BENZAMIDE COMPOUNDS

专利摘要:
compounds of formula (i) are provided in the present invention. such compounds, as well as their pharmaceutically acceptable salts and compositions, are useful for the treatment of diseases or conditions, which include conditions characterized by excessive cell proliferation, such as cancer and tumors, as well as viral infections, such as hiv.
公开号:BR112020014160A2
申请号:R112020014160-7
申请日:2019-01-08
公开日:2020-12-08
发明作者:Joseph Robert Pinchman；Peter Qinhua HUANG；Kevin Duane Bunker；Rakesh Kumar Sit；Ahmed Abdi Samatar
申请人:Recurium Ip Holdings, Llc；
IPC主号:

专利说明:

[0001] [0001] This order claims the priority of US Serial Order No. 62 / 615,857, filed on January 10, 2018, which is hereby incorporated by reference in its entirety, for multiple purposes. FIELD OF THE INVENTION
[0002] [0002] This application relates to compounds that are Bcl-2 inhibitors and methods of using them to treat conditions characterized by excessive cell proliferation, such as cancer and tumors, and viral infections, such as infection with the immunodeficiency virus (HIV). DESCRIPTION OF THE INVENTION
[0003] [0003] Bcl-2 plays a role in regulating cell death, including apoptosis, necrosis and autophagy. Consequently, changes in the expression and function of Bcl-2 contribute to the pathogenesis and progression of human cancers and tumors, and can facilitate certain viral infections, such as HIV. SUMMARY
[0004] [0004] Some embodiments provide a compound of Formula (|) or a pharmaceutically acceptable salt thereof.
[0005] [0005] Some embodiments disclosed herein refer to a pharmaceutical composition which may include an effective amount of one or more compounds of Formula (Il), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination of the same.
[0006] [0006] Some embodiments described herein refer to a method for treating a cancer or tumor described herein that may include administering an effective amount of a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt. of the same) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (1) or 11Mm pharmaceutically acceptable lime thereof) to an individual subject to a canker described herein. Other embodiments described herein refer to the use of an effective amount of a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer or tumor described herein. Still other embodiments described herein refer to an effective amount of a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) to treat a cancer or tumor described herein.
[0007] [0007] Some embodiments described herein refer to a method for inhibiting replication of a malignant growth or tumor described herein which may include bringing the growth or tumor into contact with an effective amount of a compound described herein (for example, a compound of Formula (1), or a pharmaceutically acceptable salt thereof). Other embodiments described herein refer to the use of an effective amount of a compound described herein (for example, a compound of Formula (1), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament to inhibit the replication of malignant growth or a tumor described here. Still other embodiments described herein refer to an effective amount of a compound described herein (for example, a compound of Formula (1), or a pharmaceutically acceptable salt thereof) in inhibiting the replication of a malignant growth or a tumor described herein.
[0008] [0008] Some embodiments described herein refer to a method for treating a cancer described herein which may include contacting a malignant growth or a tumor, described herein, with an effective amount of a compound described herein (for example, a compound of the Formula (1), or a pharmaceutically acceptable salt thereof). Other modalities described here refer to the use of an affectionate dressing of a cenmnAcIN aci decerita (Nor avamnlA 11mMm enmnanactIA da
[0009] [0009] Some embodiments described herein refer to a method for inhibiting Bcl-2 activity which may include administering an effective amount of a compound described herein (for example, a compound of Formula (1), or a pharmaceutically acceptable salt of the itself) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (|), or a pharmaceutically acceptable salt thereof) to an individual and may also include contacting a cell that expresses Bcl-2 with an effective amount of a compound described herein (for example, a compound of Formula (1), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described in the present invention (for example, a compound of formula (1 ), or a pharmaceutically acceptable salt thereof). Other embodiments described herein refer to the use of an effective amount of a compound described herein (for example, a compound of Formula (1), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament to inhibit Bcl-2 activity. in an individual, or in the manufacture of a drug to inhibit Bcl-2 activity, the use of which includes contacting a cell that expresses Bcl-2. Still other embodiments described herein refer to an effective amount of a compound described herein (for example, a compound of Formula (!), Or a pharmaceutically acceptable salt thereof) to inhibit Bcl-2 activity in an individual; or to inhibit Bcl-2 activity by contacting a cell that expresses Bcl-2.
[0010] [0010] Some embodiments described herein refer to a method for relieving and / or treating an infection caused by HIV which may include administering an effective amount of a compound described herein (for example, a compound of Formula (1) or a pharmaceutically salt. acceptable composition thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV latency reversing agent, or a pharmaceutically salt acceptable, to an individual suffering from HIV infection; and may also include contact of an HIV-infected cell with a compound described in the present invention (for example, a compound of Formula (1), or a pharmaceutically acceptable salt thereof), and an effective amount of a latency of HIV, or a pharmaceutically acceptable salt thereof.
[0011] [0011] Some embodiments described herein refer to a method of reducing the population of HIV-infected cells, which may include administering an effective amount of a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt of the same) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt the same, to an individual suffering from HIV infection; and may also include contact of an HIV-infected cell with a compound described in the present invention (for example, a compound of Formula (1), or a pharmaceutically acceptable salt thereof), and an effective amount of a latency of HIV, or a pharmaceutically acceptable salt thereof.
[0012] [0012] Some modalities described herein refer to a method of reducing the recurrence of an infection caused by HIV in an individual which may include administering an effective amount of a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, to an individual suffering from HIV infection; and may also include contact of an HIV-infected cell with a compound described in the present invention (for example, a compound of Formula (1), or a pharmaceutically acceptable salt thereof), and an effective amount of a latency of HIV, or a pharmaceutically acceptable salt thereof.
[0013] [0013] Some modalities described herein refer to a method for ameliorating or treating an infection caused by HIV which may include administering an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an agent HIV latency reverser, or a pharmaceutically acceptable salt thereof, to an individual suffering from HIV infection; and it may also include contacting an HIV-infected cell with a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof. Other embodiments described herein refer to the use of an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, in the making a drug to improve or treat an HIV infection; or in the manufacture of a drug to improve or treat an infection caused by HIV, the use of which includes putting an HIV-infected cell in contact with the drug. Still other embodiments described herein refer to an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, to improve or treating an HIV infection in an individual suffering from HIV infection; or to improve or treat an HIV infection by contact of an HIV-infected cell.
[0014] [0014] Some modalities described herein refer to a method of reducing the population of HIV-infected cells, which may include administering an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of a HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, to an individual suffering from HIV infection; and may also include contacting an HIV-infarcted cell in a nihilone of the nrotaine with a pharmaceutically acceptable lime thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof. Other embodiments described herein refer to the use of an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug to reduce the population of cells infected by HIV; or in the manufacture of a drug to reduce the population of cells infected with HIV, the use of which includes putting a cell infected with HIV in contact with the drug. Still other embodiments described herein refer to an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, to reduce the population of HIV-infected cells in an individual suffering from HIV infection; or to reduce the population of HIV-infected cells by contacting an HIV-infected cell.
[0015] [0015] Some modalities described herein refer to a method of reducing the recurrence of an infection caused by HIV in an individual which may include administering an effective amount of a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, to an individual suffering from HIV infection; and may also include contacting an HIV-infected cell with an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt of the same. Other modalities described here refer to the use of an effective amount of 1 m inihidnr of the nroetaine Rel qaA1rmMm pharmaceutically acceptable lime of mMmetsmaAo in an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicine to reduce the recurrence of an HIV infection in an individual suffering from HIV infection; or to reduce the recurrence of an infection caused by HIV, the use of which includes putting a cell infected with HIV in contact with the drug. Still other embodiments described herein refer to an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, to reduce the recurrence of an HIV infection in an individual suffering from HIV infection; or to reduce the recurrence of an HIV infection by contacting an HIV-infected cell.
[0016] [0016] These and other modalities are described in more detail below. BRIEF DESCRIPTION OF THE DRAWINGS
[0017] [0017] Figure 1 shows examples of HIV latency reversing agents.
[0018] [0018] Figure 2 shows examples of Bcl protein inhibitors.
[0019] [0019] Figure 3 shows examples of compounds of Formula (1).
[0020] [0020] Figures 4A, 4B and 4C show examples of compounds of Formula (1).
[0021] [0021] Figure 5 shows a graph illustrating HIV test data for the examples of the compounds of Formula (1). DETAILED DESCRIPTION
[0022] [0022] Bcl-2 is a critical regulator of programmed cell death (apoptosis). Bcl-2 belongs to a family of B 2 cell lymphoma (BCL-2) proteins, which includes both pro-apoptotic proteins (such as Bak, Bax, Bim, Bid, tBid, Bad, Bik, PUMA, Bnip-1 , Hrk, Bmf and Noxa) as anti-apoptotic proteins (such as Bcl-2, Bcl-Xr, Bcl-W, Mcl-1 and Bcl-2A1). For example, under normal conditions, Bcl-2 inhibits apoptosis, in part, preventing the activation of Bak and Bax. Activation of the intrinsic apoptosis pathway (for example, by cell stress) inhibits Bcl-2, activating, causing Rak to Rav Ecscas mitrandine mitochondria and facilitate the narmeahilization of the outer mitochondrial membrane, releasing cytochrome c and Smac. This initiates the caspase signaling pathway, which ultimately results in cell death. The deregulation of Bocl-2 leads to the sequestration of proteins that promote cell death, which causes the evasion of apoptosis. This process contributes to malignancy and facilitates cell survival under other disadvantageous conditions, such as during a viral infection. For example, transcriptionally active HIV can consequently generate a fragment of the caspase protein. This fragment binds and activates the pro-apoptotic Bak. However, this fragment also binds to, and is sequestered by, Bcl-2, reducing its effectiveness in inducing cell death. Inhibition of Bcl-2 interrupts the sequestration of pro-apoptotic proteins, restoring apoptotic signaling and promoting programmed cell death for damaged cells. Therefore, inhibition of Bcl-2 has the potential to improve or treat cancers and tumors, as well as improve or treat certain viral infections in combination with other agents. Definitions
[0023] [0023] Except where otherwise stated, all technical and scientific terms used in the present invention have the same meaning as is commonly understood by one skilled in the art. All patents, orders, published orders and other publications mentioned herein are hereby incorporated by reference in their entirety except where otherwise specified. In the event that there are a plurality of definitions for a term, those in this section prevail unless otherwise specified.
[0024] [0024] Whenever a group is described as being "optionally substituted", that group can be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as being "unsubstituted or substituted" if substituted, the substituent (s) can be selected from one or more of the indicated substituents. If no substituent is indicated, it is understood that the group "optionally substituted" or "substituted" indicated may be substituted with one or more groups individually 6, indifferently calarinhadene a nartir dae alauila feeds cycloalkylalkyl, - cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl (alkyl), cycloalkyl (alkyl), heteroaryl (alkyl), heterocyclyl (alkyl), hydroxyl, alkoxyl, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-tiocarbamyl, C- starch, N-starch, S-sulfonamido, N-sulfonamido, C-carboxyl, O-carboxyl, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, an amino, a monosubstituted amine group, a disubstituted amine group, an amine ( monosubstituted alkyl) and a disubstituted amine (alkyl).
[0025] [0025] For use in the present invention, "Ca to Cv" where "a" and "b" are whole numbers refer to the number of carbon atoms in a group. The indicated group can contain from "a" to "b", including carbon atoms. Thus, for example, a "C1: C4 alkyl" group refers to all alkyl groups having 1 to 4 carbons, that is, CH3-, CH3CH2-, CHa3CH2CH2, (CH3) 2CH-, CHaCH2CH2C0H2- , CH3CH2CH (CH3) - and (CH3) 3C-. If no "a" and "b" are assigned, the broader range described in these definitions must be assumed.
[0026] [0026] If two "R" groups are described as "taken together", the R groups and the atoms to which they are attached can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. For example, without limitation, if Rº and Rº of an NRºRº group are indicated by being "taken together", this means that they are covalently linked together to form a ring: AND
[0027] [0027] For use in the present invention, the term "alkyl" refers to a completely saturated aliphatic hydrocarbon group. The alkyl portion can be branched or straight chain. Examples of branched alkyl groups include, but are not limited to, isopropyl, sec-butyl, t-butyl and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like. The alkyl group can have from 1 to 30 numeric as "1 to 30", it refers to each integer in the given range; for example, "1 to 30 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms etc., up to and including 30 carbon atoms, although this definition also covers the occurrence of the term "alkyl" where no numerical range is designated). The alkyl group can also be a medium-sized alkyl having 1 to 12 carbon atoms. The alkyl group can also be a lower alkyl having 1 to 6 carbon atoms. An alkyl group can be substituted or unsubstituted.
[0028] [0028] For use in the present invention, the term "alkylene" refers to a bivalent, completely saturated, straight chain aliphatic hydrocarbon group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene and octylene. An alkylene group can be represented by vv, followed by the number of carbon atoms, followed by an "*". For example,
[0029] [0029] The term "alkenyl" used in the present invention refers to a monovalent straight or branched chain radical of two to twenty carbon atoms containing a double carbon bond including, but not limited to, 1-propenyl, 2 -propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like. An alkenyl group can be unsubstituted or substituted.
[0030] [0030] The term "alkynyl" used in the present invention refers to a monovalent straight or branched chain of two to twenty carbon atoms containing a carbon triple bond including, but not limited to, 1-propynyl, 1 -butinyl, 2-butinyl and the like. An alkynyl group can be unsubstituted or substituted.
[0031] [0031] For use in the present invention, "cycloalkyl" refers to a fully saturated mono or multicyclic hydrocarbon ring system (without double or triple bonds). When composed of two or more rings, the rings can be joined in a fused, bridged or spiro shape. For use in the present invention, the term "fused" refers to two rings that have two atoms and a bond in common. For use in the present invention, the term "bridged cycloalkyl" refers to compounds in which cycloalkyl contains a bond of one or more atoms that connect non-adjacent atoms. For use in the present invention, the term "spiro" refers to two rings that have an atom in common and the two rings are not connected by a bridge. Cycloalkyl groups can contain from 3 to 30 atoms in one or more rings, from 3 to 20 atoms in one or more rings, from 3 to 10 atoms in one or more rings, from 3 to 8 atoms in one or more rings, or 3 to 6 atoms in one or more rings. A cycloalkyl group can be unsubstituted or substituted. Examples of monocycloalkyl groups include,
[0032] [0032] For use in the present invention, "cycloalkenyl" refers to a mono or multicyclic hydrocarbon ring system (such as bicyclic) that contains one or more double bonds in at least one ring; although, if there are more than one, the double bonds cannot form a pi electron system completely relocated across all rings (otherwise, the group would be "aryl", as defined here). Cycloalkenyl groups can contain 3 to 10 atoms in one or more rings, 3 to 8 atoms in one or more rings, or 3 to 6 atoms in one or more rings. When composed of two or more rings, the rings can be connected in a fused, bridged or spiro shape. A cycloalkenyl group can be unsubstituted or substituted.
[0033] [0033] For use in the present invention, "aryl" refers to a monocyclic or multicyclic (such as bicyclic) carbocyclic (such as bicyclic) aromatic ring system (including fused ring systems in which two carbocyclic rings share a chemical bond) that has a pi electron system completely relocated in all rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a Ce-C14 aryl group, a C6-C10 aryl group, or a Cs aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group can be substituted or unsubstituted.
[0034] [0034] For use in the present invention, "heteroaryl" refers to a monocyclic or multicyclic aromatic ring system (such as bicyclic) (a ring system with a fully delocalized pi electron system) that contains one or more heteroatoms (for example, 1, 2 or 3 heteroatoms), that is, an element other than carbon, including, but not limited to, nitrogen, oxygen and sulfur. The number of atoms in one or more rings of a heteroaryl group can vary. For example, the heteroaryl group may contain 4 to 14 atoms in one or more rings, 5 to 1N atoms NnO € 8 IM AV MAIS anáie A Ea RB atamás NAS IM ALT MAIS ANnáie PAMA NAVA carbon atoms and a heteroatom; eight carbon atoms and two hetero atoms; seven carbon atoms and three hetero atoms; eight carbon atoms and a hetero atom; seven carbon atoms and two hetero atoms; six carbon atoms and three hetero atoms; five carbon atoms and four hetero atoms; five carbon atoms and a hetero atom; four carbon atoms and two hetero atoms; three carbon atoms and three hetero atoms; four carbon atoms and a hetero atom; three carbon atoms and two hetero atoms; or two carbon atoms and three hetero atoms. In addition, the term "heteroaryl" includes fused ring systems in which two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2, 3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopirazo |, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine , pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinoline and triazine. A heteroaryl group can be substituted or unsubstituted.
[0035] [0035] For use in the present invention, "heterocyclyl" or "heteroalicyclic" refers to a monocyclic, bicyclic and tricyclic ring system of three, four, five, six, seven, eight, nine, ten, and up to 18 members wherein the carbon atoms, together with 1 to 5 hetero atoms constitute the said ring system. A heterocycle can optionally contain one or more unsaturated bonds located in such a way, however, that a fully delocalized pi electron system does not occur in all rings. The one or more heteroatoms are a different element from carbon including, but not limited to, oxygen, sulfur and nitrogen. A heterocycle can also contain one or more carbonyl or thiocarbonyl functionalities, in order to make the definition include oxo systems and thio systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings swim around in a melted pharma within aA11 easnirn Dara 1166 in the present invention, the term "fused" refers to two rings having two atoms and a common bond.
[0036] [0036] As used here, "aralkyl" and "aryl (alkyl)" refer to an aryl group connected, as a substituent, through a lower alkylene group. The lower alkylene and aryl group of an aralkyl can be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl and naphthylalkyl.
[0037] [0037] As used herein, "heteroaralkyl" and "heteroaryl (alkyl)" refer to a heteroaryl group connected, as a substituent, through a lower alkylene group. The lower alkylene and heteroaryl group of the heteroaralkyl can be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl and imidazolylalkyl and their benzo-fused analogs.
[0038] [0038] A "heteroalicyclic (alkyl)" and "heterocyclyl (alkyl)" refer to a heterocyclic or heteroalicyclic group connected, as a substituent, through a lower alkylene group. The lower alkylene and the heterocyclyl of one (heteroalkyl) alkyl may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-ylmethyl), piperidin-4-yl (ethyl), piperidin-4-yl (propyl), tetrahydro-2H-thiopyran-4- useful (methyl) and 1,3-thiazinan-4-yl (methyl).
[0039] [0039] As used herein, the term "hydroxyl" refers to an -OH group.
[0040] [0040] As used herein, "alkoxy" refers to the formula -OR in which R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl) , heteroaryl (alkyl) or heterocyclyl (alkyl), as defined in the present invention. A non-limiting list of alkoxyls is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, ter-butoxy, phenoxy and benzoxy. An alkoxy can be substituted or unsubstituted.
[0041] [0041] For use in the present invention, "acyl" refers to a hydrogen, alquila - aluioanila - alauminila arila hatarnarila hoatarncielila —arillalaiila)
[0042] [0042] A "cyan" group refers to a "-CN" group.
[0043] [0043] The term "halogen atom" or "halogen", for use in the present invention, means any of the stable radio atoms in column 7 of the periodic table of elements, such as fluorine, chlorine, bromine and iodine.
[0044] [0044] A "thiocarbonyl" group refers to a "-C (= S) R" group in which R can be the same as that defined in relation to O-carboxyl. A thiocarbonyl can be substituted or unsubstituted.
[0045] [0045] An "O-carbamyl" group refers to a "-OC (= O) N (RaARs)" group in which Ra and Rg can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl , a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl). An O-carbamyl can be substituted or unsubstituted.
[0046] [0046] An "N-carbamyl" group refers to a "ROC (= O) N (Ra) -" group in which R and Ra can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, an cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl)). An N-carbamyl can be substituted or unsubstituted.
[0047] [0047] An "O-thiocarbamyl" group refers to an "-OC (= S) -N (RaARg)" group in which Ra and Rg can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, an cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl). An O-thiocarbamyl can be substituted or unsubstituted.
[0048] [0048] An "N-thiocarbamyl" group refers to an "ROC (= S) N (Ra) -" group in which R and Ra can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, an cycloalkyl, a cycloalkenyl, aryl, heteroaryl,
[0049] [0049] A "C-starch" group refers to a "-C (= O) N (RaRg)" group in which Ra and Rg can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl , a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl) .. A C-starch can be substituted or unsubstituted.
[0050] [0050] An "N-starch" group refers to an "RC (= O) N (Ra) -" group in which R and Ra can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, an cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl). An N-starch can be substituted or unsubstituted.
[0051] [0051] An "S-sulfonamido" group refers to a "-SO2N (RaRsg)" group in which Ra and Rg can independently be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl , heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl))) A S-sulfonamido can be substituted or unsubstituted.
[0052] [0052] An "N-sulfonamido" group refers to an "RSO2N (Ra) -" group in which R and Ra can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl) 'or heterocyclyl (alkyl)) à An N-sulfonamido can be substituted or unsubstituted.
[0053] [0053] An "O-carboxyl" group refers to an "RC (= 0) O-" group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl , heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl), as defined herein. An O-carboxyl can be substituted or unsubstituted.
[0054] [0054] The terms "ester" and "C-carboxyl" refer to a group "-C (= O0) OR" in which R can be equal to that defined in relation to O-carboxyl. An ester and a C-carboxyl can be substituted or unsubstituted.
[0055] [0055] A "nitro" group refers to a "-NO> 2" group.
[0056] [0056] A "sulfenyl" group refers to a "- SR" group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl) , aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl). A sulfenyl can be substituted or unsubstituted.
[0057] [0057] A "sulfinyl" group refers to a "-S (= O) R" group in which R can be the same as that defined in relation to sulfenyl. A sulfinyl can be substituted or unsubstituted.
[0058] [0058] A "sulfonyl" group refers to a "SO2R" group n in which R can be the same as that defined with respect to sulfenyl. A sulfonyl can be substituted or unsubstituted.
[0059] [0059] As used in the present invention, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., monohaloalkyl, dihaloalkyl, trihaloalkyl and poly - haloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, - trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl and pentafluoroethyl. A haloalkyl can be substituted or unsubstituted.
[0060] [0060] For use in the present invention, "haloalkoxy" refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (for example, monohaloalkoxy, dihaloalkoxy and trihaloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. A haloalkoxy can be substituted or unsubstituted.
[0061] [0061] The term "amino" and "unsubstituted amino", as used here, refers to an aruine “NH.
[0062] [0062] A "monosubstituted amine" group refers to a "-NHRa" group in which Ra can be an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl), as defined herein. An Ra can be substituted or not substituted. A monosubstituted amine group can include, for example, a monoalkylamine group, a C1-Cs monoalkylamine group, a monoarylamine group, a Ce6-C1o monoarylamine group and the like. Examples of monosubstituted amino groups include, but are not limited to, -NH (methyl), -NH (phenyl) and the like.
[0063] [0063] A "disubstituted amine" group refers to a "-NRaARg" group in which Ra and Rg can independently be an alkyl, an alkenyl, an alkynyl, a cycloalkyl an heteroaryl aryl cycloalkenylay, heterocyclyl, cycloalkyl (alkyl ), aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl), as defined herein. Ra, and Rg can be independently substituted or unsubstituted. A disubstituted amino group can include, for example, a dialkylamine group, a C1-Cs dialkylamine group, a diarylamine group, a Cs-C10 diarylamine group and the like. Examples of disubstituted amino groups include, but are not limited to, -N (methyl) 2, -N (phenyl) (methyl), -N (ethyl) (methyl) and the like.
[0064] [0064] As used in the present invention, the group "monosubstituted amine (alkyl)" refers to a monosubstituted amine group as provided herein connected, as a substituent, through a lower alkylene group. A monosubstituted (alkyl) amine can be substituted or unsubstituted. A monosubstituted amino (alkyl) group can include, for example, a monoalkylamino (alkyl) group, a monoalkylamino (C1-Cs alkyl) group, a monoaryl (amino) group, a monoarylamino group (Cs-C1yl alkyl) and the like. Examples of monosubstituted amine (alkyl) groups include, but are not limited to, -CH2oNH (methyl), —CH2NH (phenyl), -CH2CH2aNH (methyl), -CH2CH2aNH (phenyl) and the like.
[0065] [0065] As used in the present invention, the term "disubstituted (alkyl) amine" refers to a disubstituted amine, as provided herein, connected, as a substituent, by means of a lower alkylene group. A disubstituted (alkyl) amine can be substituted or unsubstituted. A disubstituted amino (aquyl) group may include, for example, a dialkylamino (alkyl) group, a C1- Cse dialkylamino group (C1-Cs alkyl), a diarylamino group (alkyl), a Ce-Cio diarylamino group (C1- alkyl) Cs) and the like. Examples of disubstituted amine (alkyl) groups include, but are not limited to —-CHaN (methyl>), -CH2N (phenyl) (methyl) -NCH> (ethyl) (methyl), -CH2CH2aN (methyl) -, -CH2CHaN (phenyl) (methyl), = -NCH2CH> 2 (ethyl) (methyl) and the like.
[0066] [0066] When the number of substituents is not specified (for example, haloalkyl), there may be one or more substituents present. For example, "haloalkyl" can include one or more of the same or different halogens. As another example, "C1-C3-alkoxyphenyl" can include one or more of the same or different alkoxy groups containing one, two or three atoms.
[0067] [0067] For use in the present invention, a radical indicates species with a single unpaired electron, so that the species containing the radical can be covalently linked to another species. Therefore, in this context, a radical is not necessarily a free radical. Instead, a radical indicates a specific portion of a larger molecule. The term "radical" can be used interchangeably with the term "group".
[0068] [0068] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not interrupt the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (for example, hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2.3-dihydrogen phosphate -hydroxypropyl). Pharmaceutical salts can also be obtained by the reaction of an aramenic CAM 1iM Aramide RAMPANANESIA with aliphatic al-carhalic and aromatic acids, for example, formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, methanesulfonic. , p-toluenesulfonic, triluoroacetic, benzoic, salicylic, 2-oxopentanedioic or naphthalenesulfonic. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium, potassium or lithium salt, an alkaline earth metal salt , such as a calcium salt or a magnesium salt, a carbonate salt, a bicarbonate salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, C1-C7 alkylamine , cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine. For compounds of Formula (I), those skilled in the art understand that when a salt is formed by protonation of a nitrogen-based group (for example, NH> 2), the nitrogen-based group can be associated with a charge positive (for example, NH can become NH3 *) and the positive charge can be balanced by a negatively charged counterion (such as CI).
[0069] [0069] Cells latently infected with HIV harbor transcriptionally silent viruses that can still replicate to produce active HIV. The term "HIV latency reversal agent" refers to an agent (including small molecules and proteins) that stimulates HIV transcription, converting latently infected cells with HIV into cells that express HIV replication. HIV latency reversal agents include, but are not limited to, protein kinase C agonists (such as prostratin, briostatin-1 and ingenol), PD-1 inhibitors (such as nivolumab, pembrolizumab, BGB-A317, pidilizumab, AMP -224, AMP-514, PDROO01, REGN2810 and MEDIO680), PD-L1 inhibitors (such as atezolizumab, durvalumab, avelumab and BMS-936559), HDAC inhibitors (such as vorinostat, panobinostate, romidepsin and valproic acid), phorol esters (such as 12-myristate-13-acetate and (S) -tert-butyl-2- (4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2-f] [1 , 2,4] triazolo [4,3-a] [1 4Jdiazepin-6-yl) phorbol acetate) and bromodomain inhibitors (such as JQ1, | I-BET762, OTX015, | -BET151, CPI203, PFI-
[0070] [0070] The term "Bcl protein inhibitor" refers to an agent (including small molecules and proteins) that inhibit the binding of an anti-apoptotic Bol protein (such as Bcl-2, Bcl-X., Bcl-W, Mcl-1 and Bcl-2A1) to a pro-apoptotic Bcl protein (such as Bak, Bax, Bim, Bid, tBid, Bad, Bik, PUMA, Bnip-1, Hrk, Bmf and Noxa). Bcl protein inhibitors include, but are not limited to, venetoclax, navitoclax, obatoclax, S55746, APG-2575, ABT-737, AMG176, AZD5991 and APG-
[0071] [0071] It should be understood that, in any compound described here that has one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center can independently be of R configuration or S configuration or a mixture thereof. Thus, the compounds provided herein can be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. Furthermore, it is understood that, in any compound described herein as having one or more double bonds that generate geometric isomers that can be defined as E or Z, each double bond can be independently E or Z a mixture thereof. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.
[0072] [0072] It should be understood that when the compounds presented in the present invention have unfilled valences, then the valences must be filled with hydrogens or their isotopes, for example, hydrogen-1 (protium) and hydrogen-2 (deuterium).
[0073] [0073] It should be understood that the compounds described herein can be labeled isotopically. Substitution by isotopes such as deuterium can provide certain therapeutic advantages resulting from greater metabolic stability, such as, for example, a longer half-life in vivo or lower dosage required. Each chemical element, as represented in a compound structure, can include any isotope of said element. For example, in a compound structure, a hydrogen atom can be explicitly shown or understood to be present in the compound. In any position of the compound in which a hydrogen atom can be present, this atom can be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Accordingly, the reference in the present invention to a compound encompasses all potential isotopic forms, unless the context clearly indicates otherwise.
[0074] [0074] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystalline packaging arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain stoichiometric or non-stoichiometric amounts of a solvent, and can be formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol or the like. Hydrates are formed when the solvent aria Al Aalctnalatas dog farmaoas loving sealant is alkenal Alám dieen in the compounds provided here can exist in unsolvated forms, as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
[0075] [0075] When a range of values is provided, it is understood that the upper and lower limits, and each intervening value between the upper and lower limits of the range, is covered by the modalities.
[0076] [0076] The terms and expressions used in this application, as well as their variations, especially in the appended claims, except where otherwise indicated, should be interpreted as open and not limiting. As examples of the aforementioned, the term "including" should be interpreted to mean "including, without limitation," "including, but not limited to," or the like; the term "comprising", for use in the present invention, is synonymous with "including", "containing" or "characterized by", and is inclusive or open and does not exclude additional elements or steps of the method not mentioned; the term "having" must be interpreted as "having at least"; the term "includes" should be interpreted as "includes but is not limited to"; the term "example" is used to provide examples of the item under discussion, not an exhaustive or limiting list; and the use of terms such as "preferred", "preferred", "desired" or "desirable", and words of similar meaning should not be understood to imply that certain resources are critical, essential, or even important to the structure or function, but it merely intends to highlight alternative or additional features that may or may not be used in a specific modality. Furthermore, the term "comprising" must be interpreted as a synonym for the expressions "has at least" or "includes at least". When used in the context of a compound, composition or device, the term "comprising" means that the compound, composition or device includes at least the mentioned features or components, but can also include additional features or components.
