gli1 expression.
Example 706
PC3 transplantation tumor model. The tumor growth inhibitory activity of the compounds of the present invention was evaluated on a model of human prostate cancer PC-3 nude mouse transplantable tumor. This compound was dissolved in CMC containing 0.2% tween 80. BALB/cA-nude mice were 5 weeks old. An equal amount of PC-3 tumor cell suspension was implanted into mice, and several days later, mice now bearing 60-150 cubic mm tumors were randomized into control and treatment groups (n = 6). The compounds are administered orally in a form that is orally administered,50mg/kg BID, 21 consecutive days tumor volume V1/2 × axb was calculated according to the standard formula2Where a and b denote length and width, respectively. The results for the compound of example 284 are shown in FIG. 3.
The disclosures of all articles and documents referred to in this application, including patents, are incorporated herein by reference in their entirety.
It is understood that the examples and embodiments described herein are for illustrative purposes only. All embodiments disclosed as one aspect of the invention may be combined with embodiments of another aspect of the invention in any suitable manner, unless explicitly excluded herein. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope of the invention. It is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims or the equivalents thereof. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims (34)

1. A compound of the formula
Or a pharmaceutically acceptable salt thereof, wherein
R1Is pyridyl, wherein said pyridyl is optionally substituted with one or more R8Substitution;
wherein R is8Is halogen, -CN, -OH, -SH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-NH(C1-C6Alkyl) -OH, -C1-C6alkoxy-OH, -C1-C6Alkoxy radical- (C1-C6Alkoxy group), C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Halogenoalkoxy, hydroxy (C)1-C6Alkyl group), (C)1-C6Alkoxy) C1-C6Alkyl, amino (C)1-C6Alkyl), -S (C)1-C6Alkyl), -CO2H、-CO2(C1-C6Alkyl), -C (O) (C)1-C6Alkyl), -CON (H) OR80、-CONH2、-CONH(C1-C6Alkyl), -CON (C)1-C6Alkyl radical)2、-NHCO(C1-C6Alkyl) or-NHCO2(C1-C6Alkyl), wherein each alkyl, alkenyl, alkynyl, alkoxy is optionally-CO on a substitutable carbon2(C1-C6Alkyl) OR-CON (H) OR80Substitution;
R2is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C3-C8Cycloalkyl, aryl, heteroaryl, heterocyclyl, wherein each alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with one or more R at a substitutable position10Substitution;
wherein R is10Is halogen, -CN, -OH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical、C1-C6Haloalkyl, C1-C6Halogenoalkoxy, hydroxy (C)1-C6Alkyl group), (C)1-C6Alkoxy) C1-C6Alkyl, amino (C)1-C6Alkyl), -CO2H、-CO2(C1-C6Alkyl), -CONH2、-CONH(C1-C6Alkyl), -CON (C)1-C6Alkyl radical)2、CON(H)OR80、-NHCO(C1-C6Alkyl), or-NHCO2(C1-C6Alkyl), wherein each alkyl, alkenyl, alkynyl, alkoxy is optionally substituted on a substitutable carbon by one R102The substitution is carried out by the following steps,
wherein R is102is-COR104Wherein R is104Is- (C)1-C6) Alkoxy, -NHOR80or-NR7R110，
Wherein R is110Is aryl or heteroaryl, each aryl or heteroaryl being optionally substituted by up to three halogens, -OH, -SH, -NO2、-NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Halogenoalkoxy, hydroxy (C)1-C6Alkyl) substitution;
wherein R is7Is hydrogen or optionally substituted by C1-C4Alkoxycarbonyl substituted C1-C8An alkyl group; wherein R is80Is hydrogen or a hydroxy protecting group;
R3is hydrogen, halogen, -CN, -OH, -SH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C3-C8Cycloalkyl, aryl, heteroaryl, heteroA cyclic group;
a is-N (R)7)C(O)-、-N(R7)C(O)O-、-C(O)N(R7)-、-N(R7)C(O)N(R7)-、-OC(O)N(R7)-、-S(O)2-、-S(O)2N(R7)-、-OS(O)2N(R7)-、-N(R7)S(O)2-, or-OS (O)2O-；
Each R5Independently hydrogen, halogen, -CN, -OH, -SH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Halogenoalkoxy, hydroxy (C)1-C6Alkyl) wherein each alkyl is optionally substituted with one or more R at substitutable positions10Substitution;
each Z is independently N or CR6Provided that only one Z is N; and
each R6Independently hydrogen, halogen, -CN, -OH, -SH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Halogenoalkoxy, hydroxy (C)1-C6Alkyl), amino (C)1-C6Alkyl) wherein each alkyl is optionally substituted with one or more R at substitutable positions10Substitution;
wherein the aryl group is a 6-to 10-membered aryl group; the heteroaryl group is a five-or six-membered heteroaryl group in which 1 to 4 ring atoms are heteroatoms selected from oxygen, nitrogen, sulfur, the remaining ring atoms are carbon; said heterocyclyl contains 5 to 10 ring atoms, of which 1 to 4 are heteroatoms selected from oxygen, nitrogen, sulphur and the remaining ring atoms are carbon.
