GCN2 inhibitors and uses thereof
阅读说明：本技术 Gcn2抑制剂及其用途 (GCN2 inhibitors and uses thereof ) 是由 M·布莱奇 J-D·凯瑞尔 董慧君 S·迪朗特 M·S·伊诺 G·埃泰克塞巴里尔艾贾迪 于 2019-01-28 设计创作，主要内容包括：本发明提供化合物、其组合物和使用其的方法。本发明化合物及其药学上可接受的组合物是GCN2激酶的有效抑制剂。(The present invention provides compounds, compositions thereof, and methods of using the same. The compounds of the present invention and pharmaceutically acceptable compositions thereof are potent inhibitors of GCN2 kinase.)
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
ring A is selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is optionally fused to a 5-6 membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated spiroheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or
Het, wherein Het is a 4-8 membered saturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated spiroheterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated bridged bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
ring B is
Each R is independently hydrogen or an optionally substituted group selected from C1-6An aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
Two R groups optionally together form a divalent C2-4An alkylene chain;
two R groups optionally together with their intervening atoms form an optionally substituted 3-7-membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R' is independently hydrogen or C optionally substituted with halogen 1-3An aliphatic group;
each R1Independently hydrogen, halogen, -CN, -NO2，-C(O)R，-C(O)OR，-C(O)NR2，-C(O)NRS(O)2R，-C(O)N＝S(O)R2，-NR2，-NRC(O)R，-NRC(O)NR2，-NRC(O)OR，-NRS(O)2R，-NRS(O)2NR2，-OR，-ON(R)SO2R，-P(O)R2，-SR，-S(O)R，-S(O)2R，-S(O)(NH)R，-S(O)2N(R)2，-S(NH2)2(O)OH，-N＝S(O)R2，-CH3，-CH2OH，-CH2NHSO2CH3，-CD3，-CD2NRS(O)2R, or R; or:
two R1The radicals optionally together form ═ O or ═ NH; or
Two R1The radicals optionally together forming a divalent C2-4An alkylene chain;
each R2Independently hydrogen, halogen, -CN, -C (O) N (R')2，-OR’，-N(R’)2，-S(O)2R，-S(O)2N(R)2-O-phenyl, or an optionally substituted group selected from C1-3Aliphatic, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R3is hydrogen, halogen, -CN, -OR ', -N (R')2Or an optionally substituted group selected from C1-3Aliphatic, phenyl, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R4is hydrogen, halogen, -CN, -OR, -N ═ S (O) R2，-N(R)2Or an optionally substituted group selected from C1-3Aliphatic, 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 7-12 membered saturated or partially unsaturated spiroheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
m is 0, 1, 2, 3, 4 or 5;
n is 0, 1 or 2;
p is 0 or 1; and
q is 0 or 1.
2. The compound of claim 1, wherein ring a is Het.
3. The compound of claim 2, wherein Het is a 4-8 membered saturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated spiroheterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
4. The compound of claim 1, wherein ring B is
5. The compound of claim 1, wherein each R1Independently hydrogen, halogen, -CN, -C (O) R, -C (O) OR, -C (O) NR2，-C(O)NRS(O)2R，-C(O)N＝S(O)R2，-NR2，-NRC(O)R，-NRC(O)NR2，-NRC(O)OR，-NRS(O)2R，-NRS(O)2NR2，-OR，-ON(R)SO2R，-P(O)R2，-SR，-S(O)R，-S(O)2R，-S(O)(NH)R，-S(O)2N(R)2，-S(NH2)2(O)OH，-N＝S(O)R2，-CH3，-CH2OH，-CH2NHSO2CH3，-CD3，-CD2NRS(O)2R, or R.
6. The compound of claim 1, wherein each R2Independently hydrogen, halogen, -CN, -C (O) N (R')2，-OR’，-N(R’)2Or an optionally substituted group selected from C1-3Aliphatic, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
7. The compound of claim 1, wherein R3Is hydrogen, halogen, -CN, -OR ', -N (R')2Or an optionally substituted group selected from C1-3Aliphatic, or having 1-4 members independently selected from nitrogenA 5-6 membered monocyclic heteroaromatic ring of a heteroatom of oxygen or sulfur.
8. The compound of claim 1, wherein R 4Is hydrogen, halogen, -CN, -OR, -N (R)2Or an optionally substituted group selected from C1-3Aliphatic, 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 7-12 membered saturated or partially unsaturated spiroheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
9. The compound of claim 1, wherein ring B is
10. The compound of claim 9, having one of formulas IV-a, IV-b, or IV-c:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 9, having one of formulas XIII-a, XIII-b, or XIII-c:
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 9, having one of formulas XIV-a, XIV-b, or XIV-c:
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 9, having one of formulas XV-a, XV-b, or XV-c:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1, wherein ring B is
15. The compound of claim 14, having one of formulas VI-a, VI-b, or VI-c:
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1, wherein ring B is
17. The compound of claim 16, having one of formulas XII-a, XII-b, or XII-c:
Or a pharmaceutically acceptable salt thereof.
18. The compound of claim 16, having one of formulas XVI-a, XVI-b, or XVI-c:
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 16, having one of formulas XVII-a, XVII-b, or XVII-c:
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 16, having one of formulas XVIII-a, XVIII-b, or XVIII-c:
or a pharmaceutically acceptable salt thereof.
21. The compound of claim 16, having one of formulas XIX-a, XIX-b, or XIX-c:
or a pharmaceutically acceptable salt thereof.
22. The compound of claim 16, having one of formulas XX-a, XX-b, or XX-c:
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 16, having one of formulas XXI-a, XXI-b, or XXI-c:
or a pharmaceutically acceptable salt thereof.
24. A compound according to any one of claims 1 to 23, wherein m is 1, 2, 3, 4 or 5, especially 1, 2 or 3.
25. The compound of claim 1, wherein the compound is selected from those described in table 1.
26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
27. A method of inhibiting GCN2 in a patient or a biological sample comprising administering to said patient or contacting said biological sample with a compound according to any one of claims 1 to 25 or a pharmaceutical composition thereof.
28. A method of treating a GCN 2-mediated disorder, disease, or condition in a patient, comprising administering to the patient a compound according to any one of claims 1 to 25, or a pharmaceutical composition thereof.
29. The method of claim 28, wherein the GCN 2-mediated disorder, disease, or condition is selected from the group consisting of an inflammatory condition, an immunological condition, an autoimmune condition, an allergic condition, a rheumatic condition, a thrombotic condition, cancer, an infection, a neurodegenerative disease, a degenerative disease, a neuroinflammatory disease, a cardiovascular disease, and a metabolic condition.
30. The method of claim 29, wherein the cancer is selected from the group consisting of a solid tumor and a tumor of the blood and immune system, wherein the solid tumor is derived from the group consisting of: epithelial, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, genitourinary tract, lymphatic system, stomach, larynx, bone (including chondrosarcoma and Ewing's sarcoma), germ cells (including embryonic tissue tumors), and/or lung tumors derived from the group of: monocytic leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma, neurofibromatosis, angiosarcoma, breast cancer and/or malignant melanoma.
31. The method of claim 29, wherein the autoimmune condition is rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis,syndrome or transplant rejection.
32. The method of claim 29, wherein the metabolic condition is diabetes.
33. The method of claim 29 wherein the degenerative disease is osteoarthritis.
34. The method of claim 29, wherein the inflammatory condition is asthma, inflammatory bowel disease, or giant cell arteritis.
35. The method of claim 29, wherein the cardiovascular disease is ischemic injury.
36. The method of claim 29, wherein the neurodegenerative disease is alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis-the dutch type, cerebral amyloid angiopathy, creutzfeldt-jakob disease, frontotemporal dementia, huntington's disease, or parkinson's disease.
37. The method of claim 29, wherein the infection is caused by: leishmania, mycobacteria (including Mycobacterium leprae, Mycobacterium tuberculosis and/or Mycobacterium avium), Plasmodium, human immunodeficiency virus, Epstein Barr virus, herpes simplex virus, or hepatitis C virus.
38. The method of claim 28, wherein the GCN 2-mediated disorder, disease, or condition is cancer and the method further comprises administering a second agent for treating cancer.
Technical Field
The present invention relates to compounds and methods for inhibiting general amino acid regulation repression of 2 kinase ("GCN 2"). The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.
Background
GCN2 (general amino acid regulated repression 2) is a ubiquitously expressed protein kinase that is involved in the eukaryotic cellular response to amino acid deficiencies (Castilho et al, 2014). The absence of one or more amino acids in the cell results in the accumulation of unloaded homologously transported RNAs (tRNAs), which are directly bound by GCN2, leading to activation and phosphorylation of the eukaryotic initiation factor 2 α (eIF2 α) kinase on serine 51 (Wek et al, 1989; Dong et al, 2000). Phosphorylation of eIF2 α initiates protein translation, which results in reduced translation of most mRNAs, resulting in reduced overall amino acid utilization. Meanwhile, eIF2 α phosphorylation increases translation of specific subtypes of mRNAs containing certain upstream open reading frames in their 5 'untranslated regions (5' -UTRs), such as the mammalian transcription factor ATF4(Vattem and Wek,2004), which promotes restoration of protein homeostasis. GCN2 is therefore a key determinant of the fate of cells in response to amino acid consumption.
Induction of cellular responses to amino acid deficiencies is increasingly becoming an important mechanism for modulating the mammalian immune system, especially in certain disease states including cancer and autoimmunity. Various immunosuppressive cell types involved in controlling the immune response under these circumstances, including tolerogenic dendritic cells, myeloid-derived suppressor cells (MDSCs), tolerogenic/M2 macrophages, and cancer cells themselves, have each been reported to utilize amino acid depletion to inhibit T-cell responses (Munn et al, 2004; Munn et al, 2005; Rodriguez et al, 2010; Whyte et al, 2011; Uyttenhovet al, 2003). This is achieved by coupling the intracellular transport of amino acids with overexpression of amino acid catabolic enzymes in these cells, such as the tryptophan catabolic enzymes indoleamine 2,3 dioxygenase (IDO) and tryptophan 2,3 dioxygenase (TDO), and the arginine catabolic enzymes arginase 1 and 2(ARG1, ARG 2). As a result, these cells are able to reduce the local extracellular concentration at the location of a particular amino acid and thus induce GCN2 activity in nearby T-cells in an antigen-specific manner (Munn et al, 2004). Depletion of local tryptophan or arginine concentrations (e.g., by IDO-or ARG 1-expressing dendritic cells) has been reported to induce proliferation arrest and anergy in T-cells in a GCN 2-dependent manner in both in vitro and in vivo mouse systems (Munn et al, 2005; Rodriguez et al, 2007; Fletcher et al, 2015). Furthermore, the induction and/or maintenance of MDSCs and immunosuppressive regulatory T-cells (T-regs) may also depend on GCN2 activity under amino acid depletion conditions (Fletcher et al, 2015; Fallarino et al, 2006). Finally, other work suggests that IDO activation of GCN2 in tolerogenic macrophages is a key mechanism for inhibiting the systemic autoimmune response to apoptotic cells (Ravishankar et al, 2015). These findings identify GCN2 as a potential key effector of the immunosuppressive effects of amino acid consumption associated with various disease states.
Early cancers require avoidance of host anti-cancer immunity to develop (Corthay, 2014). This can be achieved as follows: modulate tumor antigen presentation and/or actively suppress immune attack using tumor immune evasion mechanisms. High expression of amino acid catabolic enzymes such as IDO and ARG1 has been observed in most cancer patients of various tumor types, both in the cancer cells themselves and in the immunosuppressive host cell types that accumulate in the tumor, tumor draining lymph nodes and/or peripheral circulation (Uyttenhove et al, 2003; Pilotte et al, 2012; Zea et al, 2005). Amino acid consumption can therefore be a powerful and widespread immune evasion mechanism that suppresses anti-cancer immunity. In line with this, it has been determined in several syngeneic mouse tumor models that amino acid consumption in tumors and tumor draining lymph nodes is a resistance mechanism to existing immunooncology agents, including checkpoint receptor blocking antibodies (Holmgaard et al, 2013; Spranger et al, 2014). On this basis, inhibitors of IDO and TDO are currently progressing in clinical trials for cancer and inhibitors of additional amino acid catabolic enzymes are in preclinical development. Accordingly, inhibitors of GCN2 may also be useful in cancer treatment and to render effective anti-cancer immune responses by disrupting nodal effector signals of amino acid depletion in the immune system. Gene excision of GCN2 is well tolerated in mice under standard growth conditions (Zhang et al, 2002), and inhibitors of GCN2 may have broader utility than inhibitors of the amino acid catabolic enzyme alone, since GCN2 responds to the consumption of several different amino acids.
Furthermore, GCN2 activation and overexpression have been observed in various human tumors compared to normal tissue (Ye et al, 2010; Wang et al, 2013). Consumption of GCN2 reduced the growth of mouse embryonic fibroblasts and human cancer cells in vitro under severe amino acid or glucose consumption, and blocked the growth of human tumor xenografts in mice (Ye et al, 2010). Thus GCN2 inhibitors may have a direct anticancer effect, as they frequently disrupt the nutrient supply in the tumor microenvironment.
For these reasons, there is a need to develop GCN2 inhibitors that are effective and selective in the treatment of cancer, either as single agents or in combination with, for example, anti-CTLA 4 and anti-PD 1/PD-L1 checkpoint blocking antibodies.
Summary of The Invention
It has now been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are potent GCN2 kinase inhibitors. The compounds have the general formula I:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described herein.
The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful in the treatment of various diseases, disorders, or conditions associated with the modulation of signal transduction pathways involving GCN2 kinase. The disease, disorder or condition includes those described herein.
The compounds provided by the invention are also useful for studying the GCN2 enzyme in biological and pathological phenomena; studying intracellular signal transduction pathways occurring in body tissues; and comparative evaluation of novel GCN2 inhibitors or other modulators of kinase, signal transduction pathways, and cytokine levels in vitro or in vivo.
Detailed description of certain embodiments
1. General description of certain embodiments of the invention:
the compounds of the present invention and compositions thereof are useful as inhibitors of GCN2 protein kinase. In certain embodiments, provided compounds inhibit GCN 2.
In certain embodiments, the present invention provides compounds of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
ring A is selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is optionally fused to a 5-6 membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated spiroheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or
Het, wherein Het is a 4-8 membered saturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated spiroheterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated bridged bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
ring B is
Each R is independently hydrogen or an optionally substituted group selected from C1-6An aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
Two R groups optionally together form a divalent C2-4An alkylene chain;
two R groups optionally together with their intervening atoms form an optionally substituted 3-7-membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R' is independently hydrogen or C optionally substituted with halogen 1-3An aliphatic group;
each R1Independently hydrogen, halogen, -CN, -NO2，-C(O)R，-C(O)OR，-C(O)NR2，-C(O)NRS(O)2R，-C(O)N＝S(O)R2，-NR2，-NRC(O)R，-NRC(O)NR2，-NRC(O)OR，-NRS(O)2R，-NRS(O)2NR2，-OR，-ON(R)SO2R，-P(O)R2，-SR，-S(O)R，-S(O)2R，-S(O)(NH)R，-S(O)2N(R)2，-S(NH2)2(O)OH，-N＝S(O)R2，-CH3，-CH2OH，-CH2NHSO2CH3，-CH3，-CH2OH，-CH2NHSO2CH3，-CD3，-CD2NRS(O)2R, or R; or:
two R1Radical (I)Optionally together form ═ O or ═ NH; or
Two R1The radicals optionally together forming a divalent C2-4An alkylene chain;
each R2Independently hydrogen, halogen, -CN, -C (O) N (R')2，-OR’，-N(R’)2，-S(O)2R，-S(O)2N(R)2-O-phenyl, or an optionally substituted group selected from C1-3Aliphatic, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R3is hydrogen, halogen, -CN, -OR ', -N (R')2Or an optionally substituted group selected from C1-3Aliphatic, phenyl, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R4is hydrogen, halogen, -CN, -OR, -N ═ S (O) R2，-N(R)2Or an optionally substituted group selected from C1-3Aliphatic, 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 7-12 membered saturated or partially unsaturated spiroheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
m is 0, 1, 2, 3, 4 or 5;
n is 0, 1 or 2;
p is 0 or 1; and
q is 0 or 1.
2. Compounds and definitions:
the compounds of the present invention include those generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise specified. For the purposes of the present invention, according to the Handbook of Chemistry and Physics,75thThe CAS version of Ed identifies the chemical elements of the periodic table. Additionally, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, university science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry",5thEd.,Ed.:Smith,M.B.and March,J.,John Wiley&Sons, New York:2001, the entire contents of which are incorporated herein by reference.
The term "aliphatic" or "aliphatic radical" as used herein means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but which is not aromatic (also referred to herein as a "carbocycle", "cycloaliphatic", or "cycloalkyl"), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In certain embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, while in still other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In certain embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C that is fully saturated or contains one or more units of unsaturation, but is not aromatic 3-C6A hydrocarbon having a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and mixtures thereof such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl.
As used herein, the term "bridged bicyclic ring" refers to any bicyclic ring system having at least one bridge, i.e., a saturated or partially unsaturated carbocyclic or heterocyclic ring. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or valencies connecting two bridgeheads, where a "bridgehead" is any backbone atom of the ring system that is bonded to three or more backbone atoms (excluding hydrogens). In certain embodiments, the bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridging bicyclic groups are well known in the art and include those described below, wherein each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted with one or more substituents described for the aliphatic group. Additionally or alternatively, any substitutable nitrogen bridging the bicyclic groups is optionally substituted. Exemplary bridged bicyclic rings include:
The term "lower alkyl" refers to C1-4Linear or branched alkyl. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
The term "lower haloalkyl" refers to C substituted with one or more halogen atoms1-4Linear or branched alkyl.
The term "heteroatom" means oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; quaternized form of any basic nitrogen; or a heterocyclic substitutable nitrogen such as N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).
The term "unsaturated" as used herein means that the moiety has one or more units of unsaturation.
As used herein, the term "divalent C1-8(or C)1-6) Saturated or unsaturated, linear or branched hydrocarbon chain "refers to linear or branched divalent alkylene, alkenylene, and alkynylene chains, as defined herein.
The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e. - (CH)2)n-, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.
The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.
As used herein, the term "cyclopropylalkenyl" refers to a divalent cyclopropyl group of the structure:
the term "halogen" means F, Cl, Br or I.
The term "aryl" alone or as part of a larger moiety as used in "aralkyl", "aralkoxy", or "aryloxyalkyl" refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and wherein each ring of the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, anthracenyl, and the like, which may carry one or more substituents. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings such as indanyl, phthalimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
The terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy" refer to groups having from 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; 6, 10 or 14 pi electrons shared by a circular array; and 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-" as used herein also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings in which the residue or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, and pyrido [2,3-b ] -1, 4-oxazin-3 (4H) -one. Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl" or "heteroaromatic", any of which terms includes optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.
As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic residue" and "heterocycle" are used interchangeably and refer to a stable 5-to 7-membered monocyclic or 7-10-membered bicyclic saturated or partially unsaturated heterocyclic moiety having, in addition to carbon atoms, one or more, preferably 1 to 4, heteroatoms as defined hereinbefore. When used to refer to a ring atom of a heterocyclic ring, the term "nitrogen" includes substituted nitrogens. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N-substituted pyrrolidinyl).
The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic residues include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diaza
As used herein, the term "partially unsaturated" refers to a cyclic moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.
As described herein, the compounds of the present invention may contain an "optionally substituted" moiety. Generally, the term "substituted," whether or not the antecedent "optionally" means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have suitable substituents at each substitutable position of the group, and where more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable" as used herein refers to a compound that is not substantially altered when subjected to conditions that allow for one or more of its preparation, detection, and in certain embodiments its recovery, purification, and use in the intent disclosed herein.
Suitable monovalent substituents on the carbon atom which the "optionally substituted" group may replace are independently halogen; - (CH)2)0- 4Ro；-(CH2)0-4ORo；-O(CH2)0-4Ro，-O-(CH2)0-4C(O)ORo；-(CH2)0-4CH(ORo)2；-(CH2)0-4SRo；-(CH2)0-4Ph, which may be RoSubstitution; - (CH)2)0-4O(CH2)0-1Ph, which may be RoSubstitution; -CH ═ CHPh, which may be represented by RoSubstitution; - (CH)2)0-4O(CH2)0-1-pyridyl, which may be substituted with RoSubstitution; -NO2；-CN；-N3；-(CH2)0-4N(Ro)2；-(CH2)0- 4N(Ro)C(O)Ro；-N(Ro)C(S)Ro；-(CH2)0-4N(Ro)C(O)NRo 2；-N(Ro)C(S)NRo 2；-(CH2)0-4N(Ro)C(O)ORo；-N(Ro)N(Ro)C(O)Ro；-N(Ro)N(Ro)C(O)NRo 2；-N(Ro)N(Ro)C(O)ORo；-(CH2)0-4C(O)Ro；-C(S)Ro；-(CH2)0-4C(O)ORo；-(CH2)0-4C(O)SRo；-(CH2)0-4C(O)OSiRo 3；-(CH2)0-4OC(O)Ro；-OC(O)(CH2)0-4SR-，-SC(S)SRo；-(CH2)0-4SC(O)Ro；-(CH2)0-4C(O)NRo 2；-C(S)NRo 2；-C(S)SRo；-(CH2)0- 4OC(O)NRo 2；-C(O)N(ORo)Ro；-C(O)C(O)Ro；-C(O)CH2C(O)Ro；-C(NORo)Ro；-(CH2)0-4SSRo；-(CH2)0-4S(O)2Ro；-(CH2)0-4S(O)2ORo；-(CH2)0-4OS(O)2Ro；-S(O)2NRo 2；-(CH2)0-4S(O)Ro；-(CH2)0-4S(O)(NRo)Ro；-N(Ro)S(O)2NRo 2；-N(Ro)S(O)2Ro；-N(Ro)S(O)(NRo)Ro 2；-N(ORo)Ro；-N＝S(O)Ro 2；-N(ORo)SO2Ro；-C(NH)NRo 2；-P(O)2Ro；-P(O)Ro 2；-OP(O)Ro 2；-OP(O)(ORo)2；-SiRo 3；-(C1-4Straight-chain or branched alkylene) O-N (R)o)2(ii) a Or- (C)1-4Straight or branched alkylene) C (O) O-N (R)o)2Wherein each RoMay be substituted and independently is hydrogen, C, as defined below1-6Aliphatic, -CH2Ph，-O(CH2)0-1Ph，-CH2- (5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, although defined above, two independently occurring RoTogether with their intervening atoms, form a 3-12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.
Ro(or two independently occurring RoA ring formed with the spacer atoms) is independently halogen, - (CH)2)0-2Rλ- (halogenated R)λ)，-(CH2)0-2OH，-(CH2)0-2ORλ，-(CH2)0-2CH(ORλ)2(ii) a -O (halo R)λ)，-CN，-N3，-(CH2)0-2C(O)Rλ，-(CH2)0-2C(O)OH，-(CH2)0-2C(O)ORλ，-(CH2)0-2SRλ，-(CH2)0-2SH，-(CH2)0-2NH2，-(CH2)0-2NHRλ，-(CH2)0-2NRλ 2，-NO2，-SiRλ 3，-OSiRλ 3，-C(O)SRλ，-(C1-4Straight-chain OR branched alkylene) C (O) ORλor-SSRλWherein each RλIs unsubstituted or substituted with only one or more halogen in the case of a "halo" prefix, and is independently selected from C 1-4Aliphatic, -CH2Ph，-O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. RoSuitable divalent substituents on saturated carbon atoms include ═ O and ═ S.
Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: o, S, NNR* 2，＝NNHC(O)R*，＝NNHC(O)OR*，＝NNHS(O)2R*，＝NR*，＝NOR*，-O(C(R* 2))2-3O-, or-S (C (R)* 2))2-3S-, wherein each independently occurs R*Selected from hydrogen, C which may be substituted as defined below1-6An aliphatic, or unsubstituted, 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents bound to the carbon substitutable vicinal to the "optionally substituted" group include: -O (CR)* 2)2-3O-, in which each occurrence of R is independent*Selected from hydrogen, C which may be substituted as defined below1-6An aliphatic, or unsubstituted, 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
R*Suitable substituents on the aliphatic radical include halogen, -Rλ- (halogenated R)λ)，-OH，-ORλ-O (halo R)λ)，-CN，-C(O)OH，-C(O)ORλ，-NH2，-NHRλ，-NRλ 2or-NO2Wherein each RλIs unsubstituted or substituted with only one or more halogen in the case of a "halo" prefix, and is independently C1-4Aliphatic, -CH2Ph，-O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Suitable substituents on the nitrogen which may be substituted by an "optionally substituted" group include
Suitable substituents on the aliphatic radical are independently halogen, -Rλ- (halogenated R)λ)，-OH，-ORλ-O (halo R)λ)，-CN，-C(O)OH，-C(O)ORλ，-NH2，-NHRλ，-NRλ 2or-NO2Wherein each RλIs unsubstituted or substituted with only one or more halogen in the case of a "halo" prefix, and is independently C1-4Aliphatic, -CH2Ph，-O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
As used herein, the term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts are described in detail, for example, in j.pharmaceutical Sciences, 1977, 66, 1-19 to s.m. berge et al, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, bisulfates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, caproates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.
Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4And (3) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cation salts formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.
Unless otherwise indicated, structures described herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structures; for example, the R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the present application are intended to be within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise indicated, structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, having the structure of the invention includes replacing hydrogen with deuterium or tritium or 13C or14Carbon-enriched carbon-substituted compounds are within the scope of the invention. According to the invention, the compounds are used, for example, as analytical tools, probes in biological tests or as therapeutic agents. In certain embodiments, R of a provided compoundxContaining one or more deuterium atoms.
The term "inhibitor" as used herein is defined as a compound that binds to and/or inhibits GCN2 with a measurable affinity. In certain embodiments, the inhibitor has an IC of less than about 50 μ M, less than about 1 μ M, less than about 500nM, less than about 100nM, less than about 10nM, or less than about 1nM50And/or binding constants.
The compounds of the invention may be tethered to a detectable moiety. It is recognized that the compounds are useful as imaging agents. One of ordinary skill in the art will recognize that detectable moieties can be attached to provided compounds via suitable substituents. As used herein, the term "suitable substituent" refers to a moiety that is capable of covalent attachment to a detectable moiety. Such moieties are well known to those of ordinary skill in the art and include groups containing, for example, carboxylate moieties, amino moieties, thiol moieties, or hydroxyl moieties, to name a few. It is to be appreciated that the moiety can be linked to the provided compound directly or via a chain-based group such as a divalent saturated or unsaturated hydrocarbon chain. In certain embodiments, the moieties may be attached by click chemistry. In certain embodiments, the moiety may be attached by 1, 3-cycloaddition of an azide to an alkyne, optionally in the presence of a copper catalyst. Methods of using click chemistry are known in the art and include those described by Rostovtsev et al, Angew. chem. int. Ed.2002,41,2596-99 and Sun et al, Bioconjugate chem.,2006,17, 52-57.
As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that is capable of being detected, such as a primary label and a secondary label. Primary labels such as radioactive isotopes (e.g. tritium,32P，33P，35s or14C) Mass spectrometric tags and fluorescent labels are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent moieties.
The term "secondary label" as used herein refers to moieties such as biotin and various protein antigens, which require the presence of a second intermediate to generate a detectable signal. For biotin, the second intermediate may include a streptavidin-enzyme conjugate. For antigen labeling, the second intermediate may comprise an antibody-enzyme conjugate. Some fluorophores act as secondary labels because they transfer energy to another group during non-radiative Fluorescence Resonance Energy Transfer (FRET), while the second group generates a detection signal.
The terms "fluorescent label", "fluorochrome" and "fluorophore" as used herein refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include, but are not limited to: alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), carboxyrhodamine 6G, carboxy-X-Rhodamine (ROX), cascading yellow blue, cascading yellow coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), danesensulfonyl, dialklyminocoumarin, 4', dichlorocoumarin, 5' -dichlorocoumarin, fluorescent red-2-7-erythrosine, eosin-7, NEEDM, FAM, hydroxycoumarins, IRDyes (IRD40, IRD 700, IRD 800), JOE, Lissamine rhodamine B, Marina blue, methoxycoumarin, naphthofluorescein, Oregon green 488, Oregon green 500, Oregon green 514, Pacific blue, PyMPO, pyrene, rhodamine B, rhodamine 6G, rhodamine green, rhodamine red, Rhodol green, 2',4',5',7' -tetra-bromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas red-X.
The term "mass spectrometry tag" as used herein refers to any moiety that is uniquely detectable by Mass Spectrometry (MS) detection techniques due to its mass. Examples of mass spectrometric tags include electrophoretic release tags such as N- [3- [4 '- [ (p-methoxytetrafluorobenzyl) oxy ] phenyl ] -3-methylglyceridonyl ] isoperieridate, 4' - [2,3,5, 6-tetrafluoro-4- (pentafluorophenoxy) ] methylacetophenone, and derivatives thereof. The synthesis and use of these mass spectrometry tags is described in U.S. Pat. nos. 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020 and 5,650,270. Other examples of mass spectrometry tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying length and base composition, oligopeptides, oligosaccharides, and other synthetic polymers of varying length and monomer composition. A wide variety of organic molecules (biomolecules or synthetic compounds) in the appropriate mass range (100-.
The terms "measurable affinity" and "measurably inhibits" as used herein means a measurable change in GCN2 protein kinase activity between a sample comprising a compound of the invention or a composition thereof and GCN2 protein kinase and an equivalent sample comprising GCN2 protein kinase, in the absence of said compound or composition thereof.
3. Description of the exemplary embodiments:
as described above, in certain embodiments, the present invention provides compounds of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
ring A is selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is optionally fused to a 5-6 membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated spiroheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or
Het, wherein Het is a 4-8 membered saturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated spiroheterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated bridged bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring B is
Each R is independently hydrogen or an optionally substituted group selected from C1-6An aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
Two R groups optionally together form a divalent C2-4An alkylene chain;
two R groups optionally together with their intervening atoms form an optionally substituted 3-7-membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R' is independently hydrogen or C optionally substituted with halogen1-3An aliphatic group;
each R1Independently hydrogen, halogen, -CN, -NO2，-C(O)R，-C(O)OR，-C(O)NR2，-C(O)NRS(O)2R，-C(O)N＝S(O)R2，-NR2，-NRC(O)R，-NRC(O)NR2，-NRC(O)OR，-NRS(O)2R，-NRS(O)2NR2，-OR，-ON(R)SO2R，-P(O)R2，-SR，-S(O)R，-S(O)2R，-S(O)(NH)R，-S(O)2N(R)2，-S(NH2)2(O)OH，-N＝S(O)R2，-CH3，-CH2OH，-CH2NHSO2CH3，-CD3，-CD2NRS(O)2R, or R; or:
two R1The radicals optionally together form ═ O or ═ NH; or
Two R1The radicals optionally together forming a divalent C2-4An alkylene chain;
each R2Independently hydrogen, halogen, -CN, -C (O) N (R')2，-OR’，-N(R’)2，-S(O)2R，-S(O)2N(R)2-O-phenyl, or an optionally substituted group selected from C1-3Aliphatic, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R3Is hydrogen, halogen, -CN, -OR ', -N (R')2Or an optionally substituted group selected from C1-3Aliphatic, phenyl, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R4is hydrogen, halogen, -CN, -OR, -N ═ S (O) R2，-N(R)2Or an optionally substituted group selected from C1-3Aliphatic, 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 7-12 membered saturated or partially unsaturated spiroheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
m is 0, 1, 2, 3, 4 or 5;
n is 0, 1 or 2;
p is 0 or 1; and
q is 0 or 1.
As defined previously and described herein, Ring A is selected from the group consisting of a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is optionally fused to a 5-6 membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated spiroheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a phenyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a phenyl ring, a phenyl, A 5-6 membered monocyclic heteroaromatic ring of a heteroatom of oxygen or sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or Het wherein Het is a 4-8 membered saturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated spiroheterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated bridged bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In certain embodiments, ring a is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In certain embodiments, ring a is phenyl. In certain embodiments, ring a is an 8-10 membered bicyclic aromatic carbocyclic ring. In certain embodiments, ring a is a 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally fused to a 5-6 membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, ring a is a 7-12 membered partially unsaturated spirocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, ring a is a 7-12 membered partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, ring a is a 7-12 membered partially unsaturated bridged bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, ring a is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, ring a is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In certain embodiments, ring a is Het. In certain embodiments, ring a is a 4-8 membered saturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, ring a is a 7-12 membered saturated spirocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, ring a is a 7-12 membered saturated bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, ring a is a 7-12 membered saturated bridged bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In certain embodiments, ring a isIn certain embodiments, ring a is
In certain embodiments, ring a isIn certain embodiments, ring a is
In certain embodiments, ring a isIn certain embodiments, ring a is
In certain embodiments, ring a isIn certain embodiments, ring a isIn certain embodiments, ring a isIn certain embodiments, ring a is
In certain embodiments, ring a isIn certain embodiments, ring a isIn certain embodiments, ring a isIn certain embodiments, ring a is
In certain embodiments, ring a is selected from those described in table 1 below.
As previously defined and described herein, ring B is
In certain embodiments, ring B is In certain embodiments, ring B is
In certain embodiments, ring B is selected from those described in table 1 below.
As defined above and described herein, each R is independently hydrogen or an optionally substituted group selected from C1-6An aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R groups optionally together form a divalent C 2-4An alkylene chain; or two R groups optionally together with their intervening atoms form an optionally substituted 3-7-membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In certain embodiments R is hydrogen. In certain embodiments R is optionally substituted C1-6An aliphatic group. In certain embodiments R is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In certain embodiments R is optionally substituted phenyl. In certain embodiments R is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In certain embodiments R is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments R is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments R is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments two R groups are optionally taken together to form a divalent C2-4An alkylene chain. In certain embodiments two R groups are optionally taken together with their spacer atoms Forming an optionally substituted 3-7-membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In certain embodiments, R is selected from those described in table 1 below.
As defined above and described herein, each R' is independently hydrogen or C optionally substituted with halogen1-3An aliphatic group.
In certain embodiments, R' is hydrogen. In certain embodiments, R' is C optionally substituted with halogen1-3An aliphatic group.
In certain embodiments, R' is selected from those described in table 1 below.
Each R is as defined above and described herein1Independently hydrogen, halogen, -CN, -NO2，-C(O)R，-C(O)OR，-C(O)NR2，-C(O)NRS(O)2R，-C(O)N＝S(O)R2，-NR2，-NRC(O)R，-NRC(O)NR2，-NRC(O)OR，-NRS(O)2R，-NRS(O)2NR2，-OR，-ON(R)SO2R，-P(O)R2，-SR，-S(O)R，-S(O)2R，-S(O)(NH)R，-S(O)2N(R)2，-S(NH2)2(O)OH，-N＝S(O)R2，-CH3，-CH2OH，-CH2NHSO2CH3，-CD3，-CD2NRS(O)2R, or R; or: two R1The radicals optionally together form ═ O or ═ NH; or two R1The radicals optionally together forming a divalent C2-4An alkylene chain.
In certain embodiments, R1Is hydrogen. In certain embodiments, R1Is a halogen. In certain embodiments, R1is-CN. In certain embodiments, R1is-NO2. In certain embodiments, R1is-C (O) R. In certain embodiments, R1is-C (O) OR. In certain embodiments, R1is-C (O) NR2. In certain embodiments, R1is-C (O) NRS (O)2And R is shown in the specification. In certain embodiments, R 1is-C (O) N ═ S (O) R2. In thatIn certain embodiments, R1is-NR2. In certain embodiments, R1is-NRC (O) R. In certain embodiments, R1is-NRC (O) NR2. In certain embodiments, R1is-NRC (O) OR. In certain embodiments, R1is-NRS (O)2And R is shown in the specification. In certain embodiments, R1is-NRS (O)2NR2. In certain embodiments, R1is-OR. In certain embodiments, R1is-ON (R) SO2And R is shown in the specification. In certain embodiments, R1is-P (O) R2. In certain embodiments, R1is-SR. In certain embodiments, R1is-S (O) R. In certain embodiments, R1is-S (O)2And R is shown in the specification. In certain embodiments, R1is-S (O) (NH) R. In certain embodiments, R1is-S (O)2N(R)2. In certain embodiments, R1is-S (NH)2)2(O) OH. In certain embodiments, R1is-N ═ S (O) R2. In certain embodiments, R1is-CD3. In certain embodiments, R1is-CD2NRS(O)2And R is shown in the specification. In certain embodiments, R1Is R. In certain embodiments, two R are1The radicals optionally together form ═ O or ═ NH. In certain embodiments, two R are1The radicals optionally together forming a divalent C2-4An alkylene chain.
In certain embodiments, R1Is fluorine. In certain embodiments, R 1Is chlorine. In certain embodiments, R1Is methyl. In certain embodiments, R1Is ethyl. In certain embodiments, R1is-OH. In certain embodiments, R1is-OCH3. In certain embodiments, R1is-CH2And (5) OH. In certain embodiments, R1is-CH2And (C) CN. In certain embodiments, R1is-CF3. In certain embodiments, R1is-CH2NH2. In certain embodiments, R1is-COOH. In certain embodiments, R1is-NH2。
In certain embodiments, two R are1The group forms ═ O. In certain embodiments, two R are1The radical forms ═ NH. In certain embodiments, two R are1Radical formation
In certain embodiments, R1Is that
In certain embodiments, R1Is that
In certain embodiments, R1Is thatIn certain embodiments, R1Is that
In certain embodiments, R1Is thatIn certain embodiments, R1Is thatIn certain embodiments, R1Is thatIn certain embodiments, R1Is thatIn certain embodiments, R1Is thatIn certain embodiments, R1Is thatIn certain embodiments, R1Is that
In certain embodiments, R1Is thatIn certain embodiments, R1Is that
In certain embodiments, R1Is thatIn certain embodiments, R1Is that
In certain embodiments, R1Is that
In certain embodiments, R1Is that
In certain embodiments, R1Is thatIn certain embodiments, R1Is thatIn certain embodiments, R1Is thatIn certain embodiments, R1Is that
In certain embodiments, R1Is thatIn certain embodiments, R1Is that
In certain embodiments, R1Is that
In certain embodiments, R1Is that
In certain embodiments, R1Is that
In certain embodiments, R1Selected from those described in table 1 below.
Each R is as defined above and described herein2Independently hydrogen, halogen, -CN, -C (O) N (R')2，-OR’，-N(R’)2，-S(O)2R，-S(O)2N(R)2-O-phenyl, or an optionally substituted group selected from C1-3Aliphatic, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In certain embodiments, R2Is hydrogen. In certain embodiments, R2Is a halogen. In some embodimentsIn, R2is-CN. In certain embodiments, R2is-C (O) N (R')2. In certain embodiments, R2is-OR'. In certain embodiments, R2is-N (R')2. In certain embodiments, R2is-S (O)2And R is shown in the specification. In certain embodiments, R2is-S (O) 2N(R)2. In certain embodiments, R2is-O-phenyl. In certain embodiments, R2Is optionally substituted C1-3An aliphatic group. In certain embodiments, R2Is an optionally substituted phenyl group. In certain embodiments, R2Is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, R2Is an optionally substituted 4-8 membered saturated monocyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In certain embodiments, R2Is fluorine. In certain embodiments, R2Is chlorine. In certain embodiments, R2Is bromine. In certain embodiments, R2Is methyl. In certain embodiments, R2Is ethyl. In certain embodiments, R2is-CF3. In certain embodiments, R2Is that
In certain embodiments, R2Is thatIn certain embodiments, R2Is thatIn certain embodiments, R2Is thatIn certain embodiments, R2Is thatIn certain embodiments, R2Is that
At a certain pointIn some embodiments, R2Is that
In certain embodiments, R2Is that
In certain embodiments, R2Selected from those described in table 1 below.
R is as defined hereinbefore and described3Is hydrogen, halogen, -CN, -OR ', -N (R')2Or an optionally substituted group selected from C1-3Aliphatic, phenyl, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In certain embodiments, R3Is hydrogen. In certain embodiments, R3Is a halogen. In certain embodiments, R3is-CN. In certain embodiments, R 3is-OR'. In certain embodiments, R3is-N (R')2. In certain embodiments, R3Is optionally substituted C1-3An aliphatic group. In certain embodiments, R3Is an optionally substituted phenyl group. In certain embodiments, R3Is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In certain embodiments, R3Selected from those described in table 1 below.
R is as defined hereinbefore and described4Is hydrogen, halogen, -CN, -OR, -N ═ S (O) R2，-N(R)2Or an optionally substituted group selected from C1-3Aliphatic, 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 7-12 membered saturated or partially unsaturated spiroheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In certain embodiments, R4Is hydrogen. In certain embodiments, R4Is a halogen. In certain embodiments, R4is-CN. In certain embodiments, R4is-OR. In certain embodiments, R4is-N ═ S (O) R2. In certain embodiments, R4is-N (R)2. In certain embodiments, R4Is optionally substituted C1-3An aliphatic group. In certain embodiments, R 4Is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, R4Is an optionally substituted 7-12 membered saturated or partially unsaturated spirocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, R4Is fluorine. In certain embodiments, R4Is chlorine. In certain embodiments, R4Is methyl. In certain embodiments, R4is-CF3. In certain embodiments, R4is-OH. In certain embodiments, R4Is that
In certain embodiments, R4Is that
In certain embodiments, R4Is that
At a certain pointIn some embodiments, R4Selected from those described in table 1 below.
As defined previously and described herein, m is 0, 1, 2, 3, 4, or 5.
In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5.
In certain embodiments, m is 1, 2, or 3.
In certain embodiments, m is selected from those described in table 1 below.
As defined above and described herein, n is 0, 1 or 2.
In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2.
In certain embodiments, n is selected from those described in table 1 below.
As defined above and described herein, p is 0 or 1.
In certain embodiments, p is 0. In certain embodiments, p is 1.
In certain embodiments, p is selected from those described in table 1 below.
As defined above and described herein, q is 0 or 1.
In certain embodiments, q is 0. In certain embodiments, q is 1.
In certain embodiments, q is selected from those described in table 1 below.
In certain embodiments, the present invention provides compounds of formula I wherein ring a is Het, thereby forming compounds of formula II:
or a pharmaceutically acceptable salt thereof, wherein each ring B, R1，R2，R3，R4M, n, p and q are as defined above and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein ring a is Het and ring B isThereby forming a compound of formula III:
or a pharmaceutically acceptable salt thereof, wherein each Het, R1，R2，R3，R4M, n, p and q are as defined above and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein ring a is piperidinyl, piperazinyl, or morpholinyl, and ring B isThereby forming a compound of formula IV-a, IV-b or IV-c, respectively:
or a pharmaceutically acceptable salt thereof, wherein each R1，R2，R3，R4M, n, p and q are as defined above and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein ring a is Het and ring B is
or a pharmaceutically acceptable salt thereof, wherein each Het, R1，R2，R3，R4M, n, p and q are as defined above and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein ring a is piperidinyl, piperazinyl, or morpholinyl, and ring B isWhereby a compound of formula VI-a, VI-b or VI-c, respectively, is formed:
or a pharmaceutically acceptable salt thereof, wherein each R1，R2，R3，R4M, n, p and q are as defined above and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein ring a is Het and ring B
or a pharmaceutically acceptable salt thereof, wherein each Het, R1，R2，R3，R4M, n, p and q are as defined above and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein ring a is piperidinyl, piperazinyl, or morpholinyl, and ring B isThereby forming a compound of formula VIII-a, VIII-b or VIII-c, respectively:
or a pharmaceutically acceptable salt thereof, wherein each R1，R2，R3，R4M, n, p and q are as defined above and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein ring a is Het and ring B is
or a pharmaceutically acceptable salt thereof, wherein each Het, R 1，R2，R3，R4M, n, p and q are as defined above and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein ring a is piperidinyl, piperazinyl, or morpholinyl, and ring B isThereby forming a compound of formula X-a, X-b or X-c, respectively:
or a pharmaceutically acceptable salt thereof, wherein each R1，R2，R3，R4M, n, p and q are as defined above and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein ring a is Het and ring B is
or a pharmaceutically acceptable salt thereof, wherein each Het, R1，R2，R3，R4M, n, p and q are as defined above and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein ring a is piperidinyl, piperazinyl, or morpholinyl, and ring B is
or a pharmaceutically acceptable salt thereof, wherein each R1，R2，R3，R4M, n, p and q are as defined above and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein n is 1, p is 1, q is 1, R 2is-CF3，R3Is hydrogen, R4Is hydrogen, ring A is piperidinyl, piperazinyl or morpholinyl, and ring B isWhereby compounds of formula XIII-a, XIII-b or XIII-c, respectively, are formed:
or a pharmaceutically acceptable salt thereof, wherein each R1And m is as defined hereinbefore and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein n is 1, p is 1, q is 1, R2Is chlorine, R3Is hydrogen, R4Is hydrogen, ring A is piperidinyl, piperazinyl or morpholinyl, and ring B isThereby forming a compound of formula XIV-a, XIV-b or XIV-c, respectively:
or a pharmaceutically acceptable salt thereof, wherein each R1And m is as defined hereinbefore and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein n is 1, p is 1, q is 1, R2is-CHF2，R3Is hydrogen, R4Is hydrogen, ring A is piperidinyl, piperazinyl or morpholinyl, and ring B is
or a pharmaceutically acceptable salt thereof, wherein each R1And m is as defined hereinbefore and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein n is 1, p is 1, q is 1, R 2is-CF3，R3Is hydrogen, R4Is hydrogen, ring A is piperidinyl, piperazinyl orMorpholinyl, and ring B isThereby forming a compound of formula XVI-a, XVI-b or XVI-c, respectively:
or a pharmaceutically acceptable salt thereof, wherein each R1And m is as defined hereinbefore and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein n is 1, p is 1, q is 1, R2Is chlorine, R3Is hydrogen, R4Is hydrogen, ring A is piperidinyl, piperazinyl or morpholinyl, and ring B is
or a pharmaceutically acceptable salt thereof, wherein each R1And m is as defined hereinbefore and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein n is 1, p is 1, q is 1, R2is-CHF2，R3Is hydrogen, R4Is hydrogen, ring A is piperidinyl, piperazinyl or morpholinyl, and ring B isWhereby a compound of formula XVIII-a, XVIII-b or XVIII-c, respectively, is formed:
or a pharmaceutically acceptable salt thereof, wherein each R1And m is as defined hereinbefore and in the embodiments hereinBoth separately and in combination as described.