[0077] [0077] In relation to the use of substantially any terms in the plural and / or nina cinauilar in the nracanta invancrão n <ºe varcadaoe in the tenicra swim go from the nliural nara singular number and / or from singular to plural, as appropriate to the context and / or application. The various permutations in the singular / plural can be expressly presented here for reasons of clarity. The indefinite article "one" or "one" does not exclude a plurality. The mere fact that certain measures are mentioned in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope. Compounds
[0078] [0078] Some embodiments disclosed herein refer to a compound of Formula (|) or to a pharmaceutically acceptable salt thereof, having revealed in the present invention structure: Rº
[0079] [0079] In some embodiments, R 'may be halogen, such as fluorine, chlorine, bromine or iodine. In some embodiments, R * may be fluoro. In some embodiments, R 'may be chlorine. In some embodiments, R 'may be hydrogen.
[0080] [0080] In some embodiments, R 'may be substituted or unsubstituted C1-6 alkyl. For example, in some embodiments, R * may be substituted C1-6 alkyl. In other embodiments, R 'may be unsubstituted C1-Cs alkyl. Examples of C1-Cs alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and linear) and hexyl (branched and linear). In some embodiments, R 'may be unsubstituted methyl or unsubstituted ethyl.
[0081] [0081] In some embodiments, R 'may be a substituted or unsubstituted C1-Cs haloalkyl, a substituted or unsubstituted C1-Cs monohaloalkyl, a substituted or unsubstituted C1-Cs dihaloalkyl, a C1 trihaloalkyl -Cs substituted or unsubstituted, a substituted or unsubstituted C1-Cs tetrahaloalkyl or a substituted or unsubstituted C1-Cs pentahaloalkyl. In some embodiments, R * can be an unsubstituted -CHF2, -CF3, = CH2CF3 or -CF2CH; 3
[0082] [0082] In some embodiments, R 'may be a substituted or unsubstituted C3-Cemonocyclic or bicyclic cycloalkyl. For example, in some embodiments, R 'may be a substituted monocyclic C3-6s cycloalkyl. In other embodiments, R 'may be an unsubstituted monocyclic C3-Cs cycloalkyl. Examples of monocyclic or bicyclic C3-Cs cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, [1.1.1] bicyclopentyl and cyclohexyl.
[0083] [0083] In some embodiments, R * may be a substituted or unsubstituted C1i-alkoxy. For example, in some embodiments, R * may be a substituted C1-C6 alkoxy. In other embodiments, R * may be an unsubstituted C1-Cs alkoxy. Examples of suitable C1-Cs alkoxy groups include, but are not limited to, methoxy, Atávi nonronávi iennhronávi nX-hutávi ienhuitávi tarebhutávi nantávi (ramified and linear chain) and hexoxy (branched and linear chain). In some embodiments, R 'may be an unsubstituted methoxy or an unsubstituted ethoxy.
[0084] [0084] In some embodiments, R 'may be an unsubstituted C1-C6g monoalkylalkyl, for example, methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, isobutylamine, tert-butylamine, pentylamine (straight and branched chain) and hexylamine (branched and straight chain). In some embodiments, R * may be methylamine or ethylamine.
[0085] [0085] In some embodiments, R 'may be an unsubstituted C1-Cs dialkylamine. In some embodiments, each C1-Cs alkyl in the C1-Cs dialkylamine is the same. In other embodiments, each C1-Cs alkyl in the C1-Cs dialkylamine is different. Examples of suitable C1-Cs dialkylamine groups include, but are not limited to, dimethylamine, diethylamine, (methyl) (ethyl) amine, (methyl) (isopropyl) amine and (ethyl) (isopropyl) amine.
[0086] [0086] In some embodiments, m can be 0. When m is O, those skilled in the art understand that the ring to which R is fixed is not replaced. In some modalities, m can be 1. In some modalities, m can be 2. In some modalities, m can be 3.
[0087] [0087] In some modalities, an R may be unsubstituted C; -Cs alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (straight and branched chain) and hexyl (straight and branched chain) )) and any other R , if present, can be independently selected from halogen (for example, fluoro or chloro), a substituted or unsubstituted C1-C6 alkyl group (such as those described in the present invention), a group substituted or unsubstituted C1-Cs haloalkyl (like those described in the present invention) and a substituted or unsubstituted monocyclic or bicyclic C3-Cs cycloalkyl (like those described in the present invention). In some embodiments, each R can be independently selected from an unsubstituted C1-Cs alkyl, such as those described herein.
[0088] [0088] In some modalities, m can be 2; and each R it can be geminal. In some embodiments, m can be 2; and each R it can be vicinal. In some embodiments, m can be 2; and each R it may be unsubstituted methyl. In some embodiments, m can be 2; and each R it may be unsubstituted geminal methyl.
[0089] [0089] In some modalities, two groups R they can be taken together with the atom (s) to which they are attached to form a substituted or unsubstituted monocyclic C3-Cs cycloalkyl. For example, in some modalities, two groups R they can be taken together with the atom (s) to which they are attached to form a substituted monocyclic C3-CÊ cycloalkyl, such as those described herein. In other modalities, two groups R they can be taken together with the atom (s) to which they are attached to form an unsubstituted monocyclic C3-Cs cycloalkyl, such as those described herein. In some modalities, two groups R they can be taken together with the atom to which they are attached to form an unsubstituted cyclopropyl.
[0090] [0090] In some modalities, two groups R they can be taken together with the atom (s) to which they are attached to form a substituted or unsubstituted 3- to 6-membered monocyclic heterocyclyl. For example, in some modalities, two groups R can be taken together with the atom (s) to which they are attached to form a 3- to 6-membered substituted monocyclic heterocyclic In other embodiments, two R they can be taken together with the atom (s) to which they are attached to form an unsubstituted monocyclic 3- to 6-membered monocyclic heterocyclyl. In some embodiments, the substituted 3- to 6-membered monocyclic heterocyclyl can be substituted on one or more nitrogen atoms. Examples of substituted or unsubstituted 3- to 6-membered heterocyclic groups include, but are not limited to, azidirine, oxiran, azetidine, oxethane, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, piperidine, tetrahydropyran, piperazine, morpholine, thiomorpholine and dioxane. INNA11 In different modalities R3 node car
[0092] [0092] In some modalities, Rº can be XR% º. In some embodiments, X can be -O-. In some embodiments, X can be -S-. In some embodiments, X can be -NH-. In some modalities, R% * º can be
[0093] [0093] In some embodiments, R º may be a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments, R * º may be a 5 to 10 membered monocyclic heteroaryl substituted. In other embodiments, R * º may be a 5 to 10 membered substituted bicyclic heteroaryl. In some embodiments, R * º may be an unsubstituted 5- to 10-membered monocyclic heteroaryl. In other modalities, Rº * º may be an unsubstituted 5 to 10 membered bicyclic heteroaryl. Examples of substituted or unsubstituted monocyclic or bicyclic 5- to 10-membered heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, TCaniada = aAl mjesasaAl maesavTAl ImqAmvuATAl dinasAl IiqAAtiassAl ielhazsl niviediaa piririaa piriria; , pyrrole-furans, pyrrole-thiophenes, indole, isoindole, indolizine, indazole, benzimidazole, azaindoles, azaindazoles, purine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, quinoline, isoquinoline, y quinoxaline, quinine, quinine, quinine, quinine naphthyridine, pyrido-pyrimidines and pteridine.
[0094] [0094] In some modalities, Rº can be hydrogen. In some modalities, R $ may be halogen. In some modalities, Rº can be fluoro or chloro.
[0095] [0095] In some modalities, Rº can be NO2. In some modalities, Rº can be cyan. In some modalities, Rº can be halogen.
[0096] [0096] In some modalities, Rº may be an unsubstituted Ci-s haloalkyl, such as those described here. In some modalities, Rº can be —-CF3.
[0097] [0097] In some modalities, Rº can be S (ORº. In some modalities, Rº can be SO2Rº. In some modalities, Rº can be SO2CF3.
[0098] [0098] In some embodiments, Rº may be substituted or unsubstituted C1-6 alkyl. For example, in some embodiments, Rº may be substituted C1-6 alkyl, such as those described here. In some embodiments, Rº may be unsubstituted C1-6 alkyl, such as those described here.
[0099] [0099] In some modalities, Rº can be a substituted or unsubstituted C3- Cemonocyclic or bicyclic cycloalkyl. For example, in some embodiments, Rº may be a monocyclic or substituted bicyclic C3-6 cycloalkyl. In other modalities, Rº may be an unsubstituted monocyclic or bicyclic C3-Cs cycloalkyl. Examples of monocyclic or bicyclic C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, [1.1.1] bicyclopentyl and cyclohexyl.
[0100] [0100] In some modalities, Rº may be a substituted or unsubstituted C1-Cs haloalkyl, such as those described here. In some modalities, Rº can be -CF3.
[0101] [0101] In some modalities, Rº can be —X '- (AIkKI)) - R'. In some embodiments, X * can be -O-. In some embodiments, X * can be -S-. In some embodiments, X * can be -NH-.
[0102] [0102] In some embodiments, AIKk * can be - (CH2): - 4— * not substituted, for which "*" represents the point of attachment to R '. In some embodiments, AIK * can be O O, &. GU OO CATTLE,
[0103] [0103] In some embodiments, Alk '* may be $ —C-Ca alkylene— + substituted, for which "*" represents the point of attachment to the R ”. For example, in some embodiments, AIKk * can be substituted methylene, substituted ethylene, substituted propylene or substituted butylene. In some ways, Alk it can be monosubstituted, disubstituted or tri-substituted. In some embodiments, AIk 'may be monosubstituted with a halogen (such as fluoro or chloro) or unsubstituted C + -C3 alkyl, such as those described herein. In other embodiments, AIlk 'may be a monosubstituted C1-Cs haloalkyl, such as those described herein. In some embodiments, AIkK 'can be monosubstituted with fluoro or unsubstituted methyl. In some embodiments, AIk 'can be substituted with a fluoro and unsubstituted C1-C3 alkyl, such as those described herein. In other embodiments, AIk * can be substituted with an unsubstituted C1-C3 haloalkyl, such as those described herein, and an unsubstituted C1-C3 alkyl, such as those described herein. In some embodiments, AIk * can be replaced with fluoro and unsubstituted methyl. In some embodiments, Alk 'can be disubstituted with two independently selected unsubstituted C1-C3 alkyl groups, such as those described herein. In
[0104] [0104] In some modalities, AlKk * can be selected from: F CI CF; . 2 * AND EO OT SOR SOS A REA,
[0105] [0105] In some modalities, n can be O. When n is O, those skilled in the art understand that X 'is directly connected to R ”. In some embodiments, n may be 1.
[0106] [0106] In some embodiments, R 'may be a monosubstituted, substituted or unsubstituted amino group. For example, R 'may be a monosubstituted amino group with substituted or unsubstituted C1-Cs alkyl, substituted or unsubstituted C2-Cs alkenyl, substituted or unsubstituted C2-Cs alkynyl, monocyclic or bicyclic cycloalkyl substituted or unsubstituted, a substituted or unsubstituted monocyclic or bicyclic C6-C10o aryl, a substituted or unsubstituted monocyclic or bicyclic 5-membered heteroaryl; a substituted or unsubstituted 3 to 10 membered monocyclic or bicyclic heterocyclyl, a substituted or unsubstituted monocyclic or bicyclic C3a-Ce (unsubstituted C1-Cs alkyl), a monocyclic Cs-Cio aryl (unsubstituted C1-Cs alkyl) or substituted or unsubstituted bicyclic, a substituted or unsubstituted 5- to 10-membered heteroaryl (unsubstituted C1-Cs alkyl) or a substituted or unsubstituted 3- to 10-membered heterocyclic (unsubstituted C1-Cs alkyl). Examples of suitable monosubstituted amino groups include, but are not limited to, -NH (methyl), —NH (isopropyl), -NH (cyclopropyl), -NH (phenyl), -NH (benzyl) and -NH (pyridin-3 -ila).
[0107] [0107] In some embodiments, R 'may be a substituted or unsubstituted amino group. For example, R 'may be an amino group substituted with two substituents independently selected from a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-Cs alkenyl,
[0108] [0108] In some embodiments, R * can be selected from a substituted or unsubstituted N-carbamyl, a substituted or unsubstituted C-starch and a substituted or unsubstituted N-starch.
[0109] [0109] In some embodiments, R 'may be a substituted or unsubstituted C3-C10 cycloalkyl. In some embodiments, R 'may be a substituted or unsubstituted C3-Cyomonocyclic cycloalkyl. In other modalities, R it may be a substituted or unsubstituted C3-C10 cycloalkyl, for example, a bridged, fused or spiro C3-C10 cycloalkyl. Suitable substituted or unsubstituted monocyclic or bicyclic C3-C10 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro [3.3] heptyl, spiro [2.3] hexyl, spiro [3.4] octyl, spiro [3.5] nonila, spiro [3 6] decila, spiro [2.4] heptyla, spiro [4.4] nonila, spiro [4.5] decila, spiro (2.5] octyl, spiro [ 3.5] nonyl, bicycles [1.1.1] pentyl, bicycles [2.1.1] hexyl, bicycles [2.2.1] heptyla, decahydronaphthalenyl, octahydro-1H-indenyl, neta-hydronantalanila hinielaMA 9 Olnctila hicielal9 1 Olnantila é hicielalR 9 Nhanftila
[0110] [0110] In some embodiments, R 'may be a substituted or unsubstituted Cs-C10o spirocycloalkyl. In some embodiments, R 'may be a substituted Cs-C10o spirocycloalkyl. In other embodiments, R may be an unsubstituted Cs-C10 spirocycloalkyl. In some embodiments R 'may be a cyclopropyl-cyclobutyl spiroalkyl, —cyclopropyl-cyclopentyl spiroalkyl, —cyclopropyl-cyclohexyl spiroalkyl, —cyclopropyl -— cycloheptyl spiroalkyl, —cyclopropyl — cyclooctyl spiroalkyl, —cyclobutyl-cycloalkyl —Cyclobutyl-cyclobutyl spiroalkyl, - cyclobutyl-cyclopentyl spiroalkyl, —cyclobutyl-cyclohexyl spiroalkyl, —cyclobutyl-cycloheptyl — spiroalkyl, “—cyclopentyl-cyclopropyl - spiroalkyl,“ —cyclopentyl — cyclobylpyro, cycloalkyl, spiroalkyl cyclopentyl-cyclohexyl spiroalkyl, —cyclohexyl-cyclopropyl spiroalkyl, —cyclohexyl-cyclobutyl spiroalkyl, —cyclohexyl-cyclopentyl spiroalkyl, —cycloheptyl-cyclopropyl spiroalkyl, —cyclohexyl-cyclohexyl-cyclohexyl-cyclohexyl octyl-cyclopropyl spiroalkyl.
[0111] [0111] In some embodiments, R 'may be a substituted or unsubstituted 3 to 10 membered heterocyclic. In some modalities, R it can be a substituted 3 to 10 membered heterocyclyl. In other modalities, R it can be an unsubstituted 3 to 10 membered heterocyclic. In some embodiments, R 'may be a substituted or unsubstituted 3 to 10 membered monocyclic heterocyclic. In other embodiments, R 'may be a substituted or unsubstituted 5 to 10 membered heterocyclic, for example, a fused, bridged or spiro 5 to 10 membered heterocyclyl. Suitable 3- to 10-membered substituted or unsubstituted heterocyclyl groups include, but are not limited to, azidirine, oxirane, azetidine, oxetane, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, piperidine, tetrahydropyran, piperazine, morpholine, thiomorpholine, dioxane, 2-azaspiro [3,3] heptane, 2-oxaspiro [3,3] heptane, 2,6-diazaspiro [3,3] heptane, 2-oxa-6-azaspiro [3,3] heptane, 2-azaspiro [ 3.4] octane, 6-oxaspiro [3,4] octane, 6-0xa-2-azaspiro [3,4] octane, 7-0xa-2-azaspiro [3,5] nonane, 7-oxaspiro [3, 5] nonane and 2-0xa-8-azaspiro [4,5] decane. In some embodiments, in the 2 2 10 mambhros maonNACíflica au hicíelica eubhetituitu au unsubstituted can be connected to the rest of the molecule through a nitrogen atom. In other embodiments, the substituted or unsubstituted 3- to 10-membered monocyclic or bicyclic heterocyclyl can be connected to the rest of the molecule through a carbon atom. In some embodiments, the 3- to 10-membered monocyclic or bicyclic heterocyclyl can be substituted by one or more nitrogen atoms.
[0112] [0112] In some embodiments, R 'may be a substituted or unsubstituted 6-membered spiroheterocyclyl. In some modalities, R it can be a substituted 6 to 10-membered spiroheterocyclyl. In other modalities, R it may be an unsubstituted 6 to 10 membered spiroheterocyclyl. In some embodiments, R 'may be azaspiro-octane, azaspiro-heptane, azaspiro-octane, oxaspiro-hexane, oxaspiro-heptane, oxaspiro-octane, diazaspiro-hexane, diazaspiro-heptane, diazaspiro-octane, dioxaspiro-hexane, dioxaspiro-hexane - heptane, dioxaspiro-octane, oxa-azaspiro-hexane, oxa-azaspiro-heptane or oxazaziro-octane. Suitable 3- to 10-membered substituted or unsubstituted heterocyclic groups include, but are not limited to, 2-azaspiro [3,3] heptane, 2-oxaspiro [3,3] heptane, 2,6-diazaspiro [3,3] heptane, 2-oxa-6-azaspiro [3,3] heptane, 2-azaspiro [3,4] octane, 6-oxaspiro [3,4] octane, 6-0xa-2-azaspiro [3,4] octane, 7-o0xa- 2-azaspiro [3,5] nonane, 7-oxaspiro [3,5] nonane and 2-oxa-8-azaspiro [4,5] decane. In some embodiments, the 6 to 10-membered substituted or unsubstituted heterocyclic can be connected to the rest of the molecule through a nitrogen atom. In other embodiments, the substituted or unsubstituted 6 to 10-membered spiroheterocyclyl can be connected to the rest of the molecule through a carbon atom. In some embodiments, the 6 to 10-membered spiroheterocyclyl can be replaced by one or more nitrogen atoms.
[0113] [0113] In some embodiments, R 'may be hydroxyl or starch.
[0114] [0114] In some modalities, R may not be replaced. In other embodiments, R 'can be substituted. In some modalities, R ” can be filled with 1 to 9 indeterminate indentations within 11 unsubstituted C1-C6 alkyl (as described in the present invention), an unsubstituted C1-Cs alkoxy (as described in the present invention), fluoro, chlorine, hydroxy and - SO> z- (unsubstituted C1-C6 alkyl). For example, the C1-Cse6 alkoxy groups, C3-C1o cycloalkyl, 3-10 membered heterocyclyl, monosubstituted amino group, disubstituted amino group, N-carbamyl, C-starch and R 'N-starch can be substituted with 1 or 2 substituents independently selected from any of the aforementioned substituents.
[0115] [0115] In some modalities, R can be EXMO AX <XINnt <XXON ENNOXOo ENOXONH ENO OCL ENO FX »FOX o EXCOXO,,,, nº, IOCP (OO) ECO EQ OO) IO xo BU SOD AO
[0116] [0116] In some modalities, R can be O. O. O. o o OO DO OCH OXCi FDC EXOXU o LL o HO Hr o N | O o o HN N XN N
[0117] [0117] In some modalities, R Can be
[0118] [0118] In some modalities, Rº can be -Xº- (CHR $) - (AlIk2), - X * -Rº. In some modalities, X can be the-. In some modalities, X can be - S-. In some modalities, X can be -NH-. In some modalities, X can be the-. In some modalities, Xº can be -S-. In some modalities, X can be -NH-. In some modalities, Xº can it be -NH-— and X can be -S-. In some modalities, X can it be -O-— and X can be —S-. In some modalities, X can it be -NH- and X can be the-. In some modalities, X can it be -O— and Xº can be the-.
[0119] [0119] In some modalities, AIk can be - (CH2) 1-4— * unsubstituted, for which "*" represents the point of attachment to X *. In some ways, Alk it may be unsubstituted methylene, unsubstituted ethylene, unsubstituted propylene or unsubstituted butylene. In some modalities, AIk can be N7
[0120] [0120] In some modalities, AIk can be $ -— to Alkylene Cr-Cy— + substituted, for which "*" represents the point of attachment to the X . In some modalities, AIk it can be substituted methylene, substituted ethylene, substituted propylene or substituted butylene. In some ways, Alk it can be monosubstituted, disubstituted or tri-substituted. In some modalities, AIkK it can be monosubstituted with fluoro or unsubstituted C1-C3 alkyl, such as those described herein. In some ways, Alk it can be monosubstituted with fluoro or unsubstituted methyl. In some modalities, AIKk it can be disubstituted with a fluoro and an unsubstituted C1-C3 alkyl, such as those described herein. In some modalities, AIlkK it can be substituted with a fluoro and an unsubstituted methyl. In some modalities, AIKk can be disubstituted with two independently selected unsubstituted C1-C3a alkyl groups, such as those described herein. In some ways, Alk it can be replaced with unsubstituted methyl.
[0121] [0121] In some modalities, AIk can be selected from: dA XKZÁLE DA OVAR AA ON CF; ON F ONLY and CF;
[0122] [0122] In some modalities, p can be O. When p is O, those skilled in the art understand that the group (CHRº $) is directly connected to X *. In some embodiments, p can be 1.
[0123] [0123] In some embodiments, the substituted or unsubstituted 3-substituted or unsubstituted C1-Cs alkyl (C1-Cs alkyl), such as those described herein.
[0124] [0124] In some embodiments, Rê may be a substituted or unsubstituted 6 to 10 membered spiroheterocyclyl (C1- C alkyl).
[0125] [0125] In some embodiments, Rô can be a C1-Cs dialkylamino (C1- Cs alkyl), for example, a C-Cs dialkylamino (ethyl), C1-Cs dialguylamino (propyl), C1-Cs dialkylamino (butyl), dialkylamino C1-Ce (pentyl) or dialkylamino C1-Ce (hexyl). In some embodiments, each C1-Cs alkyl group on the C1-Cs dialkylamine may be the same. In other embodiments, each C1-Cs alkyl group on the C1-Cs dialkylamine may be different. The substituted or unsubstituted C1-Ce dialkylamino (C1-Cs alkyl) includes, but is not limited to, -N (methyl) to, -N (ethyl) -, -N (n-propyl)., -N (isopropyl ) 2, -N (t-butyl) -, -N (ethyl) (methyl), -N (isopropyl) (methyl), -N (t-butyl) (methyl) and -N (isopropyl) (ethyl); each connected to a substituted or unsubstituted C1-Cs alkyl group.
[0126] [0126] In some embodiments, Rê may be a substituted or unsubstituted dimethylamino (C1-Cs6 alkyl), for example, - Yes! | & - - | SP OS OS FR FR, ALL GU A,
[0127] [0127] In some embodiments, Rº may be a substituted or unsubstituted C1-C monoalkylamino (C1-Cs6 alkyl), for example, a C1-Cs monoalkylamino (butyl), C1-Ce monoalkylamino (pentyl) or C1- monoalkylamino Ce (hexyl) substituted or unsubstituted. In some embodiments, the unsubstituted C1-Cs alkyl of the C1-Ce monoalkylamino (C1-Cs alkyl) may be unsubstituted C1-C 'alkyl, such as those described herein.
[0128] [0128] In some modalities, Rº may not be replaced. In other modalities, Rº can be replaced. In some embodiments, Rº can be substituted with 1 or 2 substituents independently selected from an unsubstituted C1-Cs alkyl (like those described in this document), an unsubstituted C1-Cs alkoxy (like those described in this document), a C1- dialkylamine Unsubstituted Cs (like those described in this document), an unsubstituted acyl (C1-Cs alkyl) (eg acetyl or benzoyl), an unsubstituted Cr-carboxy (eg -CO2H, -CO> -C1- alkyl) Cs, -CO> z-cycloalkyl (C3a-Cs or -CO> -aryl C6-C10), fluoro, chloro and hydroxy. For example, the heterocyclyl (C1-Cs alkyl), C1-Ce dialkylamino (C1-C6 alkyl) and C1-Ce monoalkyl (C1-Cs alkyl) groups of 3 to 10 members of R $ can be substituted with 1 or 2 substituents independently selected from any of the aforementioned substituents.
[0129] [0129] In some modalities, Rº can be: / N YEAR O Í. on Nx MC Nú, Fo NV E ERRA A, the Non NON, x NA or DA.
[0130] [0130] In some modalities, Rº can be / = = = Aa DC Dara DIO SOS = AN / o OH NON or XT:
[0131] [0131] In some modalities, Rº may be a substituted or unsubstituted Cg-Ciomonocyclic or bicyclic aryl. In some modalities, Rº can be a Cg-C19 Monocyclic or substituted bicyclic aryl. In other modalities, Rº can be an unsubstituted Cs-Cio Monocyclic or bicyclic aryl. In some embodiments, Rº can be a substituted phenyl or a substituted naphthyl. In some embodiments, Rº may be unsubstituted phenyl or unsubstituted naphthyl.
[0132] [0132] In some embodiments, Rº may be a substituted or unsubstituted 5 to 10 membered heteroaryl. In some modalities, Rº can be a substituted 5 to 10 membered heteroaryl. In other modalities, Rº can be an unsubstituted 5 to 10 membered heteroaryl. In some embodiments, Rº can be a substituted or unsubstituted monocyclic 5- to 10-membered heteroaryl. In other modalities, Rº can be a substituted or unsubstituted 5 to 10 membered heteroaryl heteroaryl. Suitable 5- to 10-membered monocyclic or bicyclic heteroaryls include, but are not limited to, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyridine, pyridine, pyrimine, pyrazine, pyrrole-pyrroles, pyrrole-furans, pyrrole-thiophenes, indole, isoindole, indolizine, indazole, benzimidazole, azaindoles, benzofuran purinay, isobenzofuran, benzothiophene, isobenzothiophene, quinoline, isoquinoline, quinoxidine, quinoline, quinine, quinine, quinine , pyrido-pyrimidines and pteridine.
[0133] [0133] In several modalities, Rº is hydrogen or halogen. For example, a modality provides a compound of Formula (|) or a pharmaceutically acceptable salt thereof, where: R 'is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted C1-Cs alkyl, a haloalkyl Substituted or unsubstituted C1-Cs, substituted or unsubstituted C3-Cs cycloalkyl, substituted or unsubstituted C1-Cs alkoxy, unsubstituted C1-Cs monoalkylamine and unsubstituted C1-Cs dialkylamine;
[0134] [0134] In some modalities, R is selected from the group consisting of X-RX, E + For example, a modality provides a compound of Formula (1) or a pharmaceutically acceptable salt thereof, where: R 'is selected from the group consisting of hydrogen, halogen , substituted or unsubstituted C1-Cs alkyl, substituted or unsubstituted C1-Cs haloalkyl, substituted or unsubstituted C3-Cs cycloalkyl, substituted or unsubstituted C1-Cs alkoxy, unsubstituted C1-Cs monoalkylamine unsubstituted C1-Cs dialkylamine; each R is independently selected from the group consisting of halogen, a substituted or unsubstituted C1-Cs alkyl, a substituted or unsubstituted C1-Cs haloalkyl and a substituted or unsubstituted C3-Cs cycloalkyl; or when m is 2 or 3, each R is independently selected from the group consisting of halogen, a substituted or unsubstituted C1-Cs alkyl, a substituted or unsubstituted C1-Cs haloalkauyl and a substituted or unsubstituted C-Cs cycloalaiyl, or two R groups, along with the atom (s) to which they are attached, forms a substituted or unsubstituted C3-Cs cycloalkyl or a substituted 3- to 6-membered heterocyclyl or not replaced;
[0135] [0135] In some modalities, R is selected from the group consisting of X-RA, =. + and Xº and X are -NH-. For example, one embodiment provides a compound of Formula (1) or a pharmaceutically acceptable salt thereof, where: R 'is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted C1-Cs alkyl, a haloalkyl Substituted or unsubstituted C1-Cs, substituted or unsubstituted C3-Cs cycloalkyl, substituted or unsubstituted C1-Cs alkoxy, unsubstituted C1-Cs monoalkylamine and unsubstituted C1-Cs dialkylamine; each R is independently selected from the group consisting of halogen, a substituted or unsubstituted C1-Cs alkyl, a substituted or unsubstituted C1-Cs haloalkyl and a substituted or unsubstituted C3-C6 cycloalkyl; or when m is 2 or 3, each R is independently selected from the group consisting of halogen, a substituted or unsubstituted C1-Cs alkyl, a substituted or unsubstituted C1-Cs haloalkyl and a substituted or unsubstituted C3-Cs cycloalkyl, or two R groups, together with the (s) atom (s) to which they are attached, forms a substituted or unsubstituted C3-Cs cycloalkyl or a 3- to 6-membered heterocyclyl. substituted or unsubstituted:
[0136] [0136] In some embodiments, R * is as described above, with the proviso that it is not -CH2F, -CHF2 or -CF3; Rº is selected from the group consisting of X-R 5, Sã + and Xº and X are -NH-. For example, one embodiment provides a compound of Formula (1) or a pharmaceutically acceptable salt thereof, where: R 'is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted C1-Cs alkyl, a haloalkyl Substituted or unsubstituted C1-Cs, a substituted or unsubstituted C3-Cs cycloalkyl, a substituted or unsubstituted C1-Cs alkoxy, an unsubstituted C1-Cs monoalkylamine and an unsubstituted C1-Cs dialkylamine, with the proviso that R 'is not -CH2F, -CHF2 or -CF3; each R is independently selected from the group consisting of halogen, a substituted or unsubstituted C1-Cs alkyl, a substituted or unsubstituted C1-Cs haloalkyl and a substituted or unsubstituted C3-C6 cycloalkyl; or when m is 2 or 3, each R is independently selected from the group consisting of halogen, a substituted or unsubstituted C1-Cs alkyl, a substituted or unsubstituted C1-Cs haloalkyl and a substituted or unsubstituted C3-Cs cycloalkyl, or two R groups, together with ( s) atom (s) to which they are attached, forms a substituted or unsubstituted C3-Cs cycloalkyl or a 3- to 6-membered heterocyclyl, whether or not substituted replaced; R3 is selected from the arupo which consists of X-R% $ A. FROG
[0137] [0137] In some embodiments, R 'is -CH2F, -CHF2 or -CF3. Rº is selected from the group consisting of X-R , o. + and Xº and X are -NH-. For example, one embodiment provides a compound of Formula (1) or a pharmaceutically acceptable salt thereof, where: R * is -CH2F, -CHF2 or -CF3; each R is independently selected from the group consisting of halogen, a substituted or unsubstituted C1-Cs alkyl, a substituted or unsubstituted C1-Cs haloalkyl and a substituted or unsubstituted C3-C6 cycloalkyl; or when m is 2 or 3, each R is independently selected from the group consisting of halogen, a substituted or unsubstituted C1-Cs alkyl, a substituted or unsubstituted C1-Cs haloalkyl and a substituted or unsubstituted C3-Cs cycloalkyl, or two R groups, together with ( s) atom (s) to which they are attached, forms a substituted or unsubstituted C3-Cs cycloalkyl or a 3- to 6-membered heterocyclyl, whether or not substituted replaced; R is selected from the group consisting of X-R *,
[0138] [0138] In some modalities, R is selected from the group consisting of WVR3A
[0139] [0139] In some embodiments, the compound of Formula (Il), or a pharmaceutically acceptable salt thereof, can be selected from a compound of Formula (la), Formula (lb), Formula (Ic) and Formula (Id ):
[0140] [0140] In some modalities of Formulas (la), (Ib), (Ic) and / or (Id), Rº can be hydrogen, * * o.