2. The compound of claim 1, wherein
Each R5Independently isHydrogen, halogen, -CN, -OH, -SH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, wherein
Each alkyl group is optionally substituted with one or more R10Substitution;
wherein R is10Is halogen, -CN, -OH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Haloalkoxy, -CO2H、-CO2(C1-C6Alkyl), -CONH2、-CONH(C1-C6Alkyl), -CON (C)1-C6Alkyl radical)2、-CON(H)OH、-NHCO(C1-C6Alkyl) or-NHCO2(C1-C6Alkyl groups).
3. The compound of claim 2, wherein
Each R5Independently hydrogen, optionally substituted by one or more R10Substituted C1-C6An alkyl group.
4. A compound according to any one of claims 1 to 3, having the general formula:
5. the compound of claim 4, wherein R5Is hydrogen, C optionally substituted in substitutable positions by one or more halogens1-C6An alkyl group.
6. The compound of claim 5, wherein R5Is hydrogen.
7. The compound of claim 5, wherein R5Is C1-C6An alkyl group.
8. The compound of claim 7, wherein R5Is methyl.
9. The compound of claim 1, wherein each Z is CR6。
10. The compound of claim 9, wherein each R6Independently hydrogen, halogen, -CN, -OH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy, or C1-C6A haloalkoxy group.
11. The compound of claim 10, wherein each R6Independently is hydrogen, halogen, or C1-C6An alkyl group.
12. The compound of claim 11, wherein each R6Independently hydrogen.
13. The compound of claim 1, wherein R3Is hydrogen, halogen, -CN, -OH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, or C3-C8A cycloalkyl group.
14. The compound of claim 13, wherein R3Is hydrogen, halogen, -CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, or C3-C8A cycloalkyl group.
15. The compound of claim 14, wherein R3Is C1-C6Alkyl radical, C1-C6Haloalkyl, or C1-C6A haloalkoxy group.
16. The compound of claim 15, wherein R3Is C1-C6Alkyl or C1-C6A haloalkyl group.
17. The compound of claim 16, wherein R3Is methyl or trifluoromethyl.
18. The compound of claim 1, wherein A is-N (R)7)C(O)-、-C(O)N(R7) -, or-S (O)2N(R7)-。
19. The compound of claim 18, wherein A is-N (R)7)C(O)-。
20. The compound of claim 1, wherein R2Is hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C8Cycloalkyl, aryl, heteroaryl, wherein each alkyl, cycloalkyl, aryl, or heteroaryl group is optionally substitutedBy one or more R in substitutable positions10And (4) substitution.
21. The compound of claim 20, wherein R2Is C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C8Cycloalkyl, aryl, heteroaryl, wherein each alkyl, cycloalkyl, or aryl group is optionally substituted with one or more R at substitutable positions10And (4) substitution.
22. The compound of claim 21, wherein R2Is C1-C6Alkyl or C1-C6A haloalkyl group.
23. The compound of claim 22, wherein R2Is C1-C6An alkyl group.
24. The compound of claim 23, wherein R2Is a tert-butyl group.
25. The compound of claim 1, wherein-A-R2is-N (R)7)C(O)(C1-C6Alkyl groups).
26. The compound of claim 1, wherein-A-R2is-NHC (O) (tert-butyl).
27. The compound of claim 1, wherein R1Is one or more R8Substituted pyridyl wherein R8Is halogen, -CN, -OH, -SH, -NH2、-NH(C1-C6Alkyl), -N (C)1-C6Alkyl radical)2、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Halogenoalkoxy, hydroxy (C)1-C6Alkyl group), (C)1-C6Alkoxy) C1-C6Alkyl, amino (C)1-C6Alkyl), -S (C)1-C6Alkyl), -CO2H、-CO2(C1-C6Alkyl), -C (O) (C)1-C6Alkyl), -CONH2、-CONH(C1-C6Alkyl), -CON (C)1-C6Alkyl radical)2、-NHCO(C1-C6Alkyl) or-NHCO2(C1-C6Alkyl), wherein each alkyl, alkenyl, alkynyl, alkoxy is optionally-CO on a substitutable carbon2(C1-C6Alkyl) or-CON (H) OH.