In certain embodiments, the present invention provides compounds of formula I wherein n is 1, p is 1, q is 1, R 2Is cyclopropyl, R3Is hydrogen, R4Is hydrogen, ring A is piperidinyl, piperazinyl or morpholinyl, and ring B isThereby forming a compound of formula XIX-a, XIX-b or XIX-c, respectively:
or a pharmaceutically acceptable salt thereof, wherein each R1And m is as defined hereinbefore and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein n is 1, p is 1, q is 1, R2Is azetidinyl, R3Is hydrogen, R4Is hydrogen, ring A is piperidinyl, piperazinyl or morpholinyl, and ring B isThereby forming a compound of formula XX-a, XX-b or XX-c, respectively:
or a pharmaceutically acceptable salt thereof, wherein each R1And m is as defined hereinbefore and described in the embodiments herein, both individually and in combination.
In certain embodiments, the present invention provides compounds of formula I wherein n is 1, p is 1, q is 1, R2Is thatR3Is hydrogen, R4Is methyl, ring A is piperidinyl, piperazinyl or morpholinyl, and ring B isWhereby a compound of formula XXI-a, XXI-b or XXI-c, respectively, is formed:
or a pharmaceutically acceptable salt thereof, wherein each R1And m is as defined hereinbefore and described in the embodiments herein, both individually and in combination.
Exemplary compounds of the invention are described in table 1 below.
TABLE 1 exemplary Compounds of formula I
In certain embodiments, the present invention provides a compound described in table 1 above, or a pharmaceutically acceptable salt thereof.
In certain embodiments, the present invention provides a complex comprising GCN2 and an inhibitor.
4. General methods for providing the Compounds of the invention
The compounds of the present invention may be prepared or isolated by synthetic and/or semi-synthetic methods generally known to those skilled in the art for analogous compounds and by the methods described in detail in the examples herein.
In the following schemes, where a particular protecting group ("PG"), leaving group ("LG"), or conversion condition is described, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and conversion conditions are also suitable and are also contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, mechanics, and Structure, M.B.Smith and J.March,5thEdition,John Wiley&Sons,2001,Comprehensive Organic Transformations,R.C.Larock,2ndEdition,John Wiley&Sons,1999, and Protecting Groups in Organic Synthesis, T.W.Greene and P.G.M.Wuts,3rdedition,John Wiley&Sons,1999, the entire contents of each of which are incorporated herein by reference.
As used herein, the phrase "leaving group" (LG) includes, but is not limited to, halogens (e.g., fluoride, chloride, bromide, iodide), sulfonates (e.g., mesylate, tosylate, besylate, brosylate, m-nitrobenzenesulfonate, triflate), diazo, and the like.
As used herein, the phrase "oxygen protecting group" includes, for example, carbonyl protecting groups, hydroxyl protecting groups, and the like. Hydroxy Protecting Groups are well known in the art and include Protecting Groups in Organic Synthesis, T.W.Greene and P.G.M.Wuts,3rdedition,John Wiley&Sons,1999, which is incorporated herein by reference in its entirety. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of the ester include formate, acetate, carbonate and sulfonate. Specific examples include formates, benzoylformates, chloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionates, 4-oxopentanoates, 4,4- (ethylenedithio) pentanoates, pivaloates (pivaloyl), crotonates, 4-methoxy-crotonates, benzoates, p-benzylbenzoates, 2,4, 6-trimethylbenzoates, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2, 2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, vinyl, allyl and p-nitrobenzyl. Examples of the silyl ether include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl, trityl, tert-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy) methyl, benzyloxymethyl, β - (trimethylsilyl) ethoxymethyl, and tetrahydropyranyl ether. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3, 4-dimethoxybenzyl, O-nitrobenzyl, p-halobenzyl, 2, 6-dichlorobenzyl, p-cyanobenzyl, and 2-and 4-picolinyl.
Amino Protecting groups are well known in the art and include Protecting Groups in OrganicSynthesis,T.W.Greene and P.G.M.Wuts,3rdedition,John Wiley&Sons,1999, which is incorporated herein by reference in its entirety. Suitable amino protecting groups include, but are not limited to, arylalkyl amines, carbamates, cyclic imides, allylamines, amides, and the like. Examples of such groups include t-Butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxycarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl and the like.
Scheme 1: general scheme for the preparation of compounds of formula I, wherein Ring B is a pyrimidine attached from the 2-position to the bicyclic core, R3Is hydrogen, R4Is hydrogen, p is 1, and q is 1.
In scheme 1 above, each of the rings A, R1，R2M and n are as defined above and below and as described in classes and subclasses herein.
Scheme 2: general scheme for the preparation of compounds of formula I, wherein Ring B is a pyrimidine attached from the 2-position to the bicyclic core, R3Is hydrogen, R4Is hydrogen, n is 1, p is 1, and q is 1.
In scheme 2 above, each of the rings A, R1，R2And m is as defined above and below and as described in classes and subclasses herein.
Scheme 3: general scheme for the preparation of compounds of formula I, wherein Ring B is a pyrimidine attached from the 2-position to the bicyclic core, R3Is hydrogen, R4Is hydrogen, p is 1, and q is 1.
In scheme 3 above, each of the rings A, R1，R2M and n are as defined above and below and as described in classes and subclasses herein.
Scheme 4: general scheme for the preparation of compounds of formula I, wherein Ring B is a pyrimidine attached from the 4-position to the bicyclic core, R3Is hydrogen, R4Is hydrogen, n is 1, p is 1, and q is 1.
In scheme 4 above, each of the rings A, R1，R2And m is as defined above and below and as described in classes and subclasses herein.
It will be appreciated by those skilled in the art that the compounds of formula I may contain one or more stereocenters and may exist as racemic or diastereomeric mixtures. Those skilled in the art will also appreciate the many methods known in the art for separating isomers to obtain stereoenriched or stereopure isomers of those compounds, including but not limited to HPLC, chiral HPLC, stepwise crystallization of diastereomeric salts, kinetic enzymatic resolution (e.g., by fungal, bacterial or animal-derived lipases or esterases), and formation of covalent diastereomeric derivatives with an enantiomerically enriched reagent.
Those skilled in the art will appreciate that various functional groups in the compounds of the present invention, such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens, and nitriles, can be interconverted by techniques well known in the art, including, but not limited to, reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. "March's Advanced organic chemistry",5thEd.,Ed.:Smith,M.B.and March,J.,John Wiley&Sons, New York:2001, the entire contents of which are incorporated herein by reference. Such interconversion may entail one or more of the aforementioned techniques, and certain methods of synthesizing the compounds of the present invention are described in the examples (illustrative) section below.
5. Application, formulation and administration
a. Pharmaceutically acceptable compositions
According to a further embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of the compound in the compositions of the invention is effective to measurably inhibit GCN2 protein kinase or a mutant thereof in a biological sample or in a patient. In certain embodiments, the amount of the compound in the compositions of the invention is effective to measurably inhibit GCN2 protein kinase or a mutant thereof in a biological sample or in a patient. In certain embodiments, the compositions of the present invention are formulated for administration to a patient in need thereof. In certain embodiments, the compositions of the present invention are formulated for oral administration to a patient.
The term "patient" as used herein means an animal, preferably a mammal, and most preferably a human.
The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylic acids, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
By "pharmaceutically acceptable derivative" is meant any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present invention which, when administered to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or an inhibitory active metabolite or residue thereof.
As used herein, the term "inhibitory active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of GCN2 protein kinase or a mutant form thereof.
The compositions of the invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oleaginous suspensions. These suspensions may be formulated according to the techniques known in the art with suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that may be used are, inter alia, water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium.
For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersants commonly used in formulating pharmaceutically acceptable dosage forms including emulsions and suspensions. Other surfactants commonly used such as Tweens, Spans and other emulsifying agents or bioavailability enhancers commonly used to prepare pharmaceutically acceptable solid, liquid or other dosage forms may also be used for formulation purposes.
The pharmaceutically acceptable compositions of the present invention may be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, suspensions or aqueous solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. Where aqueous suspensions are desired for oral use, the active ingredient is combined with emulsifying and suspending agents. Certain sweetening, flavoring or coloring agents may also be added, if desired.
Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. The materials include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutically acceptable compositions of the present invention may also be administered topically, particularly where the target of treatment includes areas or organs readily accessible by topical administration, including ocular, dermal or small bowel diseases. Suitable topical formulations are readily prepared for use in each of these areas or organs.
Local administration in the small intestine can be carried out in rectal suppository formulations (see above) or in suitable enema formulations. Topical transdermal patches may also be used.
For topical administration, the provided pharmaceutically acceptable compositions may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Topical carriers for the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the provided pharmaceutically acceptable compositions can be formulated as suitable lotions or creams containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic pH adjusted sterile saline, or preferably as solutions in isotonic pH adjusted sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic applications, the pharmaceutically acceptable compositions may be formulated as ointments such as petrolatum.
The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. The compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solvents or dispersants.
Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. The formulation may be administered with or without food. In certain embodiments, the pharmaceutically acceptable compositions of the present invention are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.
The amount of a compound of the present invention that can be combined with a carrier material to produce a composition in single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, the provided compositions should be formulated so as to be capable of administering to a patient receiving these compositions a dose of inhibitor of 0.01-100mg/kg body weight/day.
It will also be understood that the specific dose and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of secretion, drug composition, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of the compound of the present invention in the composition also depends on the specific compound in the composition.
b. Use of compounds and pharmaceutically acceptable compositions
The compounds and compositions described herein are generally useful for inhibiting GCN2 kinase activity.
The activity of a compound of the invention as an inhibitor of GCN2 or a mutant form thereof may be tested in vitro, in vivo or in a cell line. In vitro tests include assays for the determination of phosphorylation activity and/or subsequent functional outcome or inhibition of ATPase activity of activated GCN2 or a mutant form thereof. An alternative in vitro test quantifies the ability of an inhibitor to bind to GCN 2. Inhibitor binding can be measured as follows: radiolabelling the inhibitor prior to binding, isolating the inhibitor/GCN 2 complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding can be determined by performing a competition experiment in which the new inhibitor is incubated with GCN2 bound to a known radioligand. Detailed test conditions for compounds useful as GCN2 or mutant inhibitors thereof in the present invention are described in the examples below.
As used herein, the terms "treat," "treating," and "therapy" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof, as described herein. In certain embodiments, treatment may be administered after one or more symptoms have occurred. In other embodiments, the treatment may be administered in the absence of symptoms. For example, treatment may be given to susceptible individuals prior to the onset of symptoms (e.g., taking into account the history of symptoms and/or taking into account genetic or other susceptibility factors). Treatment may also be continued after the symptoms have been eliminated, for example with the aim of preventing or delaying their recurrence.
The provided compounds are inhibitors of one or more GCN2 and are therefore useful for treating one or more disorders associated with GCN2 activity. Thus, in certain embodiments, the present invention provides methods of treating a GCN 2-mediated disorder comprising the step of administering to a patient in need of a compound of the present invention or a pharmaceutically acceptable composition thereof.
As used herein, the term "GCN 2-mediated" disorder, disease, and/or condition as used herein means any disease or other deleterious condition in which GCN2 or a mutant thereof is known to have an effect. Accordingly, yet another embodiment of the invention relates to treating or reducing the severity of one or more diseases in which GCN2 or a mutant form thereof is known to have an effect.
In certain embodiments, the present invention provides methods of treating one or more disorders, diseases and/or conditions, wherein the disorder, disease or condition is selected from the group consisting of an inflammatory condition, an immunological condition, an autoimmune condition, an allergic condition, a rheumatic condition, a thrombotic condition, cancer, an infection, a neurodegenerative disease, a degenerative disease, a neuroinflammatory disease, a cardiovascular disease, and a metabolic condition.
In certain embodiments, the cancer to be treated is a solid tumor or a tumor of the blood and immune system.
In certain embodiments, the cancer is a solid tumor, wherein the solid tumor is derived from the group consisting of: epithelial, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, genitourinary tract, lymphatic system, stomach, larynx, bone (including chondrosarcoma and Ewing's sarcoma), germ cells (including embryonic tissue tumors), and/or tumors of the lung, derived from the group of: monocytic leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma, neurofibromatosis, angiosarcoma, breast cancer and/or malignant melanoma.
In certain embodiments, the autoimmune condition is rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis,
In certain embodiments, the metabolic condition is diabetes.
In certain embodiments, the degenerative disease is osteoarthritis.
In certain embodiments, the inflammatory condition is asthma, inflammatory bowel disease, or giant cell arteritis.
In certain embodiments, the cardiovascular disease is ischemic injury.
In certain embodiments, the neurodegenerative disease is alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis-the dutch type, cerebral amyloid angiopathy, creutzfeldt-jakob disease, frontotemporal dementia, huntington's chorea, or parkinson's disease.
In certain embodiments, the infection is caused by: leishmania, mycobacteria (including Mycobacterium leprae, Mycobacterium tuberculosis and/or Mycobacterium avium), Plasmodium, human immunodeficiency virus, Epstein Barr virus, herpes simplex virus, or hepatitis C virus.
In addition, the present invention provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt or hydrate or solvate thereof, for the manufacture of a medicament for the treatment of an inflammatory condition, an immunological condition, an autoimmune condition, an allergic condition, a rheumatic condition, a thrombotic condition, cancer, an infection, a neurodegenerative disease, a degenerative disease, a neuroinflammatory disease, a cardiovascular disease, or a metabolic condition.
c. Combination therapy
Additional therapeutic agents that are commonly administered to treat a particular condition or disease may be administered in combination with the compounds and compositions of the present invention depending on the condition or disease to be treated. As used herein, an additional therapeutic agent that is typically administered to treat a particular disease or condition is known as "suitable for the disease or condition being treated.
In certain embodiments, the invention provides methods of treating the disclosed diseases or conditions comprising administering to a patient in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and concurrently or sequentially co-administering an effective amount of one or more additional therapeutic agents, such as those described herein. In certain embodiments, the method comprises co-administering an additional therapeutic agent. In certain embodiments, the method comprises co-administering two additional therapeutic agents. In certain embodiments, the combination of the disclosed compounds and one or more additional therapeutic agents act synergistically.
The compounds of the present invention may also be used in combination with known therapeutic procedures such as administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiation therapy.
The compounds of the invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapies being in the form of fixed combinations, or the compounds of the invention and one or more other therapeutic compounds being administered staggered or independently of one another, or the fixed combinations and one or more other therapeutic compounds being administered in combination. Additionally or additionally, particularly for tumor treatment, the compounds of the present invention can be administered in combination with chemotherapy, radiation therapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof. Long-term treatment may also serve as an adjunct treatment during other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's state after tumor regression, or even chemopreventive treatment, e.g. in at-risk patients.
In certain embodiments, the provided combination or composition thereof is administered in combination with a further therapeutic agent.
Examples of agents with which the combinations of the invention may also be combined include, but are not limited to: agents for the treatment of alzheimer's disease such asAnd
In certain embodiments, the combination therapies of the invention or pharmaceutically acceptable compositions thereof are administered in combination with a monoclonal antibody or siRNA therapeutic.
Those additional agents may be administered separately from the combination therapy provided as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the present invention in a single composition. If administered as part of a multiple dosing regimen, the two active agents can be administered simultaneously, sequentially, or within a time period that is spaced apart from each other (typically within 5 hours of each other).
As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with the present invention. For example, the combination of the invention may be administered with a further therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
The amount of the one or more additional therapeutic agents present in the compositions of the present invention may not exceed the amount that would normally be administered in a composition containing the therapeutic agent as the only active agent. Preferably, the amount of the one or more additional therapeutic agents in the compositions of the present disclosure ranges from about 50% to 100% of the amount typically present in a composition comprising the agent as the sole therapeutically active agent. In certain embodiments, one or more additional therapeutic agents are administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the normally administered amount of the agent. As used herein, the phrase "generally administered" means an approved amount of an FDA-approved therapeutic agent administered according to the FDA label leaflet.
In one embodiment, the present invention provides a composition comprising a compound of formula I and one or more additional therapeutic agents. The therapeutic agent may be administered with the compound of formula I, or may be administered before or after the compound of formula I is administered. Suitable therapeutic agents are described in further detail below. In certain embodiments, a compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, the compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.
In yet another embodiment, the present invention provides a method of treating an inflammatory disease, disorder or condition by administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents. The additional therapeutic agent may be a small molecule or recombinant biological agent and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac And celecoxib, colchicineCorticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., probenecid, allopurinol, febuxostatSulfasalazine
In yet another embodiment, the present invention provides a method of treating gout comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac
In yet another embodiment, the present invention provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolacAnd celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, sulfasalazine
In certain embodiments, the present invention provides methods of treating osteoarthritis comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolacAnd celecoxib, diclofenac, cortisone, hyaluronic acid (b)
In certain embodiments, the invention provides methods of treating lupus comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac
In certain embodiments, the present invention provides methods of treating inflammatory bowel disease comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from mesalazineSulfasalazineAntidiarrheal agents such as diphenoxylateAnd loperamide
In certain embodiments, the present invention provides methods of treating asthma comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from the group consisting ofBeta-2 agonists such as salbutamol
In certain embodiments, the present invention provides methods of treating COPD comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from beta-2 agonists such as salbutamolL-salbutamol
in certain embodiments, the present invention provides methods of treating HIV comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from nucleoside reverse transcriptase inhibitors such as zidovudineAbacavir
In yet another embodiment, the present inventionThere is also provided a method of treating a hematologic malignancy comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from rituximab
In yet another embodiment, the present invention provides a method of treating a solid tumor comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from rituximab
In yet another embodiment, the invention provides a method of treating a hematologic malignancy comprising administering to a patient in need thereof a compound of formula I and an inhibitor of the hedgehog (hh) signaling pathway. In certain embodiments, the hematological malignancy is DLBCL (Ramirez et al, "Defining a functional factors in the activating of a hedgehog signaling in a differential large B-cell lymphoma," leuk. res. (2012), published online on day 7-17, and incorporated herein by reference in its entirety).
In yet another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL) comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from rituximab
In another embodiment, the present invention provides a method of treating multiple myeloma comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from the group consisting of bortezomib And dexamethasonehedgehog signaling inhibitors, BTK inhibitors, JAK/pan JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors and lenalidomide in combination therewith
In yet another embodiment, the invention provides a treatmentA method of macroglobulinemia comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from chlorambucil
In certain embodiments, the present invention provides methods of treating alzheimer's disease comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from donepezil
In yet another embodiment, the invention provides a method of treating organ transplant rejection or graft versus host disease comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from the group consisting of steroids, cyclosporine, FK506, rapamycin, hedgehog signaling inhibitors, BTK inhibitors, JAK/pan JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.
In yet another embodiment, the invention provides a method of treating or reducing the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a BTK inhibitor, wherein the disease is selected from inflammatory bowel disease, arthritis, Systemic Lupus Erythematosus (SLE), vasculitis, Idiopathic Thrombocytopenic Purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, still's disease, juvenile arthritis, diabetes, myasthenia gravis, george's thyroiditis, Ord's thyroiditis, grave's disease, autoimmune thyroiditis, sjogren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, guillain-barre's syndrome, acute disseminated encephalomyelitis, addison's disease, ocular clonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, reiter's syndrome, takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, wegener's granulomatosis, psoriasis, systemic alopecia, Behcet's disease, chronic fatigue, familial autonomic dysfunction, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative diseases, rejection of transplanted organs or tissues, acquired immune deficiency syndrome (AIDS, also known as HIV), type I diabetes, graft-versus-host disease, transplantation, infusion, anaphylaxis, allergy (e.g. to plant pollen, latex, drugs, foods, insect poisons, animal hair, animal dander, allergy to dust mites or cockroach shells), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, crohn's disease, cystitis, lacrimal gland inflammation, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondritis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-schonein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin a nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, a B-cell proliferative disorder, such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-hodgkin lymphoma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt's lymphoma/leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or mast cell cancer (e.g., mast cell tumor, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, diseases of the bone and joint, including but not limited to rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis, and reiter's disease), Behcet's disease, sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastasis, thromboembolic disorders (e.g., myocardial infarction, angina, restenosis after angioplasty, restenosis after aortic coronary artery bypass, stroke, transient ischemia, peripheral arterial occlusive disorder, pulmonary embolism, deep venous thrombosis), inflammatory pelvic disease, urethritis, sunburn of the skin, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergy, crohn's disease, irritable bowel syndrome, ulcerative colitis, sjogren's disease, tissue transplant rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, Chronic Obstructive Pulmonary Disease (COPD), autoimmune adenosis (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, goodpasture's syndrome, atherosclerosis, addison's disease, parkinson's disease, alzheimer's disease, diabetes, septic shock, Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia gravis, george's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, guillain-barre syndrome, Behcet's disease, scleroderma, mycosis fungoides-like, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia/reperfusion injury), and graves ' disease.
In yet another embodiment, the invention provides a method of treating or reducing the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a PI3K inhibitor, wherein the disease is selected from the group consisting of cancer, neurodegenerative disorders, angiogenic disorders, viral diseases, autoimmune diseases, inflammatory disorders, hormone-related diseases, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, Chronic Myelogenous Leukemia (CML), Chronic Lymphocytic Leukemia (CLL), liver diseases, pathological immune conditions involving T cell activation, cardiovascular disorders, and CNS disorders.
In a further embodiment, the invention provides a method of treating or reducing the severity of a disease, comprising administering to a patient in need thereof a compound of formula I and a PI3K inhibitor, wherein the disease is selected from benign or malignant tumors, cancers or solid tumors, sarcomas, glioblastomas, neuroblastomas, multiple myeloma or gastrointestinal tract cancers, in particular colon cancer or colorectal adenoma or head and neck tumor, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasias of epithelial character, adenomas, adenocarcinomas, keratoacanthomas, epidermoid carcinomas, large cell carcinomas, non-small cell lung cancer, lymphoma (including, for example, non-hodgkin lymphoma (NHL) and hodgkin lymphoma (also known as hodgkin's or hodgkin's disease)), breast cancer, follicular cancer, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma or leukemia, diseases including Cowden syndrome, Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases in which the PI3K/PKB pathway is abnormally activated, asthma of any type or origin, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection, Acute Lung Injury (ALI), adult/Acute Respiratory Distress Syndrome (ARDS), chronic obstructive pulmonary disease, respiratory tract or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airway hyperreactivity resulting from other drug therapy, especially other inhaled drug therapy, bronchitis of any type or origin, including but not limited to acute, arachidic, catarrhal, croupy, chronic or phthinoid bronchitis, pneumoconiosis (inflammatory (general occupational) disease of the lungs, frequently accompanied by airway obstruction, chronic or acute, and caused by repeated inhalation of dust), including for example aluminosis, anthracosis, asbestosis, stone-deposition disease, eyelash exfoliation, siderosis, silicosis, tobacco poisoning and gossypium, Loffler's syndrome, eosinophils, pneumonia, parasite (especially metazoan) invasion (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including syndrome), eosinophilia granulomatosis and eosinophil-related disorders affecting the airways caused by drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, acquired epidermolysis bullosa, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory diseases involving autoimmune reactions or having autoimmune composition or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, ad hoc sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine eye diseases, graves 'disease, sarcoidosis, alveolitis/alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with or without nephrotic syndrome, including, for example, nephrotic syndrome or minimal change nephropathy, restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic attacks and congestive heart failure, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, huntington's disease, and cerebral ischemia, and neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity and hypoxia.