[0141] [0141] In some modalities of Formulas (la), (Ib), (Ic) and / or (Id), Rº can be nitro or -SO2CF3. In some modalities of Formulas (la), (Ib), (Ic) and / or (Id), R 'can be fluoro, chloro, -CH3, -CH2CH3, -CHF2, —-CF3, -CH2C0F3, -CF2CHa, -OCHs, —OCH2CH3, -NHCH3, —-NHCH2CH3, —N (CH3)) or -N (CH2CH3). In some modalities of Formulas (la), (lb), (Ic) and / or (Id), can Rº be -O-R or —-NH-R ”. In some modalities of Formulas (la), (Ib), (Ic) and / or (Id), Rº can be -O-Alk'- R7 or —-NH-AIK'-R . In some modalities of Formulas (la), (Ib), (Ic) and / or (Id), AIK it can be unsubstituted methylene, unsubstituted ethylene or monosubstituted ethylene with -CH3. In some modalities of Formulas (la), (Ib), (Ic) and / or (Id), R 'can be an unsubstituted cyclohexanyl or a cyclohexanyl substituted with one or two substituents independently selected from hydroxyl, amino , fluoro and unsubstituted C1-C3 alkyl (such as those described in the present invention). In some embodiments of this paragraph, R 'may be a substituted or unsubstituted monocyclic 5- or 6-membered heterocyclyl, for example, pyrrolidine,
[0142] [0142] Examples of a compound of Formula (1) include:
[0143] [0143] Figure 3 provides the chemical names and structures for the examples of the compounds of Formula (1) mentioned above, in which R it is hydrogen or halogen, along with other examples of such compounds. In one embodiment, the compound of Formula (i) is a compound selected from Figure 3, or a pharmaceutically acceptable salt of any of the compounds mentioned in Figure 3. Figures 4A, 4B and 4C provide the chemical names and structures for the examples of the compounds of Formula (1) mentioned above, in which R is X-R%, ha ha ROS or *; along with other examples of such compounds, including those where R 'is any of those previously mentioned for R' except that R 'is not -CH2F, -CHF> or -CF3, and X * and Xº are —-NH- (Figure 4A); those in which R 'is any of the above mentioned options for R', and X * and X º are —-O- (Figure 4B); and those where R 'is -CH2F, -CHF2 or -CF3, and X and X are -NH- (Figure 4C). In one embodiment, the compound of Formula (1) is a compound selected from Figures 3, 4A, 4B and / or 4C, or a pharmaceutically acceptable salt of any of the compounds mentioned in Figures 3, 4A, 4B and / or 4C. In one embodiment, the compound of Formula (1) is a compound selected from Figure 3, or a pharmaceutically acceptable salt of any of the compounds mentioned in Figure 3. In one embodiment, the compound of Formula (1) is a compound selected from Figure 4A, or a pharmaceutically acceptable salt of any of the compounds mentioned in Figure 4A. In one embodiment, the compound of Formula (1) is a compound selected from Figure 4B, or a pharmaceutically acceptable salt of any of the compounds mentioned in Figure 4B. In one embodiment, the compound of Formula (|) is a compound selected from Figure 4C, or a pharmaceutically acceptable salt of any of the compounds mentioned in Figure 4C.
[0144] [0144] In some embodiments, a compound of Formula (1), or a pharmaceutically acceptable salt thereof, may have increased metabolic and / or plasma stability. In some embodiments, a compound of Formula (1), or a pharmaceutically acceptable salt thereof, may be more resistant to hydrolysis and / or more resistant to enzymatic transformations. In some embodiments, a compound of Formula (1), or a pharmaceutically acceptable salt thereof, may have improved properties. A non-limiting list of exemplifying properties includes, but is not limited to, increased biological half-life, greater bioavailability, greater potency, a sustained in vivo response, increased dosing intervals, decreased dosage amounts, reduced toxicity, reduced quantities necessary for the treatment of disease conditions, a reduction in morbidity or mortality in clinical results, reduction or prevention of opportunistic infections, greater adherence of the individual and greater compatibility with other drugs. In some embodiments, a compound of Formula (1), or a pharmaceutically acceptable salt thereof, may have more potent anticancer activity (for example, lower CEs5so in a cell replication assay) compared to the current standard of treatment (such as venetoclax). In some embodiments, a compound of Formula (1), or a pharmaceutically acceptable salt thereof, may have more potent antiviral activity (for example, a lower CEso in an HIV replication assay) compared to the current standard of treatment ( such as dolutegravir). Synthesis
[0145] [0145] The compounds of Formula (l)) or their pharmaceutically acceptable salts, can be produced by those skilled in the art in various ways using known techniques, as detailed in the teachings provided herein. For example, in one embodiment, the compounds of Formula (1) are mutagenized according to the acnral acsamama 1 ennfarmea here mAacíIradao
[0146] [0146] In general, reaction coupling reactions between compounds of General Formulas A and B to form compounds of Formula (1), as illustrated in general scheme 1, can be carried out in a similar manner to the reactions as described in the present invention in the Examples, by properly adjusting the reagents and conditions described in the Examples. Any preliminary reaction steps necessary to form the starting compounds of General Formula A and B, or other precursors, can be performed by persons skilled in the art. In general scheme 1, R1, R2à, Rº R4, Rº and m can be as described here. General scheme 1 nº R $ O, OH O. N
[0147] [0147] Some embodiments described herein refer to a pharmaceutical composition that may include an effective amount of one or more compounds described herein (for example, a compound of Formula (l)) or a pharmaceutically acceptable salt thereof and a carrier , diluent, pharmaceutically acceptable excipient or combination thereof.
[0148] [0148] The term "pharmaceutical composition" refers to a mixture of one or more compounds and / or salts disclosed herein with other chemical components, such as diluents or vehicles. The pharmaceutical composition facilitates the administration of the compound to an organism. The pharmaceutical compositions can also be nihilates in the camnAnSIAS CAM iINnNNrFaAánicas Au ANArnánicas acid hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. The pharmaceutical compositions will generally be adapted to the specific intended route of administration.
[0149] [0149] The term "physiologically acceptable" defines a vehicle, diluent or excipient that does not interrupt the activity and biological properties of the compound, nor cause appreciable damage or injury to an animal to which the application of the composition is intended.
[0150] [0150] For use in the present invention, a "vehicle" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly used vehicle that facilitates the absorption of many organic compounds in an individual's cells or tissues.
[0151] [0151] For use in the present invention, a "diluent" refers to an ingredient in a pharmaceutical composition that has no appreciable pharmacological activity, but may be pharmaceutically necessary or desirable. For example, a diluent can be used to increase the volume of a potent drug whose mass is too small for manufacture and / or administration. It can also be a liquid for dissolving a drug to be administered by injection, ingestion or inhalation. A form of diluent common in the art is a buffered aqueous solution, for example, but without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.
[0152] [0152] For use in the present invention, an "excipient" refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, volume, consistency, stability, binding capacity, lubrication, disintegration capacity, etc. ., to the composition. For example, stabilizers such as antioxidants and metal chelating agents are excipients. In one embodiment, the pharmaceutical composition comprises an antioxidant and / or a metal chelating agent. A "thinner" is a type of excipient.
[0153] [0153] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions in which they are mixed with other active ingredients, such as, for example, in combination therapy, or vehicles, diluents, excipients or combinations of the same. The appropriate formulation depends on the chosen route of administration. Techniques for the formulation and administration of the compounds described herein are known to those skilled in the art.
[0154] [0154] The pharmaceutical compositions disclosed herein can be manufactured in a known manner, for example, by means of conventional mixing, dissolving, granulating, dragee production, levigation, emulsification, encapsulation, trapping or compacting processes. In addition, the active ingredients are contained in an effective amount to achieve their intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein can be supplied as salts with pharmaceutically compatible counterions.
[0155] [0155] There are multiple techniques for administering a compound, salt and / or composition including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral administration, including intramuscular, subcutaneous injections, intravenous, intramedullary, intraperitoneal, intraventricular, intraperitoneal, intranasal and intraocular. In some embodiments, a compound of Formula (Il), or a pharmaceutically acceptable salt thereof, can be administered orally.
[0156] [0156] It is also possible to administer the compound, salt and / or composition in a local and non-systemic way, for example, through injection or implantation of the compound directly in the affected area, often in a sustained release or deposit formulation. In addition, the compound can be administered in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted and absorbed selectively by the organ. For example, the intranasal or pulmonary release to achieve an iA daAraNa eAAnNdAdirão recsniratária nada car daecajiával
[0157] [0157] The compositions can, if desired, be presented in a packaging or dispensing device that can contain one or more unit dosage forms containing the active ingredient. The package may, for example, comprise a metal or plastic sheet, such as a blister-type package. The packaging or dispensing device may be accompanied by instructions for administration. The packaging or dispenser may also be accompanied by a notice associated with the container according to the form suggested by a government agency that regulates the manufacture, use or sale of pharmaceutical products, the notice of which reflects the agency's approval of the form of the drug for human or veterinary administration. Such a warning, for example, may be the U.S. Food and Drug Administration (FDA) approved label for prescription drugs, or the approved package insert. Compositions that may include a compound and / or salt described herein, formulated in a compatible pharmaceutical carrier can also be prepared, placed in a suitable container and labeled for the treatment of an indicated condition. Uses and methods of treatment
[0158] [0158] Some embodiments described herein refer to a method for treating a cancer or tumor described herein that may include administering an effective amount of a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt of the same) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) to an individual who has a cancer described herein. Other embodiments described herein refer to the use of an effective amount of a compound described herein (for example, a compound of Formula (|) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer or tumor described herein. Still other modalities here described refer to 2a 1u1 an aviantiladea aficaz dae 11mMm enmhnAcstiIA aqacuiita dacerita (in the example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition which includes a compound described herein (for example, a compound compound of Formula (1) or a pharmaceutically acceptable salt thereof) to treat a cancer or tumor described herein.
[0159] [0159] Some embodiments described herein refer to a method for inhibiting the replication of a malignant growth or tumor described herein which may include bringing the growth or tumor into contact with an effective amount of a compound described herein (for example, a compound of Formula (II), or a pharmaceutically acceptable salt thereof). Other embodiments described herein refer to the use of an effective amount of a compound described herein (for example, a compound of Formula (Il), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament to inhibit the replication of malignant growth or a tumor described here. In some embodiments, use may include putting the growth or tumor in contact with the drug. Still other embodiments described herein refer to an effective amount of a compound described herein (for example, a compound of Formula (II), or a pharmaceutically acceptable salt thereof) in inhibiting the replication of a malignant growth or a tumor described herein.
[0160] [0160] Some modalities described herein refer to a method for treating a cancer described herein which may include contacting a malignant growth or a tumor, described herein, with an effective amount of a compound described herein (for example, a compound of the Formula (II), or a pharmaceutically acceptable salt thereof). Other embodiments described herein refer to the use of an effective amount of a compound described herein (for example, a compound of Formula (1), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein. In some embodiments, the use may include putting the malignant growth or a tumor described here in contact with the drug. Still other modalities described here refer to an affectionate treatment of a cnmhnAcIN acniuiil decerita (Nor avemnlhoh 11m cenmnncIN da
[0161] [0161] Examples of malignant growths, suitable cancers and tumors include, but are not limited to: bladder cancers, brain cancers, breast cancers, bone marrow cancers, cervical cancers, colorectal cancers, esophageal cancers, hepatocellular cancers , lymphoblastic leukemias, follicular lymphomas, lymphoid malignancies of T-cell or B-cell origin, melanomas, myeloid leukemias, Hodgkin's lymphoma, non-Hodgkin's lymphoma, head and neck cancers (including oral cancers), ovarian cancers, lung cancers of non-small cells, chronic lymphocytic leukemias, myelomas (including multiple myelomas), prostate cancer, small cell lung cancer, spleen cancers, polycythemia vera, thyroid cancers, endometrial cancer, stomach cancers, gallbladder cancer, cancers bile duct, testicular cancers, neuroblastomas, osteosarcomas, Ewing's tumor and Wilms' tumor.
[0162] [0162] As described in the present invention, a malignant growth, cancer or tumor can become resistant to one or more antiproliferative agents. In some embodiments, a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) can be used to treat and / or attenuate malignant growth, cancer or tumor, which has become resistant to one or more antiproliferative agents (such as one or more Bcl-2 inhibitors). Examples of antiproliferative agents that an individual may have developed resistance to include, but are not limited to, Bcl-2 inhibitors (such as venetoclax, navitoclax, obatoclax, S55746, APG-1252, APG-2575 and ABT-737). In some embodiments, the malignant growth, cancer or tumor that has become resistant to one or more antiproliferative agents may be a malignant growth, cancer or tumor described herein.
[0163] [0163] Some embodiments described herein refer to a method for inhibiting Bcl-2 activity which may include administering an effective amount of a compound described herein (for example, a compound of Formula (!), Or a pharmaceutically acceptable salt of the itself) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (|), or a pharmaceutically acceptable salt thereof) to an individual and may also include contacting a cell that expresses Bcl-2 with an effective amount of a compound described herein (for example, a compound of Formula (1), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described in the present invention (for example, a compound of formula (1 ), or a pharmaceutically acceptable salt thereof). Other embodiments described herein refer to the use of an effective amount of a compound described herein (for example, a compound of Formula (1), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament to inhibit Bcl-2 activity. in an individual, or in the manufacture of a drug to inhibit Bcl-2 activity, the use of which includes contacting a cell that expresses Bcl-2. Still other embodiments described herein refer to an effective amount of a compound described herein (for example, a compound of Formula (|), or a pharmaceutically acceptable salt thereof) to inhibit Bcl-2 activity in an individual; or to inhibit Bcl-2 activity by contacting a cell that expresses Bcl-2.
[0164] [0164] Some embodiments described herein refer to a method for relieving and / or treating an infection caused by HIV which may include administering an effective amount of a compound described herein (for example, a compound of Formula (1) or a pharmaceutically salt. acceptable composition thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV latency reversing agent, or a pharmaceutically salt acceptable, to an individual suffering from HIV infection; and also nothing to include in the context of the 11th infarcted caliphil with no HIV in the 11mMm compound described in the present invention (for example, a compound of Formula (1), or a pharmaceutically acceptable salt thereof), and an effective amount of a latency of HIV, or a pharmaceutically acceptable salt thereof. Other embodiments described herein refer to the use of an effective amount of a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament to ameliorate or treat an infection caused by HIV in an individual suffering from HIV infection; or in the manufacture of a drug to improve or treat an infection caused by HIV, the use of which includes putting an HIV-infected cell in contact with the drug. Still other embodiments described herein refer to an effective amount of a compound described herein (for example, a compound of Formula (|) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, to improve or treat an HIV infection in an individual suffering from HIV infection; or to improve or treat an HIV infection by contact of an HIV-infected cell. In some embodiments, the cells can be in an individual. In some embodiments, the cells can be CD4 + T cells. In some embodiments, CD4 + T cells may be in an individual.
[0165] [0165] Some embodiments described herein refer to a method of reducing the population of HIV-infected cells, which may include administering an effective amount of a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt of the same) or a pharmaceutical composition which includes a compound described herein (for example, a ramnnASIA Aa FámrmMula (ND anniuiim cal pharmaraniticamenta acaitával of the same at 11IMmMA the effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, to an individual suffering from HIV infection, and may also include contact of an HIV-infected cell with a compound described in the present invention (for example, a compound of Formula (1), or a pharmaceutically acceptable salt thereof ), and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof. Other modalities described herein refer to the use of an effective amount of a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicine to reduce the population of HIV-infected cells in an individual suffering from infection caused by HIV. HIV; or to reduce the population of cells infected with HIV, the use of which includes putting a cell infected with HIV in contact with the drug. Still other embodiments described herein refer to an effective amount of a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, to reduce the population of HIV-infected cells in an individual suffering from HIV infection; or to reduce the population of HIV-infected cells by contacting an HIV-infected cell. In some embodiments, the cells can be in an individual. In some embodiments, the cells can be CD4 + T cells. In some embodiments, CD4 + T cells may be in an individual.
[0166] [0166] Some of the modalities described here refer to a method of reducing the recurrence of an infection caused by HIV in an individual which may include administering 11ma effective aviantiladea of 11IM96m eAenmnsnceiA aci decerita (nnr eavamnlAeA 11Mm compound of Formula (1) or a salt pharmaceutically acceptable thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV latency reversing agent, or a salt pharmaceutically acceptable product, to an individual suffering from HIV infection; and may also include contact of an HIV-infected cell with a compound described in the present invention (for example, a compound of Formula (1), or a pharmaceutically acceptable salt thereof), and an effective amount of a latency of HIV, or a pharmaceutically acceptable salt thereof. Other embodiments described herein refer to the use of an effective amount of a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicine to reduce the recurrence of an infection caused by HIV in an individual suffering from infection caused by HIV; or to reduce the recurrence of an infection caused by HIV, the use of which includes putting a cell infected with HIV in contact with the drug. Still other embodiments described herein refer to an effective amount of a compound described herein (for example, a compound of Formula (1) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, to reduce the recurrence of an HIV infection in an individual suffering from HIV infection; or to reduce the recurrence of an HIV infection by contacting an HIV-infected cell. In some embodiments, the cells can be in an individual. In some embodiments, the cells can be CD4 + T cells. In some embodiments, CD4 + T cells may be in an individual.
[0167] [0167] Some of the modalities described herein refer to a method to improve or treat an infection caused by HIV which may include administering an affective ammunition to the 11mMm inihbilar nrontaine Rel au im pharmaceutically acceptable, and an effective amount of a reversing agent latency of HIV, or a pharmaceutically acceptable salt thereof, to an individual suffering from HIV infection; and it may also include contacting an HIV-infected cell with a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof. Other embodiments described herein refer to the use of an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, in the making a drug to improve or treat an HIV infection; or in the manufacture of a drug to improve or treat an infection caused by HIV, the use of which includes putting an HIV-infected cell in contact with the drug. Still other embodiments described herein refer to an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, to improve or treating an HIV infection in an individual suffering from HIV infection; or to improve or treat an HIV infection by contact of an HIV-infected cell. In some embodiments, the cells can be in an individual. In some embodiments, the cells can be CD4 + T cells. In some embodiments, CD4 + T cells may be in an individual.
[0168] [0168] Some modalities described herein refer to a method of reducing the population of HIV-infected cells, which may include administering an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of a HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, to an individual suffering from HIV infection; and it may also include contacting an infarcted rally in an HIV 1m inihidhr of the nratain Rel AaumM (mm pharmaceutically acceptable lime thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof. described herein refer to the use of an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug to reduce the population of HIV-infected cells, or in the manufacture of a drug to reduce the population of HIV-infected cells, the use of which includes putting an HIV-infected cell in contact with the drug. described refer to an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, to reduce the population of HIV-infected cells in an individual suffering from HIV infection; or to reduce the population of HIV-infected cells by contacting an HIV-infected cell. In some embodiments, the cells can be in an individual. In some embodiments, the cells can be CD4 + T cells. In some embodiments, CD4 + T cells may be in an individual.
[0169] [0169] Some modalities described herein refer to a method of reducing the recurrence of an infection caused by HIV in an individual which may include administering an effective amount of a compound described herein (for example, a compound of Formula (|) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (|) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, to an individual suffering from HIV infection; and it may also include contacting an HIV-infected cell with an affective avantiladea of an inhaled nretaine Rel qaurim pharmaceutically acceptable lime thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof. Other embodiments described herein refer to the use of an effective amount of a Bol protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, in the manufacture a drug to reduce the recurrence of an HIV infection in an individual suffering from HIV infection; or to reduce the recurrence of an infection caused by HIV, the use of which includes putting a cell infected with HIV in contact with the drug. Still other embodiments described herein refer to an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, to reduce the recurrence of an HIV infection in an individual suffering from HIV infection; or to reduce the recurrence of an HIV infection by contacting an HIV-infected cell. In some embodiments, the cells can be in an individual. In some embodiments, the cells can be CD4 + T cells. In some embodiments, CD4 + T cells may be in an individual.
[0170] [0170] In some embodiments, the HIV latency reversing agent may be a protein kinase C agonist, a PD-1 inhibitor, a PD-L1 inhibitor, an HDAC inhibitor, a phorbol ester or an inhibitor of bromodomain. In some embodiments, the HIV latency reversing agent may be a protein kinase C agonist, which includes, but is not limited to, prostratin, briostatin-1 and ingenol. In some embodiments, the HIV latency reversing agent may be a PD-1 inhibitor, which includes, but is not limited to, nivolumab, pembrolizumab, BGB-A317, pidilizumab, AMP-224, AMP-514, PDROO1, REGN2810 and MEDIO680. In some embodiments, the HIV latency-reversing agent may be a PD-L1 inhibitor, which includes, but is not limited to, atezolizumab, durvalumab, and the evaluation of RMS 0O26EEO. HDAC inhibitor, which includes, but is not limited to, vorinostat, panobinostat, romidepsin and valproic acid. In some embodiments, the HIV latency reversing agent may be a phorbol ester, which includes, but is not limited to, 12-myristate-13-acetate and (S) -tert-butyl-2- (4- (4 - chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-6-yl)> acetate of forbol. In some embodiments, the HIV latency reversing agent may be a bromodomain inhibitor, which includes, but is not limited to, JQ1, | - BET762, OTX015, I-BET151, CPI203, PFI-1, MS436, CPI-0610 , RVX2135, FT-1101, BAY 1238097, INCBO054329, TEN-010, GSK2820151, ZENOO3694, BAY-299, BMS-986158, ABBV-075 and GS-5829. In some embodiments, a combination of two or more HIV latency reversing agents can be used.
[0171] [0171] In some embodiments, the Bcl protein inhibitor of Formula (|) may be a selective inhibitor of Bcl-2, a selective inhibitor of Bcl-X, a selective inhibitor of BcIl-W, a selective inhibitor of Mcl- 1 or a selective inhibitor of Bcl-2A1. In some embodiments, the Bcl protein inhibitor of Formula (1) may inhibit more than one Bcl protein. In some embodiments, the Bcl protein inhibitor may be an inhibitor of Bcl-2 activity and one of Bcl-X ,, Bcl-W, Mcl-1 and Bcl-2A1. In some embodiments, the Bcl protein inhibitor may be an inhibitor of Bcl-X activity, and one of Bcl-W, Mcl-1 and Bcl-2A1. In some embodiments, the Bcl protein inhibitor of Formula (1) can inhibit both Bcl-2 and Bcel-X1. In some embodiments, the Bcl protein inhibitor may be venetoclax, navitoclax, obatoclax, ABT-737, S55746, AT-101, APG-1252, APG-2575, AMG176 or AZD5991, or a combination of any of the previously mentioned.
[0172] [0172] In some embodiments, methods of relieving or treating an HIV infection may also include the use of one or more agents selected from a non-nucleoside reverse transcriptase inhibitor (NNRTI), a nucleoside reverse transcriptase inhibitor (NRTI) , a protease inhibitor (PI), a fusion / entry inhibitor, a tape transfer integrase inhibitor (INSTI), an HIV vaccine, a further antiretroviral taranism against HIV in the environment, or a salt pharmaceutically acceptable from any of the above. In some embodiments, the individual suffering from the infection caused by is not using an agent selected from a non-nucleoside reverse transcriptase inhibitor (NNRTI), a nucleoside reverse transcriptase inhibitor (NRTI), a protease inhibitor (PI), a fusion / entry inhibitor, a tape transfer integrase inhibitor (INSTI), an HIV vaccine, another HIV antiretroviral therapy compound and combinations thereof, or a pharmaceutically acceptable salt of any of the above.
[0173] [0173] Examples of suitable NNRTIs include, but are not limited to, delavirdine (Rescriptor & O), efavirenz (SustivaO), etravirine (IntelenceO), nevirapine (ViramuneO), rilpivirine (EdurantO), doravirine and pharmaceutically acceptable salts of any of those previously mentioned , and / or a combination thereof. Examples of suitable NRTIs include, but are not limited to, abacavir (ZiagenO), adefovir (Hepsera &), amdoxovir, apricitabine, censavudine, didanosine (VidexO), elvucitabine, emtricitabine (Emtriva & O), entecavir (BaracludeO), lamivina) racivir, stampidine, stavudine (Zerit &), tenofovir disoproxil (including VireadO), tenofovir alafenamide, zalcitabine (Hivid & O), zidovudine (Retroviro) and pharmaceutically acceptable salts of any of the above, and / or a combination thereof. Examples of vaccines include, but are not limited to, Heplislav &, ABX-203, INO-1800 and pharmaceutically acceptable salts of any of the above, and / or combinations thereof. Examples of suitable protease inhibitors include, but are not limited to, atazanavir (ReyatazO), darunavir (Prezista &), fosamprenavir (LexivaO), indinavir (CrixivanO), lopinavir / ritonavir (KaletraO), nelfinavir (ViraceptO), ritonavir (Norv) and saquinavir (InviraseO). Examples of suitable fusion / entry inhibitors include, but are not limited to, enfuvirtide (FuzeonO), maraviroc (SelzentryO), vicriviroc, apliviroc, ibalizumab, fostemsavir and PRO-140. Examples of suitable INSTIs include, but are not limited to, raltegravir (IsentressO), dolutegravir (TivicayO) and elvitegravir (VitekaO).
[0174] [0174] Two types of HIV were characterized, HIV-1 and HIV-2. HIV-1 is a more virulent and more infectious strain, and has a global prevalence. HIV-2 is considered less virulent and geographically confined. In some embodiments, an effective amount of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes an effective amount of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, may be effective against HIV-1. In some embodiments, an effective amount of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes an effective amount of a compound of Formula (|), or a pharmaceutically acceptable salt thereof, can be effective against HIV-2. In some embodiments, a compound described herein (for example, a compound of Formula (1), or a pharmaceutically acceptable salt thereof) may be effective in treating both HIV genotypes (HIV-1 and HIV-2).
[0175] [0175] Various indicators for determining the effectiveness of a method for treating an HIV infection are known to those skilled in the art. Examples of suitable indicators include, but are not limited to, a reduction in viral load, a reduction in plasma viral load, a reduction in viral replication, a reduction in time to seroconversion (undetectable virus in the patient's serum), an increase in CD4 + T lymphocyte count, a reduction in the population of HIV-infected cells, a reduction in morbidity or mortality in clinical outcomes and / or a reduction in the rate of opportunistic infections. Similarly, successful therapy with an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (1), or a pharmaceutically acceptable salt thereof) and an effective amount of a reversing agent HIV latency, or a pharmaceutically acceptable salt thereof, can reduce the incidence of opportunistic infections in HIV-infected individuals.
[0176] [0176] In some embodiments, an effective amount of a compound of Formula (|), or a pharmaceutically acceptable salt thereof, is an amount that is effective in reducing the population of CD4 + T lymphocyte cells that harbor HIV to undetectable levels.
[0177] [0177] In some embodiments, an effective amount of a compound of Formula (|), or a pharmaceutically acceptable salt thereof, is an amount that is effective in increasing CD4 + T-cell counts of less than about 200 cells / mL even more than about 1,200 cells / ml. In some embodiments, an effective amount of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, is an amount that is effective in increasing CD4 + T lymphocyte counts from less than about 200 cells / mL to more than than about 500 cells / ml.
[0178] [0178] After a period of time, infectious agents can develop resistance to one or more therapeutic agents. The term "resistance", as used herein, refers to a viral strain that exhibits a delayed, decreased and / or null response to (a) therapeutic agent (s). In some cases, the virus sometimes mutates or produces variations that are resistant or partially resistant to certain drugs. For example, after treatment with an anti-viral agent, the viral load of an individual infected with a resistant virus can be reduced to a lesser degree compared to the amount in viral load reduction experienced by an individual infected with a non-resistant strain. In some embodiments, a compound of Formula (1), or a pharmaceutically acceptable salt thereof, may be supplied to an individual infected with an HIV strain that is resistant to one or more different anti-HIV agents (for example, an agent used in a conventional treatment standard). Examples of anti-HIV agents include, but are not limited to, non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (Pls), fusion / entry inhibitors, integrase inhibitors of ribbon transfer (INSTIs), HIV vaccines and combinations thereof, or pharmaceutically acceptable salts of any of the above.
[0179] [0179] Several known Bcl-2 inhibitors can cause one or more undesirable side effects in the individual being treated.
[0180] [0180] The one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof, which can be used to treat, alleviate and / or inhibit the replication of a cancer, malignant tumor or tumor, in which inhibition of Bcl-2 activity is beneficial, it is provided in any of the modalities described here in the section entitled "Compounds". For example, in various embodiments, the methods and uses described above in the Uses and Treatment Methods section of the present disclosure are performed in the manner described (generally involving cancer, malignant growth and / or tumor) using a compound of Formula (1) in which Rº is hydrogen or halogen, or a pharmaceutically acceptable salt thereof.
[0181] [0181] In other embodiments, the methods and uses described above in the Uses and Treatment Methods section are performed in the manner described (usually involving cancer, malignant growth and / or tumor) using a compound of Formula (1) in which R is X-R%, t t 24 4
[0182] [0182] In other embodiments, the methods and uses described above in the Uses and Treatment Methods section of the present disclosure are carried out in the manner described (generally involving cancer, malignant growth and / or tumor) using a compound of Formula (1) in which Rº is XR *, tt A 7 Nº NNH or +; and in which X 'and X are -NH-.