28. The compound of claim 27, said R8Is halogen, C1-C6Alkoxy radical, C1-C6A haloalkoxy group.
29. A pharmaceutical composition comprising a compound according to any one of claims 1-28 and a pharmaceutically acceptable carrier, solvent, adjuvant or diluent.
30. Use of the compound of claims 1-28 for the preparation of a medicament for inhibiting hedgehog pathway signaling.
31. Use of a compound of claims 1-28 for the manufacture of a medicament for the treatment of cancer.
32. The use of claim 31, wherein the cancer is basal cell carcinoma, lung cancer, liver cancer, medulloblastoma, melanoma, breast cancer, pancreatic cancer, or prostate cancer.
33. Use of a compound according to claims 1-28 for the preparation of a medicament for inhibiting angiogenesis.
34. The compound of claim 1 which is
2, 2-dimethyl-N- [5- [6- (6-methyl-2-pyridyl) imidazo [2,1-f ] pyridazin-2-yl ] -2- (trifluoromethyl) phenyl ] propionamide;
2, 2-dimethyl-N- [5- [6- (5-methyl-2-pyridyl) imidazo [2,1-f ] pyridazin-2-yl ] -2- (trifluoromethyl) phenyl ] propionamide;
2, 2-dimethyl-N- [5- [6- (4-methyl-2-pyridyl) imidazo [2,1-f ] pyridazin-2-yl ] -2- (trifluoromethyl) phenyl ] propionamide;
2, 2-dimethyl-N- [5- [6- (3-methyl-2-pyridyl) imidazo [2,1-f ] pyridazin-2-yl ] -2- (trifluoromethyl) phenyl ] propionamide;
2, 2-dimethyl-N- [ 2-methyl-5- [6- [2- (trifluoromethyl) -3-pyridinyl ] imidazo [2,1-f ] pyridazin-2-yl ] phenyl ] propionamide;
2, 2-dimethyl-N- [ 2-methyl-5- [6- [4- (trifluoromethyl) -3-pyridinyl ] imidazo [2,1-f ] pyridazin-2-yl ] phenyl ] propionamide;
n- (5- (6- (pyridin-2-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (6-methoxypyridin-2-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (6-methylpyridin-2-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (5-methylpyridin-2-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (4-methylpyridin-2-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (3-methylpyridin-2-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (pyridin-4-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (6-methoxypyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (6-fluoropyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (2-methoxypyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (2-fluoropyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (3-fluoropyridin-4-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (2-fluoropyridin-3-yl) -7, 8-dimethylimidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (7, 8-dimethyl-6- (pyridin-2-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (2-fluoropyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
n- (2-methyl-5- (6- (2-methylpyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (5- (6- (5-chloro-2-fluoropyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
n- (5- (6- (2, 6-difluoropyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
n- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (2- (trifluoromethyl) -5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (5- (6- (2-methylpyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (2-methyl-5- (6- (6- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (5- (6- (2-chloropyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (2-morpholinylpyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (2-ethyl-5- (6- (6- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (2-methyl-5- (3-methyl-6- (6- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (5- (6- (2-fluoro-4-methylpyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide
N- (5- (6- (5-aminopyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (2-aminopyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (2-ethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (2-methyl-5- (3-methyl-6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (2-methyl-5- (6- (4- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (5- (6- (2-fluoropyridin-4-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
n- (5- (6- (5-chloropyridin-2-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
n- (5- (6- (2-methylpyridin-4-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (3-methoxypyridin-4-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (4-methylpyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (4-methoxypyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (5- (6- (4-chloropyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2- (trifluoromethyl) phenyl) pivaloamide;
n- (2-methyl-5- (6- (3- (trifluoromethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (5- (6- (6 '-chloro-2, 3' -bipyridin-5-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
n- (5- (6- (6-aminopyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
n- (5- (6- (5-methoxypyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
n- (5- (6- (6-hydroxypyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
n- (5- (6- (5-hydroxypyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
n- (5- (6- (2-hydroxypyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
n- (5- (6- (5-fluoropyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