The compounds and compositions according to the methods of the present invention may be administered in any amount and by any route of administration effective to treat or reduce the severity of cancer, autoimmune disorders, proliferative disorders, inflammatory disorders, neurodegenerative or neurological disorders, schizophrenia, bone-related disorders, liver diseases or cardiac disorders. The precise amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular agent and its mode of administration, and the like. For ease of administration and uniformity of dosage, the compounds of the present invention are preferably formulated in dosage unit form. The phrase "dosage unit form" as used herein refers to physically discrete units of a reagent suitable for use in the patient to be treated. However, it will be understood that the total daily use of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound used; the particular composition used; the age, weight, general health, sex, and diet of the patient; the time of administration, the route of administration, and the rate of secretion of the particular compound employed; the duration of treatment; drugs used in combination or concomitantly with the specified compounds, and the like well known in the medical arts. The term "patient" as used herein means an animal, preferably a mammal, and most preferably a human.
The pharmaceutically acceptable compositions of the present invention can be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (powders, ointments or drops), buccally, as an oral or nasal spray, etc., to humans and other animals, depending on the severity of the infection to be treated. In certain embodiments, to achieve the desired therapeutic effect, the compounds of the present invention may be administered orally or parenterally one or more times per day at daily dosage levels of from about 0.01mg/kg to about 50mg/kg and preferably from about 1mg/kg to about 25mg/kg of the subject's body weight.
Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that can be used are, inter alia, water, ringer's solution, U.S. p. and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil can be employed for this purpose including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of the compounds of the invention, it is often desirable to delay the absorption of the compounds injected subcutaneously or intramuscularly. This can be achieved by using liquid suspensions of crystalline or amorphous materials of poor water solubility. The rate of absorption of the compound is then dependent on its rate of dissolution, which in turn may depend on crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered compound form is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot dosage forms were prepared as follows: the microcapsule matrix of the compound is formed in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations were also prepared as follows: the compounds are embedded in liposomes or microemulsions that are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared as follows: the compounds of the present invention are mixed with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In the solid dosage form, the active compound is mixed with: at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dibasic calcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and plaque detackifying clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and can also have a composition such that they release the active ingredient(s) only, or preferentially, in certain parts of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
The active compound can also be in the form of microcapsules with one or more of the excipients mentioned above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulation art. In the solid dosage form, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. As is common practice, the dosage form may also contain additional substances other than inert diluents, for example, tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also have a composition such that they release the active ingredient(s) only, or preferentially, in certain parts of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and, if desired, with any preservatives or buffers. Ophthalmic formulations, ear drops and eye drops are also contemplated within the scope of the invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. The dosage form can be prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
According to one embodiment, the present invention relates to a method of inhibiting protein kinase activity in a biological sample comprising the step of contacting said biological sample with a compound of the present invention or a composition comprising said compound.
According to yet another embodiment, the present invention relates to a method of inhibiting GCN2 or a mutant form thereof in a biological sample comprising the step of contacting said biological sample with a compound of the present invention or a composition comprising said compound.
The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof; a biopsy from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.
Inhibition of protein kinase or GCN2 protein kinase or mutant activities thereof in a biological sample can be used for various purposes known to those skilled in the art. Examples of such intentions include, but are not limited to, blood transfusion, organ-transplantation, biological sample storage and biological testing.
Yet another embodiment of the present invention relates to a method of inhibiting protein kinase activity in a patient comprising the step of administering to said patient a compound of the present invention or a composition comprising said compound.
According to yet another embodiment, the present invention relates to a method of inhibiting GCN2 or a mutant form thereof in a patient, comprising the step of administering to said patient a compound of the present invention or a composition comprising said compound. In other embodiments, the present invention provides a method of treating a disorder mediated by GCN2 or a mutant thereof in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. The obstacles are described in detail herein.
Depending on the particular condition or disease to be treated, additional therapeutic agents typically administered to treat the condition may also be present in the compositions of the invention. As used herein, an additional therapeutic agent that is typically administered to treat a particular disease or condition is known as "suitable for the disease or condition being treated.
The compounds of the invention may also be used in advantageous combinations with other antiproliferative compounds. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; an anti-estrogen agent; a topoisomerase I inhibitor; a topoisomerase II inhibitor; a microtubule active compound; an alkylating compound; (ii) a histone deacetylase inhibitor; compounds that induce a cellular differentiation process; a cyclooxygenase inhibitor; an MMP inhibitor; an mTOR inhibitor; an antineoplastic antimetabolite; a platinum compound; compounds that target/reduce protein or lipid kinase activity and other anti-angiogenic compounds; a compound that targets, reduces or inhibits protein or lipid phosphatase activity; gonadorelin agonists; an antiandrogen; a methionine aminopeptidase inhibitor; a matrix metalloproteinase inhibitor; bisphosphates; a biological response modifier; an anti-proliferative antibody; heparanase inhibitors; ras oncogenic isoform inhibitor; inhibitors of telomerase; a proteasome inhibitor; compounds for the treatment of hematological malignancies; compounds that target, decrease or inhibit Flt-3 activity; hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide
The term "antiestrogen" as used herein relates to compounds that antagonize the effects of estrogen at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is sold under the trade name NolvadexTMAnd (4) marketing. Raloxifene hydrochloride is sold under the trade name EvstaTMAnd (4) marketing. Fulvestrant can be sold under the trade name FaslodexTMAdministration is carried out. The combination of the invention comprising a chemotherapeutic agent as an anti-oestrogen agent is particularly useful for the treatment of oestrogen receptor positive tumours such as breast tumours.
The term "antiandrogen" as used herein relates to any substance capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (Casodex)TM). The term "gonadorelin agonist" as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be sold under the trade name ZoladexTMAdministration is carried out.
In certain embodiments, the one or more additional therapeutic agents is an androgen receptor inhibitor. Approved androgen receptor inhibitors for use in the present invention include enzalutamide (b)
in certain embodiments, the one or more additional therapeutic agents are Selective Estrogen Receptor Modulators (SERMs), which interfere with the synthesis or activity of estrogen. Approved SERMs for use in the present invention include raloxifene (A)
The term "topoisomerase I inhibitor" as used herein includes, but is not limited to, topotecan, germactecan, irinotecan, camptothecin and analogs thereof, 9-nitrocamptothecin, and macromolecular camptothecin conjugates PNU-166148. Irinotecan can be marketed, for example, under the trademark CamptosarTMAdministration is carried out. Topotecan is available under the trade name HycamptinTMAnd (4) marketing.
The term "topoisomerase II inhibitor" as used herein includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as CaelyxTM) Daunorubicin, epirubicin, idarubicin and nerubicin, anthraquinone, mitoxantrone and losoxantrone, and podophyllotoxin, etoposide and teniposide. Etoposide is sold under the trade name EtopophosTMAnd (4) marketing. Teniposide is marketed under the trade name VM 26-Bristol, doxorubicin under the trade name AcribilastinTMOr AdriamycinTMAnd (4) marketing. Epirubicin is available under the trade name Farmorubicin TMAnd (4) marketing. Idarubicin is available under the trade name ZavedosTMAnd (4) marketing. Mitoxantrone is marketed under the trade name Novantron.
The term "microtubule active agent" relates to microtubule stabilizing, microtubule destabilizing compounds and tubulin polymerization inhibitors, including but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; colchicine and epothilones and derivatives thereof. Taxol is available under the trade name TaxolTMAnd (4) marketing. Docetaxel having the trade name TaxotereTMAnd (4) marketing. Vinblastine sulfate is available under the trade name Vinblastatin R.PTMAnd (4) marketing. Vincristine sulfate is sold under the trade name FarmistinTMAnd (4) marketing.
The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide under the trade name CyclostinTMAnd (4) marketing. Ifosfamide is sold under the trade name HoloxanTMAnd (4) marketing.
The term "histone deacetylase inhibitor" or "HDAC inhibitor" relates to compounds that inhibit histone deacetylase and have antiproliferative activity. Including but not limited to suberoylanilide hydroxamic acid (SAHA).
The term "antineoplastic antimetabolites" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folate antagonists such as pemetrexed. Capecitabine is sold under the trade name XelodaTMAnd (4) marketing. Gemcitabine is available under the trade name GemzarTMAnd (4) marketing.
The term "platinum compound" as used herein includes, but is not limited to, carboplatin, cisplatin and oxaliplatin. Carboplatin can be marketed, for example, in the form of carboplatinTMAdministration is carried out. Oxaliplatin can be marketed, for example, under the trademark EloxatinTMAdministration is carried out.
The term "target/reduce protein or lipid kinase activity; or a protein or lipid phosphatase activity; or other anti-angiogenic compounds "as used herein include, but are not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, decrease or inhibit platelet-derived growth factor-receptor (PDGFR) activity, such as compounds that target, decrease or inhibit PDGFR activity, particularly compounds that inhibit PDGF receptors, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, decrease or inhibit fibroblast growth factor-receptor (FGFR) activity; c. C ) Compounds that target, decrease or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as compounds that target, decrease or inhibit the activity of IGF-IR, in particular compounds that inhibit the kinase activity of IGF-I receptor, or antibodies that target extracellular regions of the IGF-I receptor or its growth factors; d) a compound that targets, decreases or inhibits the activity of the Trk receptor tyrosine kinase family, or an ephrin B4 inhibitor; e) compounds that target, decrease or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, decrease or inhibit Ret receptor tyrosine kinase activity; g) compounds that target, decrease or inhibit the activity of Kit/SCFR receptor tyrosine kinases, such as imatinib; h) compounds that target, decrease or inhibit the activity of the C-Kit receptor tyrosine kinases (part of the PDGFR family), such as compounds that target, decrease or inhibit the activity of the C-Kit receptor tyrosine kinase family, in particular compounds that inhibit the C-Kit receptor, such as imatinib; i) compounds that target, decrease or inhibit the activity of the c-Abl family member, its gene-fusion product (e.g. BCR-Abl kinase) and the mutant, such as compounds that target, decrease or inhibit the activity of the c-Abl family member and its gene fusion product, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib or nilotinib (AMN 107); PD180970 from ParkeDavis; AG 957; NSC 680410; PD 173955; or dasatinib (BMS-354825); j) compounds that target, decrease or inhibit the activity of protein kinase c (pkc) and Raf family members of the serine/threonine kinase class, MEK, SRC, JAK/pan JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family members, and/or cyclin dependent kinase family (CDK) members, including staurosporine derivatives, such as medetoline; examples of other compounds include UCN-01, safrog, BAY 43-9006, bryostatin 1, piperacillin; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531/LY 379196; an isoquinoline compound; FTIs; PD184352 or QAN697(P13K inhibitor) or AT7519(CDK inhibitor); k) compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, such as compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, including imatinib mesylate (Gleevec) TM) Or tyrphostin such as tyrphostin A23/RG-50810; AG 99; tyrphostin AG 213; tyrphostin AG 1748; tyrphostin AG 490; tyrphostin B44; tyrphostin B44(+) enantiomer; tyrphostin AG 555; AG 494; tyrphostin AG 556, AG957 and adaphostin (4- { [ (2, 5-dihydroxyphenyl) methyl]Amino } -benzoic acid adamantyl ester; NSC 680410, adaphortin); l) compounds that target, reduce or inhibit the activity of receptor tyrosine kinases (EGFR1 ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and mutant epidermal growth factor family thereof, such as compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family, in particular compounds, proteins or antibodies that inhibit EGF receptor tyrosine kinase family such as EGF receptors, ErbB2, ErbB3 and ErbB4 members or bind to EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin)TM) Cetuximab (Erbitux)TM) Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo- [2,3-d ]A pyrimidine derivative; m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds targeting, decreasing or inhibiting the activity of c-Met, in particular compounds inhibiting the kinase activity of the c-Met receptor, or antibodies targeting the extracellular region of c-Met or binding to HGF, n) compounds targeting, decreasing or inhibiting the kinase activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan JAK), including but not limited to PRT-062070, SB-1578, baricitinib, palitinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and lucocotinib; o) compounds that target, decrease or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictelisib, PF-4691502, BYL-719, dactylisib, XL-147, XL-765, and idelalisib; and; and q) compounds that target, decrease or inhibit the effects of hedgehog protein (Hh) or smooth receptor (SMO) pathway signaling, including but not limited to cyclopamine, vismodedJi, itraconazole, eriodegib, and IPI-926 (saridegib).
The term "PI3K inhibitor" as used herein includes, but is not limited to, compounds having inhibitory activity against one or more enzymes of the phosphatidylinositol-3-kinase family including, but not limited to, PI3K α, PI3K γ, PI3K, PI3K β, PI3K-C2 α, PI3K-C2 β, PI3K-C2 γ, Vps34, p110- α, p110- β, p110- γ, p110-, p85- α, p85- β, p55- γ, p150, p101 and p 87. Examples of PI3K inhibitors useful in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictelisib, PF-4691502, BYL-719, dactylisib, XL-147, XL-765, and idelalisib.
The term "BTK inhibitor" as used herein includes, but is not limited to, compounds having inhibitory activity against Bruton's Tyrosine Kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.
The term "SYK inhibitor" as used herein includes, but is not limited to, compounds having inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fortatinib.
Further examples of BTK inhibiting compounds and conditions that can be treated with said compounds in combination with the compounds of the present invention can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.
Further examples of SYK inhibiting compounds and conditions that can be treated with said compounds in combination with the compounds of the invention can be found in WO2003063794, WO2005007623 and WO2006078846, the entire contents of which are incorporated herein by reference.
Further examples of PI3K inhibitory compounds and conditions that can be treated with said compounds in combination with the compounds of the invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554 and WO2007044729, the entire contents of which are incorporated herein by reference.
Further examples of JAK inhibitory compounds and conditions that can be treated with said compounds in combination with the compounds of the invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, the entire contents of which are incorporated herein by reference.
Other anti-angiogenic compounds include compounds with other mechanisms of activity (e.g., not associated with protein or lipid kinase inhibition), such as thalidomide (Thalomid)TM) And TNP-470.
Examples of proteasome inhibitors for use in combination with the compounds of the present invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN 9708.
Compounds targeting, decreasing or inhibiting the activity of a protein or lipid phosphatase are for example phosphatase 1, phosphatase 2A or CDC25 inhibitors, such as okadaic acid and derivatives thereof.
Compounds that induce a cellular differentiation process include, but are not limited to, retinoic acid, α - γ -or-tocopherol or α - γ -or-tocotrienol.
The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives, such as celecoxib (Celebrex) TM) Rofecoxib (Vioxx)TM) Etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acids, such as 5-methyl-2- (2 '-chloro-6' -fluoroanilino) phenylacetic acid, lumiracoxib.
The term "bisphosphonates" as used herein includes, but is not limited to, etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid and zoledronic acid. Etidronic acid is known under the trade name DidronelTMAnd (4) marketing. Clodronic acid is available under the trade name BonefosTMAnd (4) marketing. Telophosphonic acid is available under the trade name SkelidTMAnd (4) marketing. Pamidronic acid is available under the trade name ArediaTMAnd (4) marketing. Alendronic acid is sold under the trade name FosamaxTMAnd (4) marketing. Ibandronic acid is available under the trade name BondranatTMAnd (4) marketing. Risedronic acid under the trade name ActonelTMAnd (4) marketing. Zoledronic acid is known under the trade name ZometTMAnd (4) marketing. The term "mTOR inhibitor" relates to compounds that inhibit the mammalian target of rapamycin (mTOR) and which have antiproliferative activitySubstances such as sirolimus
The term "heparanase inhibitor" as used herein refers to a compound that targets, reduces or inhibits the degradation of heparin sulphate. The term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to a lymphokine or interferon.
The term "Ras oncogenic isoform inhibitor" such as H-Ras, K-Ras or N-Ras as used herein refers to a compound that targets, reduces or inhibits Ras oncogenic activity; for example, "farnesyl transferase inhibitors" such as L-744832, DK8G557 or R115777 (Zarnestra)TM). The term "telomerase inhibitor" as used herein refers to a compound that targets, decreases or inhibits telomerase activity. Compounds that target, decrease or inhibit telomerase activity are in particular compounds that inhibit the telomerase receptor such as telomestatin.
The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, reduces or inhibits methionine aminopeptidase activity. Compounds that target, decrease or inhibit methionine aminopeptidase activity include, but are not limited to, bengamide and derivatives thereof.
The term "proteasome inhibitor" as used herein refers to a compound that targets, decreases or inhibits proteasome activity. Compounds that target, decrease or inhibit proteasome activity include, but are not limited to, bortezomib (Velcade)TM) And MLN 341.
The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used herein includes, but is not limited to, collagen peptide mimetic and non-peptide mimetic inhibitors, tetracycline derivatives, e.g., the hydroxamic acid peptide mimetic inhibitor batimastat and its orally available analog marimastat (BB-2516), prinomastat (AG3340), metastat (NSC683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ 996.
The term "compound for use in the treatment of hematological malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit FMS-like tyrosine kinase receptor (Flt-3R) activity; interferons, 1- β -D-arabinofuranosyl cytosine (ara-c) and bisufan; and ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase.
Compounds that target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R), in particular compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, meldotetralin, staurosporine derivatives, SU11248 and MLN 518.
The term "HSP90 inhibitor" as used herein includes, but is not limited to, targeting, reducing or inhibiting HSP90 intrinsic atpase activity; a compound that degrades, targets, reduces or inhibits HSP90 client proteins via the ubiquitin proteosome pathway. Compounds that target, decrease or inhibit HSP90 intrinsic atpase activity, in particular compounds, proteins or antibodies that inhibit the atpase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin related compounds; radicicol and HDAC inhibitors.
The term "anti-proliferative antibody" as used herein includes, but is not limited to, trastuzumab (Herceptin)TM) trastuzumab-DM 1, Abiraterosa, Bevacizumab (Avastin)TM) Rituximab (rituximab)PRO64553 (anti-CD 40) and 2C4 antibodies. By antibody is meant an intact monoclonal antibody, a polyclonal antibody, a multispecific antibody formed from at least 2 intact antibodies, and an antibody fragment that exhibits the desired biological activity.
For the treatment of Acute Myeloid Leukemia (AML), the compounds of the invention can be used in combination with standard leukemia therapies, in particular in combination with therapies for the treatment of AML. In particular, the compounds of the present invention can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs used to treat AML, such as daunorubicin, doxorubicin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin and PKC 412.
Other anti-leukemic compounds include, for example, Ara-C (pyrimidine analog), which is a 2' - α -hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are the purine analogs of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, decrease or inhibit Histone Deacetylase (HDAC) activity, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of an enzyme known as histone deacetylase. Specific HDAC inhibitors include MS275, SAHA, FK228 (original name FR901228), trichostatin A and compounds disclosed in US 6,552,065 including but not limited to N-hydroxy-3- [4- [ [ [2- (2-methyl-1H-indol-3-yl) -ethyl ] ]-amino group]Methyl radical]Phenyl radical]-2E-2-acrylamide or a pharmaceutically acceptable salt thereof and N-hydroxy-3- [4- [ (2-hydroxyethyl) {2- (1H-indol-3-yl) ethyl]-amino group]Methyl radical]Phenyl radical]-2E-2-acrylamide or a pharmaceutically acceptable salt thereof, in particular lactate. Somatostatin receptor antagonists as used herein refers to compounds that target, treat or inhibit somatostatin receptors such as octreotide and SOM 230. Tumor cell damage pathways refer to pathways such as ionizing radiation. The term "ionizing radiation" referred to above and below is intended to mean ionizing radiation that is electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Radiation therapy is the provision of ionizing radiation and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and practice of Oncology, device et al, eds.,4thEdition,Vol.1,pp.248-275(1993)。
Also included are EDG binding agents and ribonucleotide reductase inhibitors. The term "EDG binding agent" as used herein refers to a class of immunosuppressive agents that modulate lymphocyte recirculation, such as FTY 720. The term "ribonucleotide reductase inhibitor" refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytarabine (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are in particular hydroxyurea or 2-hydroxy-1H-isoindole-1, 3-dione derivatives.
Especially monoclonal antibodies which also include those compounds, proteins or VEGFSuch as 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or a pharmaceutically acceptable salt thereof, 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine succinate; angiostatinTM；EndostatinTM(ii) a Anthranilamide; ZD 4190; ZD 6474; SU 5416; SU 6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamers such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2IgGI antibodies, Angiozyme (RPI 4610) and bevacizumab (Avastin)TM)。
Photodynamic therapy as used herein refers to the use of certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as VisudyneTMAnd porfimer sodium.
Angiogenesis inhibiting steroids as used herein refers to compounds that block or inhibit angiogenesis such as anecortave, triamcinolone, hydrocortisone, 11-alpha-epihydrocortisone, cortixolone, 17 alpha-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone and dexamethasone.
Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.
Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; a biological response modifier, preferably a lymphokine or interferon; an antisense oligonucleotide or oligonucleotide derivative; shRNA or siRNA; or various compounds or compounds having other or unknown mechanisms of action.
The compounds of the present invention are also useful as combination therapy compounds in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine substances, particularly for the treatment of obstructive or inflammatory respiratory diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of the drug or as a means of reducing the required dose or possible side effects of the drug. The compound of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately before, simultaneously with or after the other drug substance. Accordingly, the present invention includes a combination of a compound of the invention as described hereinbefore and an anti-inflammatory, bronchodilatory, antihistamine or antitussive drug substance, said compound of the invention and said drug substance being in the same or different pharmaceutical compositions.
Suitable anti-inflammatory agents include steroids, especially glucocorticosteroids such as budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; a non-steroidal glucocorticoid receptor agonist; LTB4 antagonists such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such as cilomilast ( GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004(Bayer), SCH-351591(Schering-Plough), Alopeptine (Almirall prodesFarma), PD189659/PD168787(Parke-Davis), AWD-12-281(Asta medical), CDC-801(Celgene), SeICID (TM) CC-10004(Celgene), VM554/UM565(Vernalis), T-440(Tanabe), KW-4490(Kyowa Hakko Kogyo); an A2a agonist; an A2b antagonist; and beta-2 adrenoceptor agonists such as salbutamol (salbutamol), metaproterenol, terbutaline, salmeterol fenoterol, procaterol, and in particular formoterol and pharmaceutically acceptable salts thereof. Suitable bronchodilatory drugs include anticholinergic or antimuscarinic compounds, especially ipratropium bromide, oxitropium bromide, tiotropium bromide salts and CHF 4226(Chiesi), and glycopyrronium bromide.
Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratadine, desloratadine, diphenhydramine and fexofenadine hydrochloride, activistine, astemizole, azone
Other useful combinations of the compounds of the invention with anti-inflammatory agents are those in combination with chemokine receptor antagonists, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, in particular CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists such as N- [ [4- [ [ [6, 7-dihydro-2- (4-methylphenyl) -5H-benzo-cyclohepten-8-yl ] carbonyl ] amino ] phenyl ] -methyl ] tetrahydro-N, N-dimethyl-2H-pyran-4-ammonium chloride (TAK-770).
In certain embodiments, the one or more additional therapeutic agents is a Poly ADP Ribose Polymerase (PARP) inhibitor. In certain embodiments, the PARP inhibitor is selected from olapari (r) (a.i.)AstraZeneca); lukapari (R) (Lukapari)
The term "Bcl-2 inhibitor" as used herein includes, but is not limited to, compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2) including, but not limited to, ABT-199, ABT-731, ABT-737, apocosypol, the pan Bcl-2 inhibitor of Ascenta, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (InfinityPharmaceutics/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), Navkkera (and analogs thereof, see US 90739), NH-1(Shenayn pharmaceutical University), Obakura (and analogs thereof, see WO2004106328), S-001 (Glauceuticals), the series of compounds of TW, and Mioclavia. In certain embodiments, the Bcl-2 inhibitor is a small molecule therapeutic. In certain embodiments, the Bcl-2 inhibitor is a peptidomimetic.