[0183] [0183] In other modalities, the methods and uses described above in the Uses and Treatment Methods section are performed in the manner described (usually involving cancer, malignant growth and / or tumor) using a compound of Formula (1), in which
[0184] [0184] In other embodiments, the methods and uses described above in the Uses and Treatment Methods section are performed in the manner described (usually involving cancer, malignant growth and / or tumor) using a compound of Formula (1), where R ' is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-Cs alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-Cs cycloalkyl, substituted or unsubstituted C1-Cs alkoxy an unsubstituted C1-Cs monoalkylamine and an unsubstituted C1-Cs dialkylamine; R $ is X-R%, WA t
[0185] [0185] In other embodiments, the methods and uses described above in the Uses and Treatment Methods section are performed in the manner described (usually involving cancer, malignant growth and / or tumor) using a compound of Formula (1) in which R is -CH2F, -CHF2 or -CF3; R is X-R%,
[0186] [0186] The one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof, which can be used to treat and / or alleviate an infection caused by HIV and / or reduce the recurrence of an infection caused by HIV and / or reducing the population of HIV-infected cells, in which inhibition of Bcl-2 activity is beneficial, is provided in any of the modalities described here in the section entitled "Compounds". For example, in various embodiments, the methods and uses described above in the Uses and Treatment Methods section of the present disclosure are carried out in the manner described (generally involving HIV) using a compound of Formula (1) in which R it is hydrogen or halogen, or a pharmaceutically acceptable salt thereof.
[0187] [0187] In other embodiments, the methods and uses described above in the Uses and Treatment Methods section are performed in the manner described (usually involving HIV) using a compound of Formula (1) in which R is X-R%, RN t x x
[0188] [0188] In other embodiments, the methods and uses described above in the Uses and Treatment Methods section of the present disclosure are carried out in the manner described (usually involving HIV) using a compound of Formula (1) in which R is XR%, Ns te where X 'and X are -NH-.
[0189] [0189] In other modalities, the methods and uses described above in the Uses and Treatment Methods section are performed in the manner described (usually involving HIV) using a compound of Formula (1), where R 'is selected from the group consisting of hydrogen , halogen, substituted or unsubstituted C1-Cs alkyl, substituted or unsubstituted C1-Cs haloalkyl, substituted or unsubstituted C3-Cs cycloalkyl, substituted or unsubstituted C1-Cs alkoxy, C1-Cs monoalkylamine; unsubstituted and an unsubstituted C1-Cs dialkylamine, with the proviso that R 'is not -CH2F, -CHF2 or -CF3; Rº is X-R% , ha to ROS or *; eX 'and Xº are -NH-.
[0190] [0190] In other embodiments, the methods and uses described above in the Uses and Treatment Methods section are performed in the manner described (usually involving HIV) using a compound of Formula (1) in which R is X-R%, ha Ni ao or *; and in which X 'and X are the-.
[0191] [0191] In other embodiments, the methods and uses described above in the Uses and Treatment Methods section are performed in the manner described (usually involving HIV) using a compound of Formula (1) in which R * is -CH2F, -CHF2 or - CF3; Rº is X-R , No * ROS or *;
[0192] [0192] For use in the present invention, an "individual" refers to an animal that is the object of treatment, observation or experiment. "Animal" includes cold and warm-blooded invertebrates and vertebrates, such as fish, molluscs, reptiles and, in particular, mammals. "Mammalian" includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates such as monkeys, chimpanzees and monkeys, and, in particular, humans. In some embodiments, the individual may be human. In some modalities, the individual may be a child and / or a baby, for example, a child or baby with a fever. In other modalities, the individual may be an adult.
[0193] [0193] As used here, the terms "treat", "treatment", "treating", "therapeutic," and "therapy" do not necessarily mean the total cure or suppression of the disease or condition. Any relief from any unwanted signs or symptoms of the disease or condition, to any extent, can be considered treatment and / or therapy. In addition, treatment may include actions that can worsen the overall feeling of well-being or the appearance of the patient.
[0194] [0194] The terms "therapeutically effective amount" and "effective amount" are used to indicate an amount of an active compound, or pharmaceutical agent, that induces the indicated biological or medicinal response. For example, a therapeutically effective amount of compound, salt or composition may be the amount necessary to treat, alleviate or alleviate one or more symptoms of the disease or condition, or to prolong the survival of the individual being treated. This response can occur in a tissue, a system, an animal or a human being, and includes relief from the signs or symptoms of the disease or condition being treated. The determination of an effective amount is well within the ability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds presented here required as a dose will depend on the route of administration, the type of animal, including humans, being treated, and the physical characteristics Adao animal acnacrífica canda cenncsidaradoe A decae is not going to be alleviated with caAmAbhtar 11mMmMm desired effect, but will depend on factors such as weight, diet, concomitant medication and other factors that will be recognized by those skilled in the art.
[0195] [0195] For example, an effective amount of a compound is the amount that results in: (a) the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, (b) the reduction in the size of the tumor, (c ) tumor elimination, and / or (d) long-term disease stabilization (growth arrest) of the tumor. In the treatment of lung cancer (such as non-small cell lung cancer) a therapeutically effective amount is the amount that relieves or eliminates cough, shortness of breath and / or pain. As another example, an effective amount, or a therapeutically effective amount, of a Bcl-2 inhibitor, is the amount that results in a reduction in Bcl-2 activity and / or an increase in apoptosis. The reduction in Bcl-2 activity is known to those skilled in the art and can be determined by analyzing the binding of Bcl-2 and the relative levels of cells undergoing apoptosis.
[0196] [0196] The amount of the compound of Formula (1), or a pharmaceutically acceptable salt thereof, which is required for use in the treatment will vary not only with the specific compound or salt selected, but also with the route of administration, the nature and / or the symptoms of the disease or condition being treated and the age and condition of the patient and will ultimately be selected according to the decision of the attending physician or clinician. In cases of administration of a pharmaceutically acceptable salt, dosages can be calculated as the free base. As will be understood by those skilled in the art, in certain situations, it may be necessary to administer the compounds disclosed in the present invention in amounts that exceed, or even greatly exceed, the dosage ranges described herein for the purpose of effectively and aggressively treating diseases or conditions particularly aggressive.
[0197] [0197] In general, however, an adequate dose will often be in the range of about 0.05 mg / kg to about 10 mg / kg. For example, an appropriate dose may be in the range of about 0.10 mg / kg to about 7.5 mg / kg of body weight per day, ramMA Crarca de 0 18 mall the E ON ma / ko de nasa around 0.2 mg / kg to 4.0 mg / kg body weight of the recipient per day, or any intermediate amount. The compound can be administered in unit dosage form; for example, containing from 1 to 500 mg, 10 to 100 mg, 5 to 50 mg or any intermediate amount, of active ingredient per unit dosage form.
[0198] [0198] The desired dose can be conveniently presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself can be further divided, for example, into several distinctly spaced administrations.
[0199] [0199] As will be readily apparent to the person skilled in the art, the live dosage useful to be administered and the particular mode of administration will vary depending on the age, weight, severity of the disease, the species of mammal being treated, the specific compounds employed , and the specific use for which these compounds are used. The determination of effective dosage levels, that is, the dosage levels necessary to achieve the desired result, can be performed by a person skilled in the art using routine methods, for example, clinical tests on humans, in vivo studies and in vitro studies. For example, the useful dosages of a compound of Formula (1) or its pharmaceutically acceptable salts, can be determined by comparing its in vitro activity and its in vivo activity in animal models. Such a comparison can be made by comparing it to an established drug, such as cisplatin and / or gemcitabine)
[0200] [0200] The amount and dosage range can be individually adjusted to provide plasma levels of the active portion that are sufficient to maintain the effects of modulation, or minimum effective concentration (MEC). The MEC will vary for each compound, but can be estimated from data in vivo and / or in vitro. The dosages required to achieve ECM will depend on individual characteristics and the route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Rest intervals can also be determined in 6 uen of MEC Asc compositions should be administered using a regimen that maintains plasma levels above MEC for 10 to 90% of the time, preferably between 30 to 90% and with maximum preference, between 50 to 90%. In cases of local administration or selective absorption, the effective local concentration of the drug may not be related to the plasma concentration.
[0201] [0201] It should be noted that the responsible physician knows how and when to end, stop or adjust the administration due to toxicity or organ dysfunction. Conversely, the physician in charge also knows how to adjust treatment to higher levels if the clinical response is not adequate (excluding toxicity). The magnitude of a dose administered to treat the disorder of interest varies with the severity of the disease or condition being treated and the route of administration. The severity of the disease or condition can, for example, be assessed, in part, by standard methods of assessing prognosis. In addition, the dose and perhaps the frequency of administration will also vary according to the age, body weight and response of the individual patient. A program comparable to the one discussed above can be used in veterinary medicine.
[0202] [0202] The compounds, salts and compositions shown in the present invention can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a specific compound, or a subset of the compounds, sharing certain chemical moieties, can be established by determining in vitro toxicity to a cell line, such as a mammalian cell line and, preferably, human. The results of these studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, dogs or monkeys, can be determined using known methods. The efficacy of a specific compound can be established with the use of several recognized methods, such as in vitro methods, animal models or clinical tests on human beings. Calarinnhnar a Madalena nara detarminar 2nd afircária n varcadao in the art can be guided by the state of the art choose an appropriate model, dose, route of administration and / or regimen. Examples
[0203] [0203] Additional modalities are presented in more detail in the following examples, which are in no way intended to limit the scope of the claims. Intermediate 1 3-Chloro-N-methoxy-N-methylbicyclo [1,1,1] pentane-1-carboxamide o Ao
[0204] [0204] To a stirred solution of 3-chlorobicyclo [1,1,1] pentane-1-carboxylate (10.0 g, 62.3 mmol) and N, O-dimethylhydroxylamine hydrochloride (12.15 g, 124.5 mmol) in anhydrous THF (200 mL) at -78 ° C i-PrMgCIl (2 Mem THF, 124.5 mL, 249 mmol) was added. The temperature was then raised to -50 ºC and stirred for 2 hours. The reaction was brusquely cooled with saturated aqueous NH.CI solution and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with water, brine, dried with Na> 2SO:, filtered and concentrated. The Crude product was purified by column chromatography (SiO> 2, EtOAc / petroleumether) to produce Intermediate 1 (7.30 g, 62%) as an oil. 1 H NMR (300 MHz, CDCl 3) 5 3.67 (s, 3H), 3.18 (s, 3H), 2.47 (s, 6H). Intermediate 2 2- tert-butyl ox O. 2- (1H-pyrrolo [2,3-b] pyridin-S5-yloxy) -4- (piperazin-1-yl) benzoate
[0205] [0205] A solution of tert-butyl 2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -4-fluorobenzoate (3.5 g, 10.67 mmol) in DMSO (35 mL) it was treated with piperazine (2.33 ml, 32.0 mmol) at room temperature and stirred at 100 ° C for 4 h. The reaction was cooled to room temperature and water (50 ml) was added. The mixture was extracted with EtOAc (3 x 50 ml) and the organic layers were concentrated and ground with n-pentane to produce Intermediate 2 (3.0 g, 71%) as a white solid. LC / MS (ESI) m / z 395.5 [M + H] *. Intermediate 3 4- (2-oxaspiro [3,3] heptan-6-ylmethylamino) -3-nitrobenzenesulfonamide NO, ed “%
[0206] [0206] A solution of 4-chloro-3-nitrobenzenesulfonamide (200 mg, 0.85 mmol) in CH3CN (8 mL) was treated with (2-oxaspiro [3.3] heptan-6-yl) methanamine (129 mg , 1.01 mmol) and DIPEA (0.5 mL 2.95 mmol). The mixture was heated to 90 ° C and stirred for 16 hours. The reaction was cooled to room temperature, diluted with EtOAc and washed with water and brine. The organic layer was dried with Na> 2SO2 ;, filtered and concentrated. The Crude product was purified by column chromatography (SiO> 2, EtOAc / hexanes) to produce Intermediate 3 (120 mg, 43%) as a yellow solid. NMR * H (400 MHz, DMSO-d6s) 5 8.47-8.43 (m, 2H), 7.83-7.80 (m, 1H), 7.30 (br s, 2H), 7, 22 (d, J = 9.6 Hz, 1H), 4.56 (s, 2H), 4.49 (s, 2H), 3.42-3.38 (m, 2H), 2.45-2 , 39 (m, 1H), 2.33-2.27 (m, 2H), 1.99-1.94 (m, 2H). Intermediate 4 4- (2- (2-0xa-8-azaspiro [4,5] decan-8 & -yl) ethylamino) -3-nitrobenzenesulfonamide q
[0207] [0207] Step 1: A solution of 2-0xa-8-azaspiro hydrochloride [4,5] decane (500 mg, 2.81 mmol) in CH3CN (20 mL) was treated with tert-butyl 2-bromoethylcarbamate ( 700 mg, 3.12 mmol) and K2CO; (1.55 g, 11.24 mmol) and heated to 80 ° C for 16 hours. The reaction was concentrated, diluted with water (20 ml) and extracted with EtOAc (3 x ml). The combined organic layers were dried over Na> SOO: filtered and concentrated. The residue was purified by column chromatography (SiO>, EtOAc / petroleum ether) to produce tert-butyl 2- (2-0xa-8-azaspiro [4,5] decan - & - yl) ethylcarbamate (Intermediate 4- 1) (500 mg, 62%) as an oil. NMR * H (300 MHz, DMSO-ds) 5 6.62 (br s, 1H), 3.70 (t, J = 6.9 Hz, 2H), 3.40 (s, 2H), 3.04 -2.98 (m, 2H), 2.40-2.25 (m, 4H), 1.64 (t, J = 7.5 Hz, 2H), 1.56-1.40 (m, 4H ), 1.37 (s, 9H), 1.24 (s, 2H).
[0208] [0208] Step 2: To a stirred solution of Intermediate 4-1 (500 mg, 1.76 mmol) in DCM (20 mL) was added HCI (4 M in dioxane, 10 mL) at 0 ° C. The reaction was warmed to room temperature, concentrated and ground with Et2O to produce 2- (2-0xa-8-azaspiro [4.5] decan-8-i) ethanamine dihydrochloride (intermediate 4-2) (300 mg, 66% ) as an off-white solid that was used in the next step without further purification. NMR * H (300 MHz, DMSO-ds) 5 10.84 (br s, 1H), 8.38 (br s, 3H), 3.85-3.70 (m, 2H), 3.59-3 , 40 (m, 8H), 3.12-2.90 (m, 2H), 2.05-1.60 (m, 6H).
[0209] [0209] Step 3: A solution of Intermediate 4-2 (300 mg, 1.17 mmol) in CH3CN (15 mL) was treated with 4-chloro-3-nitrobenzenesulfonamide (276 mg, 1.17 mmol) followed by DIPEA (0.82 mL, 4.68 mmol) and then heated to 80 ° C. After 16 h, the reaction was cooled to room temperature and concentrated. The crude product was purified by column chromatography (SiOz, MeOH (0.1% triethylamine) / DCM) to produce Intermediate 4 (300 mg, 66%) as a yellow solid. LC / MS (ESI) m / z 385.3 [M + H] *. Intermediate 5 2- (7-0xa-2-azaspiro [3,5] nonan-2-yl) ethanamine dihydrochloride
[0210] [0210] Step 1: 2- (7-Oxa-2-azaspiro [3,5] nonan-2-yl) tert-butyl ethyl carbamate (Intermediate 5-1) was prepared according to the procedure described in Step 1 for o Intermediate 4 using 7-0xa-2-azaspiro [3,5] hemioxalic nonane in place of 2-0xa-8-azaspiro hydrochloride [4,5] decane NMR * H (300 MHz, DMSO-d6) 5 6 , 94 (br s, 1H), 3.74 (br s, 4H), 3.51-3.42 (m, 4H), 3.10 (br s, 4H), 1.76 (br s, 4H ), 1.39 (s, 9H).
[0211] [0211] Step 2: 2- (7-0xa-2-azaspiro [3,5] nonan-2-yl) ethanamine dihydrochloride (Intermediate 5-2) was prepared according to the procedure described in Step 2 for Intermediate 4 using Intermediate 5-1 in place of Intermediate 4-1. NMR * H (300 MHz, DMSO-d6) 5 11.42 (br s, 1H), 8.3 (br s, 3H), 4.05-3.99 (m, 2H), 3.92-3 , 86 (m, 2H), 3.57-3.54 (m, 4H), 3.49-3.40 (m, 4H), 3.10-3.05 (m, 2H), 1.88 (br s, 2H), 1.72 (br s, 2H).
[0212] [0212] Step 3: A solution of Intermediate 5-2 (250 mg, 1.03 mmol) in CH3CN (13 mL) was treated with 4-chloro-3-nitrobenzenesulfonamide (226.8 mg, 1.08 mmol) followed triethylamine (0.58 mL, 4.12 mmol) at room temperature. After 16 hours, the reaction was concentrated to produce the crude product, which was purified by column chromatography (SiO2, MeOH (containing NH; 3 7N / DCM) to obtain Intermediate 5 (200 mg, 52%) as a yellow solid LC / MS (ESI) m / z 371.3 [M + H] *. Intermediate 6 4- (7-Oxaspiro [3,5] nonan-2-yl-methylamino) -3-nitrobenzenesulfonamide NH7 walnut Ox,
[0213] [0213] A solution of 7-oxaspiro [3.5] nonan-2-yl-methanamine (100 mg, 0.64 mmol) in THF (2 mL) was treated with 4-fluoro-3-nitrobenzenesulfonamide (157.6 After 16 hours, the reaction was concentrated and the residue was purified by column chromatography (SiO2, MeOH / DCM) to produce Intermediate 6 (126 mg, 55%) as a yellow solid. LC / MS (ES!) m / z 356.1 [M + H] * Intermediate 7 4 - ((4-0xaspiro [2,4] heptan-6-yl) oxy) -3-nitrobenzenesulfonamide os O is
[0214] [0214] Step 1: To a stirred solution of 1- (3-hydroxy-2- (tetrahydro-2H-pyran-2-yloxy) propyl) cyclopropanol (prepared according to CN106565706) and triphenyl phosphine (9.10 g, 34.7 mmol) in THF (50 mL), diethyl azodicarboxylate (DEAD) (5.44 mL, 34.7 mmol) was added by dropping at room temperature. After 16 hours, the reaction mixture was quenched with H2O (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with water (50 ml), dried over Na2SO2, and concentrated. The crude product was purified by column chromatography (SiO2, EtOAc / petroleum ether) to obtain 6- (tetrahydro-2H-pyran-2-yloxy) -4-oxaspiro [2.4] heptane (Intermediate 7-1) ( 3.2 g, 69% yield) as a clear yellow oil. 1 H NMR (400 MHz, CDCl 3) 5 4.65-4.63 (m, 1H), 4.59-4.56 (m, 1H), 4.02-3.85 (m, 3H), 3.53-3.48 (m, 1H), 2.25-1.95 (m, 2H), 1.89-1.76 (m, 1H), 1.72-1.68 (m, 1H ), 1.62-1.49 (m, 4H), 0.92-0.89 (m, 1H), 0.81-0.75 (m, 1H), 0.65-0.53 (m , 1H), 0.48-0.39 (m, 1H).
[0215] [0215] Step 2: To a stirred solution of Intermediate 7-1 (3.2 g, 16.1 mmol) in MeOH (32 ml) was added pyridinium p-toluenesulfonate (811 mg, 3.23 mmol) and it was stirred at 40 ° C for 5 h. The reaction mixture was concentrated, and the residue was purified by column chromatography (SiO>, EtOAc / petroleum ether) to obtain 4-oxaspiro [2.4] heptane-6-ol (Intermediate 7-2) (1, 0 g, 54% yield) as a colorless oil. GC / MS m / z 114.1 [M] *.
[0216] [0216] Step 3: To a stirred solution of Intermediate 7-2, sodium hydride (63% oil dispersion, 1.05 g, 26.3 mmol) was added at 0 ° C. After 30 minutes, a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.92 g, 8.76 mmol) in THF (5 mL) was added dropwise at 0 ° C. The reaction was warmed to room temperature and stirred for 6 h. The reaction was cooled to 0 ° C and brusquely cooled with saturated aqueous NH 4CI solution and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO2, and concentrated. The residue was triturated with Et2O and n-pentane to produce Intermediate 7 (700 mg, 25% yield) as a white solid. LC / MS (ESI) m / z 313.0 [M-HT. Intermediate 8 4- (2- (2-Oxa-6-azaspiro [3,3] heptan-6-yl) ethoxy) -3-nitrobenzenesulfonamide o, node% DAS
[0217] [0217] Intermediate 8 was prepared according to the procedure described in Step 3 for Intermediate 7, using 2- (2-0xa-6-azaspiro [3.3] heptan-6- yl) ethanol instead Intermediate 7-2. LC-MS (ESI) m / z 344.2 [M + H] *. Intermediate 9 4- (2-oxaspiro [3,3] heptan-6-ylmethoxy) -3-nitrobenzenesulfonamide only
[0218] [0218] Intermediate 9 was prepared according to the procedure described in Step 3 for the synthesis of Intermediate 7, using 2-oxaspiro [3,3] heptan-6-ylmethanol instead of Intermediate 7-2. LC-MS (ESI) m / z 327.4 [M-H].
[0219] [0219] To a stirred solution of 3-methylbicyclo [1,1,1] pentane-1-carboxylic acid (3 g, 23.8 mmol) in DCM (100 mL) was added N, O-dimethylhydroxylamine hydrochloride (3.48 g, 35.7 mmol) and EtaN (11.6 mL, 83.2 mmol) at room temperature. The mixture was then cooled to 0 ° C and T3P (50 wt% EtOAc, 6.43 g, 40.4 mmol) was added by dropping, and the reaction was warmed to room temperature. After 16 hours, the reaction was quenched with water (100 ml) and extracted with DCM (3 x 100 ml). The combined organic layers were dried over Na> zSO ;, filtered and concentrated. The residue was purified by chromatography (SiO2, EtOAc / petroleum ether) to produce Intermediate 10 as an oil (2.5 g, 62% yield). 1 H NMR (300 MHz, CDCl 3) 5 3.65 (s, 3H), 3.17 (s, 3H), 1.98 (s, 6 H), 1.18 (s, 3H). Intermediate 11 3-Fluoro-N-methoxy-N-methylbicyclo [1,1,1] pentane-1-carboxamide o
[0220] [0220] Intermediate 11 was prepared according to the procedure described for the synthesis of Intermediate 10 using 3-fluorobicyclo [1,1,1] pentane-1-carboxylic acid in place of 3-methylbicyclo acid [1,1,1 ] pentane-1-carboxylic. LC / MS (ESI) m / z 174.3 [M + H] *. Intermediate 12 3-Isopropyl-N-methoxy-N-methylbicyclo [1,1,1] pentane-1-carboxamide o YO /
[0221] [0221] Intermediate 12 was prepared according to the procedure described for the synthesis of Intermediate 10 using 3-isopropylbicyclo [1,1,1] pentane-1-carboxylic acid in place of 3-methylbicyclo acid [1,1,1 ] pentane-1-carboxylic. LC / MS (ESI) m / z 198.4 [M + H] *. Intermediate 13 3- (1 1-Difluoroethyl) - N-methoxy-N-methylbicyclo [1,1,1] pentane-1-carboxamide q
[0222] [0222] Step 1: To a stirred solution of 3- (methoxycarbonyl) bicyclo [1,1,1] pentane-1-carboxylic acid (10 g, 58.8 mmol), N, O-dimethylhydroxylamine hydrochloride ( 6.88 g, 42.4 mmol) and triethylamine (12.3 mL, 176.4 mmol) in DCM (200 mL) at 0 ° C T3P (50% solution in EtOAc, 18.8 g, 58, 8 mmol). The resulting reaction mixture was warmed to room temperature for 16 hours. The reaction mixture was quenched with water (250 ml) and extracted with DCM (3 x 250 ml). The combined organic layers were dried over Na2SO2, and concentrated. The Crude product was purified by column chromatography (SiO> 2, EtOAc / petroleum ether) to produce methyl 3- (methoxy (methyl) carbamoyl) bicyclo [1,1,1] pentane-1-carboxylate (Intermediate 13- 1) (9.5 g, 76% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3) 5 3.69 (s, 3H), 3.68 (s, 3H), 3.19 (s, 3H), 2.38 (s, 6H).
[0223] [0223] Step 2: To a stirred solution of Intermediate 13-1 (5 g, 23.5 mmol) in THF (100 mL) at -78 ° C was added MeMgBr (3M in Et2O, 31.3 mL, 93.8 mmol). After stirring for 2 h at -78 ºC, the reaction was quenched with
[0224] [0224] Step 3: A solution of Intermediate 13-2 (2.3 g, 13.6 mmol) in DCM (50 mL) at -78 ° C was added, dripping, DAST (6.62 g, 41.0 mmol). After the addition, the temperature was raised to room temperature. After 16 hours, the reaction mixture was cooled to -78 ° C and carefully cooled with saturated aqueous NaHCO solution; (100ml). The mixture was extracted with DCM (3 x 100 ml) and the combined organic layers were dried over Na2SO2, filtered and concentrated. The crude product was purified by column chromatography (SiO>, EtOAc / petroleum ether) to produce methyl 3- (1,1-difluoroethyl) bicyclo [1,1,1] pentane-1-carboxylate (Intermediate 13- 1) (1.8 9, 69% yield) as a clear oil. NMR * H (400 MHz, CDCIs) 5 3.70 (s, 3H), 2.12 (s, 6H), 1.55 (t, J = 18.0 Hz, 3H).
[0225] [0225] Step 4: To a stirred solution of Intermediate 13-3 (1.8 g, 9.46 mmol) and N, O-dimethylhydroxylamine hydrochloride (0.923 g, 9.46 mmol) in anhydrous THF (40 ml) at -78 ° C i-PrMgCl (2M in THF, 18.9 ml, 37.8 mmol) was added. The reaction mixture was heated to -50 ° C and stirred for 2 h. The reaction mixture was quenched with saturated aqueous NHLCI solution (50 ml) and extracted with EtOAc (3 x 75 ml). The combined organic layers were dried over Na> 2SOs, filtered and concentrated. The crude product was purified by column chromatography (SiO>, EtOAc / petroleum ether) to produce Intermediate 13 (1.79, 82%) as a clear oil. LC / MS (ESI) m / z 220.4 [M + H] *. Intermediate 14 4- [I (1-methyl-4-piperidinyl) methylJamino] -3-nitrobenzenesulfonamide so Manso
[0226] [0226] The solution of (1-methylpiperidin-4-yl) netanamine (1 g, 7.80 mmol) in THF (75 mL), 4-fluoro-3-nitrobenzenesulfonamide (1.71 g, 7.80 mmol) followed by triethylamine (3.15 g, 31.2 mmol) and the reaction was stirred at room temperature. After 16 hours, the reaction was concentrated, diluted with water (50 ml) and extracted with 10% MeOH in DCM (3 x 50 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (C18, HCO> 2H (aq.) 0.1% / MeCN) to obtain 650 mg of 4 - ((1-methylpiperidin-4-yl) methylamino) -3-nitrobenzenesulfonamide as formate salt. The compound was dissolved in 10% MeOH in DCM (50 ml) and washed with saturated aqueous NaHCO solution. The organic layer was dried with Na2SOA4, filtered and concentrated to yield Intermediate 14 as a yellow solid (510 mg, 20% yield). LC / MS (ESI) m / z 329.2 [M + H] *. Intermediate 15 4 - ((((4-Fluoro-1-methylpiperidin-4-yl) methyl) amino) -3-nitrobenzenesulfonamide NO, nO
[0227] [0227] Step 1: To a stirred solution of tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate (2.00 g, 8.61 mmol) in THF (30 mL), was added 4- fluoro-3-nitrobenzenesulfonamide (2.08 g, 9.47 mmol) followed by triethylamine (4.8 mL, 34.45 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction was then concentrated, and the resulting residue was diluted with 10% MeOH-DCM (50 ml) and washed with ice water (5 x 50 ml). The organic layer was dried with Na2SO4: filtered and concentrated. The crude product was purified by trituration with Et2O to produce tert-butyl 4-fluoro-4 - (((2-nitro-4-sulfamoylphenyl) amino) methyl) piperidine-1-carboxylate (Intermediate 18E-1) (1 REA 42% yield) 1 C / MS (APCD m / 7 2323 10 IM = CeHIOS + H1IF
[0228] [0228] Step 2: To a stirred solution of Intermediate 15-1 (1.6 g, 3.70 mmol) in 1,4-dioxane (10 mL) at 0 ° C was added HCI (4 M HCl in 1.4 -dioxane, 20 mL). The reaction was warmed to room temperature and stirred for 6 hours. The reaction was concentrated and triturated with Et2O to produce 4 - ((((4-fluoropiperidin-4-yl) methyl) amino) -3-nitrobenzenesulfonamide hydrochloride (Intermediate 15-2) (1.3 g, 96%) as a yellow solid. LC / MS (ESI) m / z 333.1 [Ci2H17FN1404S + H] *.
[0229] [0229] Step 3: To a stirred solution of Intermediate 15-2 (430 mg, 1.35 mmol) in MeOH (15 mL) was added paraformaldehyde (81 mg, 2.71 mmol) at 0 ° C. After 15 minutes, NACNBH; 3 (128 mg, 2.03 mmol) was added and the reaction was warmed to room temperature. After 18 h, the REACTION was brusquely cooled with saturated aqueous solution of NAHCO; (15 ml) and the reaction was extracted with DCM (3 x 100 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was triturated with Et2O, followed by EtOAc / hexane 1: 1 to produce Intermediate 15 (340 mg, 25% yield) as a yellow solid. LC / MS (ESI) m / z 347.1 [M + H] *. Intermediate 16 4 - (((1r, 4r) -4- (dimethylamino) cyclohexyl)> amino) -3-nitrobenzenesulfonamide
[0230] [0230] To a stirred solution of trans-N ', N'-dimethylcyclohexane-1,4-diamino dihydrochloride (350 mg, 1.39 mmol) in THF (10 mL) was added 4-fluoro-3- nitrobenzenesulfonamide (322 mg, 1.39 mmol) followed by triethylamine (844 mg, 8.34 mmol). After stirring for 16 h at room temperature, the reaction was concentrated and triturated with EtOAc and Etr2O to produce the crude product. The product was further purified by HPLC (75:25 to 1:99 NH.OAc (aq): CH3CN) 10 mM to provide Intermediate 16 as a yellow solid. LC / MS (ESI) m / z 343.1 [M + H] *.