n- (5- (6- (6-chloropyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
methyl 8- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenylamino) -8-oxooctanoate;
methyl 6- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenylamino) -6-oxohexanoate;
N1-hydroxy-N8- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1, 2-b)]Pyridazin-2-yl) phenyl) octanediamide;
8- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenylamino) -8-oxooctanoic acid;
ethyl 4- (4- (2- (4-methyl-3-pivaloylamidophenyl) imidazo [1,2-b ] pyridazin-6-yl) -6- (trifluoromethyl) pyridin-2-yloxy) butanoate;
ethyl 4- (5- (2- (4-methyl-3-pivaloylamidophenyl) imidazo [1,2-b ] pyridazin-6-yl) -6- (trifluoromethyl) pyridin-2-yloxy) butanoate;
ethyl 3- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenylamino) -3-oxopropanoate;
4- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenylamino) -4-oxobutanoic acid ethyl ester;
N1-hydroxy-N6- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1, 2-b)]Pyridazin-2-yl) phenyl) adipamide;
2- (4-methyl-3- (6- (trifluoromethyl) pyridin-2-yl) phenyl) -6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazine;
n- (2-methyl-5- (6- (4- (trifluoromethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (2-methyl-5- (6- (5- (trifluoromethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (2-methyl-5- (6- (6- (trifluoromethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
6- (2- (4-methyl-3-pivaloylamidophenyl) imidazo [1,2-b ] pyridazin-6-yl) nicotinic acid;
n- (5- (6- (6- (hydroxymethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
4-methoxy-6- (2- (4-methyl-3-pivaloylamidophenyl) imidazo [1,2-b ] pyridazin-6-yl) nicotinic acid;
ethyl 2- (5- (2- (4-methyl-3-pivaloylamidophenyl) imidazo [1,2-b ] pyridazin-6-yl) -6- (trifluoromethyl) pyridin-2-yloxy) acetate;
n-tert-butyl-2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) benzamide;
n- (5- (6- (6-acetylamino-2-methylpyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
n- (5- (6- (6-acetamidopyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
N-methyl-N- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
methyl 2- (N- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloylamido) acetate;
methyl 7- (N- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloylamino) heptanoate;
1-methyl-N- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) cyclopropylcarboxamide;
n- (2-methyl-5- (6- (5- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
5- (2- (4-methyl-3-pivaloylamidophenyl) imidazo [1,2-b ] pyridazin-6-yl) picolinamide;
6- (2- (4-methyl-3-pivaloylamidophenyl) imidazo [1,2-b ] pyridazin-6-yl) nicotinamide;
8- ((2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) amino) -8-oxooctanoic acid;
n1- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -N8- ((tetrahydro-2H-pyran-2-yl) oxy) octanediamide;
n- (5- (6- (6-aminopyridin-2-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
N1-hydroxy-N8- (6- (2- (4-methyl-3-pivaloylamidophenyl) imidazo [1,2-b ] pyridazin-6-yl) pyridin-2-yl) octanediamide;
n- (5- (6- (2-cyanopyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
2-cyano-2-methyl-N- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) propionamide;
3-amino-2, 2-dimethyl-N- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) -2, 3-dihydroimidazo [1,2-b ] pyridazin-2-yl) phenyl) propionamide;
3- (3- ((2-aminophenyl) amino) -3-oxo-1-propen-1-yl) -N- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) benzamide;
n- (2-aminophenyl) -3- (3- (N- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) sulfamoyl) phenyl) acrylamide;
3- (3- (hydroxyamino) -3-oxo-1-propen-1-yl) -N- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) benzamide;
n-hydroxy-3- (3- (N- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) sulfamoyl) phenyl) acrylamide;
n- (2-ethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -1-methylcyclopropylcarboxamide;
3,3, 3-trifluoro-2, 2-dimethyl-N- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) propionamide;
n- (4-chloro-2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (5- (3-chloro-6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) -2-methylphenyl) pivaloamide;
n- (2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (2-cyclopropyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pyrrolidine-2-carboxamide;
1-tert-butyl-3- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) urea;
1-methyl-N- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pyrrolidine-2-carboxamide;
1-ethyl-N- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pyrrolidine-2-carboxamide;
n- (4-fluoro-2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (2-chloro-4-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
1-cyclopropyl-3- (2-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) urea;
n- (2, 4-difluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -1-methylcyclopropylcarboxamide;
1- (2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -3-cyclopropylurea;
3- (2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -1, 1-diethylurea;
n- (2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pyrrolidine-1-carboxamide;