In certain embodiments, the one or more additional therapeutic agents are inhibitors of anti-apoptotic proteinsSuch as BCL-2. Approved anti-apoptotic agents that may be used with the present invention include venetocalax (R)
The structure of The active compounds identified by code, common name or trade name can be taken from The real edition of The standard outline "The Merck Index" or from databases such as The Patent International (e.g. IMS world publications).
The compounds of the present invention may also be used in combination with known therapeutic procedures such as administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiation therapy.
The compounds of the invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapies being in the form of fixed combinations, or the compounds of the invention and one or more other therapeutic compounds being administered staggered or independently of one another, or the fixed combinations and one or more other therapeutic compounds being administered in combination. Additionally or additionally, particularly for tumor treatment, the compounds of the present invention can be administered in combination with chemotherapy, radiation therapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof. Long-term treatment may also serve as an adjunct treatment during other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's state after tumor regression, or even chemopreventive treatment, e.g. in at-risk patients.
Those additional agents may be administered separately from the compound-containing compositions of the present invention as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the present invention in a single composition. If administered as part of a multiple dosing regimen, the two active agents can be administered simultaneously, sequentially, or within a time period that is spaced apart from each other (typically within 5 hours of each other).
As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with the present invention. For example, a compound of the invention may be administered with a further therapeutic agent either simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
The amount of both the compound of the invention and the additional therapeutic agent (in those compositions comprising the additional therapeutic agent as described above) that can be combined with the carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Preferably, the compositions of the invention should be formulated so as to allow the administration of a dose of the compound of the invention of 0.01 to 100mg/kg body weight/day.
In those compositions comprising an additional therapeutic agent, the additional therapeutic agent and the compound of the invention may act synergistically. Thus, the amount of additional therapeutic agent in the composition is less than that required in a monotherapy employing only that therapeutic agent. In the composition, a dose of 0.01 to 1,000 μ g/kg body weight/day of an additional therapeutic agent can be administered.
The amount of additional therapeutic agent present in the compositions of the present invention does not exceed the amount that would normally be administered in a composition containing the therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure ranges from about 50% to 100% of the amount typically present in a composition comprising that agent as the only therapeutically active agent.
The compounds of the present invention or pharmaceutical compositions thereof may also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents and catheters. For example, vascular stents have been used to overcome restenosis (the vessel wall narrows again after injury). However, patients using stents or other implantable devices are at risk for clot formation or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of the invention are yet another embodiment of the invention.
Exemplary immuno-oncology Agents
In certain embodiments, the one or more additional therapeutic agents are immuno-oncology agents. As used herein, the term "immuno-oncology agent" refers to an agent effective to enhance, stimulate and/or up-regulate an immune response in a subject. In certain embodiments, administration of the immuno-oncology agent and the compounds of the invention have a synergistic effect in the treatment of cancer.
The immuno-oncology agent can be, for example, a small molecule drug, an antibody, or a biomolecule or small molecule. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In certain embodiments, the antibody is a monoclonal antibody. In certain embodiments, the monoclonal antibody is humanized or derived from a human.
In certain embodiments, the immuno-oncology agent is (i) an agonist of a stimulatory (including co-stimulatory) receptor or (ii) an antagonist of a T cell inhibitory (including co-inhibitory) signal, both of which cause amplification of an antigen-specific T cell response.
Some of the stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to costimulatory or cosuppressive receptors is the B7 family, which includes B7-1, B7-2, B7-H1(PD-L1), B7-DC (PD-L2), B7-H2(ICOS-L), B7-H3, B7-H4, B7-H5(VISTA) and B7-H6. Yet another family of membrane bound ligands that bind to co-stimulatory or co-inhibitory receptors are TNF family molecules that bind to homologous TNF receptor family members, including CD40 and CD40L, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137(4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, xedr, TACI, APRIL, BCMA, LIGHT, DcR3, HVEM, VEGI/TL1 42, TRAMP/DR 3927, EDAR, 1, xrr, FAS 2, TNFR 5, beta 5, TNFR, beta/DR α toxin, TNF α, and q β.
In certain embodiments, the immuno-oncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF- β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate an immune response.
In certain embodiments, the combination of a compound of the invention and an immuno-oncology agent is capable of stimulating a T cell response. In certain embodiments, the immuno-oncology agent is: (i) antagonists of proteins that inhibit T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) agonists of proteins that stimulate T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD 28H.
In certain embodiments, the immuno-oncology agent is an antagonist of an NK cell inhibitory receptor or an agonist of an NK cell activating receptor. In certain embodiments, the immuno-oncology agent is an antagonist of KIR such as lirilumab.
In certain embodiments, the immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies, including RG7155(WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008(WO 11/140249; WO 13169264; WO 14/036357).
In certain embodiments, the immuno-oncology agent is selected from an agonist linked to a positive co-stimulatory receptor, a blocker that attenuates signal transduction through inhibitory receptors, an antagonist, and one or more agents that systemically increase the frequency of appearance of anti-tumor T cells, an agent that overcomes different immunosuppressive pathways in the tumor microenvironment (e.g., blocks inhibitory receptor linkage (e.g., PD-L1/PD-1 interaction), depletes or inhibits Tregs (e.g., depletes with an anti-CD 25 monoclonal antibody (e.g., daclizumab) or with ex vivo anti-CD 25 beads), inhibits metabolic enzymes such as IDO, or reverses/prevents T cell energy or depletion), and an agent that triggers innate immune activation and/or tumor site inflammation.
In certain embodiments, the immuno-oncology agent is a CTLA-4 antagonist. In certain embodiments, the CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In certain embodiments, the antagonistic CTLA-4 antibody is yerboy (ipilimumab) or tremelimumab.
In certain embodiments, the immuno-oncology agent is a PD-1 antagonist. In certain embodiments, the PD-1 antagonist is administered by infusion. In certain embodiments, the immuno-oncology agent is an antibody, or antigen-binding portion thereof, that specifically binds a programmed death-1 (PD-1) receptor and inhibits PD-1 activity. In certain embodiments, the PD-1 antagonist is an antagonistic PD-1 antibody. In certain embodiments, the antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO 2012/145493). In certain embodiments, the immuno-oncology agent can be pidilizumab (CT-011). In certain embodiments, the immuno-oncology agent is a recombinant protein consisting of the extracellular region of PD-L2(B7-DC) fused to the Fc portion of IgG1, referred to as AMP-224.
In certain embodiments, the immuno-oncology agent is a PD-L1 antagonist. In certain embodiments, the PD-L1 antagonist is an antagonistic PD-L1 antibody. In certain embodiments, the PD-L1 antibody is MPDL3280A (RG 7446; WO2010/077634), durvalumab (MEDI4736), BMS-936559(WO2007/005874), and MSB0010718C (WO 2013/79174).
In certain embodiments, the immuno-oncology agent is a LAG-3 antagonist. In certain embodiments, the LAG-3 antagonist is an antagonistic LAG-3 antibody. In certain embodiments, the LAG3 antibody is BMS-986016(WO10/19570, WO14/08218), or IMP-731 or IMP-321(WO08/132601, WO 009/44273).
In certain embodiments, the immuno-oncology agent is a CD137(4-1BB) agonist. In certain embodiments, the CD137(4-1BB) agonist is an agonistic CD137 antibody. In certain embodiments, the CD137 antibody is Ulvacizumab or PF-05082566(WO 12/32433).
In certain embodiments, the immuno-oncology agent is a GITR agonist. In certain embodiments, the GITR agonist is an agonistic GITR antibody. In certain embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518(WO006/105021, WO009/009116), or MK-4166(WO 11/028683).
In certain embodiments, the immuno-oncology agent is an indoleamine (2,3) -dioxygenase (IDO) antagonist. In certain embodiments, the IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS: f001287(Bristol-Myers Squibb); phy906/KD108 (phytoeutica); kynurenine decomposing enzyme (Kynase, Kyn Therapeutics); and NLG-919(WO09/73620, WO009/1156652, WO11/56652, WO 12/142237).
In certain embodiments, the immuno-oncology agent is an OX40 agonist. In certain embodiments, the OX40 agonist is an agonist OX40 antibody. In certain embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.
In certain embodiments, the immuno-oncology agent is an OX40L antagonist. In certain embodiments, the OX40L antagonist is an antagonistic OX40 antibody. In certain embodiments, the OX40L antagonist is RG-7888(WO 06/029879).
In certain embodiments, the immuno-oncology agent is a CD40 agonist. In certain embodiments, the CD40 agonist is an agonist CD40 antibody. In certain embodiments, the immuno-oncology agent is a CD40 antagonist. In certain embodiments, the CD40 antagonist is an antagonist CD40 antibody. In certain embodiments, the CD40 antibody is lucalumumab or daclizumab.
In certain embodiments, the immuno-oncology agent is a CD27 agonist. In certain embodiments, the CD27 agonist is an agonist CD27 antibody. In certain embodiments, the CD27 antibody is varliumab.
In certain embodiments, the immuno-oncology agent is MGA271(to B7H3) (WO 11/109400).
In certain embodiments, the immuno-oncology agent is abamectin, adalimumab, afutuzumab, alemtuzumab, malamumab, aprezumab, atezolimab, avelumab, lantemozumab, BMS-936559, rituxuzumab, durvalumab, epacadostat, epratuzumab, indoximod, ibruzumab, integamcin, intelumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obiutuzumab, ocatatuzumab, ofaumab, ofatumumab, rituximab, pembrolizumab, pidilizumab, rituximab, samuzumab, or memamum.
In certain embodiments, the immuno-oncology agent is an immunostimulant. For example, antibodies that block the inhibition axis of PD-1 and PD-L1 are capable of releasing activated tumor-reactive T cells and have been shown in clinical trials to induce a durable anti-tumor response in an increased number of tumor histologies, including certain tumor types that are not conventionally considered sensitive to immunotherapy. See, e.g., Okazaki, t.et al, (2013) nat. immunol.14, 1212-1218; zou et al, (2016) sci. trans. med.8. anti-PD-1 antibody nivolumab (Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558) have shown potential to improve overall survival in RCC patients experiencing disease progression during or after previous anti-angiogenic therapy.
In certain embodiments, the immunomodulatory therapeutic specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutic agents that may be used in the invention include pomalidomide (A)
In certain embodiments, the immuno-oncology agent is a cancer vaccine. In certain embodiments, the cancer vaccine is selected from sipuleucel-T (c: (a))
In certain embodiments, the immuno-oncology agent is selected from the group consisting of JX-929 (SillaJen/formerly Jennerex Biothereutics), TK-and vaccinia growth factor-deficient vaccinia viruses engineered to express cytosine deaminase, which are capable of converting the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TG02 (targomax/original Oncos), peptidyl immunotherapeutics targeting refractory RAS mutations; and TILT-123 (TILTBiotherapics), an engineered adenovirus, named: ad5/3-E2F-delta24-hTNF α -IRES-hIL 20; and VSV-GP (vira therapeutics), Vesicular Stomatitis Virus (VSV) engineered to express the lymphocyte choriomeningitis virus (LCMV) Glycoprotein (GP), which can be further engineered to express antigens designed to enhance antigen-specific CD8+ T cell responses.
In certain embodiments, the immuno-oncology agent is a T-cell or CAR engineered to express a chimeric antigen receptor. T-cells engineered to express the chimeric antigen receptor are referred to as CAR-T cells.
The CAR constructed consisted of: a binding domain which may be derived from a natural ligand, a single chain variable fragment (scFv) derived from a monoclonal antibody specific for a cell surface antigen, and a T-cell receptor (TCR) functional end endodomain fused thereto, such as the CD3-zeta signaling region of a TCR, which is capable of generating an activation signal in T lymphocytes. In the case of antigen binding, the CAR links endogenous signal transduction pathways in effector cells and generates activation signals similar to those elicited by the TCR complex.
For example, in certain embodiments the CAR-T cell is one of those described in U.S. patent 8,906,682 (6 months; which is incorporated herein by reference in its entirety), which discloses CAR-T cells engineered to comprise an extracellular region with an antigen binding region, such as a region that binds to CD19, fused to an intracellular signaling region of a T cell antigen receptor complex zeta chain, such as CD3 zeta. When expressed in T cells, the CAR is capable of redirecting antigen recognition based on antigen binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Over 200 clinical trials are currently underway, which use CAR-T in a wide range of indications. [ https:// clinical trials. gov/ct 2/results? term ═ chimeric + antigen + receptors & pg ═ 1 ].
In certain embodiments, the immunostimulatory agent is an activator of retinoic acid receptor-associated orphan receptor gamma (ROR γ t). ROR γ t is a transcription factor with the following key roles: differentiation and maintenance of effector subtype type 17 of CD4+ (Th17) and CD8+ (Tc17) T cells, and differentiation of IL-17, such as NK cells, expressing a subset of innate immune cells. In certain embodiments, the activator of ROR γ t is LYC-55716(Lycera), which is currently evaluated in clinical trials for the treatment of solid tumors (NCT 02929862).
In certain embodiments, the immunostimulatory agent is a toll-like receptor (TLR) agonist or activator. Suitable activators of TLRs include agonists or activators of TLR9 such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG that is being investigated for use in B-cells, follicles and other lymphomas (NCT 02254772). TLR8 agonists or activators that may be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which is under investigation for head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT 02431559).
Other immuno-oncology agents that may be used in the present invention include Urucirumab (BMS-663513, Bristol-Myers Squibb), anti-CD 137 monoclonal antibody; varliumab (CDX-1127, Celldex Therapeutics), anti-CD 27 monoclonal antibody; BMS-986178(Bristol-Myers Squibb), anti-OX 40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, Innate Pharma, Bristol-Myers Squibb), anti-KIR monoclonal antibody; the monoclonal ab (IPH2201, lnnate Pharma, AstraZeneca) anti-NKG 2A monoclonal antibody; andrecaliximab (GS-5745, Gilead Sciences), anti-MMP 9 antibody; MK-4166(Merck & Co.), an anti-GITR monoclonal antibody.
In certain embodiments, the immunostimulatory agent is selected from the group consisting of eltuzumab, mifamustine, an agonist or activator of toll-like receptors, and an activator of ROR γ t.
In certain embodiments, the immunostimulatory therapeutic agent is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been tested clinically for use as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT 02689453). In certain embodiments, the immunostimulant is recombinant human interleukin 12 (rhIL-12). In certain embodiments, the IL-15-based immunotherapeutic is heterodimeric IL-15(hetIL-15, Novartis/Admune), a fusion complex of synthetic forms of endogenous IL-15 complexed with the soluble IL-15 binding protein IL-15 receptor alpha chain (IL 15: sIL-15RA), which has been tested in phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer, and squamous cell carcinoma of the head and neck (NCT 02452268). In certain embodiments, the recombinant human interleukin 12(rhIL-12) is NM-IL-12(Neumedicines, Inc.), NCT02544724, or NCT 02542124.
In certain embodiments, the immuno-oncology agent is selected from those described in Jerry l.adams et al, "biportunities for small molecules in immuno-oncology," Cancer Therapy 2015, vol.14, page 603-622, the entire contents of which are incorporated herein by reference. In certain embodiments, the immuno-oncology agent is selected from the examples described in Jerry l.adams et al table 1. In certain embodiments, the immuno-oncology agent is a small molecule that targets an immuno-oncology target selected from those listed in Jerry l.adams et al table 2. In certain embodiments, the immuno-oncology agent is a small molecule agent selected from those listed in Jerry l.adams et al table 2.
In certain embodiments, the immuno-oncology agent is selected from the group consisting of the small molecule immuno-oncology agents described in Peter L.Toogood, "Small molecule immuno-oncology therapeutic agents," Bioorganic & Medicinal chemistry letters 2018, Vol.28, pp 319-329, which is incorporated herein by reference in its entirety. In certain embodiments, the immuno-oncology agent is an agent that targets a pathway described in Peter l.
In certain embodiments, the immuno-oncology agent is selected from the group consisting of those described in Sandra L.Ross et al, "Bispecific T cell engageThe antisense constructs can be found in the middle of a cell kill ", PLoS ONE 12(8) e0183390, the entire contents of which are incorporated herein by reference. In certain embodiments, the immuno-oncology agent is a bispecific T cell adaptor
Exemplary immune checkpoint inhibitors
In certain embodiments, the immune-oncology agent is an immune checkpoint inhibitor as described herein.
The term "checkpoint inhibitor" as used herein relates to an agent for preventing cancer cells from evading the immune system of a patient. One of the major mechanisms of anti-tumor immune disruption is called "T-cell depletion", which is due to chronic exposure to antigens leading to upregulation of inhibitory receptors. These inhibitory receptors act as immune checkpoints to prevent uncontrolled immune responses.
PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4(CTLA-4, B and T lymphocyte attenuating genes (BTLA; CD272), T cell immunoglobulin and mucin region-3 (Tim-3), lymphocyte activation gene-3 (Lag-3; CD223), and others often referred to as checkpoint regulators act as molecular "gatekeepers" that allow extracellular information to command cell cycle progression and whether other intracellular signaling processes should proceed.
In certain embodiments, the immune checkpoint inhibitor is an antibody to PD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) to prevent receptor binding to the inhibitory ligand PDL-1, thereby overriding the ability of tumors to suppress host anti-tumor immune responses.
In one aspect, the checkpoint inhibitor is a biological therapeutic or a small molecule. In yet another aspect, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. In a further aspect, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDLl, PDL2, PDl, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In additional aspects, the checkpoint inhibitor interacts with a ligand selected from CTLA-4, PDLl, PDL2, PDl, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof checkpoint protein. In one aspect, the checkpoint inhibitor is an immunostimulant, a T cell growth factor, an interleukin, an antibody, a vaccine, or a combination thereof. In yet another aspect, the interleukin is IL-7 or IL-15. In a particular aspect, the interleukin is glycosylated IL-7. In an additional aspect, the vaccine is a Dendritic Cell (DC) vaccine.
Checkpoint inhibitors include any agent that blocks or inhibits the inhibitory pathways of the immune system in a statistically significant manner. The inhibitor may comprise a small molecule inhibitor or may comprise an antibody or antigen-binding fragment thereof that binds to and blocks or inhibits an immune checkpoint receptor, or an antibody that binds to and blocks or inhibits an immune checkpoint receptor ligand. Exemplary checkpoint molecules that may be targeted for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belonging to the CD2 family of molecules and expressed on all NK, γ and memory CD8+ (α β) T cells), CD160 (also known as BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies or antigen binding fragments thereof, other binding proteins, biological therapeutic agents or small molecules that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049. Exemplary immune checkpoint inhibitors include tremelimumab (CTLA-4 blocking antibody), anti-OX 40, PD-Ll monoclonal antibody (anti-B7-Hl; MEDI4736), MK-3475(PD-1 blocking agent), Nivolumab (anti-PDl antibody), CT-011 (anti-PDl antibody), BY55 monoclonal antibody, AMP224 (anti-PDLl antibody), BMS-936559 (anti-PDLl antibody), MPLDL3280A (anti-PDLl antibody), MSB0010718C (anti-PDLl antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-Ll, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.
In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In certain embodiments, the checkpoint inhibitor is selected from nivolumab
in certain embodiments, the checkpoint inhibitor is selected fromFrom lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumabAnd tremelimumab.
In certain embodiments, the immune checkpoint inhibitor is REGN2810(Regeneron), an anti-PD-1 antibody, which is specific for a cancer cell in the basal cell carcinoma (NCT 03132636); NSCLC (NCT 03088540); squamous cell carcinoma of skin (NCT 02760498); lymphoma (NCT 02651662); and melanoma (NCT03002376) patients; pidilizumab (curetech), also known as CT-011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (
In certain embodiments, the checkpoint inhibitor is an inhibitor of protein-3 containing T-cell immunoglobulin mucin (TIM-3). TIM-3 inhibitors that may be used in the present invention include TSR-022, LY3321367 and MBG 453. TSR-022(Tesaro) is an anti-TIM-3 antibody that is being studied for solid tumors (NCT 02817633). LY3321367(EliLilly) is an anti-TIM-3 antibody that is being studied for solid tumors (NCT 03099109). MBG453(Novartis) is an anti-TIM-3 antibody, which is being studied for late stage malignancy (NCT 02608268).
In certain embodiments, the checkpoint inhibitor is an inhibitor of the T cell immune receptor with Ig and ITIM domains or of the immune receptor TIGIT on certain T cells and NK cells. TIGIT inhibitors that may be used in the present invention include BMS-986207(Bristol-Myers Squibb), anti-TIGIT monoclonal antibody (NCT 02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT 03119428).
In certain embodiments, the checkpoint inhibitor is an inhibitor of lymphocyte activation gene-3 (LAG-3). LAG-3 inhibitors that may be used in the present invention include BMS-986016 and REGN3767 and IMP 321. BMS-986016(Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied for glioblastoma and glioma sarcoma (NCT 02658981). REGN3767(Regeneron) is also an anti-LAG-3 antibody and is being studied for malignancy (NCT 03005782). IMP321(Immutep s.a.) is a LAG-3-Ig fusion protein, being studied for melanoma (NCT 02676869); adenocarcinoma (NCT 02614833); and metastatic breast cancer (NCT 00349934).
Checkpoint inhibitors that may be used with the present invention include OX40 agonists. OX40 agonists that are being investigated in clinical trials include PF-04518600/PF-8600(Pfizer), i.e., agonizing anti-OX 40 antibodies, renal cancer for metastasis (NCT03092856) and advanced cancers and tumors (NCT 02554812; NCT 05082566); GSK3174998(Merck), an agonist anti-OX 40 antibody, in the stage 1 cancer test (NCT 02528357); MEDI0562(Medimmune/AstraZeneca), an agonistic anti-OX 40 antibody, for advanced solid tumors (NCT02318394 and NCT 02705482); MEDI6469, an agonistic anti-OX 40 antibody (Medimmune/AstraZeneca), for colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCT01303705) patients; and BMS-986178(Bristol-MyersSquibb), an agonistic anti-OX 40 antibody, for advanced cancer (NCT 02737475).
Checkpoint inhibitors that may be used with the present invention include CD137 (also referred to as 4-1BB) agonists. CD137 agonists studied in clinical trials include utomobil (PF-05082566, Pfizer), i.e. agonistic anti-CD 137 antibodies, for diffuse large B-cell lymphoma (NCT02951156) and advanced cancers and tumors (NCT02554812 and NCT 05082566); uruglizumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD 137 antibody, is used for melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT 02658981).
Checkpoint inhibitors that may be used with the present invention include CD27 agonists. CD27 agonists studied in clinical trials include varliumab (CDX-1127, Celldex Therapeutics), i.e., agonizing anti-CD 27 antibodies, for squamous cell head and neck cancer, ovarian cancer, colorectal cancer, renal cell carcinoma, and glioblastoma (NCT 02335918); lymphoma (NCT 01460134); and glioma and astrocytoma (NCT 02924038).
Checkpoint inhibitors that may be used with the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists studied in clinical trials include TRX518(Leap Therapeutics), i.e. agonizing anti-GITR antibodies, for malignant melanoma and other malignant solid tumors (NCT01239134 and NCT 02628574); GWN323(Novartis), an agonistic anti-GITR antibody, for solid tumors and lymphomas (NCT 02740270); INCAGN01876(Incyte/Agenus), an agonistic anti-GITR antibody, for advanced cancer (NCT02697591 and NCT 03126110); MK-4166(Merck), an agonistic anti-GITR antibody, was used in solid tumors (NCT02132754) and MEDI1873 (Medmimmune/AstraZeneca), a hexameric GITR-ligand molecule that agonizes the Fc domain of human IgG1, in advanced solid tumors (NCT 02583165).