[0231] [0231] To the stirred solution of (4-methylmorpholin-2-yl) methanamine (400 mg, 3.07 mmol) in THF (25 mL) was added 4-fluoro-3-nitrobenzenesulfonamide (609 mg, 2.76 mmol) followed by triethylamine (1.24 g, 12.28 mmol). After mixing at room temperature for 16 h, the reaction was concentrated and the resulting crude was diluted with 10% MeOH-DCM (50 ml) and washed with ice water (3 x 50 ml). The organic layer was dried over Na2SO2, filtered and concentrated. The crude product was triturated with Et2O / pentane to produce Intermediate 17 (600 mg, 65% yield) as a yellow solid. LC / MS (ESI) m / z 331.2 [M + H] *. Intermediate 17A (R) -4 - ((((4-methylmorpholin-2-yl) methyl) amino) -3-nitrobenzenesulfonamide “" &%
[0232] [0232] 4 - ((4-Methylmorpholin-2-yl) methylamino) -3-nitrobenzenesulfonamide racemic (400 mg) was subjected to separation by chiral SFC (Chiralpak AD-H column (250 x 30 mm), 5 yu, 30 % MeOH) to produce 4 - ((4-methylmorpholin-2-iNmethylamino) -3-nitrobenzenesulfonamide (160 mg) as the first peak eluted (RT = 3.06 min) with 99.6% ee. LC / MS ( ESI) m / z 331.2 [M + H] *. The absolute stereochemistry was arbitrarily attributed to Intermediate 17A. Intermediate 17B (S) -4 - ((((4-methylmorpholin-2-yl)] methyl) amino) - 3-nitrobenzenesulfonamide
[0233] [0233] 4 - ((4-Methylmorpholin-2-yl) methylamino) -3-nitrobenzenesulfonamide racemic (400 mg) was subjected to separation by chiral SFC (Chiralpak AD-H column (250 x 30 mm), 5 yu, 30 % MeOH) to produce 4 - ((4-methylmorpholin-2-iN) methylamino) -3-nitrobenzenesulfonamide (150 mg) as the second peak eluted (RT = 3.64 min) with 99.8% ee. LC / MS (ESI) m / z 331.2 [M + H] *. Absolute stereochemistry was arbitrarily attributed to Intermediate 17B. Intermediate 18 4 - (((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrobenzenesulfonamide o A
[0234] [0234] Intermediate 18 was prepared following a procedure described in WO2014 / 165044A1. LC / MS (ESI) m / z 344.1 [M + H] *. Intermediate 19 2- (Dietoxymethyl) -5,5-dimethylcyclohexan-1-one OEt
[0235] [0235] To a solution of triethyl orthoformate (1.32 L, 7.923 mol) in DCM (8.0 L) at -30 ºC was added BF3-OEt2 (1.244 L, 9.9 mmol) by dripping for 30 minutes . The reaction mixture was heated to 0 ºC and stirred for 30 minutes. The reaction mixture was then cooled to -78 ºC and 3.3 dimethylcyclohexanone (500 g, 3.96 mol) and N, N-diisopropylethylamine (2.08 L, 11.9 mmol) were added by dripping and the reaction was stirred for 2 h at the same temperature. The reaction was then carefully poured into a mixture of saturated aqueous NaHCO solution; (25 L) and DCM (10 L). The resulting mixture was stirred for 15 min at room temperature and the organic layer was separated. The aqueous layer was extracted with DCM (2 x 10 L) and the combined organic layers were washed with 10% NaCl (aq.) Solution (5 L), dried with Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (SiO> 2, EtOAc / petroleum ether) to produce Intermediate 19 (750 g, 83%) as a pale yellow oil. NMR * H (400 MHz, CDCl3) 5 4.83 (d, J = 6.0 Hz, 1H), 3.73-3.57 (m, 4H), 2.56-2.53 (m, 1H ), 2.20-2.14 (m, 2H), 2.11 - 2.10 (m, 1H), 1.81 (m, 1H), 1.62-1.56 (m, 2H), 1.21 - 1.17 (m, 6H), 1.01 (s, 3H), 0.91 (s, 3H). Intermediate 20 Benzyl 2-Bromo-4 4-dimethylcyclohex-1-ene-1-carboxylate STO
[0236] [0236] Step 1: A solution of NaCIO> (11.08 g, 122.5 mmol) in water (100 mL) was added dropwise to a stirred mixture of 2-bromo-4,4-dimethylcyclohex- 1-ene-1-carbaldehyde (19 g, 87.5 mmol), CH3CN (100 mL), NaH2PO, (2.72 g, 22.75 mmol), water (40 mL) and 30% H2O02 (aq.) (15 mL) at 10 ° C. After completion, the reaction was poured into a saturated aqueous solution of Na2CO; (200 ml) and washed with Et2O (200 ml). The aqueous phase was poured into 1N HCl solution (500 ml) and extracted with Et2O (3 x 200 ml). The combined organic layers were dried with Na> SO ;, filtered and concentrated. The crude compound was further washed with water and dried to obtain 2-bromo +, 4-dimethylcyclohex-1-ene-1-carboxylic acid (Intermediate 20-1) (15 gq, 73% yield) as a white solid. LC / MS (ESI) m / z 231.0 [M-H].
[0237] [0237] Step 2: To a stirred solution of Intermediate 20-1 (10 g, 42.9 mmol) in DMF (100 mL) was added K2CO; 3 (17.79 g, 128.7 mmol), followed by bromide benzyl (14.67 g, 85.8 mmol) at 0 ºC, and the reaction was heated until extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (3 x 200 ml), dried over Na> 2SO:, filtered and concentrated. The crude product was purified by column chromatography (SiO>, EtOAc / petroleum ether) to produce Intermediate 20 (11 g, 79% yield) as a colorless oil. NMR * H (400 MHz, CDCl3) 5 7.43-7.32 (m, 5H), 5.22 (s, 2H), 2.45-2.38 (m, 4H), 1.44 (t , J = 5.6 Hz, 2H), 0.97 (s, 6H); GC / MS m / z 322.1 [M] *. Intermediate 21 3- (difluoromethyl) - N-methoxy-N-methylbicyclo [1,1,1] pentane-1-carboxamide o / oil Io
[0238] [0238] Step 1: A stirred solution of methyl 3-formylbicyclo [1,1,1] pentane-1-carboxylate (7.5 g, 48.7 mmol) in DCM (100 mL) was cooled to -78 ° C ºC, and treated with DAST (19.3 mL, 146.1 mmol) by drip and heated to room temperature. After 6 h, the reaction mixture was cooled to -78 "ºC and abruptly cooled with saturated aqueous NaHCO3 solution (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried with Naz2SO4 ;, filtered and concentrated to produce methyl 3- (difluoromethyl) bicyclo [1,1,1] pentane-1-carboxylate (Intermediate 21-1) (7 gd) as an oil viscous. This was used in the next step without further purification. 1 H NMR (300 MHz, CDCl 3) 5 5.71 (t, J = 56.1 Hz, 1H), 3.70 (s, 3H), 2.15 (s, 6H).
[0239] [0239] Step 2: To a stirred solution of Intermediate 21-1 (7 g, 39.74 mmol) in anhydrous THF (70 mL) was added N, O-dimethylhydroxylamine hydrochloride (3.89 g, 39, 74 mmol) at -78 ° C, followed by i-PrMgCl (2 Min THF, 79.5 mL, 159 mmol). The reaction was heated to -50 ° C and stirred for 2 h. The reaction mixture was then quenched with saturated aqueous NHaCI solution (100 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers were dried over Na> 2SO2, filtered and concentrated. The crude product was purified by column chromatography (SiO> 2, EtOAc / petroleum ether) to produce Intermediate 21 (49, 40% yield in two steps). NMR * H (400 MHz, CDCl3) 5 5.72 (t, J = 56.4 Hz, 1H), 3.68 (s, 3H), 3.19 (s, 3H), 2.20 (s, 68H); LC / MS (ESI) m / z 206.1 [M + H] *. Intermediate 22 4 4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-ene-1-carbaldehyde H OF
[0240] [0240] Step 1: A solution of 1-iodo-3-methylbicyclo [1,1,1] pentane (30 g, 144.20 mmol) in THF (225 mL) was cooled to -78 ºC and sec-butyl- lithium (1.4 M in cyclohexane, 154.50 mL, 216.30 mmol) was added dropwise for 1 h. The resulting pale yellow suspension was stirred at -78 ºC for 10 min and then heated to 0 ºC and stirred for 80 minutes. The reaction mixture was then cooled to -78 "ºC, and a solution of Intermediate 19 (24.67 g, 108.15 mmol) in THF (75 mL) was added dropwise for 20 minutes. After 10 minutes, the REACTION was heated to 0 ºC for 1 h. The reaction mixture was then brusquely cooled with saturated aqueous NH4 Cl solution (300 ml) and extracted with Et2O (2 x 450 ml). The combined organic layers were dried with Na-SO ;, filtered and concentrated to produce 2- (dietoxymethyl) -5,5-dimethyl-1- (3-methylbicyclo [1,1,1] pentan-1-yl) cycle -hexan-1-0l (Intermediate 22-1) (31 g, crude product) as a pale yellow oil. This was used in the next step without further purification.
[0241] [0241] Step 2: A solution of Intermediate 22-1 (62 g, 199.69 mmol) in 1,4-dioxane (1.24 L), was treated with 2 N HCl (aq.) (299.5 mL , 599.2 mmol) at room temperature and then heated to 70 ºC. After 16 h, the reaction was cooled to room temperature, poured into water (1.25 L) and extracted with Et2O0 (2 x 750 mL). The combined organic layers were dried over Na2SO2, filtered and concentrated. The crude product was purified by column chromatography (SiO>, EtOAc / natrálasi nara ether neodiisir A Intermediate 99 (DR 4 UU 4 from rondimantaoa am 9 atanracl as a yellow oil. NMR 'H (400 MHz, CDCI3): 5 10 , 28 (s, 1H), 2.25-2.22 (m, 2H), 1.94 (s, 6H), 1.92 (br s, 2H), 1.35-1.32 (m, 2H), 1.19 (s, 3H), 0.90 (s, 6H) Intermediate 23 2- (3-ethylbicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex -1-eno-1-carbaldehyde oo
[0242] [0242] Step 1: To a stirred solution of [1,1,1] propellan (0.19 M in Et2O / pentane), 128.6 mmol) at -78 ºC was added Etl (18.7 9, 257, 38 mmol). The reaction was warmed to room temperature and stirred for 3 days in the dark. The reaction was then concentrated to O “C to produce 1-ethyl-3-iodobicyclo [1,1,1] pentane (Intermediate 23-1) (21.2 g, 74% yield) as a yellow oil. NMR * H (400 MHz, CDCl3) 5 2.17 (s, 6H), 1.52 (q, J = 8.0 Hz, 2H), 0.84 (t, J = 7.2 Hz, 3H) .
[0243] [0243] Step 2: To a stirred solution of Intermediate 23-1 (10.90 g, 49.1 mmol) in Et2O (75 mL) at -78 ° C was added sec-BuLi (1.4 M in cyclohexane , 50 mL, 70.0 mmol). After 10 minutes, the reaction was warmed to room temperature and stirred for 1 hour. The reaction mixture was then cooled to -78 ºC and treated with a solution of 2- (dietoxymethyl) -5,5-dimethylcyclohexan-1-one (8 g, 35.0 mmol) in Et2O (25 mL ). After 1 h, the reaction was heated to 0 ° C and stirred for 2 h. The reaction was quenched with saturated aqueous NHaCl solution (20 ml) and extracted with EtOAc (3 x 70 ml). The combined organic layers were then dried with Na2SO4; filtered and concentrated to provide 8.5 g of 2- (dietoxymethyl) -1- (3-ethylbicyclo [1,1,1] pentan-1-yl) -5 , 5-dimethylcyclohexan-1-ol (Intermediate 23-2). This was used in the next step without further purification.
[0244] [0244] Step 3: A solution of Intermediate 23-2 (8.5 g, crude) in acetone (80 mL), was treated with 2 N HCl (aq.) (20 mL) at room temperature and then heated to 75 ºC. After 24 h, the reaction was concentrated and then diluted with water (50 ml) and extracted with EtsO (3 x 250 ml) The combined organic layers were washed with saturated aqueous NaHCO3 solution, dried with Na2SO; and concentrated. The crude product was purified by column chromatography (SiO> 2, Et2O0 / petroleum ether) to produce Intermediate 23 (3.9 g, 48% yield in 2 steps) as a brown oil. NMR * H (400 MHz, CDCl3) 5 10.30 (s, 1H), 2.26-2.22 (m, 2H), 1.93-1.92 (m, 2H), 1.89 (s , 6H), 1.49 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 6.4 Hz, 2H), 0.89 (s, 6H), 0.87 (t , J = 7.6 Hz, 3H).
[0245] [0245] Step 1: Preparation of CF2HI (based on a procedure by Cao, P. et. Al. J. Chem. Soc., Chem. Commun. 1994, 737-738): performed in two batches in parallel: One The mixture of KI (94 g, 568 mol), MeCN (228 ml) and water (18 ml) was heated to 45 ºC and treated with 2,2-difluoro-2- (fluorosulfonyl) acetic acid (50 9, 284 mmol) in MeCN (50 mL) by dripping for 4 h. The reaction mixture was then cooled to 0 ºC, and diluted with pentane (150 ml) and water (125 ml). The aqueous layer was washed with pentane (150 ml) and the combined organic layers from both reactions were washed with saturated aqueous solution of NAHCO; (200 mL), and dried over Na2SO; to obtain 500 mL of difluoromethyl iodide solution. The solution was washed with more water (2 x 200 ml) to remove residual acetonitrile, and dried over Na2SO4. to obtain difluoroiodomethane (Intermediate 24-1) (0.15 M in pentane, 400 mL, 11% yield). NMR * H (400 MHz, CDCl3) 5 7.67 (t, J = 56.0 Hz, 1H).
[0246] [0246] Step 2: To a stirred solution of [1,1,1] propellan (0.53 M in Et2O, 52 mL, 27.56 mmol) at —40 “C Intermediate 24-1 (0, 15 M in pentane, 200 mL, 30 mmol). The reaction mixture was warmed to room temperature, protected from light and stirred for 2 days. The reaction was then
[0247] [0247] Step 3: A solution of Intermediate 24-2 (30 g, 122.94 mmol) in THF (225 mL) was cooled to -78 ° C and sec-butyl lithium (1.4 M in cyclohexane, 219 mL, 306.7 mmol) was added dropwise over 1 h. The resulting pale yellow suspension was stirred at -78 ° C for 10 min and the temperature was raised to 0 ° C and stirred for 80 minutes. The reaction mixture was then cooled to -78 ° C, and a solution of Intermediate 19 (21 g, 92.20 mmol) in THF (75 mL) was added dropwise for 20 minutes. After 10 minutes, the reaction was heated to 0 ºC for 1 h. The reaction mixture was brusquely cooled with saturated aqueous NH.CI solution (450 ml) and extracted with Et2O (2 x 300 ml). The combined organic layers were dried with Na> SO ;, filtered and concentrated to produce 2- (dietoxymethyl) -1- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1-i1) -5,5- dimethylcyclohexan-1-ol (Intermediate 24-3) (31 g, crude product) as a pale yellow oil. The crude product was used in the next step without further purification.
[0248] [0248] Step 4: Intermediate 24 was prepared following the procedure described in Step 2 for Intermediate 22 using Intermediate 24-3 in place of Intermediate 22-1 (38% in 2 steps). NMR '* H (400 MHz, CDCl3): 5 10.26 (s, 1H), 5.73 (t, J = 56.0 Hz, 1H), 2.29-2.25 (m, 2H), 2.18 (s, 6H), 1.94-1.93 (m, 2H), 1.37 (t, J = 6.8 Hz, 2H), 0.91 (s, 6H). Intermediate 25 4 4-dimethyl-2- (3- (trifluoromethyl) bicyclo [1,1,1] pentan-1-yl) cyclohex-1-ene-1-carbaldehyde o The F.C
[0249] [0249] Step 1u To a stirred solution of 1-iodo-3- (trifluoromethyl) bicycle [1,1,1] pentane (5.00 g, 19.1 mmol) in Et2O0 (100 mL) at -78 ºC below adinsianadaea car Rul ii 1 AM qm havana sin 126º2 ml 10 N2 mmaAl Anráe 1N minutes at -78 ºC, the reaction was heated to 0 ºC and stirred for 1 hour. The reaction mixture was then cooled to - / 78 “C and then a solution of Intermediate 19 (3.63 g, 15.90 mmol) in Et2O (50 mL) was added. After 1 hour, the reaction was heated to 0 ºC and stirred for 2 h and then heated to room temperature for 1 h. The reaction mixture was quenched with saturated aqueous NH4 Cl solution (100 ml) and extracted with Et2O (3 x 150 ml). The organic layers were then dried with Na2SO2, filtered and concentrated to produce 2- (dietoxymethyl) -5,5-dimethyl-1- (3- (trifluoromethyl) bicyclo [1,1,1] pentan-1-yl ) cyclohexanol (Intermediate 25-1) (7 g, crude product) as a brown oil. The crude product was used in the next step without further purification.
[0250] [0250] Step 2: Intermediate 25 was prepared following the procedure described in Step 3 for Intermediate 23 using Intermediate 25-1 in place of Intermediate 23-2. NMR * H (400 MHz, CDCl3) 5 10.23 (s, 1H), 2.29 (s, 6H), 2.28-2.26 (m, 2H), 1.92 (t, J = 2 , 0 Hz, 2H), 1.36 (t, J = 6.8 Hz, 2H), 0.91 (s, 6H). Intermediate 26 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxide) -4- (4 - ((2- (3-chlorobicyclo [1,1,1] pentan-1- il) - 4 A-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoic oH7oH O O
[0251] [0251] Step 1: A solution of 5-iodine-4,4-dimethylpent-1-ene (9.85 g, 44.0 mmol) in pentane (100 mL) was treated with t-BuLi (64.6 mL , 1.7 Mem n-pentane, 109.9 mmol) at -78 ° C under inert atmosphere. After 1 h, a solution of Intermediate 1 (5 g, 26.4 mmol) in THF (20 mL) was added and the mixture was stirred at -78 ° C for 1 h. The reaction was then heated to -30 ° C for 30 minutes and stirred for 1 h. The reaction is brought to room temperature and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water, dried with Na> 2SO:, filtered and concentrated. The product was purified by column chromatography (SiO>, EtOAc / petroleum ether) to produce 1- (3-chlorobicyclo [1,1,1] pentan-1-i1) -3,3-dimethyl-hex-5- en-1-one (Intermediate 26-1) (7 9, 70%) as an oil. NMR * H (300 MHz, CDCl3) 5 5.83-5.69 (m, 1H), 5.05- 4.96 (m, 2H), 2.36 (s, 6H), 2.30 (s , 2H), 2.09 (d, J = 7.5 Hz, 2H), 0.98 (s, 6H).
[0252] [0252] Step 2: A solution of Intermediate 26-1 (3.1 9g, 13.7 mmol) and acrylonitrile (2.18 g, 41.0 mmol) in degassed DCM (120 mL) was drip treated for 2 h with a 2nd generation Hoveyda Grubbs' "catalyst solution (343 mg, 0.55 mmol) in DCM (5 mL) at 45 ° C. The reaction was stirred at 45 ° C for 48 h, cooled to room temperature, concentrated and absorbed into Celite.The residue was purified by column chromatography (SiO> 2, EtOAc / petroleum ether) to yield 7- (3-chlorobicyclo [1,1,1] pentan-1-yl) -5,5- dimethyl-7-0x0-hept-2-enonitrile (Intermediate 26-2) as a mixture of E / Z isomers (1.3 g, 38%) as a clear colorless oil LC / MS (ESI) m / z 252 , 1 [M + H] *.
[0253] [0253] Step 3: A solution of Intermediate 26-2 (700 mg, 2.78 mmol) in MeOH (20 mL) was treated with Pd / C (10% by weight, 170 mg) and stirred under an atmosphere of H2 (1 atm) for 2 h. The reaction was purged with N. and the reaction mixture was filtered through Celte and concentrated to provide 7- (3-chlorobicyclo [1,1,1] pentan-1-yl) -5,5-dimethyl-7 -oxo- heptanonitrile (Intermediate 26-3) (550 mg, 77%) as a clear colorless oil. NMR * H (300 MHz, CDCl3) 5 2.37 (s, 6H), 2.35-2.30 (m, 4H), 1.66-1.55 (m, 2H), 1.52-1 , 44 (m, 2H), 0.98 (s, 6H).
[0254] [0254] Step 4: A solution of Intermediate 26-3 (1.19, 4.34 mmol, 1 eq) in THF (20 mL) was treated with 4 À (100 mg) and 15-crown- molecular sieves. (956 mg, 4.34 mmol) and was placed in an oil bath preheated to 70 ºC. After 2 minutes, the reaction was treated with t-BuONa (2.09 g, 21.7 mmol) in a single portion. After 5 h, the reaction was cooled to room temperature and poured into a saturated aqueous NHaCI stirring solution. The aqueous phase was washed with NCM (2 v IE ml).
[0255] [0255] Step 5: To a stirred solution of Intermediate 26-4 (400 mg, 1.70 mmol) in anhydrous DCM (20 mL) at -78 ° C, DIBAL-H (2.55 mL, 1 Mem toluene) was added , 2.55 mmol). The reaction was warmed to room temperature. After 4 h, the reaction was cooled to 0 ºC, brusquely cooled with 2 M HCI (aq.) (40 ml) and warmed to room temperature. The reaction mixture was diluted with water and extracted with DCM (2 x 40 ml) and the combined organic layers were dried with Na> zSO ;, filtered and concentrated to produce 2- (3-chlorobicyclo [1,1,1] Jpentan -1- i1) -4,4-dimethyl - cyclohex-1-enocarbaldehyde - (Intermediate —26-5) (400 mg, quantitative). This compound was used directly in the next step without further purification. NMR * H (300 MHz, CDCl3) 5 10.19 (s, 1H), 2.44 (s, 6H), 2.30-2.22 (m, 2H), 1.90 (s, 2H), 1.35 (t, J = 6 Hz, 2H), 0.90 (s, 6H).
[0256] [0256] Step 6: To a stirred solution of Intermediate 26-5 (300 mg, 1.26 mmol) in DCM (10 mL) was added Intermediate 2 (544 mg, 1.38 mmol) and NaABH (OAc) s (347 mg, 1.64 mmol) at room temperature. After 16 h, NaBH (OAc) 3 (347 mg, 1.64 mmol) was added. After 48 hours, the reaction was quenched with MeOH (0.2 mL) at 0 ° C, warmed to room temperature and concentrated. The residue was diluted with DCM and washed with saturated aqueous NaHCO; 3. The aqueous layer was washed with DCM (3 x 25 ml) and the combined organic layers were dried over Naz2SO2, filtered and concentrated. The residue was purified by column chromatography (SiO>, EtOAc / petroleum ether) to yield 2- (1H-pyrrolo [2,3-b] pyridin-5-yl-Oxy) -4- (4 - ((2 - tert-Butyl (3-chlorobicyclo [1,1 1] pentan-1-yl) -4,4-dimethylcyclohex-1-en-iN) methyl) piperazin-1-yl) (Intermediate 26-6 ) (220 mg, 44.6 mmol; 28%) as a white solid. LC / MS (ESI) m / z 617.3 [M + H] *.
[0257] [0257] Step 7: To a solution of Intermediate 26-6 (125 mg, 0.20 mmol) in NOM O mlba 0 º ºC is added and TEA (120 mo 199 mma The mixture is heated to room temperature and stirred for 3 h , and concentrated to provide the 2- (1H-pyrrolo [2,3-b] pyridin-5-yl-Oxy) -4- (4 - ((2- (3-chlorobicyclo [1,1 , 1] pentan- 1-i1) -4 4-dimethylcyclohex-1-en-yl) methyl) piperazin-1-yl) benzoic (140 mg, quantitative) as a white solid LC / MS (ESI) m / z 561.3 [C32H37CIN.O03 + H] *. Intermediate 27 Acid 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((2- (3 -fluorobicyclo [1,1,1] pentan-1- i1) -4 4-dimethylcyclohex-1-en-1-yl)] netyl) piperazin-1-yl) benzoic OH oH
[0258] [0258] Step 1: 1- (3-fluorobicyclo [1,1,1] pentan-1-i1) -3,3-dimethyl-hex-5-en-1-one (Intermediate 27-1) was prepared following the procedure described in Step 1 for Intermediate 26 using Intermediate 11 in place of Intermediate 1. NMR * H (300 MHz, CDCI3) 5 5.84-5.69 (m, 1H), 5.06-4.96 (m, 2H), 2.34 (s, 2H), 2.29 (d, J = 2.4 Hz, 6H), 2.10 (d, J = 7.2 Hz, 2H), 0.99 (s, 6H).
[0259] [0259] Step 2: E / Z-7- (3-fluorobicyclo [1,1,1] pentan-1-i1) -5,5-dimethyl-7-0x0-hept-2-enonitrile (Intermediate 27-2 ) was prepared following the procedure described in Step 2 for Intermediate 26 using Intermediate 27-1 in place of Intermediate 26-1. LC / MS (ESI) m / z 236.3 [M + H] *.,
[0260] [0260] Step 3: 7- (3-fluorobicyclo [1,1,1] pentan-1-i1) -5,5-dimethyl-7-0x0- heptanonitrile (Intermediate 27-3) was prepared following the procedure described in Step 3 for Intermediate 26 using Intermediate 27-2 in place of Intermediate 26-2. NMR * H (400 MHz, CDCl3) 5 2.36 (s, 2H), 2.32 (t, J = 6.8 Hz, 2H), 2.31 (d, J = 2.8 Hz, 6H) , 1.64-1.58 (m, 2H), 1.51-1.47 (m, 2H), 0.99 (s, 6H).
[0261] [0261] Step 4: 2- (3-fluorobicyclo [1,1,1] pentan-1-yl) -4,4-dimethylcyclohex-1-
[0262] [0262] Step 5: 2- (3-fluorobicyclo [1,1,1] pentan-1-yl) -4,4-dimethylcyclohex-1-enocarbaldehyde (Intermediate 27-5) was prepared following the procedure described in Step 5 for Intermediate 26 using Intermediate 27-4 in place of Intermediate 26-4. NMR * H (300 MHz, CDCl3) 5 10.19 (s, 1H), 2.37-2.34 (m, 6H), 2.30-2.25 (m, 2H), 1.93 (br s, 2H), 1.40-1.35 (m, 2H), 0.91 (s, 6H).
[0263] [0263] Step 6: To a stirred solution of Intermediate 27-5 (100 mg, 0.45 mmol) in EtOH (4 mL) was added Intermediate 2 (195 mg, 0.49 mmol) and ACOH (cat.) at room temperature for 15 min. The resulting reaction mixture was cooled to 0 ° C and NaCNBH; (42 mg, 0.675 mmol) was added and the reaction was warmed to room temperature. After 16 h, the reaction was concentrated and the residue was diluted with saturated aqueous NaHCO solution; (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2SO, and concentrated. The crude compound was purified by column chromatography (SiO>, EtOAc / petroleum ether) to obtain 2- (1H-pyrrolo [2,3-b] pyridin-S5-yl-Oxy) -4- (4 - (( 2- (3-fluorobicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex-1-en-yl) methyl) piperazin-1-yl) tert-butyl benzoate (Intermediate 27 -6) as a white solid (40 mg, 15% yield). LC / MS (ESI) m / z 601.7 [M + H] *.
[0264] [0264] Step 7 2- (1H-pyrrole [2,3-b] pyridin-S5-yl-Oxyxy) -4- (4 - ((2- (3-fluorobicyclo [1,1,1] pentan- 1-i1) -4,4-dimethylcyclohex-1-en-yl)] methyl) piperazin-1-yl) benzoyl, like the TFA salt, was prepared following the procedure described in Step 7 for Intermediate 26 using of Intermediate 27-6's reaction in place of Intermediate 26-6. LC / MS (ESI) m / z 545.4 [Ca2H37FN403 + H] *. Intermediate 28 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1 1 ] pentan-1-yl) cyclohex-1-en-1-yl)] methyl) piperazin-1-yl) benzoic
[0265] [0265] Step 1: 3,3-dimethyl-1- (3-methylbicyclo [1,1,1] pentan-1-yl) nex-5-en-1-one (Intermediate 28-1) was prepared following the procedure described in Step 1 for Intermediate 26 using Intermediate 10 in place of Intermediate 1. NMR '* H (300 MHz, CDCI3) 5 5.86-5.71 (m, 1H), 5.04-4.97 (m, 2H), 2.28 (s, 2H), 2.09 (d, J = 7.8 Hz, 2H), 1.85 (s, 6H), 1.12 (s, 3H), 0 , 97 (s, 6H).
[0266] [0266] Step 2: E / Z-5,5-dimethyl-7- (3-methylbicyclo [1,1,1] pentan-1-i1) -7-0x0-hept-2-enonitrile (Intermediate 28-2 ) was prepared following the procedure described in Step 2 for Intermediate 26 using Intermediate 28-1 in place of Intermediate 26-1. LC / MS (ESI) m / z 232.3 [M + H] *,
[0267] [0267] Step 3: 5,5-dimethyl-7- (3-methylbicyclo [1,1,1] pentan-1-i1) -7-0x0- heptanonitrile (Intermediate 28-3) was prepared following the procedure described in Step 3 for Intermediate 26 using Intermediate 28-2 in place of Intermediate 26-2. NMR '* H (400 MHz, CDCl3) 5 2.33-2.29 (m, 4H), 1.86 (s, 6H), 1.64-1.56 (m, 2H), 1.50- 1.45 (m, 2H), 1.18 (s, 3H), 0.98 (s, 6H).
[0268] [0268] Step 4: 4,4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-enocarbonitrile (Intermediate 28-4) was prepared following the procedure described in Step 4 for Intermediate 26 using Intermediate 28-3 in place of Intermediate 26-3. LC / MS (ESI) m / z 216.4 [M + H] *.
[0269] [0269] Step 5: Intermediate 22 was prepared following the procedure described in Step 5 for Intermediate 26 using Intermediate 28-4 in place of Intermediate 26-4. LC / MS (ESI) m / z 219.3 [M + H] *.