ethyl 2-chloro-4-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl carbamate;
n- (2-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (2-chloro-4-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -2, 2-dimethylbutanamide;
n- (2-chloro-4-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -3,3, 3-trifluoro-2, 2-dimethylpropionamide;
n- (2-chloro-4-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -4,4, 4-trifluoro-3-methylbutanamide;
n- (2-chloro-4-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -2, 2-dimethylpentanamide;
n- (2- (2- (trifluoromethyl) pyridin-3-yl) -5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pivaloamide;
n- (2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -2, 2-dimethylbutanamide;
n- (2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -3,3, 3-trifluoro-2, 2-dimethylpropionamide;
n- (2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -4,4, 4-trifluoro-3-methylbutanamide;
n- (2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -2, 2-dimethylpentanamide;
2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenylcarbamic acid isopropyl ester;
n- (2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -3, 3-difluoroazetidine-1-carboxamide;
n- (2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) cyclohexylcarboxamide;
n- (2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) cyclopentylcarboxamide;
n- (2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -3, 3-dimethylbutanamide;
ethyl 2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl carbamate;
n- (2-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -1-methylcyclopropylcarboxamide;
n- (2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -3,3, 3-trifluoropropionamide;
n- (2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) cyclopropylcarboxamide;
n- (2-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) cyclohexylcarboxamide;
n- (2-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) cyclopentylcarboxamide;
n- (2-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -3, 3-dimethylbutanamide;
3,3, 3-trifluoro-N- (2-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) propionamide;
n- (2-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) cyclopropylcarboxamide;
ethyl 2-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl carbamate;
2-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenylcarbamic acid isopropyl ester;
3, 3-difluoro-N- (2-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) azetidine-1-carboxamide;
1, 1-diethyl-3- (2-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) urea;
n- (2-fluoro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pyrrolidine-1-carboxamide;
n- (2-ethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) cyclohexylcarboxamide;
n- (2-ethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) cyclopentylcarboxamide;
n- (2-ethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -2, 2-dimethylbutanamide;
n- (2-ethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -3,3, 3-trifluoro-2, 2-dimethylpropionamide;
n- (2-ethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -3, 3-dimethylbutanamide;
n- (2-ethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -3,3, 3-trifluoropropionamide;
1, 1-diethyl-3- (2-ethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) urea;
n- (2-ethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) pyrrolidine-1-carboxamide;
n- (2-ethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -3, 3-difluoroazetidine-1-carboxamide;
n- (2-ethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -3-methyloxetane-3-carboxamide;
2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) benzenesulfonamide;
2-chloro-N-methyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) benzenesulfonamide;
n-tert-butyl-2-chloro-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) benzenesulfonamide;
2-chloro-N, N-dimethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) benzenesulfonamide;
2-chloro-N-ethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) benzenesulfonamide;
2-chloro-N-cyclopropyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) benzenesulfonamide;
2-chloro-N, N-diethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) benzenesulfonamide;
or a pharmaceutically acceptable salt of any of the above compounds.
HK13114185.1A 2010-12-22 2011-12-22 2-arylimidazo[1,2-b]pyridazine,2-phenylimidazo[1,2-a]pyridine, and 2-phenylimidazo[1,2-a]pyrazine derivatives HK1186732B (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US201061426216P 2010-12-22 2010-12-22
US61/426,216 2010-12-22
US201161514833P 2011-08-03 2011-08-03
US61/514,833 2011-08-03
US201161523688P 2011-08-15 2011-08-15
US61/523,688 2011-08-15
PCT/US2011/066837 WO2012088411A1 (en) 2010-12-22 2011-12-22 2-arylimidazo[1,2-b]pyridazine, 2-phenylimidazo[1,2-a]pyridine, and 2-phenylimidazo[1,2-a]pyrazine derivatives

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HK1186732A1 HK1186732A1 (en) 2014-03-21
HK1186732B true HK1186732B (en) 2017-08-18

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