Checkpoint inhibitors that may be used in the present invention include inducible T-cell costimulator (ICOS, also known as CD278) agonists. ICOS agonists studied in clinical trials include MEDI-570 (Medimone), an agonistic anti-ICOS antibody, for lymphoma (NCT 02520791); GSK3359609(Merck), an agonistic anti-ICOS antibody, for phase 1 (NCT 02723955); JTX-2011 (journal Therapeutics), an agonistic anti-ICOS antibody, was used for phase 1 (NCT 02904226).
Checkpoint inhibitors that may be used with the present invention include killer cell IgG-like receptor (KIR) inhibitors. KIR inhibitors studied in clinical trials include lirilumab (IPH2102/BMS-986015, input Pharma/Bristol-Myers Squibb), i.e., anti-KIR antibodies, for leukemia (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT 01592370); IPH2101(1-7F9, lnnate Pharma) for myeloma (NCT01222286 and NCT 01217203); and IPH4102 (lnnate Pharma), an anti-KIR antibody, which binds to three domains of the long cytoplasmic tail (KIR3DL2) for lymphoma (NCT 02593045).
Checkpoint inhibitors that may be used in the present invention include CD47 inhibitors of CD47 interaction with signal-regulating protein alpha (SIRPa). CD47/SIRPa inhibitors studied in clinical trials include ALX-148(AlexoTherapeutics), an antagonistic variant that binds to CD47 and prevents CD 47/SIRPa-mediated signal transduction (SIRPa), for phase 1 (NCT 03013218); TTI-621(SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein consisting of the N-terminal CD 47-binding domain linked to SIRPa and the Fc domain of human IgG1, which functions by binding to human CD47 and preventing its delivery of "no-feed" signals to macrophages, for phase 1 clinical trials (NCT02890368 and NCT 02663518); CC-90002(Celgene), an anti-CD 47 antibody, for leukemia (NCT 02641002); and Hu5F9-G4(Forty Seven, Inc.), for colorectal and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338) and lymphoma (NCT 02953509).
Checkpoint inhibitors that may be used in the present invention include CD73 inhibitors. CD73 inhibitors studied in clinical trials include MEDI9447(Medimmune), an anti-CD 73 antibody, for solid tumors (NCT 02503774); and BMS-986179(Bristol-Myers Squibb), an anti-CD 73 antibody, for solid tumors (NCT 02754141).
Checkpoint inhibitors that may be used with the present invention include agonists of stimulators of the interferon gene protein (STING, also known as transmembrane protein 173, or TMEM 173). STING agonists studied in clinical trials include MK-1454(Merck), a synthetic cyclic dinucleotide agonist for lymphoma (NCT 03010176); and ADU-S100(MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclic dinucleotide for phase 1 (NCT02675439 and NCT 03172936).
Checkpoint inhibitors that may be used with the present invention include CSF1R inhibitors. CSF1R inhibitors studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor, for colorectal, pancreatic, metastatic and advanced cancers (NCT02777710) and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST), and ovarian cancer (NCT 02452424); and IMC-CS4(LY3022855, Lilly), an anti-CSF-1R antibody, for pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT 02718911); and BLZ945(4- [2((1R,2R) -2-hydroxycyclohexylamino) -benzothiazol-6-yloxy ] -pyridine-2-carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R for advanced solid tumors (NCT 02829723).
Checkpoint inhibitors that may be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors studied in clinical trials include monelizumab (IPH2201, nnate Pharma), an anti-NKG 2A antibody, for head and neck tumors (NCT02643550) and chronic lymphocytic leukemia (NCT 02557516).
In certain embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, astuzumab, or pidilizumab.
Examples (illustrations)
As described in the examples below, in certain exemplary embodiments, the compounds are prepared according to the following general procedures. It will be appreciated that although the general methods describe the synthesis of certain compounds of the invention, the general methods described below and other methods known to those of ordinary skill in the art can be applied to all of the compounds as described herein and to each of the subclasses and classes of these compounds.
Preparation 1: 3- (4-methylthiopyrimidin-2-yl) -6- (trifluoromethyl) imidazo [1,2-a ] pyridine
NBS (165.2mg, 0.928mmol) was added to 2- [ (E) -2-ethoxyvinyl]A solution of-4-methylsulfanyl-pyrimidine (181.4mg, 0.924mmol) in 1, 4-dioxane (5.5mL) and water (2mL) and the reaction mixture was stirred at ambient temperature for 15 min. 5- (trifluoromethyl) pyridin-2-amine (150mg, 0.925mmol) was added and the reaction mixture was heated at 65-75 ℃ for 7 h. The mixture was cooled to ambient temperature and saturated NaHCO 3Aqueous solution diluted and extracted with DCM. The combined organic extracts were dried (MgSO)4) Filtering and concentrating under reduced pressure. The residue was purified by column chromatography (silica, EtOAc/petroleum ether gradient) to afford 3- (4-methylthiopyrimidin-2-yl) -6- (trifluoromethyl) imidazo [1,2-a]Pyridine (165mg, 58%); ESV-MS M/z 311.1(M + H).
The following compounds were prepared using procedures analogous to those described for preparation 1:
6-chloro-3- (4-methylthiopyrimidin-2-yl) imidazo [1,2-a ] pyridine with 5-chloropyridin-2-amine;
6-chloro-7-fluoro-3- (4-methylthiopyrimidin-2-yl) imidazo [1,2-a ] pyridine with 5-chloro-4-fluoro-pyridin-2-amine;
6-bromo-7-fluoro-3- (4-methylthiopyrimidin-2-yl) imidazo [1,2-a ] pyridine with 5-bromo-4-fluoro-pyridin-2-amine;
6-chloro-7-fluoro-3- (4- (methylthio) pyrimidin-2-yl) imidazo [1,2-a ] pyridine with 5-chloro-4-fluoropyridin-2-amine.
Preparation 2: 3- (4-Chloropyrimidin-2-yl) -6- (trifluoromethyl) imidazo [1,2-a ] pyridine
Sulfonyl chloride (174.9 μ L, 2.160mmol) was added to 3- (4-methylthiopyrimidin-2-yl) -6- (trifluoromethyl) imidazo [1,2-a]Pyridine (165mg, 0.532mmol) and concentrated HCl (47.1. mu.L, 37% w/w, 0.860mmol) in MeCN (13mL) and the reaction mixture was stirred for 5 min. Dropwise addition of cooled saturated NaHCO 3The aqueous solution and the mixture were stirred for 10 minutes. For treatingThe resulting precipitate was separated by filtration, washed with water and dried to give 3- (4-chloropyrimidin-2-yl) -6- (trifluoromethyl) imidazo [1,2-a]Pyridine (125mg, 79%).
The following compounds were prepared using a procedure similar to that described for preparation 2:
6-chloro-3- (4-chloropyrimidin-2-yl) imidazo [1,2-a ] pyridine with 6-chloro-3- (4-methylthiopyrimidin-2-yl) imidazo [1,2-a ] pyridine;
6-chloro-3- (4-chloropyrimidin-2-yl) -7-fluoro-imidazo [1,2-a ] pyridine with 6-chloro-7-fluoro-3- (4-methylthiopyrimidin-2-yl) imidazo [1,2-a ] pyridine;
6-bromo-3- (4-chloropyrimidin-2-yl) -7-fluoro-imidazo [1,2-a ] pyridine with 6-bromo-7-fluoro-3- (4-methylthiopyrimidin-2-yl) imidazo [1,2-a ] pyridine;
6-chloro-3- (4-chloropyrimidin-2-yl) -7-fluoro-imidazo [1,2-a ] pyridine with 6-chloro-7-fluoro-3- (4- (methylthio) pyrimidin-2-yl) imidazo [1,2-a ] pyridine.
4-chloro-2- { 6-phenoxyimidazo [1,2-a ] pyridin-3-yl } pyrimidine
4-chloro-2- { 6-methanesulfonylimidazo [1,2-a ] pyridin-3-yl } pyrimidine
3- (4-Chloropyrimidin-2-yl) -N-cyclopropylimidazo [1,2-a ] pyridine-6-sulfonamide
3- (4-Chloropyrimidin-2-yl) imidazo [1,2-a ] pyridine-6-sulfonamides
Preparation 3: 3-bromo-6- (difluoromethyl) imidazo [1,2-a ] pyridine
(diethylamino) thio-trifluoride (528.5 μ L, 4.00mmol) was added dropwise to 3-bromoimidazo [1,2-a ] pyridine-6-carbaldehyde (450mg, 2.00mmol) in DCM (4.5mL) at 0 deg.C. After 2.5 hours, additional (diethylamino) sulfur trifluoride (150 μ L, 1.135mmol) was added and the reaction stirred at room temperature for 16 hours. The crude mixture was diluted with methanol and purified by ion exchange SCX-2 column to afford 3-bromo-6- (difluoromethyl) imidazo [1,2-a ] pyridine (310mg, 63%); ESV-MSm/z 247.0(M + H).
Preparation 4: 2- [6- (difluoromethyl) imidazo [1,2-a ] pyridin-3-yl ] pyrimidin-4-ol
Step 1: 6- (difluoromethyl) -3- (4-methoxypyrimidin-2-yl) imidazo [1,2-a ] pyridine
Reacting 3-bromo-6- (difluoromethyl) imidazo [1,2-a]Pyridine (120mg, 0.486mmol), tributyl- (4-methoxypyrimidin-2-yl) stannane (200. mu.L, 0.583mmol) and PdCl2(PPh3)2(102.3mg, 0.146mmol) were combined in DMF (4mL), degassed with nitrogen and heated at 120 ℃ for 16 h. The mixture was allowed to cool, filtered and then purified by reverse phase chromatography (C18; MeCN/water/0.05% TFA as eluent) to afford 6- (difluoromethyl) -3- (4-methoxypyrimidin-2-yl) imidazo [1,2-a]Trifluoroacetate salt of pyridine (97mg, 72%); ESV-MS M/z 277.1(M + H).
Step 2: 2- [6- (difluoromethyl) imidazo [1,2-a ] pyridin-3-yl ] pyrimidin-4-ol
Trimethylchlorosilane (267. mu.L, 2.107mmol) was added to a solution of 6- (difluoromethyl) -3- (4-methoxypyrimidin-2-yl) imidazo [1,2-a ] pyridine (97mg, 0.351mmol) and NaI (315.8mg, 2.107mmol) in MeCN (4mL), and the mixture was heated at 80 ℃ for 16 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was suspended in water and washed with saturated aqueous sodium thiosulfate solution. The solid was filtered, washed with water, and dried under reduced pressure to give 2- [6- (difluoromethyl) imidazo [1,2-a ] pyridin-3-yl ] pyrimidin-4-ol (75mg, 81%); ESV-MS M/z 263.1(M + H). This material was used without further purification.
Preparation 5: 3- (2-Chloropyrimidin-4-yl) -6- (trifluoromethyl) imidazo [1,2-a ] pyridine
NBS (241mg, 1.354mmol) was added to a solution of 2-chloro-4- (2-ethoxyvinyl) pyrimidine (250mg, 1.354mmol) in 1, 4-dioxane (8 mL)/water (3mL) and the reaction mixture was stirred for 15 minutes. 5- (trifluoromethyl) pyridin-2-amine (220mg, 1.357mmol) was added and the reaction mixture was heated to 80 deg.CThe mixture was heated for 3 hours. The mixture was cooled to room temperature and saturated NaHCO was used3Aqueous solution diluted and extracted with DCM. The combined organic extracts were dried (MgSO)4) Filtering and concentrating under reduced pressure. The residue was purified by flash column chromatography (silica, EtOAc/petroleum ether gradient followed by MeOH/DCM gradient) to afford 3- (2-chloropyrimidin-4-yl) -6- (trifluoromethyl) imidazo [1,2-a]Pyridine (234.5mg, 58%) as an off-white solid;1H NMR(500MHz，DMSO-d6)10.26(s，1H)，8.95(s，1H)，8.78(d，1H)，8.19(d，1H)，8.05(d，1H)，7.84(dd，1H)；19F NMR(471MHz，DMSO-d6)-60.86；ESV-MS m/z 299.1(M+H)。
preparation 6: n- [ [ (2S) -morpholin-2-yl ] methyl ] methanesulfonamide
Step 1: (S) -2- (methylsulfonylaminomethyl) morpholine-4-carboxylic acid tert-butyl ester
To a round bottom flask was added tert-butyl (2R) -2- (aminomethyl) morpholine-4-carboxylate (5g, 23mmol) and Et3N (16.1mL, 115mmol) followed by THF (100 mL). DCM (50mL) was added and the mixture was cooled to 0 ℃. Methanesulfonyl chloride (2.4mL, 30.5mmol) was added dropwise and the mixture stirred for 0.5 h then under N 2The mixture was left at ambient temperature for 16 hours under an atmosphere. Saturated NaHCO for reaction3The aqueous solution (100mL) was quenched and most of the volatiles were removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3 × 50 mL). The combined organics were in Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica; 70-100% EtOAc/petroleum ether gradient elution). The product fractions were combined and concentrated under reduced pressure. The residue was dried under reduced pressure overnight to give (S) -tert-butyl 2- (methylsulfonaminomethyl) morpholine-4-carboxylate (3.61g, 53%) as a white solid;1h NMR (500MHz, chloroform-d) 4.71-4.59(m, 1H), 3.98-3.82(m, 2H), 3.63-3.49(m, 2H), 3.38-3.24(m, 1H), 3.20-3.11(m, 1H), 3.04-2.90(m, 4H), 2.73(s, 1H), 1.49(s, 9H).
Step 2: n- [ [ (2S) -morpholin-2-yl ] methyl ] methanesulfonamide
A stirred solution of tert-butyl (2S) -2- (methanesulfonylaminomethyl) morpholine-4-carboxylate (3.6g, 12mmol) in DCM (60mL) was added TFA (9mL, 115mmol) and the reaction stirred at ambient temperature for 6 h. The solvent was removed under reduced pressure and the residue azeotroped with DCM (× 2) and diethyl ether (× 2). The residue was dispersed in methanol and passed through an ion-exchange column eluting with methanol (discarded) followed by 2M ammonia in methanol. Concentrating the filtrate under reduced pressure to provide N- [ [ (2S) -morpholin-2-yl ]Methyl radical]Methanesulfonamide (2.3g, 97%);1h NMR (500MHz, chloroform-d) 4.73(s, 1H), 3.90-3.87(m, 1H), 3.65-3.60(m, 2H), 3.26(dd, 1H), 3.09(dd, 1H), 2.99(s, 3H), 2.92-2.84(m, 3H), 2.66(dd, 1H); MS m/z: 195(M + H)+。
Preparation 7: 2- (1H-pyrazol-4-yl) morpholine
Step 1: 2- (1H-pyrazol-4-yl) morpholine-4-carboxylic acid tert-butyl ester
A mixture of tert-butyl 2- (2-oxoethyl) morpholine-4-carboxylate (5.77g, 25mmol) and DMF-DMA (6.7mL, 50mmol) in DMF (50mL) was stirred at 80 ℃ for 17 h. The reaction mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was dispersed in EtOH (100mL) and hydrazine hydrate (1.3mL, 26.5mmol) was added with stirring at ambient temperature. After 3 hours, the solvent was removed under reduced pressure and the residue was purified by chromatography (silica, PE/EtOAc gradient elution) to afford tert-butyl 2- (1H-pyrazol-4-yl) morpholine-4-carboxylate (2.35g, 37%) as a yellow solid.1H NMR (500MHz, chloroform-d) 7.63(s, 2H), 4.52(dd, 1H), 4.12(br s, 1H), 3.97-3.90(m, 2H), 3.68(td, 1H), 3.05(d, 2H), 1.51(s, 9H); MS m/z: 254.1(M + H)+。
Step 2: 2- (1H-pyrazol-4-yl) morpholine
3M HCl/methanol (45mL, 3M, 135mmol) was added to a stirred solution of tert-butyl 2- (1H-pyrazol-4-yl) morpholine-4-carboxylate (2.35g, 9.3mmol) in DCM (75mL) and the reaction was heated at reflux for 5H. The reaction was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue is dissolved in Minimum amount of DCM/MeOH and loading onto ion exchange column. The column was washed with MeOH/DCM mixture and discarded. By using 2M NH3The eluted product was washed with MeOH/DCM solution. Removal of the solvent under reduced pressure afforded 2- (1H-pyrazol-4-yl) morpholine (1.27g, 89%) as an orange solid which was used for the subsequent reaction without further purification;1h NMR (500MHz, chloroform-d) 7.60(s, 2H), 4.56(dd, 1H), 3.98(ddd, 1H), 3.77(td, 1H), 3.11(dd, 1H), 3.00(td, 1H), 2X.93-2.88(m, 2H); MS m/z: 154.2[ M + H]+。
Preparation 8: 2-methyl-6- (1H-pyrazol-4-yl) morpholine.
To an ice-bath cooled solution of 1-benzylpyrazole-4-carbaldehyde (2g, 10.7mmol) and nitromethane (7mL, 129mmol) was added Et3N (150. mu.L, 1.1 mmol). The mixture was stirred for 15 minutes with cooling and then at ambient temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography (silica, EtOAc/petroleum ether gradient elution). The relevant fractions were combined and concentrated under reduced pressure to give a colorless oil (1g, 37%); MS m/z: 248(M + H)+. This material was used directly in the subsequent reaction.
A mixture of 1- (1-benzylpyrazol-4-yl) -2-nitro-ethanol (100mg, 0.4mmol), wet Pd/C (Degussa, 20mg, 0.2mmol) in methanol (4mL) was dried at ambient temperature under H 2The mixture was stirred at 1 atmosphere for 18 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a colorless gum (90 mg); MS m/z: 218(M + H)+. This material was used directly in the subsequent reaction.
In N2Next, 2-bromopropionyl bromide (114mg, 0.5mmol) was added to ice-cold 2-amino-1- (1-benzylpyrazol-4-yl) ethanol (100mg, 0.5mmol) and Et3N (83. mu.L, 0.6mmol) in DCM (4 mL). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with DCM, 2M aqueous HCl, saturated NaHCO3Aqueous solution and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a colorless oil. The substance is dispersedIn THF (3mL), the solution was cooled in an ice bath. Sodium hydride (37mg of a 60% dispersion in mineral oil, 0.9mmol) was added and the resulting suspension was stirred at ambient temperature for 2 hours. The reaction was quenched with methanol and then diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and brine. Over MgSO4The organic phase was dried, filtered and concentrated under reduced pressure to give a pale yellow gum (100mg), MS m/z: 272(M + H)+It was used directly in the subsequent reaction without purification.
6- (1-Benzylpyrazol-4-yl) -2-methyl-morpholin-3-one (100mg, 0.4mmol) and LiAlH 4A mixture of (184. mu.L, 2M, 0.4mmol) in THF (3mL) was stirred at 60 ℃ for 1 hour. The obtained suspension was washed with Na2SO4.10H2The O pellets were quenched and stirred for 30 minutes, then filtered. The filtrate was concentrated under reduced pressure, and the residue was dispersed in methanol (2 mL). 3 drops of concentrated HCl and wet Pd/C (Degussa, 20mg, 0.02mmol) were added to the solution. At ambient temperature in H2The reaction mixture was stirred at 1 atmosphere for 18 hours. The reaction mixture was poured onto an ion-exchange column and washed with methanol (the filtrate was discarded), followed by 2M NH3And (4) eluting with a methanol solution. The filtrate was concentrated under reduced pressure to give 2-methyl-6- (1H-pyrazol-4-yl) morpholine (23mg), MS m/z: 168(M + H)+. This material was used directly in the subsequent reaction.
Preparation 9: imino (methyl) (piperidin-3-ylmethyl) - λ6Sulfanyl ketones
A mixture of tert-butyl 3- (chloromethyl) piperidine-1-carboxylate (500mg, 2.14mmol), NaSMe (3mL, 20% w/v, 8.56mmol), KI (355mg, 2.14mmol) in ethanol (10mL) was stirred at 80 ℃ for 22 h. The reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic phase was washed with brine and dried (MgSO)4) Filtration and concentration under reduced pressure afforded the product as a pale brown oil (460mg 88%) which was used in subsequent steps without further purification or characterization.
In N2Next, m-CPBA (324mg, 1.88mmol) was added to iceA cold solution of tert-butyl 3- (methylthiomethyl) piperidine-1-carboxylate (460mg, 1.88mmol) in DCM (7 mL). The reaction mixture was stirred for 20 hours and the temperature was raised to ambient temperature. The reaction mixture was diluted with DCM and washed with saturated aqueous sodium bicarbonate and brine. Organic phase over MgSO4Dried above, filtered and concentrated under reduced pressure to give a pale brown oil (460 mg); MS m/z: 262(M + H)+It was used in the subsequent steps without further purification or characterization. In N2Next, tert-butyl 3- (methylsulfinylmethyl) piperidine-1-carboxylate (5.5g, 21.0mmol), 2,2, 2-trifluoroacetamide (5.2g, 46.3mmol), diacetoxyiodobenzene (10.2g, 31.6mmol) and MgO (3.39g, 84.2mmol) were combined in DCM (250 mL). Addition of Rh2(OAc)6(0.9g, 2.0mmol) and the reaction mixture was stirred at room temperature for 16 h. The mixture was filtered through celite, washing with methanol and DCM. The filtrate and residue were concentrated under reduced pressure and dispersed in methanol (5mL) and MeCN/water (3:1) (5 mL). Adding K2CO3(17.4g, 126.0mmol) and the mixture was stirred at 90 ℃ for 2 h. The mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (Na)2SO4) Filtration and concentration under reduced pressure to provide 3- [ (methylsulfinylidene) methyl ]Tert-butyl piperidine-1-carboxylate (5.96g, quantitative yield) as an amber oil; MS m/z: 277(M + H)+It is used directly in the subsequent reaction.
3- [ (Methylsulfonamido) methyl group]Tert-butyl piperidine-1-carboxylate (600mg, 2.17mmol) in DCM (3mL) was treated with TFA (1.7mL, 21.7 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was dispersed in methanol and loaded onto an ion-exchange column. The column was eluted with MeOH/DCM (discarding the filtrate) followed by ammonia in methanol. Concentrating the filtrate under reduced pressure to provide imino (methyl) (piperidin-3-ylmethyl) - λ6-sulfanones (250mg, 65%);1h NMR (500MHz, methanol-d)4)3.34-3.24(m，1H)，3.19-3.10(m，2H)，3.10-3.07(m，3H)，3.05-2.97(m，1H)，2.60(ddd，1H)，2.52-2.43(m，1H)，2.30-2.18(m，1H)，2.08(ddtd，1H)，1.75(dq，1H)，1.61(dtq，1H)，1.37(dtd，1H)。
Preparation 10: imino (methyl) (piperidin-3-yl)Methyl) -lambda6Sulfanyl ketones
Sodium thiomethoxide (4.06g, 58mmol) was added to a solution of tert-butyl 3- (methylsulfonyloxymethyl) piperidine-1-carboxylate (8.5g, 29mmol) in ethanol (170 mL). The mixture was stirred at ambient temperature for 6 hours and then concentrated under reduced pressure. The residue was taken up in DCM with saturated NaHCO3And (4) distributing the aqueous solution. The organic phase was dried and concentrated under reduced pressure. The residue was purified by chromatography (silica, MeOH/DCM gradient elution) to afford a light yellow oil (6.9 g). The material was dissolved in DCM (100mL) and the solution was cooled in an ice bath. Meta-CPBA (6.93g, 70% pure w/w, 28mmol) was added in portions. The reaction mixture was stirred for 10 minutes after the addition was complete and then partitioned between DCM, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium thiosulfate solution. The organic phase was dried and concentrated under reduced pressure. The residue was purified by chromatography (silica, DCM/MeOH gradient elution) to afford the product as a colorless oil.