[0270] [0270] Step 6: To a stirred solution of Intermediate 22 (70 mg, 0.32 mmol)
[0271] [0271] Step 7: 2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy acid) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1] trifluoroacetate , 1,1] pentan-1-yl) cyclohex-1-enyl) mMethyl) piperazin-1-yl) benzoic was prepared following the procedure described in Step 7 for Intermediate 26 using Intermediate 28-5 in place of Intermediate 26-6. LC / MS (ESI) m / z 541.4 [Ca3HaoFN4O03 + H] *. Route B:
[0272] [0272] Step 1: A solution of t-butyl lithium (1.3 M in pentane, 60 mL, 78 mmol) was added dropwise to a solution of 1-iodo-3-methylbicyclo [1,1,1] pentane (6.5 g, 31.2 mmol) in MTBE (60 mL) at -78 ° C under N>. The reaction mixture was stirred for 1 h at -78 ° C. Lithium 2-thienylcyanoprate (0.25 M in THF, 125 mL, 31.2 mmol) was added at -78 "C, and the addition was controlled to keep the temperature below -60" * C. After the addition, the reaction mixture was heated to 0 ºC and stirred for 30 minutes. The reaction was then cooled to -78 ° C and Intermediate 20 (59, 15.5 mmol) in MTBE (5 mL) was added, followed by BF3-OEt2 (3.5 mL, 15.5 mmol). The reaction was stirred for 30 min at -78 ° C and then warmed up to room temperature. After 16 h, the reaction was cooled to 0 ºC and abruptly cooled with saturated aqueous NHaCI solution (50 ml) and H2O (50 ml). MTBE (50 mL) was then added and the reaction mixture was stirred for 20 min at room temperature. The organic layer was separated and the aqueous layer was extracted with MTRE (1d0 ml) and embedded ceramic layers were expensive in Na SN,
[0273] [0273] Etaaa 2: To a stirred solution of benzyl 4, / 4dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-ene-1-carboxylate (1 , 1 g, 3.39 mmol) in THF (40 mL) at 0 ° C, lithium aluminum hydride (386.6 mg, 10.2 mmol) was added. The reaction was warmed to room temperature and stirred for 3 h. The reaction was then cooled to 0 ºC, diluted with Et2O (40 ml) and treated with H2O (0.386 ml), 0.386 ml of 15% NaOH (aq.) Followed by H2O (1.15 ml). The reaction was warmed to room temperature, stirred for 15 minutes, and then treated with MgSO4. anhydrous. After 15 minutes, the reaction was filtered, concentrated, and purified by column chromatography (SiO>, EtOAc / petroleum ether) to provide (4,4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan -1-yl) cyclohex-1-en-1-yl) methanol (1.1 g, 68% yield) as a colorless oil. NMR * H (400 MHz, CDCl3) 5 4.15 (d, J = 5.2 Hz, 2H), 2.16-2.12 (m, 2H), 1.81 (s, 6H), 1, 68 (s, 2H), 1.32 (t, J = 6.4 Hz, 2H), 1.15 (s, 3H), 0.86 (s, 6H).
[0274] [0274] Step 3: To a stirred solution of (4,4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-en-1-yl) methanol (500 mg, 2.27 mmol) in DCM (20 mL) at 0 ° C SOCI2 (0.537 mL, 4.54 mmol) was added by dripping. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was concentrated, diluted with DCM and concentrated once more to obtain —1- (2- (chloromethyl) -5,5-dimethylcyclohex-1-en-1-yl) -3-methylbicyclo [1,1, 1] pentane (540 mg, quantitative yield) as a clear oil. This was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl 3) 5 4.19 (s, 2H), 2.15-2.11 (m, 2H), 1.85 (s, 6H), 1.70 (s, 2H), 1.34 (t, J = 6.4 Hz, 2H), 1.16 (s, 3H), 0.87 (s, 6H).
[0275] [0275] Step 4: To a stirred solution of 1- (2- (chloromethyl) -5,5-dimethylcyclo- hav1-.6n 1h. MaethilhicieclaAM 1 NMhantano (640 m 996 mma am acetone (ON mL) was added 2- ((1H-pyrrolo [2,3-b] pyridin-5-yl) Oxy) -4- (piperazin-1-yl) benzoate (798 mg, 2.26 mmol), Nal (33.90 mg, 0.22 mmol) and K2CO; (938.9 mg, 6.80 mmol) at room temperature. The reaction was then heated to reflux for 6 hours. The reaction was then cooled to room temperature, diluted with 50 ml of acetone and filtered The collected solid was washed with acetone (150 ml) and the combined filtrates were concentrated to provide 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) - 4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1- en-1-yl)] methyl) piperazin-1 -yl) methyl benzoate (1.15 g, 91% yield) as a white solid LC / MS (ESI) m / z 555.3 [M + H] *.
[0276] [0276] Step 5: To a stirred solution of 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) - 4- (4 - ((4,4-dimethyl-2- ( Methyl 3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-en-1-methyl (1-yl) piperazin-1-yl) benzoate (1.15 g, 2.075 mmol) in MeOH: THF : H2O0 (1: 1: 1) (386 mL) LiOH-H2O (261.30 mg, 6.23 mmol) was added at room temperature The reaction was heated to 30 ºC and stirred for 16 h. then removed, and the reaction was neutralized with 1N HCl extracted with DCM (3 x 70 mL). The combined organic layers were dried with Naz2SO, and concentrated to provide Intermediate 28 (940 mg, 84% yield) as a white solid. LC / MS (ESI) m / z 541.3 [M + H] *. Route C:
[0277] [0277] Step 1: A solution of methyl 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) -4) (piperazin-1-yl) benzoate (35 g, 99, 3 mmol) and Intermediate 22 (26.0 g, 119.2 mmol) in THF (700 mL) was stirred at room temperature for 20 minutes. The reaction was then cooled to O ºC and NaBH (OAc) 3 (63.15 g, 297.96 mmol) was added. After the addition, the reaction was warmed to room temperature. After 16 hours, the reaction was poured into ice water (1 L) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with 10% NaHCO 3 solution (aq.) (500 ml) and brine (500 ml). The organic layer was then dried with Na2SO4, filtered and concentrated. The crude product was purified first by chromatography on a column (SIN. EtNArlátar from the nucleus) and then ground with MeNH 6a filtered to produce 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) Oxy) -4 - (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-en-1-yl)] methyl) piperazin-1- il) methyl benzoate as an off-white solid (38 g, 70%). LC / MS (ESI) m / z 555.1 [M + H] *.
[0278] [0278] Step 2: Intermediate 28 was prepared following the procedure described in Step 5, Route B to Intermediate 28. LC / MS (ESI) m / z 541.3 [M + H] *. Intermediate 29 Acid 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((2- (3-ethylbicyclo [1,1,1] pentan-1- il) - 4 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoic OHoH CG O
[0279] [0279] Step 1: To a solution of methyl 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) -4- (piperazin-1-yl) benzoate (1.89 g , 5.38 mmol) in DMSO (25 mL) a solution of Intermediate 23 (1.5 g, 6.46 mmol) in THF (25 mL) was added at room temperature, and the reaction was stirred for 1 hour. The reaction was then cooled to 0 ºC and treated with Na (OAc) 3BH (3.42 g, 16.14 mmol) and warmed to room temperature. After 24 h, the reaction was diluted with saturated aqueous NaHCO3 solution, and extracted with 10% MeOH in DCM (4 x 50 mL). The combined organic layers were dried over Na> 2SO: s, filtered and concentrated. The crude product was purified by column chromatography (SiO> 2, Et2O / n-pentane) to provide 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4- Methyl (2- (3-ethylbicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex-1-en-1-yl)] methyl) piperazin-1-yl) benzoate (Intermediate 29-1) (149, 46% yield) as an off-white solid. LC / MS (ESI) m / z 569.4 [M + H] *.
[0280] [0280] Step 2: Intermediate 29 was prepared following the procedure described in Step 5, Route B, for Intermediate 28 using Intermediate 29-
[0281] [0281] Step 1u 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((2- (3- (difluoromethyl) bicycles [1,1,1 ] pentan-1-yl) -4,4-dimethylcyclohex-1-en-1-yl)] methyl) piperazin-1- i) methyl benzoate (Intermediate 30-1) was prepared following the procedure described in Step 1, Route C, to Intermediate 28 using Intermediate 24 in place of Intermediate 22. LC / MS (ESI) m / z 591.2 [M + H] *.
[0282] [0282] Step 2: Intermediate 30 was prepared following the procedure described in Step 5, Route B, for Intermediate 26 using Intermediate 30-1 in place of 2 - ((1IH-pyrrolo [2,3-b] pyridin -5-yl) Oxy) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-en-1- yl) methyl) piperazin-1-yl) benzoate - methyl. LC / MS (ESI) m / z 577.5 [M + H] *.
[0283] [0283] Step 1: Representative procedure (reaction was carried out in 3 parallel batches): To a stirred solution of 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) Oxy) -4- (piperazin -1-yl) methyl benzoate (2 g, 5.68 mmol) in DMSO (0.2 M, 30 mL) was added a solution of Intermediate 25 (1.72 g, 6.22 mmol) in THF (30 mL) at room temperature. After 1 h, the reaction mixture was cooled to 0 ºC and treated with NaBH (OAc) 3 (1.70 g, 17.04 mmol). The reaction was warmed to room temperature and stirred for 24 h. The reaction mixture was diluted with saturated aqueous NaHCO3 solution, and extracted with 10% MeOH in DCM (4 x 150 mL). The combined organic layers were dried over Na> 2SO4:, filtered and concentrated. The crude product was purified by column chromatography (SiO;>, EtOAc / petroleum ether) to provide 2- (1H-pyrrolo [2,3-b] pyridin-S-yloxy) -4- (4 - ((4 , Methyl 4-dimethyl-2- (3-trifluoromethyl) [1,1,1] pentan-1-yl) cyclohex-1-enyl) methyl) piperazin-1-yl) benzoate (Intermediate 31-1 ) (8.7 g, 14.29 mmol, 84% combined for three batches) as a white solid. LC / MS (ESI) m / z 609.3 [M + H] *.
[0284] [0284] Step 2: To a stirred solution of Intermediate 31-1 (8.3 g, 13.65 mmol) in MeOH: THF: H2O (1: 1: 1) (100 mL) was added LIOH-H2O (1 , 7 g, 40.95 mmol) at room temperature. The reaction mixture was then heated to 35 ° C and stirred for 16 h. The reaction mixture was concentrated, diluted with water and neutralized with 1 N HCl. The product was then extracted with 10% MeOH: DCM (3 x 150 ml). The combined organic layers were dried with Na2SO2, filtered and concentrated to provide Intermediate 31 (7.6 g, 90% yield) as a white solid. NMR * H (400 MHz, DMSO-ds) 5 11.91 (br s, 1H), 11.59 (s, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.43 (t, J = 2.8 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 6.73-6 , 71 (m,
[0285] [0285] Step 1: 3,3-dimethyl-1- (3-isopropylbicyclo [1,1,1] pentan-1-yl) ax-5-en-1-one (Intermediate 32-1) was prepared following the procedure described in Step 1 from Intermediate 26 using Intermediate 12 in place of Intermediate 1. NMR 'H (400 MHz, CDCI3) 5 5.81 - 5.74 (m, 1H), 5.04-4.97 (m, 2H), 2.31 (s, 2H), 2.10 (d, J = 7.6 Hz, 2H), 1.76 (s, 6H), 1.69-1.65 (m, 1H), 0.99 (s, 6H), 0.83 (d, J = 6.8 Hz, 6H).
[0286] [0286] Step 2: E / Z-7- (3-isopropylbicyclo [1,1,1] pentan-1-i1) -5,5-dimethyl-7-0x0- hept-2-enonitrile (Intermediate 32-2 ) was prepared following the procedure described in Step 2 for Intermediate 26 using Intermediate 32-1 in place of Intermediate 26-1. LC / MS (ESI) m / z 260.4 [M + H] *.
[0287] [0287] Step 3: 7- (3-isopropylbicyclo [1,1,1] pentan-1-yl) -5,5-dimethyl-7-0x0- heptanonitrile (Intermediate 32-3) was prepared following the procedure described in Step 3 for Intermediate 26 using Intermediate 32-2 in place of Intermediate 26-2. 1 H NMR (400 MHz, CDCl 3) 5 2.34-2.30 (m, 4H), 1.78 (s, 6H), 1.70-1.57 (m, 4H), 1.51 1.46 (m, 1H), 0.98 (s, 6H), 0.84 (d, J = 7.2 Hz, 6H).
[0288] [0288] Step 4: 2- (3-isopropylbicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex-1-anocarbhonitrile Intermediate 294) was coated with the number described in Step 4 for Intermediate 26 using Intermediate 32-3 in place of Intermediate 26-3. LC / MS (ESI) m / z 244.4 [M + H] *.
[0289] [0289] Step 5: 2- (3-isopropylbicyclo [1,1,1] pentan-1-yl) -4,4-dimethylcyclohex-1-enocarbaldehyde (Intermediate 32-5) was prepared following the procedure described in Step 5 for Intermediate 26 using Intermediate 32-4 in place of Intermediate 26-4. LC / MS (ESI) m / z 247.4 [M + H] *.
[0290] [0290] Step 6: 2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -4- (4 - ((2- (3-isopropylbicyclo [1,1 1] pentan-1-i1 ) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) tert-butyl benzoate (Intermediate 32-6) was prepared following the procedure described in Step 6, Route A, for Intermediate 28 using Intermediate 32-5 in place of Intermediate 28-5. LC / MS (ESI) m / z 625.7 [M + H] *.
[0291] [0291] Step 7: To a solution of Intermediate 32-6 (160 mg, 0.26 mmol) in DCM (5 mL) at 0 ° C, TFA (176 mg, 1.54 mmol) was added. The reaction was warmed to room temperature and stirred for 3 h. The reaction was then diluted with saturated aqueous NaHCO solution; (10 ml) and extracted with DCM (3 x 10 ml). The combined organic layers were dried with Na-> SO2, filtered and concentrated to provide Intermediate 32 as an off-white solid. LC / MS (ESI) m / z 569.6 [M + H] *. Intermediate 33 2- (1H-pyrrolo [2,3-b] pyridin-S-yloxy) -4- (4 - ((2- (3- (1,1-difluoroethyl) bicyclo [1,1,1] pentan- 1-i1) -4 4-dimethylcyclohex-1-enyl) methyl) piperazin-1-i) benzoic EN NON QO
[0292] [0292] Step 1: 1- (3- (1,1-Difluoroethyl) bicycles [1,1,1] pentan-1-i1) -3,3-dimethyl-hex-5- en-1-one (Intermediate 33-1) was prepared following the procedure described in Step 1 for Intermediate 26 using Intermediate 13 in place of Intermediate 1. NMR * H (400 MHz, CDCI3) 5 5.85-5.69 (m, 1H), 5.03-4.95 (m, 2H), 2.30 (s, 2H), 2.08 (d, J = 8.0 Hz, 2H), 2.03 (s, 6H), 1.53 (t, J = 18.0 Hz, 3H), 0.97 (s, 6H).
[0293] [0293] Step 2: E / Z-7- (3- (1,1-difluoroethyl) bicyclo [1,1,1] pentan-1-i1) -5,5-dimethyl-7-o0x0-hept-2 -enonitrile (Intermediate 33-2) was prepared following the procedure described in Step 2 for Intermediate 26 using Intermediate 33-1 in place of Intermediate 26-1. LC / MS (ESI) m / z 282.5 [M + H] *.
[0294] [0294] Step 3: 7- (3- (1,1-Difluoroethyl) bicycles [1,1,1] pentan-1-i1) -5,5-dimethyl-7-oxo-heptanonitrile (Intermediate 33-3) was prepared following the procedure described in Step 3 for Intermediate 26 using Intermediate 33-2 in place of Intermediate 26-2. NMR '* H (400 MHz, CDCl3) 5 2.34-2.31 (m, 4H), 2.06 (s, 6H), 1.66-1.57 (m, 2H), 1.55 ( t, J = 18.0 Hz, 3H), 1.51-1.46 (m, 2H), 0.99 (s, 6H).
[0295] [0295] Step 4: 2- (3- (1,1-Difluoroethyl) bicyclo [1,1,1] pentan-1-yl) -4,4-dimethylcyclohex-1-enocarbonitrile (Intermediate 33-4) was prepared following the procedure described in Step 4 for Intermediate 26 using Intermediate 33-3 in place of Intermediate 26-3. LC / MS (ESI) m / z 266.1 [M + H] *.
[0296] [0296] Step 5: 2- (3- (1,1-difluoroethyl) bicycles [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex-1-enocarbaldehyde - (Intermediate 33-5 ) was prepared following the procedure described in Step 5 for Intermediate 26 using Intermediate 33-4 in place of Intermediate 26-4. LC / MS (ESI) m / z 269.5 [M + H] *.
[0297] [0297] Step 6: 2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -4- (4 - ((2- (3- (1,1-difluoroethyl) bicycles [1,1 , 1] pentan-1-yl) -4,4-dimethylcyclohex-1-enyl) methyl) tert-butyl piperazin-1-ylbenzoate (Intermediate 33-6) was prepared following the procedure described in Step 6, Route A, for Intermediate 28 using Intermediate 33-5 in place of Intermediate 28-5 LC / MS (ESI) m / z 647.3 [M + H] *.
[0298] [0298] Step 7: Intermediate 33 was prepared following the procedure described in Step 7 for Intermediate 32 using Intermediate 33-6 in place of Intermediate 32-6. LC / MS (ESI) m / z 591.3 [M + H] *. Intermediate 34 (S) -4 - (((1 A-dioxan-2-yl) methyl) amino) -3-nitrobenzenesulfonamide NS vo, xr O o
[0299] [0299] A solution of (S) - (1,4-dioxan-2-yl) methanamine hydrochloride (500 mg, 3.25 mmol) in THF (5 mL) was treated with 4-fluoro-3-nitrobenzenesulfonamide ( 501 mg, 2.20 mmol) and DIPEA (1.65 9g, 13 mmol) and the mixture was heated to 45 ° C. After 16 h, the reaction was concentrated, triturated with MeOH and filtered to provide Intermediate 34 (500 mg, 48%) as a yellow solid. LC / MS (ESI) m / z 318.4 [M + H] ". Intermediate 35 (R) -4 - ((4 - ((2 - ((tert-butyldiphenylsily) oxy) ethyl) (methyl) amino) -1- (phenylthio) butan-2-i) amino) - 3 - ((triluoromethyl) sulfonyl) benzenesulfonamide. "DO o X Coronrs
[0300] [0300] Intermediate 35 was prepared following a procedure described in WO2012 / 017251A1. MS (ESI) m / z 780.6 [M + H] *.
[0301] [0301] Step 1: To a stirred solution of 3,3-dimethylpent-4-en-1-o0l (18.5 9, 162.01 mmol) in DCM (100 mL), was added MsCI (13.54 mL , 175.0 mmol) followed by NEt3 (33.87 mL, 243.0 mmol) at O ҼC, and the reaction was warmed to room temperature. After 4 hours, a saturated aqueous solution of NaHCO; 3 (100 ml) was added and the reaction was extracted with DCM (3 x 100 ml). The combined organic layers were dried with Na2SO2, filtered and concentrated to provide 3,3-dimethylpent-4-enyl methanesulfonate (Intermediate 36-1) (20.0 9, 64% yield) as a clear colorless oil. This was used in the next step without further purification. NMR * H (400 MHz, CDCl3) 5 5.80-5.72 (m, 1H), 5.01-4.94 (m, 2H), 4.22-4.18 (m, 2H), 2 , 99 (s, 3H), 1.81 to 1.77 (m, 2H), 1.06 (s, 6H).
[0302] [0302] Step 2: Intermediate 36-1 (20 9, 104.01 mmol) and Nal (46.77 g, 312.04 mmol) in acetone (100 mL) were added to a pressurized vial. The flask was sealed and the reaction was stirred at 100 “C for 12 h. The reaction mixture was cooled to room temperature, diluted with water (250 ml) and extracted with Et2O (3 x 200 ml). The combined organic layers were washed with saturated aqueous Na2S2O3 solution, dried with Na2SO, and evaporated to provide 5-iodo-3,3-dimethylpent-1-ene (Intermediate 36-2) (18 g, 77% yield) as a clear colorless oil. 1 H NMR (400 MHz, CDCl 3) 5 5.75-5.68 (m, 1H), 5.01- 4.92 (m, 2H), 3.09-3.05 (m, 2H), 1 , 99-1.95 (m, 2H), 1.01 (s, 6H)
[0303] [0303] Step 3: 1- (3-chlorobicyclo [1,1,1] pentan-1-i1) -4,4-dimethyl-hex-5-en-1-one (Intermediate 36-3) was prepared following the procedure described in Step 1 for Intermediate 26 reacting 36-2 in place of 5-iodo-4,4-dimethylpent-1-ene. 1H NMR (400 MHz, CDCIs) 5 5.71 - 5.63 (m, 1H), 4.97 - 4.88 (m, 2H), 2.38 (s, 6H), 2.34-2, 30 (m, 2H), 1.57-1.52 (m, 2H), 0.98 (s, 6H).
[0304] [0304] Step 4: Ozone gas was bubbled into a solution of Intermediate 36-3 (1.5 g, 6.63 mmol) in DCM (40 mL) at -78 ºC until the solution turned a blue color (-30 minutes). Then N gas. was bubbled into the reaction mixture until it became colorless. PPh3 (2.6 g, 9.94 mmol) was added in one portion and the reaction was warmed to room temperature. After 3 h, the reaction mixture was diluted with DCM (100 ml), washed with water (2 x 25 ml) and brine (50 ml). The organic layer was dried with Naz2SO2, filtered and concentrated. The crude product was purified by column chromatography (SiO> 2, EtOAc / petroleum ether) to yield 5- (3-chlorobicyclo [1,1,1] pentan-1- i1) -2,2-dimethyl-5- oxopentanal (Intermediate 36-4) as a clear colorless oil (800 mg, 53% yield). NMR * H (400 MHz, CDCl3) 5 9.41 (s, 1H), 2.39 (s, 6H), 2.38 -2.33 (m, 2H), 1.77-1.72 (m , 2H), 1.05 (s, 6H).
[0305] [0305] Step 5: To a stirred solution of diethyl cyanomethylphosphonate (619 mg, 3.50 mmol) in toluene (10 mL) at 0 ºC was added LIHMDS (1 M in toluene, 3.5 mL, 3.50 mmol ). The reaction was then warmed up to room temperature. After minutes, the solution was added dropwise at -78 ° C to a solution of Intermediate 36-4 (800 mg, 3.50 mmol) in toluene (10 mL). The reaction mixture was warmed to room temperature and stirred for 16 h. At this point, it was cooled to 0 ºC and abruptly cooled with a saturated aqueous solution of NHAaCI (20 mL). The organic phase was separated and the aqueous layer was further extracted with DCM (3 x 50 ml). The combined organic layers were dried over Na> 2SO:, filtered and concentrated. The crude product was purified by column chromatography (SiO>, EtOAc / petroleum ether) to obtain (E) -7- (3-chlorobicyclo [1,1,1] pentan-1-i1) -4,4-dimethyl -7-0x0-hept-2-enonitrile (Intermediate 36-5) as a colorless tranenating oil (A40 hand EN% yield) 1 C / MS (ES m / 7 9569 A [M4 + H1 * +
[0306] [0306] Step 6: A solution of Intermediate 36-5 (440 mg, 1.75 mmol) in MeOH (10 mL) was treated with Pd / C (25% by weight, 110 mg) and stirred under an atmosphere of H2 (1 atm) for 2 h. The reaction was then purged with N, and filtered through Celite. The Celite buffer was washed with MeOH (3 x 25 mL) and the combined organic layers were concentrated to provide 7- (3-chlorobicyclo [1,1,1] pentan-1-yl) -4,4-dimethyl-7 -oxo-heptanonitrile (Intermediate 36-6) as a clear colorless oil (360 mg, 81% yield). NMR * H (400 MHz, CDCl3) 2.41 (s, 6H), 5 2.40-2.36 (m, 2H), 2.30-2.25 (m, 2H), 1.63-1 , 56 (m, 2H), 1.50-1.46 (m, 2H), 0.89 (s, 6H).
[0307] [0307] Step 7: 2- (3-Chlorobicyclo [1,1,1] pentan-1-i1) -5,5-dimethylcyclo-ex-1-ene-1-carbonitrile (Intermediate 36-7) was prepared following the procedure described in Step 4 for Intermediate 26 by reacting Intermediate 36-3 in place of Intermediate 26-3. LC / MS (ESI) m / z 236.4 [M + H] "*.
[0308] [0308] Step 8: 5,5-Dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-eno-1-carbaldehyde (Intermediate 36-8) was prepared following the procedure described in Step 5 for Intermediate 26 using Intermediate 36-7 in place of Intermediate 26-4. NMR * H (400 MHz, CDCl3) 5 10.17 (s, 1H), 2.46 (s, 6H), 2.44 (s, 2H), 2.038 (t, J = 7.6 Hz, 2H) , 1.42-1.37 (m, 2H), 0.86 (s, 6H).
[0309] [0309] Step 9: To a stirred solution of Intermediate 36-8 (85 mg, 0.361 mmol) in EtOH (3 mL) was added tert-butyl 4- (piperazin-1-yl) benzoate (104 mg, 0.397) mmol) and ACOH (cat.). After 15 minutes, the reaction was cooled to 0 ºC, treated with NaCNBH 3 (33.6 mg, 0.535 mmol) and warmed to room temperature. After 16 h, the reaction was diluted with saturated aqueous NaHCO solution; and extracted with DCM (3 x 15 mL). The combined organic layers were dried over Na2SO2, filtered and concentrated. The crude product was purified by column chromatography (SiO ,, EtOAc / petroleum ether) to obtain 4- (4 - ((2- (3-chlorobicyclo [1,1,1] pentan-1-i1) -5, 5-dimethylcyclohex-1-en-1-yl)] methyl) piperazin-1-i) tert-butyl benzoate (Intermediate 36-9) as a white solid (80 mg, 50% yield). LC / MS (ESI) m / z 485.6 [M + H] *.
[0310] [0310] Step 10: To a stirred solution of Intermediate 36-9 (80 mg, 0.165 mMmmAI am DCM A 0º ºC was added and TEA 112 mo NOOAAGmMmMANIL The ration was warmed to room temperature and stirred for 3 h. concentrated and then diluted with saturated aqueous NaHCO solution, and extracted with DCM (3 x 10 mL). The combined organic layers were dried with Na2SO2 ;, filtered and concentrated to obtain Intermediate 36 as an off-white solid (60 mg, 85 %). LC / MS (ESI) m / z 429.5 [M + H] *. Intermediate 37 (R) -4- (4- (4-hydroxypiperidin-1-i1) -1- (phenylthio) 2-ylamino) -3- (triluoromethylsulfonyl) benzenesulfonamide nx JO
[0311] [0311] Step 1: To a stirred solution of (R) -3 (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -4- (phenylthio) butanoic acid (6.8 g, 15, 7 mmol) in DCM (70 mL) and DMF (10 mL) was added HATU (9.5 g, 25.12 mmol) followed by DIPEA (8.3 mL, 47.1 mmol) at 0 ° C. After 10 minutes, 4-hydroxypiperidine (2.4 g, 23.55 mmol) was added and the temperature was raised to room temperature. After 16 h, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4 ;, filtered and concentrated. The crude product was purified by column chromatography (SiO2 MeOH / DCM) to produce (R) - (9H-fluoren-9-yl) methyl-4- (4-hydroxypiperidin-1-i1) -4-0x0-1- (phenylthio) butan-2-ylcarbamate (Intermediate 37-1) (55 g, 68% yield) as a brown oil. LC / MS (ESI) m / z 517.6 [M + H] *.
[0312] [0312] Step 2: To a stirred solution of Intermediate 37-1 (2.75 g, 5.32 mmol) in CH3CN (20 mL) at room temperature was added diethylamine (3.3 mL, 31.92 mmol). After 16 h, the reaction was concentrated and purified by column chromatography (neutral alumina, MEOH / DCM) to produce (R) -3-amino-
[0313] [0313] Step 3: To a stirred solution of Intermediate 37-2 (0.9 g, 3.06 mmol) in anhydrous THF (12 mL) at 0 ° C was added BH3 (1 M in THF, 9.18 mL, 9.18 mmol) and the temperature was raised to 45 ºC. After 16 h, the reaction was cooled to 0 ºC and MeOH (30 mL) was added. After 1 hour, the reaction was concentrated and purified by column chromatography (C18, CH3CN / water) to produce (R) -1- (3-amino-4- (phenylthio) butyl) piperidin-4-0l (Intermediate 37- 3) (305 mg, 36% yield) as an off-white semi-solid. LC / MS (ESI) m / z 281.2 [M + H] *.
[0314] [0314] Step 4: To a stirred solution of Intermediate 37-3 (100 mg, 0.357 mmol) in DMF (1 mL) was added 4-fluoro-3- (trifluoromethylsulfonyl) benzenesulfonamide (99 mg, 0.32 mmol) followed of DIPEA (140 mg, 1.07 mmol) and the resulting reaction mixture was stirred at room temperature. After 16 h, the reaction was concentrated, diluted with water and extracted with DCM: MeOH 9: 1 (2 x 10 mL). The combined organic layers were dried over Na> SOO: filtered and concentrated. The crude product was purified by trituration with EtOAc / Et2O to produce Intermediate 37 (105 mg, 51% yield) as a white solid. LC / MS (ESI) m / z 568.1 [M + H] *. Intermediate 38 Acid 4- (4 - ((5,5-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-en-1- i) methyl) piperazin -1-yl) benzoic OHoH: v He
[0315] [0315] Step 1: 4,4-Dimethyl-1- (3-methylbicyclo [1,1,1] pentan-1-yl) nex-5-en-1-one (Intermediate 38-1) was prepared following the procedure described in Step 1 place of Intermediate 1 and 5-iodo-4,4-dimethylpent-1-ene. 1 H NMR (400 MHz, CDCl 3) 5 5.73-5.66 (m, 1H), 4.95-4.88 (m, 2H), 2.33-2.28 (m, 2H), 1 , 88 (s, 6H), 1.55-1.51 (m, 2H), 1.21 (s, 3H), 0.99 (s, 6H).
[0316] [0316] Step 2: 2,2-Dimethyl-5- (3-methylbicyclo [1,1,1] pentan-1-yl) -5-oxopentanal (Intermediate 38-2) was prepared following the procedure described in Step 4 to Intermediate 36 using Intermediate 38-1 in place of Intermediate 36-3. NMR '* H (300 MHz, CDCl3) 5 9.41 (s, 1H), 2.36-2.30 (m, 2H), 1.88 (s, 6H), 1.79-1.71 ( m, 2H), 1.18 (s, 3H), 1.05 (s, 6H).
[0317] [0317] Step 3: 4 4-dimethyl-7- (3-methylbicyclo [1,1,1] pentan-1-11) -7-0x0-hept-2-enonitrile (Intermediate 38-3) was prepared following the procedure described in Step 5 for Intermediate 36 using Intermediate 38-2 in place of Intermediate 364. LC / MS (ESI) m / z 232.5 [M + H] "*.
[0318] [0318] Step 4: 4, 4-dimethyl-7- (3-methylbicyclo [1,1,1] pentan-1-i1) -7-0x0- heptanonitrile (Intermediate 38-4) was prepared following the procedure described in Step 6 for Intermediate 36 using Intermediate 38-3 in place of Intermediate 36-5. NMR * H (400 MHz, CDCl3) 5 2.38-2.33 (m, 2H), 2.29-2.25 (m, 2H), 1.90 (s, 6H), 1.62-1 , 58 (m, 2H), 1.48-1.44 (m, 2H), 1.19 (s, 3H), 0.90 (s, 6H).
[0319] [0319] Step 5: 5,5-Dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-eno-1-carbonitrile (Intermediate 38-5) was prepared following the procedure described in Step 4 for Intermediate 26 using Intermediate 38-4 in place of Intermediate 26-3. NMR * H (400 MHz, CDCl3) 5 2.11-2.06 (m, 2H), 2.00-1.98 (m, 2H), 1.93 (s, 6H), 1.35 (t , J = 6.4 Hz, 2H), 1.18 (s, 3H), 0.90 (s, 6H).
[0320] [0320] Step 6: 5,5-Dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-eno-1-carbaldehyde (Intermediate 38-6) was prepared following the procedure described in Step 5 for Intermediate 26 using Intermediate 38-5 in place of Intermediate 26-4. NMR * H (400 MHz, CDCl3) 5 10.28 (s, 1H), 2.21-2.17 (m, 2H), 2.14 (br s, 2H), 2.00 (s, 6H) , 1.35 (t, J = 6.4 Hz, 2H), 1.20 (s, 3H), 0.88 (s, 6H).
[0321] [0321] Step 7: 4- (4 - ((5,5-dimethyl-2- (3-methylbicyclo [1,1,1] Jpentan-1-yl) cyclohex-1-en- 1 illmeatilihinarazin-1 tarebiuitililhanzoata (Intermediate 22.7 cleared following the procedure described in Step 9 for Intermediate 36 using Intermediate 38-6 in place of Intermediate 36-8. LC / MS (ESI) m / z 465.6 [M + H ] *.
[0322] [0322] Step 8: Intermediate 38 was prepared following the procedure described in Step 10 for Intermediate 36 by reacting Intermediate 38-7 in place of Intermediate 36-9. LC / MS (ESI) m / z 409.6 [M + H] *. Intermediate 39 Acid 4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-en-1- i) methyl) piperazin -1-yl) benzoic s CO
[0323] [0323] Step 1: To a stirred solution of methyl 4- (piperazin-1-yl) benzoate (1.68 g, 7.6 mmol) and Intermediate 22 (2.0 g, 9.45 mmol) in THF (20 mL) Na (OAc): BH (4.8 g, 22.8 mmol) was added at room temperature. After 16 h, the reaction was placed in an ice bath and brusquely cooled with saturated aqueous NaHCO solution; (25 mL). The reaction mixture was extracted with EtOAc (3 x 50 ml), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, EtOAc / petroleum ether) to obtain 4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1- il) cyclohex-1-en-1-yl)] methyl) piperazin-1- i) methyl benzoate (Intermediate 39-1) as a white solid (1.5 g, 46% yield). LC / MS (ESI) m / z 423.2 [M + H] *.
[0324] [0324] Step 2: Intermediate 39 was prepared following the procedure described in Step 5, Route B, for Intermediate 28 using Intermediate 39-1 in place of 2 - ((1IH-pyrrolo [2,3-b] pyridine -5-yl) Oxy) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-en-1- il)] methyl) piperazin-1-yl) benzoate - de
[0325] [0325] Step 1: 4- (4 - ((2- (3-Ethylbicyclo [1,1,1] pentan-1-yl) -4,4-dimethylcyclohex-1- en-1-yl)] methyl) piperazin-1-yl) methyl benzoate (Intermediate 40-1) was prepared following the procedure described in Step 1 for Intermediate 39 using Intermediate 23 in place of Intermediate 22. LC / MS (ESI) m / z 437 , 3 [M + H] *.
[0326] [0326] Step 1: Intermediate 40 was prepared following the procedure described in Step 2 for Intermediate 39 using Intermediate 40-1 in place of Intermediate 39-1. LC / MS (ESI) m / z 423.3 [M + H] *. Intermediate 41 4- (4 - ((4 4-dimethyl-2- (3- (trifluoromethyl) bicyclo [1,1,1] pentan-1-yl) cyclohex-1-en-1-yl)] acid Methyl) piperazin-1-yl) benzoic
[0327] [0327] Step 1: To a stirred solution of Intermediate 25 (3.5 g, 12.85 mmol) in toluene was added titanium (IV) ethoxide (3.73 g, 16.36 mmol). After minutes, a solution of methyl 4- (piperazin-1-yl) benzoate (2.35 g, 10.71 mmol) in toluene (20 mL) was added, and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then cooled to 0 ºC, and Na (OAc) 3BH (6.9 g, 32.72 mmol) was added and the reaction was warmed to room temperature. After 16 hours, the reaction was quenched with water (100 ml) at 0 ° C, and MTBE (200 ml) was added after 30 min. The reaction mixture was filtered through Celite and the collected solid was washed with DCM (2 x 100 ml). The combined organic layers were washed with saturated aqueous NaHCO2 solution, brine, dried with Na2SO2, filtered and concentrated. The crude product was purified by column chromatography (SiO> 2, EtOAc / petroleumether) to produce 4- (4 - ((4,4-dimethyl-2- (3- (trifluoromethyl) bicycles [1,1,1 ] pentan-1-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) methyl benzoate (Intermediate 41-1) (3.2 g, 63% yield) as a solid White. LC / MS (ES!) M / z 477.3 [M + H] *.
[0328] [0328] Step 2: Intermediate 41 was prepared following the procedure described in Step 2 for Intermediate 39 by reacting Intermediate 41-1 in place of Intermediate 39-1. LC / MS (ESI) m / z 463.2 [M + H] ". Intermediate 42 Acid 4- (4 - ((2- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1-yl ) -4 4-dimethylcyclohex-1-en-1-yl)] Methyl) piperazin-1-yl) benzoyl EN: N
[0329] [0329] Step 1u 4- (4 - ((2- (3- (Difluoromethyl) bicycles [1,1,1] pentan-1-i1) -4,4-
[0330] [0330] Step 1: Intermediate 42 was prepared following the procedure described in Step 2 for Intermediate 39 using Intermediate 42-1 in place of Intermediate 39-1. LC / MS (ESI) m / z 445.6 [M + H] *. Intermediate 43 (R) -4 - ((4-morpholino-1- (phenylthio) butan-2-yl) amino) -3-nitrobenzenesulfonamide
[0331] [0331] To a solution of (R) -4-morpholino-1- (phenylthio) butan-2-amine hydrochloride (900 mg, 26 mmol) in DMF (10 mL) was added 4-fluoro-3-nitrobenzenesulfonamide ( 56 mg, 2.53 mmol) followed by DIPEA (5.8 mL, 33.8 mmol) at room temperature. The reaction was then heated to 50 ° C for 4 hours. The reaction was cooled to room temperature, brusquely cooled with ice water (150 ml) and stirred at room temperature for 15 minutes. The mixture was then filtered, and the collected solid was washed with n-pentane to produce Intermediate 43 (800 mg, 66%) as a yellow solid. LCMS (ESI) m / z 467.1 [M + H] *. Intermediate 44 (R) -4 - ((4- (dimethylamino) -1- (phenylthio) butan-2-yl) amino) -3- ((triluoromethyl) sulfonyl) benzenesulfonamide
[0332] [0332] Intermediate 44 was prepared following a procedure described in WO200861208A2. LC / MS (ESI) m / z 512.2 [M + H] *. Intermediate 45 (R) -4 - ((4- (4- (dimethylamino) piperidin-1-yl) -1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) benzenesulfonamide O oO
[0333] [0333] Step 1: To a stirred solution of N, N-dimethylpiperidin-4-amine (462.5 mg, 3.61 mmol), DMAP (367.80 mg, 3.01 mmol) and EDC-HCI (863 , 75 mg, 4.51 mmol) in DCM (20 mL) - (R) 4- (phenylthio) -3 - ((4-sulfamoyl-2- ((trifluoromethyl) sulfonyl) phenyl) amino) butanoic acid ( prepared following a procedure described in WO2012017251A1) (1.5 g, 3.01 mmol) and Et3N (0.84 mL, 6.02 mmol) at room temperature. After 15 minutes, the reaction was heated to 35 ° C and stirred for 16 h. The reaction mixture was then cooled to room temperature, diluted with DCM (100 ml) and MeOH (10 ml) and washed with 10% CH3CO2H (aq.) (2 x 20 ml). The organic layer was then washed with NaHCO; 5% (aq.) (20 ml) and 5% NaCl (aq.) (20 ml) and concentrated. The crude product was purified by column chromatography (C18, CH3CN / H2O0) to provide (R) -4 - ((4- (4- (dimethylamino) piperidin-1-yl) -4-0x0-1- (phenylthio) butan-2-yl) amino) -3 - ((trifluoromethyl) sulfonyl) Denzenesulfonamide (Intermediate 45-1) (686 mg, 37% yield) LC / MS (ESI) m / z 609.3 [M + H] *.
[0334] [0334] Step 2: To a stirred solution of Intermediate 45-1 (800 mg, 1.31 mmol) in THF (15 mL) was added BH3-THF (IM in THF, 6.57 mL, 6.57 mmol) in a sealed tube. The reaction was then cooled to room temperature, and treated with MeOH (8 ml) and concentrated HCI (2 ml) and heated to 65 ºC. After 10 h, the reaction was concentrated, diluted with 2 N NaOH solution and extracted with EtOAc. The combined organic layers were dried over Na> SO ;, filtered and concentrated. The crude product was purified by column chromatography (C18, CH3CN / H2O) to produce Intermediate 45 (490 mg, 62% yield). LC / MS (ESI) m / z 595.3 [M + H] *. Intermediate 46 (R) -4- (4- (phenylthio) -3 - ((4-sulfamoyl-2- ((trifluoromethyl) sulfonyl) phenyl) amino) butyl) tert-butyl piperazine-1-carboxylate DE in TO
[0335] [0335] Step 1: (R) -terc 4- (4- (Phenylthio) -3 - (((4-sulfamoyl-2 - ((trifluoromethyl) sulfonyl) pheni!) - amino) butanoyl) piperazine-1-carboxylate -butyl (Intermediate 46-1) was prepared following the procedure described in Step 1 for Intermediate 45 using tert-butyl piperazine-1-carboxylate in place of N, N-dimethylpiperidin-4-amine. LC / MS (ESI) m / z 665.4 [M-H].
[0336] [0336] Step 2: Intermediate 46 was prepared following the procedure described in Step 2 for Intermediate 45 using Intermediate 46-1 in place of Intermediate 45-1. LC / MS (ESI) m / z 653.2 [M + H] *. Intermediate 47. 7- (Dietoxymethyl) spiro [3.5] nonan-6-one OEt "TS o
[0337] [0337] To a solution of triethyl orthoformate (7.28 mL, 43.79 mmol) in DCM (10 mL) at -30 ° C was added BF3-OEt2 (6.75 mL, 54.72 mmol) by dripping during 20 minutes. The reaction mixture was heated to 0 ºC and stirred for 20 minutes. The reaction mixture was then cooled to - / 78 “C and spiro [3.5] nonan-6-one (3.0 g, 21.89 mmol) and N N-diisopropylethylamine (11.4 ml, 35.7 mmol) were added and mixed for 90 min at the same temperature. The reaction was then carefully poured into a mixture of saturated aqueous NaHCO3 solution (20 mL) and DCM (30 mL). The resulting mixture was stirred for 15 min at room temperature and the organic layer was separated. The organic layer was washed with 1M H2SO (2 x 20 mL) and water. The organic layer was dried over Na2SO2, filtered and concentrated. The crude product was purified by column chromatography (SiO>, Et2O / petroleum ether) to produce Intermediate 47 (3.00 g, 57% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) 4.78 (d, J = 6.4 Hz, 1H), 3.72-3.56 (m, 4H), 2.48-2.45 (m, 1H), 2.38 (d, J = 1.2 Hz, 1H), 2.35 (d, J = 0.8 Hz, 1H), 1.90-1.64 (m, 10H), 1.18 (t , J = 6.8 Hz, 6H). Intermediate 48 7- (Dietoxymethyl) -6- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1-i) spiro [3,5] nonan-6-ol H O IT'S
[0338] [0338] Step 1: To a stirred solution of Intermediate 24-2 (4.67 g, 19.15 mmol) in Et2O (30 mL) under argon was added sec-BuLi (1.4 M in cyclohexane, 20 , 8 mL, 29.12 mmol) at -78 ° C and the reaction was stirred for 10 minutes at the same temperature. The temperature was then heated to 0 ° C and stirred for 1 hour. The reaction was cooled to -78 ° C and a solution of Intermediate 47 (2 g, 8.32 mmol) in Et2O (20 mL) was added dropwise for 5 hours for 1 h. The reaction mixture was brusquely cooled with saturated aqueous NHACI solution (50 ml) at 0 ° C, and extracted with Et2O (3 x 150 ml). The combined organic layers were dried with Na> 2SO ;, filtered and concentrated to provide 7- (dietoxymethyl) -6- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1- iNespiro [3,5] nonan -6-ol (Intermediate 48-1) (1.5 g, crude product) as a yellow oil, which was used in the next step without further purification.
[0339] [0339] Step 2: To a stirred solution of Intermediate 48-1 (1.5 g crude, 4.18 mmol) in 1,4-dioxane (30 mL), 2 N HCI (aq.) (7 mL) was added ) and the resulting reaction mixture was stirred at 65-70 ºC for 16 h. The reaction mixture was diluted with ice water (15 ml) and extracted with Et2O (3 x 100 ml). The combined organic layers were dried over Na> zSO2, filtered and concentrated. The product was purified by column chromatography (SiO> 2, Et2O / petroleum ether) to produce Intermediate 48 (19, 45% yield in 2 steps) as a brown oil. H NMR (400 MHz, CDCl3) 5 10.21 (s, 1H), 5.74 (t, J = 56.4 Hz, 1H), 2.22-2.19 (m, 2H), 2, 18 (s, 6H), 1.93-1.86 (m, 4H), 1.83-1.65 (m, 4H), 1.63-1.56 (m, 2H). Intermediate 49 7- (Dietoxymethyl) -6- (3-methylbicyclo [1,1,1] pentan-1-yl) spiro [3,5] nonan-6-ol O
[0340] [0340] Step 1u 7- (Dietoxymethyl) -6- (3-methylbicyclo [1,1,1] pentan-1-yl) spiro [3,5] nonan-6-0l (Intermediate 49-1) was prepared following the procedure described in Step 1 for Intermediate 48 using 1-iodo-3-methylbicyclo [1,1,1] pentane in place of Intermediate 24-2.
[0341] [0341] Step 2: Intermediate 49 was prepared following the procedure described in Step 2 for Intermediate 49 using Intermediate 49-1 in place of Intermediate 48-1. NMR * H (400 MHz, CDCl3) 5 10.23 (s, 1H), 2.23-2.20 (m, 2H), 1.96 (s, 6H), 1.89-1.71 (m , 8H), 1.58-1.55 (m, 2H), 1.16 (s, 3H). Intermediate 50 Acid 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy)> - 4- (4 - ((6- (3- (difluoromethyl) bicycles [1,1,1] pentan- 1-i) spiro [3.5] non-6-en-7-yl)] methyl) piperazin-1-i) benzoic co 8 O .
[0342] [0342] Step 1u 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((6- (3- (difluoromethyl) bicycles [1,1,1 ] pentan-1-yl) spiro [3,5] non-6-en-7-yl)] Methyl) piperazin-1- i) methyl benzoate (Intermediate 50-1) was prepared following the procedure described in Step 1 , Route C, to Intermediate 28 using Intermediate 48 in place of Intermediate 22. LC / MS (ESI) m / z 603.5 [M + H] *.
[0343] [0343] Step 2: Intermediate 50 was prepared following the procedure described in Step 5, Route B, for Intermediate 28 using Intermediate 50-1 in place of 2 - ((1H-pyrrolo [2,3-b] pyridine -5-yl) Oxy) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-en-1- yl)] methyl) piperazin-1-yl) methyl benzoate. LC / MS (ESI) m / z 589.3. Intermediate 51 Acid 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl)> Oxy) -4- (4 - ((6- (3-methylbicyclo [1,1,1] pentan-1 - i) spiro [3.5] non-6-en-7-yl)] mMethyl) piperazin-1-yl) benzoic
[0344] [0344] Step 1u 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((6- (3-methylbicyclo [1,1,1] pentan- 1-yl) spiro [3,5] non-6-en-7-yl)] Methyl) piperazin-1-yl) methyl benzoate: Intermediate 51-1 was prepared following the procedure described in Step 1, Route C to Intermediate 28 using Intermediate 49 in place of Intermediate 22. LC / MS (ESI) m / z 567.3 [M + H] *.
[0345] [0345] Step 2: Intermediate 50 was prepared following the procedure described in Step 5, Route B, for Intermediate 28 using Intermediate 51-1 in place of 2 - (((1H-pyrrolo [2,3-b] pyridin -5-yl) Oxy) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-en-1- yl)] methyl) piperazin-1-yl) methyl benzoate. LC / MS (ESI) m / z 553.3. Intermediate 52 4 - ((((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrobenzenesulfonamide o Walnut
[0346] [0346] To a stirred solution of (4-fluorotetrahydro-2H-pyran-4-yl) netanamine (450 mg, 3,388 mmol) in THF (25 mL) was added 4-fluoro-3-nitrobenzenesulfonamide (669 mg, 3, 04 mmol) followed by triethylamine (1.37 g, 13.52 mmol) at room temperature. After 16 hours, the reaction was concentrated and ground with EtOAc and Et2O. The crude product was purified by column chromatography (C18, NHaCO3H (aq.) 0.1 µM: CH3CN) to provide Intermediate 52 (220 mg, 21% yield) as a yellow solid. LC / MS (ESI) m / z 334.3 [M + H] *.
[0347] [0347] Intermediate 53 was prepared following the procedure described in Step 3 for Intermediate 7, using (4-fluorotetrahydro-2H-pyran-4-yl) methanol instead of Intermediate 7-2. LC / MS (ESI) m / z 333.5 [M-H]. Intermediate 54 4 - ((2-morpholinoethyl) amino) -3-nitrobenzenesulfonamide o NO; GQ
[0348] [0348] Intermediate 54 was prepared following a procedure described in WO2010 / 065824. LC / MS (ESI) m / z 331.2 [M + H] *. Intermediate 55 3-nitro4 - ((tetrahydro-2H-pyran-4-yl) methoxy) benzenesulfonamide o NO; streak O
[0349] [0349] Intermediate 55 was prepared following the procedure described in Step 3 for Intermediate 7, using (tetrahydro-2H-pyran-4-yl) methanol instead of Intermediate 7-2. LC / MS (ESI) m / z 315.1 [M-H]. Intermediate 56 Acid 4- (4 - ((2- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1-yl) -5,5-dimethylcyclohex-1-en-1-yl)] Methyl) piperazin-1-yl) benzoic
[0350] [0350] Step 1: 2- (dietoxymethyl) -1- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1-yl) - 4,4-dimethylcyclohexanol (Intermediate 56-1) was prepared following the procedure described in Step 1 for Intermediate 25 using Intermediate 24-2 instead of i-iodine-3 (trifluoromethi |) bicyclo [1,1,1] pentane and 2- (dietoxymethyl) -4,4-dimethylcyclo -hexanone in place of Intermediate 19. The crude product was used in the next step without purification.
[0351] [0351] Step 2: 2- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1-i1) -5,5-dimethylcyclohex-1-enocarbaldehyde (Intermediate 56-2) was prepared following the procedure described in Step 2 for Intermediate 22 using Intermediate 56-1 in place of Intermediate 22-1. NMR * H (400 MHz, CDCl3) 5 10.25 (br s, 1H), 5.74 (t, J = 56.0 Hz, 1H), 2.23-2.21 (m, 2H), 2 , 20 (s, 6H), 2.03 (br s, 2H), 1.38 (t, J = 6.4 Hz, 2H), 0.89 (s, 6H).
[0352] [0352] Step 3: To a stirred solution of methyl 4- (piperazin-1-yl) benzoate (389 mg, 1.77 mmol) in THF (10 mL) was added a solution of Intermediate 56-2 (450 mg , 1.77 mmol) in THF (5 mL) at room temperature. The reaction was stirred for 1 h, treated with Na (OAc) 3BH (1.12 g, 5.31 mmol) at 0 ° C, and then warmed to room temperature. After 16 h, MeOH (10 ml) was added and the reaction was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in DCM (20 ml) and washed with saturated aqueous NaHCO solution; (3x 10 mL). The organic layer was dried with Na2SO4: filtered and concentrated. The crude product was purified by column chromatography (SiO> 2, EtOAc / petroleum ether) to produce 4- (4 - ((2- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1-yl ) -5,5-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) methyl benzoate (Intermediate 56-3) (400 mg, 49% randimantsit AeqamaA 1m acid achrannminadao | O / MO ESN m / 7 ARO O IN LUITH
[0353] [0353] Step 4: Intermediate 56 was prepared following the procedure described in Step 5, Route B, for Intermediate 28 using Intermediate 56-3 in place of 2 - (((1H-pyrrolo [2,3-b] pyridin -5-yl) Oxy) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-en-1- yl)] methyl) piperazin-1-yl) methyl benzoate. LC / MS (ESI) m / z 445.4 [M + H] *. Intermediate 57 (R) -4 - ((4- (3-hydroxyazetidin-1-i1) -1- (phenylthio) outan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) benzenesulfonamide IT'S THE
[0354] [0354] Step 1: To a solution of (R) -4- (phenylthio) -3 - ((4-sulfamoyl-2- ((trifluoromethyl) sulfonyl) phenyl) amino) butanoic acid (1.5 g, 3, 01 mmol) and O- (benzotriazol-1-yl) -N, N, N 'N'-tetramethyluronium (TBTU) (1.09 g, 3.41 mmol) in DCM (3 mL) at 0 ºC was N-methylmorpholine (1.3 ml, 9.3 mmol) and DMF (1.5 ml) are added. The reaction was warmed to room temperature and stirred for 0.5 hour. The reaction mixture was then cooled to 0 ° C, and azetidin-3-ol (264 mg, 3.61 mmol) was added, and the reaction was warmed to room temperature. After 16 h, the REACTION was quenched with saturated aqueous NaHCO solution; (50 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers were dried over Na> SO ;, filtered and concentrated. The crude product was purified by column chromatography (SiOr MeOH / DCM) to yield (R) 4 - ((4- (3-hydroxyazetidin-1-11) -4-0x0-1- (phenylthio) butan-2-yl ) amino) -3 - ((trifluoromethyl) sulfonyl) benzenesulfonamide (Intermediate 57-1) (1.00 g, 60% yield) as an off-white solid. LC / MS (ESI) m / z 554.1.
[0355] [0355] Step 2: To a stirred solution of Intermediate 57-1 (1.0 g, 1.80 mmemaAh am TUC ON mlVa No. O fai adiriahadsa PRU.aTHE 1 M in TUC FERN ml RE mmol) and the temperature was heated to room temperature. After 1 h, the reaction mixture was heated to 55 ºC and stirred for 16 h in a sealed tube. The reaction mixture was then cooled to 0 ° C, brusquely cooled with NH3 (7.0 M in MeOH, 5 ml) to 0 ° C and warmed to room temperature. After 16 h, the reaction was concentrated and purified by column chromatography (SiO ,, MeOH / DCM) to produce Intermediate 57 (500 mg, 51% yield) as an off-white solid. LC / MS (ESI) m / z 540.3 [M + H] *. Intermediate 58 Acid 4- (4 - ((6- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1-yl) spiro [3,5] non-6-en-7- i) methyl) piperazin-1-yl) benzoic Oo:
[0356] [0356] Step 1: 4- (4 - ((6- (3- (difluoromethyl) bicycle [1,1,1] pentan-1-yl) spiro [3,5] non-6- en-7-yl )] methyl) piperazin-1-yl) methyl benzoate (Intermediate 58-1) was prepared following the procedure described in Step 3 for Intermediate 56 using Intermediate 48 in place of Intermediate 56-2. LC / MS (ESI) m / z 471.3 [M + H] *.
[0357] [0357] Step 2: Intermediate 58 was prepared following the procedure described in Step 5, Route B, for Intermediate 28 using Intermediate 58-1 in place of 2 - (((1H-pyrrolo [2,3-b] pyridin -5-yl) Oxy) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-en-1- yl)] | methyl) piperazin-1-yl) benzoate - methyl. LC / MS (ESI) m / z 457.5 [M + H] *. Intermediate 59 (R) -4 - ((4- (4- (2 - ((tert-butyldiphenylsilyl) oxy) ethyl) piperazin-1-yl) -1- (phenylthio) butan-2- i)> amino) - 3 - ((trifluoromethyl) sulfonyl) benzenesulfonamides res a meo O
[0358] [0358] Step 1: (R) -4 - ((4- (4- (2 - ((tert-butyldiphenylsilyl) oxy) ethyl) piperazin-1-11) -4-0x0- 1- (phenylthio) butan- 2-yl) amino) -3 - ((trifluoromethyl) sulfonyl) benzenesulfonamide (Intermediate 59-1) was prepared following the procedure described in Step 1 for Intermediate 45, using 1- (2 - (((tert-butyldiphenylsilyl) oxy) ethyl) piperazine instead of N N-dimethylpiperidin-4-amine. LC / MS (ESI) m / z 849.3 [M + H] *.
[0359] [0359] Step 2: Intermediate 59 was prepared following the procedure described in Step 2 for Intermediate 57 using Intermediate 59-1 in place of Intermediate 57-1. LC / MS (ESI) m / z 835.0 [M + H] *. Intermediate 60 (R) -4 - ((4 - ((2 - ((tert-butyldiphenylsily) oxy) ethyl) (ethyl) amino) -1- (phenylthio) butan-2-yl) amino) -3- Ltrifluoromethyl) sulfoni) benzenesulfonamide eFs OF
[0360] [0360] Step 1: 2 - ((tert-butyldiphenylsilyl) oxy) -N-ethylethhanamine (Intermediate 60-1) was prepared following a procedure described in WO2012 / 017251A1. LC / MS (ESI) m / z 328.4 [M + H] *.
[0361] [0361] Step 2: To a stirred solution of (R) -4- (phenylthio) -3 - ((4-sulfamoyl-2- ((trifluoromethyl) sulfonyl) phenyl) amino) butanoic acid (500 mg, 1.0 mmol) in CH3; CN (10 mL) at 0 ºC Intermediate 60-1 (328 mg, 1.01 mmol) in CH3CN (2 mL) was added, followed by N-methyl imidazole (250 mg, 3.1 mmol ) and N, N, N ', N-tetramethylchloroformamidinium (TCFH) hexafluorophosphate (308 mg, 1.1 mmol). The reaction was warmed to room temperature and stirred for 16 hours. The reaction was then. diluted with water and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated aqueous NaHCO solution; (2 x 20 ml), water (2 x 10 ml) and then brine (2 x 20 ml). The organic layer was dried with Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (SiO>, EtOAc / petroleum ether) to produce (R) -N- (2 - ((tert-butyldiphenylsilyl) oxy) ethyl) -N-ethyl-4- (phenylthio) -3 - ((4-sulfamoyl-2 - ((trifluoromethyl) sulfonyl) phenyl) amino) butanamide (Intermediate 60-2) (500 mg, 65% yield) as a yellow oil. LC / MS (ESI) m / z 808.4 [M + H] *.
[0362] [0362] Step 2: Intermediate 60 was prepared following the procedure described in Step 2 for Intermediate 57 using Intermediate 60-2 in place of Intermediate 57-1. LC / MS (ESI) m / z 794.8 [M + H] *. Intermediate 61 4 - (((2R) -4- (3-hydroxypyrrolidin-1-i1) -1- (phenylthio) butan-2-i) amino) -3- ((trifluoromethyl) sulfonyl) benzenesulfonamide that no IAGO
[0363] [0363] Step 1: 4 - (((2R) -4- (3-hydroxypyrrolidin-1-11) -4-0x0-1- (phenylthio) butan-2-yl)> amino) -3 - ((trifluoromethyl ) sulfonyl) benzenesulfonamide (Intermediate 61-1) was prepared following the procedure described in Step 1 for Intermediate 45, using pyrrolidin-3-ol instead of N, N-dimethylpiperidin-4-amine. LC / MS (ESI) m / z 568.1 [M + H] *.
[0364] [0364] Step 2: Intermediate 61 was prepared following the procedure described in Step 2 for Intermediate 57 using Intermediate 61-1 in place of Intermediate 57-1. LC / MS (ESI) m / z 554.4 [M + H] *. Intermediate 62 Acid 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((2- (3-chlorobicyclo [1,1,1] pentan-1- iNcyclohex-1-en-1-yl)] methyl) piperazin-1-i) benzoic
[0365] [0365] Step 1: 1- (3-Chlorobicyclo [1,1,1] pentan-1-yl) hex-5-en-1-one (Intermediate 62-1) was prepared following the procedure described in Step 1 to o Intermediate 26, using 5-bromopent-1-ene instead of 5-iodo-3,3-dimethylpent-1-ene. NMR * H (300 MHz, CDCl3) 5 5.84-5.66 (m, 1H), 5.03-4.97 (m, 2H), 2.48 (s, 6H), 2.44 (t , J = 7.2 Hz, 2H), 2.08-2.01 (m, 2H), 1.71-1.61 (m, 2H).
[0366] [0366] Step 2: E / Z-7- (3-chlorobicyclo [1,1,1] pentan-1-yl) -7-0xo-hept-2-enonitrile (Intermediate 62-2) was prepared following the procedure described in Step 2 for Intermediate 26 using Intermediate 62-1 in place of Intermediate 26-1. LC / MS (ESI) m / z 236.3 [M + H] *.
[0367] [0367] Step 3: 7- (3-Chlorobicyclo [1,1,1] pentan-1-yl) -7-o0xo-heptanonitrile (Intermediate 62-3) was prepared following the procedure described in Step 3 for Intermediate 26 using Intermediate 62-2 in place of Intermediate 26-2. 1H NMR (400 MHz, CDCl3) 5 2.47 (t, J = 7.2 Hz, 2H), 2.40 (s, 6H), 2.35 (t, J = 6.8 Hz, 2H), 1.70-1.62 (m, 2H), 1.61-1.55 (m, 2H), 1.48-1.41 (m, 2H).
[0368] [0368] Step 4: 2- (3-Chlorobicyclo [1,1,1] pentan-1-yl) cyclohex-1-enocarbonitrile (Intermediate 62-4) was prepared following the procedure described in Step 4 for Intermediate 26 using Intermediate 62-3 in place of Intermediate 26-3. LC / MS (ESI) m / z 208.1 [M + H] *.