Tert-butyl 3- ((methylsulfinyl) methyl) piperidine-1-carboxylate (5.5g, 21.0mmol), 2,2, 2-trifluoroacetamide (5.23g, 46.3mmol), (diacetoxyiodo) benzene (10.17g, 31.6mmol) and magnesium oxide (3.39g, 84.2mmol) were dissolved in DCM (250mL) and diacetoxy (diacetoxyrhodium) rhodium (0.9g, 2.04mmol) was added. The mixture was stirred at ambient temperature overnight then filtered through celite and concentrated under reduced pressure. The residue was dissolved in methanol (50mL) and water (10mL) and K was added2CO3(17.44g, 126.2 mmol). The mixture was stirred at ambient temperature for 3 hours and then heated at 50 ℃ for 3 days. The mixture was concentrated under reduced pressure and the residue dissolved in methanol (5mL) and acetonitrile/water (3:1 mixture, 5 mL). After 1.5 h at 90 ℃ the mixture was cooled, diluted in EtOAc and saturated with brine and NaHCO3And (4) washing with an aqueous solution. Drying the organic layer (Na)2SO4) And concentrated under reduced pressure to give tert-butyl 3- ((S-methylsulfinylidene) methyl) piperidine-1-carboxylate (5.96g) as an amber oil, which was used without further purification.
Reacting 3- [ (methylsulfinylidene) methyl group]Piperidine-1-carboxylic acidA solution of tert-butyl ester (600mg, 2.17mmol) and TFA (1.67mL, 21.71mmol) in DCM (3mL) was stirred at ambient temperature for 16 h then concentrated under reduced pressure and the residue passed through a SCX-2 column. The product was eluted with ammonia/methanol to afford imino (methyl) (piperidin-3-ylmethyl) -lambda 6-sulfanones (250mg, 65%);1h NMR (500MHz, methanol-d)4)3.34-3.24(m，1H)，3.19-3.10(m，2H)，3.10-3.07(m，3H)，3.05-2.97(m，1H)，2.60(ddd，J＝12.4，11.5，3.1Hz，1H)，2.52-2.43(m，1H)，2.30-2.18(m，1H)，2.08(ddtd，J＝30.1，10.9，3.8，1.8Hz，1H)，1.75(dq，J＝13.8，3.3Hz，1H)，1.61(dtq，J＝13.6，11.5，3.8Hz，1H)，1.37(dtd，J＝12.8，11.3，3.9Hz，1H)。
Preparation 11: 2, 5-dimethyl-3- ((methylsulfinyl) methyl) piperidine
Step 1: 1- (tert-butyl) 3-methyl-2, 5-dimethylpiperidine-1, 3-dicarboxylate
2, 5-dimethylpyridine-3-carboxylic acid methyl ester (2.6g, 15.74mmol) and PtO2(713mg, 3.14mmol) of a mixture in HCl (57mL, 3M MeOH solution, 171.1mmol) in H2Stirring under a balloon. The reaction mixture was stirred at ambient temperature for 16 hours, then filtered through celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (27mL) and triethylamine (6.6mL, 47.3mmol), DMAP (96mg, 0.79mmol) and di-tert-butyl dicarbonate (17.4mL, 1M in THF, 17.4mmol) were added successively. The reaction mixture was stirred for 16 h, then partitioned between EtOAc and water. Separating the organic layer and using NH4Cl solution, water (1X), brine (1X) and then dried (MgSO)4) Filtering and concentrating under reduced pressure. The residue was purified by chromatography (silica, 0-10% EtOAc/petroleum ether gradient elution) to afford 1- (tert-butyl) 3-methyl 2, 5-dimethylpiperidine-1, 3-dicarboxylate (1.4g, 33%) as a colorless oil containing a mixture of diastereomers;1H NMR(400MHz，methanol-d4)4.80-4.62(m，1H)，3.95-3.78(m，1H)，3.71(d，3H)，2.71(dq，1H)，2.46(dt，1H)，1.89-1.77(m，1H)，1.48(q，10H)，1.10-0.92(m，7H)。
Step 2: 3- (hydroxymethyl) -2, 5-dimethylpiperidine-1-carboxylic acid tert-butyl ester
O1-tert-butyl O3-methyl 2, 5-dimethylpiperidine-1, 3-dicarboxylate (1.40g, 5.16mmol) was dissolved in THF (42mL) and cooled to 0 ℃. Lithium borohydride (10.3mL, 2M in THF, 20.6mmol) was added and the reaction was allowed to warm to ambient temperature. After 30 minutes the reaction mixture was warmed to 50 ℃ and stirred for 16 hours. The reaction was cooled to ambient temperature and then quenched with water. The mixture was extracted with EtOAc (× 3). The combined organics were dried and concentrated under reduced pressure to afford 3- (hydroxymethyl) -2, 5-dimethyl-piperidine-1-carboxylic acid tert-butyl ester (1.25g, 100%) as a colorless oil which was used directly for the subsequent reaction without further purification;1h NMR (400MHz, methanol-d)4)4.42-4.27(m，1H)，3.82-3.68(m，1H)，3.34-3.23(m，2H)，2.33(dt，1H)，1.91(s，1H)，1.82-1.68(m，1H)，1.54-1.37(m，2H)，1.35(s，9H)，0.95-0.87(m，3H)，0.86-0.76(m，4H)。
And step 3: 2, 5-dimethyl-3- (((methylsulfonyl) oxy) methyl) piperidine-1-carboxylic acid tert-butyl ester
Methanesulfonyl chloride (2.77mL, 35.7mmol) was added to a stirred solution of tert-butyl 3- (hydroxymethyl) -2, 5-dimethylpiperidine-1-carboxylate (5.80g, 23.8mmol) and triethylamine (6.64mL, 47.7mmol) in DCM (116mL) at 0 ℃. After 30 minutes, the reaction was saturated NaHCO3The aqueous solution was quenched, stirred for 5 minutes and then separated into layers with a phase separator column. The organic phase was evaporated under reduced pressure to give tert-butyl 2, 5-dimethyl-3- (((methylsulfonyl) oxy) methyl) piperidine-1-carboxylate (7.6g), which was used directly in the subsequent step without further purification.
And 4, step 4: 2, 5-dimethyl-3- ((methylthio) methyl) piperidine-1-carboxylic acid tert-butyl ester
Sodium methyl mercaptide (9.94g, 141.8mmol) was added to a stirred solution of tert-butyl 2, 5-dimethyl-3- (((methylsulfonyl) oxy) methyl) piperidine-1-carboxylate (7.6g, 23.6mmol) in EtOH (100mL) at 0 ℃. After the addition, the cooling was removed and the reaction was heated at 60 ℃ for 16 hours. The reaction was cooled to ambient temperature, concentrated under reduced pressure and purified by column chromatography (silica, eluting with a gradient of 0-12.5% MeOH in DCM) to afford tert-butyl 2, 5-dimethyl-3- ((methylthio) methyl) piperidine-1-carboxylate (3.4g, 66%) as a colorless oil;1h NMR (500MHz, methanol-d)4)4.53-4.43(m，1H)，3.86(td，J＝13.3，4.4Hz，1H)，2.53-2.31(m，3H)，2.10(s，3H)，1.91-1.81(m，1H)，1.74-1.63(m，1H)，1.61-1.50(m，1H)，1.48(s，9H)，1.10-0.99(m，4H)，0.93(t，J＝6.4Hz，3H)。
And 5: 2, 5-dimethyl-3- ((methylsulfinyl) methyl) piperidine-1-carboxylic acid tert-butyl ester
Tert-butyl 2, 5-dimethyl-3- ((methylthio) methyl) piperidine-1-carboxylate (2g, 7.31mmol) was dissolved in DCM (73mL) and the solution was cooled to 0 ℃. m-CPBA (1.80g, 7.31mmol) was added portionwise over 5 min, the reaction stirred for an additional 5 min then quenched by addition of saturated aqueous sodium thiosulfate (40mL) and stirred for 5 min before extraction with DCM (3X 50 mL). The combined organics were washed with saturated NaHCO3The aqueous solution (2 × 40mL) was washed, filtered through a phase separator column and concentrated under reduced pressure to afford tert-butyl 2, 5-dimethyl-3- ((methylsulfinyl) methyl) piperidine-1-carboxylate (2.1g, 100%) as a colorless oil, which was used without further purification.
Step 6: 2, 5-dimethyl-3- ((methylsulfinyl) methyl) piperidine
Tert-butyl 2, 5-dimethyl-3- ((methylsulfinyl) methyl) piperidine-1-carboxylate (2.1g, 7.26mmol) was dissolved in methanol (36mL) and 4M HCl/dioxane (9.1mL, 36.3mmol) was added. The reaction was stirred at ambient temperature for 16 h and then concentrated under reduced pressure to give 2, 5-dimethyl-3- ((methylsulfinyl) methyl) piperidine (1.85g, 97%) as a white solid; MSm/z: 190.1(M + H)+。
Preparation 12: 2- (1H-pyrazol-4-yl) piperazine
A mixture of 2- (1H-pyrazol-4-yl) pyrazine (400mg, 2.7mmol), PtO2(100mg, 0.4mmol) in methanol (15mL) was H at 60psi at ambient temperature2Shake under pressure for 18 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide 2- (1H-pyrazol-4-yl) piperazine as a colorless oil, which was used directly for the subsequent reaction without purification; MS m/z: 153(M + H)+。
Preparation 13: 2, 5-dimethyl-3- (1H-pyrazol-4-yl) piperazine
To a 3-necked flask equipped with a reflux condenser and thermometer was added 3-chloro-2, 5-dimethyl-pyrazine (5mL, 40mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole-1-carboxylic acid tert-butyl ester (10g, 34mmol)/1, 4-dioxane (100 mL). Adding Pd (PPh)3)4(2g, 2mmol), and Na 2CO3(60mL, 2M, 100mmol), solution evacuation and back-fill with N2(x 2). The solution was heated and stirred at 100 ℃ overnight. The reaction mixture was cooled to ambient temperature and filtered, washed with diethyl ether. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography (silica, 0-100% [ EtOAc + 2% 2M ammonia in methanol)]-petroleum ether gradient elution). The product fractions were combined and concentrated under reduced pressure to provide 2, 5-dimethyl-3- (1H-pyrazole-4-Yl) pyrazine as a white solid (4.5g, 64%); MS m/z: 175(M + H)+。
2, 5-dimethyl-3- (1H-pyrazol-4-yl) pyrazine (4.5g, 26mmol), PtO2(1g, 4mmol) and HCl (60mL, 3M MeOH in MeOH, 200mmol) in a Parr hydrogenator at 60psi H2Shaken under pressure for 24 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide the product 2, 5-dimethyl-3- (1H-pyrazol-4-yl) piperazine as an off-white solid (4.0g, 61%); MS m/z: 181(M + H)+. This material was used for the subsequent reaction, assuming isolation of the dihydrochloride salt.
The following compounds were prepared using a method analogous to that described for preparation 213:
2-methyl-6- (1H-pyrazol-4-yl) piperazine;
3- (1H-imidazol-4-yl) -2, 5-dimethylpiperazine.
Preparation 14: dimethyl ((5-methylpiperidin-3-yl) imino) -lambda 6Sulfanyl ketones
Step 1: dimethyl ((5-methyl-pyridin-3-yl) imino) -lambda6Sulfanyl ketones
3-bromo-5-methyl-pyridine (250g, 1.439mol), iminodimethyl-lambda6Sulfane (142.6g, 1.454mol), Xantphos (24.976g, 43.16mmol), K2CO3(218.8g, 1.583mol) and tris (benzylidene acetone) dipalladium (0) (19.76g, 21.58mmol) were suspended in 1, 4-dioxane (2.4L). The reaction mixture was degassed (vacuum/nitrogen 3 cycles) and stirred at reflux at 125 ℃ for 16 h. The reaction mixture was allowed to cool to ambient temperature and then filtered through celite, washing with EtOAc. The oil was diluted with some MTBE (only enough to observe the amount of precipitation; -150 ml), seeded with several real sample crystals and stirred at ambient temperature for 2 hours. The solid was filtered and washed with minimal MTBE to provide a light pink solid which was dried in an oven at 30 ℃ under reduced pressure to provide the desired product (105.9g, 40%). The mother liquor was concentrated under reduced pressure to give 247.4g of a dark brown oil. 247.4g of the crude mixture are purified by column chromatography (3kg silica column; product is adsorbed to a 350g silica pad;0 to 10% MeOH/EtOAc). The product containing fractions were combined and concentrated under reduced pressure to afford the product (106.4g 40%) after trituration with diethyl ether. Total yield 212.3g (80%); 1H NMR(400MHz，DMSO-d6)7.97(d，J＝2.4Hz，1H)，7.92(dd，J＝1.9，0.9Hz，1H)，7.13(dq，J＝2.8，0.9Hz，1H)，3.25(s，6H)，2.22(d，J＝0.8Hz，3H)；ESV-MS m/z 185.0(M+1)+。
Step 2: 1-benzyl-3- ((dimethyl (oxo) - λ6-Thiylidene) amino) -5-methylpyridin-1-ium bromide
To dimethyl ((5-methyl-pyridin-3-yl) imino) -lambda6A solution of thioalkanone (105.9g, 574.73mmol) in MeCN (900mL) was added BnBr (69mL, 580 mmol). The mixture was stirred at 100 ℃ for 4 hours. The reaction mixture was allowed to cool to ambient temperature and the resulting precipitate was collected by filtration and washed with cold MeCN. The product was obtained as an off-white solid (158.8g, 78%);1HNMR(400MHz，DMSO-d6)8.55(s，1H)，8.48(t，J＝1.8Hz，1H)，7.87(t，J＝1.5Hz，1H)，7.58-7.49(m，2H)，7.49-7.37(m，3H)，5.67(s，2H)，3.44(s，6H)，2.41(s，3H)。ESV-MS m/z 275.1(M+1)+。
and step 3: ((1-benzyl-, 5-methyl-1, 2,5, 6-tetrahydropyridin-3-yl) imino) dimethyl-lambda6Sulfanyl ketones
At 0 ℃ in N2NaBH was then pumped via syringe pump over 2 hours4(43g, 1.137mol) of sodium hydroxide (1.6L, 0.01M 16.00mmol) solution was added dropwise to 1-benzyl-3- ((dimethyl (oxo) -lambda)6-Thiylidene) amino) -5-methylpyridin-1-ium bromide (200g, 562.9mmol) in ethanol (600 mL)/water (600 mL). The mixture was extracted with MTBE (3X 1.6L), the organics combined and washed with brine (1X 600mL), dried (MgSO4) Filtration and concentration under reduced pressure afforded the desired product (142g, 91%); 1H NMR (400MHz, chloroform-d) 7.40-7.17(m, 5H), 5.18-5.10(m, 1H), 3.58(s, 2H), 3.08(d, J ═ 1.9Hz, 6H), 3.04-2.93(m, 1H), 2.86-2.68(m, 3H), 2.55-2.40(m, 1H), 1.92(dd, J ═ 11.0, 8.2Hz, 1H), 0.95(d, J ═ 6.9Hz, 3H). ESV-MS M/z 279.1(M +1) +.
And 4, step 4: dimethyl ((5-methylpiperidine-3-)Yl) imino) -lambda6Sulfanyl ketones
Pd (OH)2(59g, 20% w/w, Degussa, 84.03mmol) was transferred to a nitrogen-filled bottle and the vessel was evacuated and refilled with nitrogen. Then ((1-benzyl-, 5-methyl-1, 2,5, 6-tetrahydropyridin-3-yl) imino) dimethyl-lambda is added6-a solution of thioalkanone (117g, 420.2mmol) in methanol (700mL) and the resulting solution were degassed by vacuum/nitrogen cycling (x 3). The atmosphere was exchanged by vacuum/hydrogen cycling and the reaction mixture was shaken on a Parr hydrogenator for 16 hours. The reaction mixture was cooled to ambient temperature and then filtered through celite and concentrated under reduced pressure leaving an orange oil which was analysed and showed incomplete reaction. The product was redissolved in methanol (700mL) and added to a Parr bottle containing dihydroxypalladium (59g, 20% w/w, 84.03 mmol). The mixture was then shaken overnight at 50 ℃ under 30psi molecular hydrogen. The reaction mixture was cooled to ambient temperature and then filtered through celite and the filtrate was concentrated under reduced pressure leaving an orange oil which was analysed by UPLC-MS-showing incomplete reaction. The mixture was again dissolved in methanol (700mL) and a Parr bottle containing dihydroxypalladium (59g, 20% w/w, 84.03mmol) was added. The mixture was shaken overnight on a Parr hydrogenator at 50 deg.C under a 30psi molecular hydrogen atmosphere. The mixture was cooled to ambient temperature and then filtered through celite and concentrated under reduced pressure to afford dimethyl ((5-methylpiperidin-3-yl) imino) -lambda 6-sulfanones (56.7g, 71%); 1H NMR (500MHz, DMSO-d)6)3.54 (masked signal, 1H), 3.09(tt, J ═ 10.8, 4.4Hz, 1H), 2.95(s, 6H), 2.89-2.74(m, 2H), 2.11(dd, J ═ 12.0, 10.3Hz, 1H), 1.92(dd, J ═ 12.1, 11.0Hz, 1H), 1.84-1.73(m, 1H), 1.58-1.44(m, 1H), 0.89(d, J ═ 12.4Hz, 1H), 0.77(d, J ═ 6.6Hz, 3H).
The following compounds were prepared using procedures analogous to those described for preparation 214:
dimethyl ((piperidin-3-yl) imino) -lambda6-a thioalkanone.
Preparation 15: 2, 5-dimethylpiperidine-3-carboxamide
Step 1: 2, 5-dimethylnicotinamide
Methyl 2, 5-lutidine-3-carboxylate (100mg, 0.61mmol) was dissolved in ammonium hydroxide (480. mu.L, 12.3mmol) and the mixture was heated to 70 ℃ in a sealed tube. After 16 h the reaction was diluted in water and the mixture concentrated under reduced pressure to give 2, 5-lutidine-3-carboxamide (91mg, 100%) as a white solid; MS m/z: 151.0(M + H)+。
Step 2: 2, 5-dimethylpiperidine-3-carboxamide
2, 5-Dimethylnicotinamide (99mg, 0.66mmol) and PtO2(30.4mg, 0.13mmol) was dissolved in methanol (3mL) and 3M HCl (1.1mL, 3.30 mmol). Degassing the mixture and reacting in H2Stirring under balloon for 90 min then concentrating the filtrate by celite and under reduced pressure afforded 2, 5-dimethylpiperidine-3-carboxamide (dihydrochloride) (150mg, 99%); MS m/z: 157.0(M + H) +。
Preparation 16: n- (((3S,5S) -4, 4-difluoro-5-methylpiperidin-3-yl) methyl) methanesulfonamide
Step 1: 3- ((1, 3-dioxoisoindolin-2-yl) methyl) -5-methyl-4-oxopiperidine-1-carboxylic acid benzyl ester
In N2Next, benzyl 3-methyl-4-oxo-piperidine-1-carboxylate (20g, 0.08mol) was dissolved in THF (300 mL). The solution was cooled to-78 ℃ and LiHMDS (1M in THF, 101.1mL, 0.1mol) was added dropwise over 20 minutes, maintaining the temperature below-70 ℃. After stirring for 90 minutes at-78 deg.C, a solution of 2- (chloromethyl) isoindoline-1, 3-dione (23.7g, 0.12mol) in THF (200mL) was added dropwise over 25 minutes, maintaining the temperature below-70 deg.C. The reaction was stirred at-78 ℃ for 1 hour then quenched by addition of saturated aqueous ammonium chloride (65mL) at-78 ℃ and the mixture allowed to warm to ambient temperature. The reaction was repeated and the two mixtures obtained were combined and extracted with EtOAc (300 mL). The organic phase was washed with saturated aqueous sodium bicarbonate (300mL) and brine (300mL) and dried (Na)2SO4) Filtering and concentrating under reduced pressure. The residue was purified by chromatography (silica, EtOAc/petroleum ether elution). Product fractions were combined and concentrated under reduced pressure and recrystallized from EtOAcThe residue provided the product as a white solid (7.56g, 23%).
Step 2: (3R,5S) -3- [ (1, 3-dioxoisoindolin-2-yl) methyl ] -4, 4-difluoro-5-methyl-piperidine-1-carboxylic acid benzyl ester
The flask was charged with benzyl 3- ((1, 3-dioxoisoindolin-2-yl) methyl) -5-methyl-4-oxopiperidine-1-carboxylate (60g, 0.15mol) and cooled in an ice/water bath. DAST (325mL, 2.5mol) was added in one portion and the mixture was stirred at ambient temperature for 3 days. The resulting yellow solution was diluted with DCM (1L) and added slowly to ice/water and solid sodium bicarbonate mixture with overhead stirring. The temperature was kept below 0 ℃ and additional sodium bicarbonate was added to maintain the pH at 7-8. The mixture was warmed to ambient temperature and the layers separated. The aqueous phase was extracted with DCM (2L). The combined organics were washed with brine and dried (Na)2SO4) Filtering and concentrating under reduced pressure. The residue was purified by chromatography (silica, EtOAc/petroleum ether elution). The product fractions were combined and concentrated under reduced pressure. The product, benzyl 3- ((1, 3-dioxoisoindolin-2-yl) methyl) -4, 4-difluoro-5-methylpiperidine-1-carboxylate, is obtained as a glass (32.5g, 51%);1h NMR (400MHz, chloroform-d) 7.89-7.64(4H, m), 7.42-7.11(5H, m), 5.15-5.03(2H, m), 4.39-4.07(3H, m), 3.83-3.66(1H, m), 2.97-2.60(2H, m), 2.56-2.31(1H, m), 2.08-1.89(1H, m), 1.05(3H, d), is a mixture of isomers.
Preparative chiral supercritical fluid chromatography (conditions:
And step 3: (3R,5S) -3- (aminomethyl) -4, 4-difluoro-5-methyl-piperidine-1-carboxylic acid benzyl ester
To (3R,5S) -3- [ (1, 3-dioxoisoindolin-2-yl) methyl]A suspension of benzyl-4, 4-difluoro-5-methyl-piperidine-1-carboxylate (9.6g, 22.4mmol) in ethanol (144mL) was added hydrazine hydrate (8.5mL, 112 mmol). The reaction mixture was heated to reflux for 5 hours and then allowed to cool toAmbient temperature was overnight. The resulting suspension was filtered and the precipitate was washed with EtOH (x 2). The filtrate was loaded on an ion exchange column (50g x 10). The column was washed with a MeOH/DCM mixture (the filtrate was discarded), then with 2M ammonia in methanol. The filtrates were combined and concentrated under reduced pressure. The residue was dispersed in methanol and concentrated under reduced pressure (× 2), then treated with heptane and concentrated under reduced pressure. The resulting yellow oil was dried under reduced pressure overnight to afford the product as a solid (6.77g), which was used directly in the subsequent reaction;1H NMR(400MHz，DMSO-d6)7.48-7.17(m，5H)，5.11(s，2H)，4.41(ddt，1H)，4.02(d，1H)，2.98(dd，1H)，2.64(s，2H)，2.41(dd，1H)，2.15-1.78(m，2H)，1.50(s，2H)，0.93(d，3H)；MS m/z：299(M+H)+。
and 4, step 4: (3S,5S) -4, 4-difluoro-3- (methanesulfonylaminomethyl) -5-methyl-piperidine-1-carboxylic acid benzyl ester
Benzyl (3R,5S) -3- (aminomethyl) -4, 4-difluoro-5-methyl-piperidine-1-carboxylate (6.6g, 22mmol) was dissolved in DCM (66mL) and cooled in an ice bath. The internal temperature reached 3 ℃. Et was added with stirring 3N (3.4mL, 24 mmol). Methanesulfonyl chloride (1.88mL, 24mmol) was added over 5 minutes at a rate that maintained the internal temperature below 10 ℃. After 30 minutes, the ice bath was removed. The solution was warmed to ambient temperature and saturated NaHCO3Aqueous solution (66mL) was quenched. The layers were separated and the aqueous layer was extracted with DCM (33 mL). The combined organics were washed with water and dried over MgSO 44Dried, filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica; gradient elution 0 to 100% EtOAc in petroleum ether). The product fractions were combined and concentrated under reduced pressure. The residue was dried under reduced pressure overnight to give a white solid (7.92 g; 95%);1H NMR(400MHz，DMSO-d6)7.45-7.31(m，5H)，7.31-7.19(m，1H)，5.12(s，2H)，4.37(d，1H)，4.18-3.94(m，1H)，3.38(ddd，1H)，3.00-2.80(m，4H)，2.68(s，2H)，2.15(s，2H)，0.95(d，3H)；MS m/z：377(M+H)+。
and 5: n- (((3S,5S) -4, 4-difluoro-5-methylpiperidin-3-yl) methyl) methanesulfonamide
To a solution of benzyl (3S,5S) -4, 4-difluoro-3- (methanesulfonylaminomethyl) -5-methyl-piperidine-1-carboxylate (7.54g, 20mmol) in DCM (113mL) was added Et3N (8.38mL, 60mmol), followed by Pd (OAc)2(1.799g, 8 mmol). Et was added over 5 min3SiH (19.20mL, 120 mmol). The solution was stirred at ambient temperature for 1 hour then divided into 6 equal portions and loaded onto an ion exchange column (50 g). The column was washed with DCM, 1:1MeOH: DCM and methanol. The filtrate was discarded. The column was washed with 2M ammonia in methanol. The filtrates were combined and concentrated under reduced pressure. The residue was azeotroped with DCM and then dispersed in methanol (45mL) and stirred with SPM32 (3-mercaptopropylethyl sulfide silica) at ambient temperature for 2 hours and then at 50 ℃ for 1 hour. The mixture was cooled and filtered through celite and the filtrate was concentrated under reduced pressure. The residue was dispersed in DCM and concentrated under reduced pressure. The residue was dried under reduced pressure overnight to afford N- (((3S,5S) -4, 4-difluoro-5-methylpiperidin-3-yl) methyl) methanesulfonamide as a white solid (4.40g, 91%); 1HNMR(400MHz，DMSO-d6)7.10(t，1H)，3.43-3.33(m，1H)，3.26-3.10(m，1H)，2.93-2.88(m，4H)，2.79(dtd，1H)，2.38-2.20(m，2H)，2.13-1.78(m，2H)，0.89(d，3H)；MS m/z：243.0(M+H)+。
Preparation 17: n- (pyrrolidin-3-ylmethyl) methanesulfonamide
Step 1: 3- (Methanesulphonylaminomethyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Methanesulfonyl chloride (222mg, 150. mu.L, 1.938mmol) was added to a stirred solution of tert-butyl 3- (aminomethyl) pyrrolidine-1-carboxylate (300mg, 1.498mmol) and triethylamine (232.3mg, 320. mu.L, 2.296mmol) in THF (10mL) under a nitrogen atmosphere and the reaction stirred at ambient temperature for 1.5 h. Reaction with DCM and saturated NaHCO3The aqueous solution diluted and the mixture was stirred for 10 minutes. The layers and aqueous layer were extracted with DCM (× 2). The combined organic extracts were dried (MgSO)4) Filtration and concentration under reduced pressure afforded 3- (methanesulfonylaminomethyl) pyrrolidine-1-carboxylic acid tert-butyl ester as a pale yellow oil, which was deprotected assuming 100% yield and purity;1H NMR(500MHz，DMSO-d6)7.11(t，J＝6.2Hz，1H)，3.40-3.35(m，1H)，3.32-3.28(m，1H)，3.23-3.15(m, 1H), 2.95-2.93(m, 3H), 2.89(s, 3H), 2.31-2.26(m, 1H), 1.93-1.88(m, 1H), 1.65-1.52(m, 1H), 1.40(s, 9H); ESV-MS M/z calculation 278.13004, found 223.1(M +1)+。
Step 2: n- (pyrrolidin-3-ylmethyl) methanesulfonamide
TFA (2.960g, 2mL, 25.96mmol) was added to a stirred solution of tert-butyl 3- (methanesulfonylaminomethyl) pyrrolidine-1-carboxylate (417mg, 1.498mmol) in DCM (20mL) and the reaction mixture was stirred at ambient temperature for 15 h. The solvent was removed under reduced pressure and the residue azeotroped with DCM (x2) and diethyl ether (x 2). The residue was passed through a 10g SCX-2 column and washed with MeOH/DCM mixture. With 2M NH 3The column was washed with MeOH/DCM mixture solution to elute the product. The solvent was removed under reduced pressure to give N- (pyrrolidin-3-ylmethyl) methanesulfonamide (227.4mg, 85%) as a pale yellow solid;1h NMR (500MHz, chloroform-d) 3.16(qd, J ═ 12.3, 6.5Hz, 2H), 3.09-3.03(m, 2H), 2.98(s, 3H), 2.94-2.89(m, 1H), 2.75(dd, J ═ 10.7, 5.0Hz, 1H), 2.40-2.32(m, 1H), 2.04-1.96(m, 1H), 1.55-1.48(m, 1H). (ii) a ESV-MS M/z179.2(M +1)+。
Preparation 18: 4-pyrrolidin-3-yl-1H-pyrazoles
Step 1: 3- (1H-pyrazol-4-yl) -2, 5-dihydropyrrole-1-carboxylic acid tert-butyl ester
Tert-butyl 4-bromopyrazole-1-carboxylate (230mg, 0.931mmol), tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydropyrrole-1-carboxylate (250mg, 0.847mmol) and potassium carbonate (1.3mL, 2M, 2.60mmol) were combined in dioxane (3mL) and the mixture degassed (x 2 vacuum cycle). Adding Pd (dppf) Cl2DCM (70mg, 0.086mmol), the mixture was degassed (x 2 vacuum cycles) and then heated at 90 ℃ overnight. The reaction mixture was partitioned between EtOAc and water. The organic phase was dried (Na)2SO4) Filtering and concentrating under reduced pressure. The residue was purified by chromatography (silica, 0-100% EtOAc/petroleum ether gradient elution). The product fractions were combined and concentrated, The product was provided as a pale yellow film (65mg, 33%) which was used for subsequent reactions. ESV-MS M/z 236.0(M +1)+。
And 2, step 3: 4-pyrrolidin-3-yl-1H-pyrazoles
Tert-butyl 3- (1H-pyrazol-4-yl) -2, 5-dihydropyrrole-1-carboxylate (550mg, 2.338mmol) was dissolved in DCM (10mL) and TFA was added. After 1 hour the reaction mixture was concentrated under reduced pressure and the residue azeotroped with DCM (× 2). The residue was dispersed in methanol (10mL) and the solution degassed (x3 vacuum-N)2Cycling). Wet Pd/C (Degussa, 200mg, 10% w/w, 0.188mmol) was added and the mixture degassed (x3 cycles). N is a radical of2The atmosphere was replaced with hydrogen (x3 cycles) and the mixture was stirred at ambient temperature. After 90 minutes the reaction mixture was filtered over celite, washing with methanol. The filtrate was concentrated under reduced pressure (cold water bath) to give crude 4-pyrrolidin-3-yl-1H-pyrazole (trifluoroacetate salt) (600mg, quantitative yield); ESV-MS M/z 136.0(M +1)+。
Preparation 19: (E) -2- (2-ethoxyvinyl) -4- (methylthio) pyrimidine
To 2-chloro-4- (methylthio) pyrimidine (56.1g, 349.3mmol) and 2M Na2CO3A suspension of aqueous solution (524mL, 1.05mol) in 1, 2-dimethoxyethane (730mL) was added 2- [ (E) -2-ethoxyvinyl]-4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (76.1g, 384 mmol). Adding Pd (PPh) 3)4(20.2g, 17.5mmol) and the mixture degassed. The reaction was placed under nitrogen and heated at reflux for 4 hours. The mixture was cooled to ambient temperature and partitioned between EtOAc (1.1L) and water (560 mL). The organic layer was washed with water (2X 560mL), the combined organic layers were re-extracted with EtOAc (280mL) and the combined organic phases were washed with brine (× 1), dried (MgSO 2)4) Filtering and concentrating under reduced pressure. The residue was purified by column chromatography (silica, eluting with 0 to 25% EtOAc/petroleum ether) to afford (E) -2- (2-ethoxyvinyl) -4- (methylthio) pyrimidine as a light yellow crystalline solid (62.4g, 91%);1h NMR (500MHz, chloroform-d) 8.18(d, J ═ 5.5Hz, 1H), 7.95(d, J ═ 1H)＝12.6Hz，1H)，6.85(d，J＝5.5Hz，1H)，5.91(d，J＝12.6Hz，1H)，4.02(q，J＝7.0Hz，2H)，2.56(s，3H)，1.40(t，J＝7.0Hz，3H)；ES+[M+H]＝197.1。
Preparation 20: 2-chloro-4- { 6-cyclopropylimidazo [1,2-a ]]Pyridin-3-yl pyrimidines
Step 1: 6-Cyclopropylimidazo [1,2-a ]]Pyridine. To a 150-mL round bottom flask was placed 6-bromoimidazo [1,2-a ]]Pyridine (5g, 22.84mmol, 1 eq, 90%), cyclopropyl boronic acid (3.1g, 34.26mmol, 1.50 eq, 95%), Pd (dppf) Cl2.CH2Cl2(2.0g, 2.33mmol, 0.10 equiv., 95%), dioxane (20mL, 224.28mmol, 9.82 equiv., 95%), K3PO4(10.2g, 45.68mmol, 2.00 equiv., 95%). The resulting solution was stirred in an oil bath at 100 ℃ overnight. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1/5). This gave 3.6g (89.67%) of 6-cyclopropylimidazo [1,2-a ] ]Pyridine, a white solid.
Step 2: 3-bromo-6-cyclopropylimidazo [1,2-a ] pyridine. A150-mL round bottom flask was charged with 6-cyclopropylimidazo [1,2-a ] pyridine (3.6g, 20.48mmol, 1 equivalent, 90%), NBS (3.8g, 20.28mmol, 0.99 equivalent, 95%), DCM (20mL, 298.87mmol, 14.59 equivalent, 95%). The resulting solution was stirred at 25 ℃ for 3 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1/5). This gave 4.3g (79.70%) of 3-bromo-6-cyclopropylimidazo [1,2-a ] pyridine as a white solid.
And step 3: 2-chloro-4- { 6-cyclopropylimidazo [1,2-a ]]Pyridin-3-yl } pyrimidine. Stirred 3-bromo-6-cyclopropylimidazo [1,2-a ] at-10 ℃ under nitrogen atmosphere]Pyridine (1.5g, 5.694mmol, 1 equiv, 90%) in THF (10mL, 117.259mmol, 21.0 equiv, 95%) was added dropwise to iprmgcl. licl (1.74g, 11.388mmol, 2 equiv, 95%). The resulting mixture was stirred at 0 degrees celsius under nitrogen for 2 hours. The above mixture was added to stirred 2, 4-dichloropyrimidine (1.07g, 6.824mmol, 1.20 equivalents, 95%) andPd(PPh3)4(0.35g, 0.285mmol, 0.05 equiv., 95%) in THF (10mL, 117.259mmol, 21.0 equiv., 95%). The resulting mixture was stirred at 70 degrees celsius for an additional 4 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1/10). This gives 1g (58.39%) of 2-chloro-4- [ 6-cyclopropylimidazo [1,2-a ] ]Pyridin-3-yl]Pyrimidine, a white solid.
The following compounds were prepared using a procedure similar to that described for preparation 20:
2-chloro-4- { 6-chloroimidazo [1,2-a ] pyridin-3-yl } pyrimidine
Preparation 21: 2-chloro-4- [ (E) -2-ethoxyvinyl ] -6-methylpyrimidine
To a stirred solution of 2, 4-dichloro-6-methylpyrimidine (246.88mg, 1.439mmol, 1.20 equivalents, 95%) 2- [ (E) -2-ethoxyvinyl at room temperature under a nitrogen atmosphere]4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (250mg, 1.199mmol, 1 eq, 95%) and K3PO4(535.84mg, 2.398mmol, 2.00 equiv., 95%) of MeCN (12.45mL, 303.230mmol, 187.63 equiv., 95%) and H2O (4mL, 210.932mmol, 364.96 equiv., 95%) were added SPhos (36.27mg, 0.084mmol, 0.07 equiv., 95%) and Pd (AcO)2(8.50mg, 0.036mmol, 0.03 equiv., 95%). The resulting mixture was stirred at room temperature under nitrogen overnight. The resulting mixture was concentrated to a small volume. The resulting mixture was diluted with brine (20 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 20mL) and dried over anhydrous MgSO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (5:1) to provide 2-chloro-4- [ (E) -2-ethoxyvinyl) ]6-methylpyrimidine (100mg, 37.78%) as a pale yellow oil.
Preparation 22: 2-chloro-4- [6- (3, 3-difluoroazetidin-1-yl) imidazo [1,2-a ] pyridin-3-yl ] -6-methylpyrimidine
Step 1: 5- (3, 3-difluoroazetidin-1-yl) -2-nitropyridine. To a stirred solution of 5-bromo-2-nitropyridine (500mg, 2.340mmol, 1 equivalent, 95%), 3, 3-difluoroazetidine hydrochloride (350.95mg, 2.574mmol, 1.1 equivalent, 95%), and Cs2CO3(4012.66mg, 11.700mmol, 5.00 equivalents, 95%) in dioxane (37.50mL, 425.622mmol, 179.71 equivalents, 95%) was added Pd2(dba)3(112.78mg, 0.117mmol, 0.05 equivalents, 95%) and xantpos (142.52mg, 0.234mmol, 0.10 equivalents, 95%) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 ℃ under nitrogen for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (1:1) to provide 5- (3, 3-difluoroazetidin-1-yl) -2-nitropyridine (200mg, 27.81%) as a pale yellow solid.
Step 2: 5- (3, 3-difluoroazetidin-1-yl) pyridin-2-amine. To a stirred solution of 5- (3, 3-difluoroazetidin-1-yl) -2-nitropyridine (175mg, 0.569mmol, 1 eq, 70%) in MeOH (56.00mL, 1747.713mmol, 2307.89 eq, 95%) was added Pd/C (318.89mg, 2.847mmol, 5 eq, 95%) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere overnight. The resulting mixture was filtered and the filter cake was washed with MeOH (3x30 mL). The filtrate was concentrated under reduced pressure. The crude product/resulting mixture was used directly in the subsequent step without further purification.
And step 3: 2-chloro-4- [6- (3, 3-difluoroazetidin-1-yl) imidazo [1,2-a ] pyridin-3-yl ] -6-methylpyrimidine. To a stirred solution of 2-chloro-4- [ (E) -2-ethoxyvinyl ] -6-methylpyrimidine (550mg, 2.630mmol, 1 eq, 95%) in H2O (18mL, 999.151mmol, 379.87 eq, 9%) and H2O (18mL, 999.151mmol, 379.87 eq, 9%) was added NBS (492.78mg, 2.630mmol, 1 eq, 95%) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. To the above mixture was added 5- (3, 3-difluoroazetidin-1-yl) pyridin-2-amine (666.51mg, 3.419mmol, 1.3 equivalents, 95%). The resulting mixture was stirred at 85 ℃ for an additional 2.5 hours. The resulting mixture was diluted with EtOAc (20 mL). The mixture was neutralized to pH 7 with saturated aqueous Na2CO3 solution. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous MgSO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with CH2Cl2/MeOH (20: 1). This gave 2-chloro-4- [6- (3, 3-difluoroazetidin-1-yl) imidazo [1,2-a ] pyridin-3-yl ] -6-methylpyrimidine (290mg, 31.85%) as a pale yellow solid.
The following compounds were prepared using a procedure similar to that described for preparation 22:
2-chloro-4- [6- (3-fluoroazetidin-1-yl) imidazo [1,2-a ] pyridin-3-yl ] pyrimidine
Preparation 23: 5- [6- (azetidin-1-yl) imidazo [1,2-a ] pyridin-3-yl ] -2-chloropyrimidine
Step 1: 1- { imidazo [1,2-a ] pyridin-6-yl } azetidine. To a 500mL round bottom flask was added 6-bromoimidazo [1,2-a ] pyridine (3.5g, 15.99mmol, 1 equivalent, 90%), azetidine (1441.3mg, 23.98mmol, 1.50 equivalents, 95%), toluene (300mL, 2678.69mmol, 167.55 equivalents, 95%), BINAP (1047.9mg, 1.60mmol, 0.10 equivalents, 95%) and t-BuONa (3234.5mg, 31.97mmol, 2.00 equivalents, 95%) at room temperature. The resulting mixture was stirred at 100 ℃ under nitrogen overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (5:1) to provide 1- [ imidazo [1,2-a ] pyridin-6-yl ] azetidine (2.5g, 78.72%) as a green solid.
Step 2: 1- { 3-Bromoimidazo [1,2-a ] pyridin-6-yl } azetidine. To a 25mL round bottom flask was added 1- [ imidazo [1,2-a ] pyridin-6-yl ] azetidine (1g, 5.03mmol, 1 equiv., 87.2%), NBS (896.0mg, 4.78mmol, 0.95 equiv., 95%) and DCM (60mL, 896.61mmol, 178.11 equiv., 95%) at room temperature. The resulting mixture was stirred at room temperature under nitrogen overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (5:1) to provide 1- [ 3-bromoimidazo [1,2-a ] pyridin-6-yl ] azetidine (1.1g, 56.25%) as a green solid.
And step 3: 5- [6- (azetidin-1-yl) imidazo [1,2-a]Pyridin-3-yl]-2-chloropyrimidine. 1- [ 3-Bromoimidazo [1,2-a ] stirred at-10 ℃ in an N2 atmosphere]Pyridin-6-yl]A solution of azetidine (200mg, 0.777mmol, 1 eq, 98%) in THF (20mL, 234.517mmol, 301.66 eq, 95%) was added dropwise. Chloro (prop-2-yl) magnesium lithium chloride (1mL, 1.084mmol, 1.39 eq, 17.5%) was added. The resulting mixture was stirred at 0 ℃ under an atmosphere of N2 for 2 hours. The mixture was added to stirred 2, 4-dichloropyrimidine (182.86mg, 1.166mmol, 1.50 eq., 95%) and Pd (PPh) at room temperature3)4(47.28mg, 0.039mmol, 0.05 eq., 95%) in THF. The resulting mixture was stirred at 80 ℃ for an additional 4 hours. Reaction at room temperature with saturated NH4And (4) quenching by using a Cl aqueous solution. The aqueous layer was extracted with EtOAc (3X20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using EA: PE (1:1) elution provided 4- [6- (azetidin-1-yl) imidazo [1,2-a]Pyridin-3-yl]2-Chloropyrimidine (120mg, 19.61%) as a green solid.
Preparation 24: 5- (3-methyl-1H-pyrazol-4-yl) piperidin-3-ol
Step 1: 5- (3-methyl-1H-pyrazol-4-yl) pyridin-3-ol. 5-Bromopyridin-3-ol (10g, 54.599mmol, 1 eq., 95%), Pd (dppf) Cl 2.CH2Cl2(2.35g, 2.730mmol, 0.05 eq, 95%), K2CO3A mixture of (11.91g, 81.898mmol, 1.50 equiv., 95%) and 3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (14.35g, 65.518mmol, 1.2 equiv., 95%) in dioxane (150.01mL, 1682.194mmol, 30.81 equiv., 95%) and H2O (29.99mL, 1664.971mmol, 28.97 equiv., 95%) was stirred at 100 ℃ under nitrogen overnight. ReducingThe resulting mixture was concentrated under pressure. The residue was purified by silica gel column chromatography using CH2Cl2MeOH (10:1) afforded 5- (3-methyl-1H-pyrazol-4-yl) pyridin-3-ol (6.5g, 61.16%) as a brown solid.
Step 2: 1-benzyl-3-hydroxy-5- (3-methyl-1H-pyrazol-4-yl) pyridin-1-ium bromide. A mixture of 5- (3-methyl-1H-pyrazol-4-yl) pyridin-3-ol (6.2g, 31.851mmol, 1 eq, 90%) and BnBr (6.88g, 0.038mmol, 1.2 eq, 95%) in MeCN (300.00mL, 6942.365mmol, 170.23 eq, 95%) was stirred at 60 ℃ under a hydrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH2Cl2MeOH (85:15) afforded 1-benzyl-3-hydroxy-5- (3-methyl-1H-pyrazol-4-yl) pyridin-1-ium bromide (9g, 73.45%) as a brown solid.
And step 3: 1-benzyl-5- (3-methyl-1H-pyrazol-4-yl) -1,2,3, 6-tetrahydropyridin-3-ol. A mixture of 1-benzyl-3-hydroxy-5- (3-methyl-1H-pyrazol-4-yl) pyridin-1-ium bromide (6.5g, 16.896mmol, 1 eq, 90%) and NaBH4(2.68g, 67.296mmol, 3.98 eq, 95%) in EtOH (260.00mL, 5643.864mmol, 251.64 eq, 95%) was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was quenched with saturated aqueous NH4Cl solution at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with CH2Cl2/MeOH (10:1) to give 1-benzyl-5- (3-methyl-1H-pyrazol-4-yl) -1,2,3, 6-tetrahydropyridin-3-ol (5g, 98.88%) as a yellow oil.
And 4, step 4: 5- (3-methyl-1H-pyrazol-4-yl) piperidin-3-ol. A mixture of 1-benzyl-5- (3-methyl-1H-pyrazol-4-yl) -1,2,3, 6-tetrahydropyridin-3-ol (3.2g, 10.692mmol, 1 eq, 90%) and Pd/C (1137.89mg, 1.069mmol, 0.10 eq, 10%) in MeOH (200.00mL, 5929.777mmol, 438.89 eq, 95%) was stirred at room temperature under a hydrogen atmosphere for 4 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (3x5 mL). The filtrate was concentrated under reduced pressure to give 5- (3-methyl-1H-pyrazol-4-yl) piperidin-3-ol (2g, 92.88%) as a colorless semisolid.
The following compounds were prepared using a procedure similar to that described for preparation 24:
3- (3-fluoro-1H-pyrazol-4-yl) -5-methylpiperidine
- 上一篇：一种医用注射器针头装配设备
- 下一篇：衣壳组装调节剂给药方案