[0369] [0369] Step 5: 2- (3-Chlorobicyclo [1,1,1] pentan-1-yl) cyclohex-1-enocarbaldehyde (Intermediate 62-5) was prepared following the procedure described in Step 5 for Intermediate 26 using Intermediate 62-4 in place of Intermediate 26-4. NMR * H (300 MHz, CDCl3) 5 10.16 (s, 1H), 2.46 (s, 6H), 2.23-2.21 (m, 2H), 2.15-2.13 (m , 2H), 1.64-1.54 (m, 4H).
[0370] [0370] Step 6: 2- (1H-pyrrolo [2,3-b] pyridin-S5-yloxy) -4- (4 - ((2- (3-chlorobicyclo [1,1,1] pentan-1- il) cyclohex-1-enyl) methyl) piperazin-1-yl) tert-butyl benzoate (Intermediate 62-6) was prepared following the procedure described in Step 6, Route A, for Intermediate 28 using Intermediate 62 -5 in place of Intermediate 22. LC / MS (ESI) m / z 589.3 [M + H] *.
[0371] [0371] Step 7: Intermediate 62 was prepared following the procedure described in Step 7 for Intermediate 32 using Intermediate 62-6 in place of Intermediate 32-6. LC / MS (ESI) m / z 533.3 [M + H] *. General procedure A: Formation of acyl sulfonamide
[0372] [0372] To a solution of sulfonamide B or corresponding acid A (1.0-1.2 equiv. Note No. 1) in DCM (0.01 to 0.1 M) at 0 ºC was added EDC-HCI (1- 2.5 equiv.) Followed by DMAP (1 to 2 equiv.). After 10 minutes, suitable acid A or sulfonamide B (1 to 1.5 equiv. Note # 1) and N-methylmorpholine (2 to 4 equiv. Note # 2) was added at 0 ° C and the reaction was heated to temperature environment or at 35 ºC. After completion, as determined by LCMS (or CCF), water was added and the reaction was extracted with DCM. The combined organic layers were dried over Na2SO, and concentrated. Crude product C was purified by 1) column chromatography (SiO>), 2) HPLC (10 mM NHaCO3H (ag): CH3CN or MeOH) or 3) trituration with an organic solvent.
[0373] [0373] To a solution of the corresponding sulfonamide B (1.0 equiv.) In DCM (0.01 to 0.1 M) at room temperature, EDC-HCI (1.5 to 1.75 equiv) was added and DMAP (1 to 2.5 equiv.). In a separate flask, the appropriate acid A (1 to 1.1 equiv.) Was dissolved in DCM (0.02 to 0.1 M) and treated with Et3N (2 equiv.). Note 1). After minutes, the acidic solution was added to the sulfonamide suspension and stirred at room temperature or heated to 35 ° C. After completion, as determined by LCMS, N, N-dimethylethylenediamine (2 to 2.5 equiv., Note # 2) was added to the reaction mixture, and the reaction was stirred for 90 min. The reaction mixture was then washed with 10% aqueous solution of ACOH (Note 5), NaHCO (agq.) And then with 5% NaCl (aq.). The organic layer was concentrated and the crude product C was purified by 1) column chromatography (SiO>), 2) HPLC (NH.CO3H (ag) 10 MM: CH3CN or MeOH) or 3) trituration with an organic solvent.
[0374] [0374] Representative example of General Procedure A: To a solution of 3-nitro-4 - (((tetrahydro-2H-pyran-4-yl) methyl) amino) benzenesulfonamide (63 mg, 0.20 mmol) in DCM ( 20 mL) EDC-HCI (58 mg, 0.30 mmol) was added followed by DMARP (49 mg, 0.40 mmol) at 0 ° C. After 10 minutes, Intermediate 26 (140 mg, 0.20 mmol) and N-methylmorpholine (0.07 mL, 0.60 mmol) were added and the reaction was warmed to room temperature. After 16 hours, water was added and the mixture was extracted with DCM. The combined organic layers were dried over Na> 2SO2, filtered and concentrated. The crude product was purified by HPLC (10:90 to 99: 1, NH.CO3H (aq.) 10 mMM / CH3CN) to produce Example 1 (69 mg, 39%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) 5 11.68 (br s, 1H), 11.42 (br s, 1H), 8.58 (br s, 1H), 8.53 (s, 1H) , 8.03 (d, J = 2.1 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.54-7.46 (m, 3H), 7.10- 7.02 (m, 1H), 6.74-6.68 (m, 1H), 6.38 (s, 1H), 6.25 (s, 1H), 3.89-3.82 (m, 2H), 3.33-3.22 (m, 4H), 3.19-3.05 (m, 4H), 2.90 (s, 2H), 2.33 (br s, 4H), 2, 29 (s, 6H), 2.05-1.95 (m, 2H), 1.95-1.82 (m, 1H), 1.69-1.57 (m, 4H), 1.32- 1.18 (m, 4H), 0.82 (s, 6H); LC / MS (ESI) m / z 858.4 [M + H] *. Example 2 2- (1H-pyrrolo [2,3-b] pyridin-5-yl-Oxy) -N- (4- (2-oxaspiro [3,3] heptan-6-yl-netylamino) -3- heptan ) -4- (4 - ((2- (3-chlorobicyclo [1,1,1] pentan-1-iI) - 4 4-dimethylcyclohex-1en- i) methyl) piperazin-1-yl) benzamide
[0375] [0375] Example 2 was prepared according to General Procedure A using Intermediate 26 and Intermediate 3. NMR * H (400 MHz, CDCI3) 5 10.13 (br s, 1H), 8.89 (d, J = 2 Hz, 1H), 8.82 (br s, 1H), 8.33 (t, J = 5.2 Hz, 1H), 8.22 (d, J = 2.8 Hz, 1H), 8.17 (dd, J = 9.4, 1.6 Hz, 1H), 7.98 (d, J = 9.6 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H ), 7.44 (br s, 1H), 6.88 (d, J = 9.2 Hz, 1H), 6.59-6.56 (m, 2H), 6.02 (s, 1H), 4.74 (s, 2H), 4.63 (s, 2H), 3.32 (t, J = 5.2 Hz, 2H), 3.15-3.05 (m, 4H), 2.89 (s, 2H), 2.55-2.45 (m, 2H), 2.38-2.28 (m, 4H), 2.25 (s, 6H), 2.08-1.95 (br s, 4H), 1.64 (s, 2H), 1.33-1.25 (m, 2H), 0.84 (s, 6H); LC / MS (ESI) m / z 870.6 [M + H] *. Example 3 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -N - ((4 - ((2- (2-0x-8-azaspiro [4,5] decan- 8- iN) ethi) amino) -3-nitropheni!) Sulfonyl) -4- (4 - ((2- (3-chlorobicyclo [1,1,1] pentan-1-i1) -4,4- dimethylcyclo- hex-1-en-1-yl) methyl) piperazin-1-yl) benzamide DL no ESTO O THE
[0376] [0376] Example 3 was prepared according to General Procedure A using Intermediate 26 and Intermediate 4. NMR * H (300 MHz, CDCI3) 5 10.18 (br s, 1H), 9.21 (br s , 1H), 8.99 (br s, 1H), 8.88 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 8.16 ( dad,
[0377] [0377] Example 4 was prepared according to General Procedure A using Intermediate 26 and Intermediate 5. 1H NMR (400 MHz, DMSO-ds) at 11.60 (s, 1H), 8.50 (br s , 1H), 8.46 (s, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.57 (d , J = 8.8 Hz, 1H), 7.45 (t, J = 2.4 Hz, 1H), 7.38 (br s, 1H), 6.93 (d, J = 9.2 Hz, 1H), 6.69 (dd, J = 9.4, 2.0 Hz, 1H), 6.34 (dd, J = 3.2, 2.0 Hz, 1H), 6.28 (d, J = 2.0 Hz, 1H), 3.60-3.38 (m, 10H), 3.16-2.95 (m, 6H), 2.89 (s, 2H), 3.38-2, 30 (m, 4H), 2.29 (s, 6H), 2.05-1.98 (m, 2H), 1.71-1.66 (m, 6H), 1.23 (t, J = 6.4 Hz, 2H), 0.82 (s, 6H), an NH proton not observed; NMR * H (400 MHz, DMSO-d6) LC / MS (ESI) m / z 913.5 [M + H] *. Example 5 2 - (((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -N - ((4 - (((7-oxaspiro [3,5] nonan-2-yl)] methyl ) amino) - 3-nitrophenyl) sulfonyl) -4- (4 - ((2- (3-chlorobicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex-1-en- 1-yl)] methyl) piperazin-1-yl) benzamide o FERN NON AND
[0378] [0378] Example 5 was prepared according to General Procedure À using Intermediate 26 and Intermediate 6. NMR * H (400 MHz, CDCI3) 5 10.13 (br s, 1H), 8.88 (d, J = 2.4 Hz, 1H), 8.81 (br s, 1H), 8.37 (t, J = 4.8 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H ), 8.17 (dd, J = 9.6, 2.4 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 2.8 Hz , 1H), 7.44 (t, J = 2.8 Hz, 1H), 6.88 (d, J = 9.6 Hz, 1H), 6.59-6.54 (m, 2H), 6 , 01 (d, J = 2.0 Hz, 1H), 3.64 (t, J = 4.8 Hz, 2H), 3.56 (t, J = 5.2 Hz, 2H), 3.39 -3.36 (m, 2H), 3.10 (br s, 4H), 2.89 (s, 2H), 2.70-2.65 (m, 1H), 2.32 (br s, 4H ), 2.24 (s, 6H), 2.14-2.09 (m, 2H), 2.01 (br s, 2H), 1.68 (t, J = 5.2 Hz, 2H), 1.63-1.56 (m, 6H), 1.25 (t, J = 6.0 Hz, 2H), 0.83 (s, 6H); LC / MS (ESI) m / z 898.4 [M + H] *. Example 6 2 - (((1H-pyrrolo [2,3-b] pyridin-S-yl) oxy) -N - ((4 - ((4-0xaspiro [2,4] heptan-6-yl) Oxy) - 3-nitrophenyl) sulfonyl) -4- (4 - ((2- (3-chlorobicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex-1- en-1-yl) methyl) piperazin-1-yl) benzamide o No FAITH Noz
[0379] [0379] Example 6 was prepared according to General Procedure A using Intermediate 26 and Intermediate 7. LC / MS (ESI) m / z 857.4 [M + H] *.
[0380] [0380] Example 7 was prepared according to General Procedure A using Intermediate 26 and Intermediate 8. LC / MS (ES!) M / z 886.5 [M + H] *. Example 8 2- (1H-pyrrolo [2,3-b] pyridin-S-yloxy) -N- (4- (2-oxaspiro [3,3] heptan-6-ylmethoxy) -3-nitrophenylsulfonyl) -4- (4 - ((2- (3-chlorobicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzamide o No Ss No , So &
[0381] [0381] Example 8 was prepared according to General Procedure A using Intermediate 26 and Intermediate 9. LC / MS (ESI) m / z 871.6 [M + H] *.
[0382] [0382] Example 9 was prepared according to General Procedure A below, using Intermediate 28 and 3-nitro-4 - ((((tetrahydro-2H-pyran-4-i) methyl) amino) benzenesulfonamide. NMR * H (400 MHz, DMSO-ds) 5 11.68 (s, 1H), 11.42 (br s, 1H), 8.58 (br s, 1H), 8.54 (s, 1H), 8.03 (s, 1H), 7.80-7.76 (m, 1H), 7.53-7.48 (m, 3H), 7.12-7.05 (m, 1H), 6, 74-6.70 (m, 1H), 6.38 (s, 1H), 6.25 (s, 1H), 3.85-3.83 (m, 2H), 3.30-3.23 ( m, 4H), 3.19-3.05 (m, 4H), 2.99 (br s, 2H), 2.38-2.32 (m, 4H), 2.05-1.95 (m , 2H), 1.93-1.85 (m, 1H), 1.75 (s, 6H), 1.67-1.58 (m, 4H), 1.30-1.20 (m, 4H ), 1.10 (s, 3H), 0.81 (s, 6H); LC / MS (ESI) m / z 838.5 [M + H] *. Example 10 2- (1H-pyrrolo [2,3-b] pyridin-S-yloxy) -4- (4 - ((2- (3-fluorobicyclo [1,1, 1] pentan-1-11) -4 , 4-dimethylcyclohex-1-enyl)] methyl) piperazin-1-yl) -N- (3-nitro-4 - (((tetrahydro-2H-pyran-4- i) methylamino) phenylsulfonyl) benzamide
[0383] [0383] Example 10 was prepared according to General Procedure A below, using Intermediate 27 and 3-nitro-4 - ((((tetrahydro-2H-pyran-4-iN) methyl) amino) benzenesulfonamide. NMR * H (300 MHz, CDCl3) 5 10.20 (br s, 2H), 9.09 (br s, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8.52 ( t, J = 5.7 Hz, 1H), 8.22-8.15 (m, 2H), 7.98 (d, J = 9.3 Hz, 1H), 7.71 (d, J = 9 , 3 Hz, 1H), 7.45 (t, J = 3.0 Hz, 1H), 6.92 (d, J = 9.3 Hz, 1H), 6.60-6.54 (m, 2H ), 6.03-6.01 (m, 1H), 4.03 (dd, J = 11.5, 3.9 Hz, 2H), 3.46-3.38 (m, 2H), 3, 27 (t, J = 6.0 Hz, 2H), 3.12-3.09 (m, 4H), 2.91 (s, 2H), 2.35-2.33 (m, 4H), 2 , 15 (d, J = 2.4 Hz, 6H), 2.09-1.95 (m, 3H), 1.77-1.62 (m, 4H), 1.51-1.38 (m , 2H), 1.27 (t, J = 6.3 Hz, 2H), 0.84 (s, 6H); LC / MS (ESI) m / z 842.4 [M + H] *. Example 11 2 - (((1H-pyrrolo [2,3-b] pyridin-S-yl) oxy) -N - ((4 - (((7-oxaspiro [3,5] nonan-2-yl) methyl) amino) - 3-nitropheni!) sulfonyl) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-en -1-yl)] methyl) piperazin-1-yl) benzamide o FERN No:
[0384] [0384] Example 11 was prepared according to General Procedure A using Intermediate 28 and Intermediate 6. NMR * H (400 MHz, CDCI3) 5 10.15
[0385] [0385] To a stirred solution of Intermediate 28 (150 mg, 0.277 mmol) in DMF (1 mL) at 0 ° C, EDC-HCI (106.2 mg, 0.554 mmol) and 1-hydroxy-7-azabenzotriazole ( 75.4 mg, 0.554 mmol). After 10 minutes, Intermediate 14 (92 mg, 0.277 mmol) and DIPEA (108 mg, 0.83 mmol) were added and the reaction was warmed to room temperature. After 48 h, water (10 ml) was added and the reaction was extracted with DCM (3 x 10 ml). The combined organic layers were dried over Na> 2SO, anhydrous, filtered and concentrated. The crude product was purified by HPLC (30:70 to 1:99, NHCO3H (aq.) 10 MM: CH3CN) to provide Example 12 as a yellow solid (6 mg, 3% yield). LC-MS (ESI) m / z 851.4 [M + H] *.
[0386] [0386] Example 13 was prepared according to General Procedure A using Intermediate 28 and Intermediate 15. NMR * H (400 MHz, CDCI3) at 9.07 (br s, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8.66 (t, J = 5.2, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.10 (dd, J = 9 , 2, 1.6 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 3.2 Hz, 1H), 6.92 (d, J = 9.2 Hz, 1H), 6.59 (dd, J = 9.2, 2.4 Hz, 1H), 6.54 (dd , J = 3.6, 2.0 Hz, 1H), 6.04 (d, J = 2.4 Hz, 1H), 3.52 (dd, J = 19.6, 6.0 Hz, 2H) , 3.11 (t, J = 4.8 Hz, 4H), 2.99 (s, 2H), 2.82-2.75 (m, 2H), 2.41-2.31 (m, 8H ), 2.06-1.97 (m, 4H), 1.74 (s, 6H), 1.65 (s, 2H), 1.33-1.22 (s, 5H), 1.10 ( s, 3H), 0.82 (s, 6H). An unobserved NH proton; LC / MS (ESI) m / z 869.5 [M + H] *. Example 14 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1,1 ] pentan-1- iD) cyclohex-1-en-1-yl)] methyl) piperazin-1-yl) -N - ((4 - (((1r, 4r) - 4- (dimethylamino) cyclo- hexyl)> amino) -3-nitrophenyl) sulfonyl) Dbenzamide
[0387] [0387] Example 14 was prepared according to General Procedure À using Intermediate 28 and Intermediate 16. LC / MS (ESI) m / z 865.5 [M + H] *. Example 15 2- (1H-pyrrolo [2,3-b] pyridin-S-yloxy) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo 1,1 1] pentan-1- il) cyclohex-1-enyl) methyl) piperazin-1-yl) -N- (4 - ((4-fluorotetrahydro-2H-pyran-4-yl)] methylamino) -3-nitrophenylsulfonyl) benzamide 78 O. oo THERE NON ” N
[0388] [0388] Example 15 was prepared according to General Procedure À using Intermediate 28 and Intermediate 52. NMR * H (400 MHz, CDCI3) 5 10.16 (br s, 1H), 8.97 (br s , 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.67 (t, J = 5.6 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H ), 8.19 (dd, J = 9.0, 2.4 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 2.4 Hz , 1H), 7.45 (t, J = 2.8 Hz, 1H), 6.98 (d, J = 9.2 Hz, 1H), 6.59 (dd, J = 9.0, 2, 4 Hz, 1H), 6.55 (dd, J = 3.2, 2.0 Hz, 1H), 6.02 (d, J = 2.4 Hz, 1H), 3.89 (dd, J = 11.8, 4.0 Hz, 2H), 3.79-3.72 (m, 2H), 3.55 (dd, J = 19.6, 6.0 Hz, 2H), 3.11-3 .09 (m, 4H), 3.00 (s, 2H), 2.36-2.33 (m, 4H), 2.05-1.95 (m, 2H), 1.94-1.75 (m, 4H), 1.74 (s, 6H), 1.64 (s, 2H),
[0389] [0389] Example 16 was prepared according to General Procedure A using Intermediate 28 and Intermediate 53. NMR * H (400 MHz, CDCI3) ô 10.16 (br s, 1H), 8.85 (br s , 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.38 (dd, J = 9.2, 24 Hz, 1H), 8.22 (d, J = 2.8 Hz , 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 2.8 Hz, 1H), 7.45 (t, J = 2.8 Hz, 1H ), 7.18 (d, J = 8.8 Hz, 1H), 6.60-6.54 (m, 2H), 6.01 (d, J = 2.0 Hz, 1H), 4.18 (d, J = 18.0 Hz, 2H), 3.91-3.87 (m, 2H), 3.81-3.74 (m, 2H), 3.12-3.10 (m, 4H ), 2.99 (s, 2H), 2.36-2.34 (m, 4H), 2.01-1.83 (m, 6H), 1.74 (s, 6H), 1.65 ( s, 2H), 1.24 (t, J = 6.0 Hz, 2H), 1.10 (s, 3H), 0.82 (s, 6H); LC / MS (ESI) m / z 857.5 [M + H] *. Example 17 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) Oxy) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1,1 pentan-1-yl) cyclohex-1-en-1-yl)] methyl) piperazin-1-yl) -N - ((4 - ((((4-methylmorpholin-2-iNmethyl) amino) -3- nitrophenyl) sulfonyl) benzamide x O. oo Oo NON O N
[0390] [0390] Example 17 was prepared according to General Procedure À using Intermediate 28 and Intermediate 17. NMR * H (400 MHz, CDCI3) 5 10.16 (br s, 1H), 8.97 (br s , 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.65 (t, J = 5.6 Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H ), 8.13 (dd, J = 9.0, 2.4 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 2.4 Hz , 1H), 7.43 (t, J = 2.8 Hz, 1H), 6.88 (d, J = 9.2 Hz, 1H), 6.58 (dd, J = 9.2, 2, 0 Hz, 1H), 6.55 (dd, J = 3.6, 2.0 Hz, 1H), 6.03 (d, J = 2.0 Hz, 1H), 3.95 (d, J = 10.4 Hz, 1H), 3.90 - 3.84 (m, 1H), 3.73 (dt, J = 11.4, 2.4 Hz, 1H), 3.49-3.36 (m , 2H), 3.12-3.09 (m, 4H), 2.99 (s, 2H), 2.77 (d, J = 11.2 Hz, 1H), 2.67 (d, J = 11.6 Hz, 1H), 2.36-2.33 (m, 4H), 2.32 (s, 3H), 2.19 (dt, J = 11.4, 3.2 Hz, 1H), 2.03-1.98 (m, 3H), 1.74 (s, 6H), 1.65 (s, 2H), 1.24 (t, J = 6.4 Hz, 2H), 1.10 (s, 3H), 0.82 (s, 6H); LC / MS (ESI) m / z 853.5 [M + H] *. Example 18 (R) -2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1 , 1,1] pentan-1-yl) cyclohex-1-en-1-yl)] methyl) piperazin-1-yl) -N - ((4 - ((((4-methylmorpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide od. re) [and] NON N. &
[0391] [0391] Example 18 was prepared according to General Procedure À using Intermediate 28 and Intermediate 17A. LC / MS (ESI) m / z 853.5 [M + H] *. Absolute stereochemistry was assigned arbitrarily. Example 19 (S) -2 - ((1H-pyrrolo [2,3-b] pyridin-S5-yl) Oxy) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1 , 1 1] pentan-1-yl) cyclohex-1-en-1-yl)] methyl) piperazin-1-yl) -N - ((4 - ((((4-methylmorpholin-2-yl) methyl ) amino) -3-nitrophenyl) sulfonyl) benzamide Noz O NOA ON NON O N
[0392] [0392] Example 19 was prepared according to General Procedure À using Intermediate 28 and Intermediate 17B. LC / MS (ESI) m / z 853.6 [M + H] *. Absolute stereochemistry was assigned arbitrarily. Example 20 2- (1H-pyrrolo [2,3-b] pyridin-S-yloxy) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan- 1- iD) cyclohex-1-enyl)] methyl) piperazin-1-yl) -N- (4 - ((((1r, 4r) -4-hydroxy-4-methylcyclohexyl)] methylamino) -3 -nitrophenylsulfonyl) benzamide
[0393] [0393] Example 19 was prepared according to General Procedure A using Intermediate 28 and Intermediate 18. LC-MS (ESI) m / z 866.5 [M + H] * Example 21 2- (1H-pyrrole [2,3-b] pyridin-S-yloxy) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex- 1-enyl) methyl) piperazin-1-yl) -N- (4- (2-morpholinoethylamino) -3-nitrophenylsulfonyl) benzamide
[0394] [0394] Example 21 was prepared according to General Procedure A using Intermediate 28 and Intermediate 54. LC / MS (ESI) m / z 853.6 [M + H] *. Example 22 2- (1H-pyrrolo [2,3-b] pyridin-S-yloxy) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1, 1] pentan- 1- yl) cyclohex-1-enyl)] methyl) piperazin-1-yl) -N- (3-nitro-4 - ((tetrahydro-2H-pyran-4- i) methoxy) phenylsulfonyl) benzamide ox. ' O. oo 0 NON CO N
[0395] [0395] Representative example of General Procedure B: To a stirred solution of Intermediate 55 (70.03 mg, 0.22 mmol) in DCM (5 mL) was added DMAP (54.02 mg, 0.44 mmol) and EDC -HCI (63.15 mg, 0.33 mmol) and DCM (5 mL). In a separate vial, Intermediate 28 (120 mg, 0.222 mmol), Et3N (0.046 mL, 0.44 mmol) and DCM (3 mL) were combined and stirred for 15 minutes. The acid-containing solution was then added slowly to the sulfonamide suspension, and the reaction mixture was stirred at room temperature. After 20 hours, N, N-dimethylethylenediamine (0.055 ml) was added to the reaction mixture, and stirring was continued for 90 minutes. The reaction mixture was then washed with 10% acetic acid solution (2 x 10 ml). Note: The organic layer was diluted with DCM (10 ml) and MeOH (3 ml), before the final separation of the aqueous layer. The organic layer was washed with NaHCO; (aq.) 5% (10 ml), 5% NaCl (aq.) (10 ml) and the organic layer was concentrated. The crude product was purified by HPLC (30:70 to 1:99, 10 mM NHACO3H (aq.): CH3CN) to produce Example 22 (55 mg, 30% yield) as a white solid. LC-MS (ESI) m / z 839.6 [M + H] * Example 23 2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -4- (4 - ((2- ( 3-ethylbicyclo [1,1,1] pentan-1-11) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) - N- (3-nitro-4 - ((tetrahydro -2H-pyran-4- i) methylamino) phenylsulfonyl) benzamide
[0396] [0396] Example 23 was prepared according to General Procedure B below, using Intermediate 29 and 3-nitro-4 - (((tetrahydro-2H-pyran-4 iN'methyl) amino) benzenesulfonamide. 1H NMR (400 MHz, DMSO-ds) 5 11.69 (s, 1H), 11.40 (br s, 1H), 8.59 (br s, 1H), 8.54 (s, 1H), 8.03 (s, 1H), 7.77 (d, J = 9.6 Hz, 1H), 7.56-7.48 (m, 3H), 7.07 (d, J = 8.8 Hz, 1H) , 6.72 (d, J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.26 (s, 1H), 3.85 (d, J = 11.2 Hz, 2H) , 3.33-3.23 (m, 4H), 3.20-3.05 (m, 4H), 3.05-2.94 (m, 2H), 2.41-2.28 (m, 4H), 2.05-1.95 (m, 2H), 1.94-1.81 (m, 1H), 1.70 (s, 6H), 1.66-1.59 (m, 4H) , 1.38 (q, J = 7.6 Hz, 2H), 1.31-1.19 (m, 4H), 0.82 (s, 6H), 0.78 (t, J = 8.0 Hz, 3H); LC / MS (ESI) m / z 852.5 [M + H] *. Example 24 2- (1H-pyrrolo [2,3-b] pyridin-S-yloxy) -4- (4 - (((2- (3-ethylbicyclo [1,1, 1] pentan-1-i1) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) - N- (4- ( (4-fluoro-1-methylpiperidin-4- i) methylamino) -3-nitrophenylsulfonyl) benzamide
[0397] [0397] Example 24 was prepared according to General Procedure B
[0398] [0398] Example 25 was prepared according to General Procedure B using Intermediate 29 and Intermediate 52. LC / MS (ESI) m / z 870.8 [M + H] *. Example 26 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((2- (3-ethylbicyclo [1,1,1] pentan-1-i1 ) -4,4- dimethylcyclohex-1-en-1-yl)] methyl) piperazin-1-yl) -N - ((4 - ((4-fluorotetrahydro-2H-pyran-4-iN) methoxy) -3-nitrophenyl) sulfonyl) benzamide ox. Ff ” N
[0399] [0399] Example 26 was prepared according to General Procedure B using Intermediate 29 and Intermediate 53. LC / MS (ESI) m / z 871.7 [M + H] *.
[0400] [0400] Example 27 was prepared according to General Procedure B using Intermediate 29 and Intermediate 18. LC / MS (ESI) m / z 880.6 [M + H] *. Example 28 2 - (((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((4,4-dimethyl-2- (3- (trifluoromethyl) bicycles [1, 1.1] pentan-1-yl) cyclohex-1-en-1-yl)] methyl) piperazin-1-yl) -N- (((3-nitro-4 - (((tetrahydro-2H-pyran -4-yl)] methyl) amino) phenyl) sulfonyl) benzamide AONÃ ” N
[0401] [0401] Example 28 was prepared according to General Procedure A proceeding 0 Intra-MU MU nn Lneite A Aatraides MH niran A iN) methyl) amino) benzenesulfonamide. NMR * H (400 MHz, DMSO-ds) 5 11.68 (s, 1 H), 11.50 (br s, 1H), 8.60 (br s, 1H), 8.55 (s, 1H) , 8.42 (d, J = 2.4 Hz, 1H), 7.82-7.77 (m, 1H), 7.53-7.49 (m, 3H), 7.12-7.08 (m, 1H), 6.73-6.70 (m, 1H), 6.39-6.38 (m, 1H), 6.25-6.23 (m, 1H), 3.87-3 , 83 (m, 2H), 3.38-3.24 (m, 4H), 3.14-3.09 (m, 4H), 2.94 (br s, 2H), 2.39-2, 31 (m, 4H), 2.11 (s, 6H), 2.04-1.98 (m, 2H), 1.90-1.85 (m, 1H), 1.68 (s, 2H) , 1.64-1.59 (m, 2H), 1.31-1.22 (m, 4H), 0.83 (s, 68H); NMR * ºF (376 MHz, DMSO-dG6, not referenced) 5 -71.53; LC / MS (ESI) m / z 892.6 [M + H] *.
[0402] [0402] Example 29 was prepared according to General Procedure B using Intermediate 31 and Intermediate 15. LC / MS (ESI) m / z 923.9 [M + H] *. Example 30 2 - (((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((4,4-dimethyl-2- (3- (trifluoromethyl) bicycles [1, 1 1] pentan-1-yl) cyclohex-1-en-1-yl)] methyl) piperazin-1-yl) -N- ((4 - ((((4-fluorotetrahydro-2H-pyran-4- il)] netyl) amino) -3-nitrophenyl) sulfonyl) benzamide o. O CAXS NON ”
[0403] [0403] Example 30 was prepared according to General Procedure B using Intermediate 31 and Intermediate 52. LC / MS (ESI) m / z 910.6 [M + H] *. Example 31 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((4,4-dimethyl-2- (3- (trifluoromethyl) bicycles [1, 1.1] pentan-1-yl) cyclohex-1-en-1-yl)] methyl) piperazin-1-yl) -N- ((4 - ((4-fluorotetrahydro-2H-pyran-4- il) methoxy) -3-nitrophenyl) sulfonyl) benzamide NO, SS O; Rn F O. oo AT NON O N
[0404] [0404] Example 31 was prepared according to General Procedure B using Intermediate 31 and Intermediate 53. LC / MS (ESI) m / z 911.6 [M + H] *. Example 32 2 - (((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((4 4-dimethyl-2- (3- (triluoromethyl) bicycle [1,1 , 1] pentan-1-yl) cyclohex-1-en-1-yl)] methyl) piperazin-1-yl) - N - ((4- (U (1r, 4r) -4-hydroxy-4-methylcyclo -hexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
[0405] [0405] Example 32 was prepared according to General Procedure B using Intermediate 31 and Intermediate 18. LC / MS (ESI) m / z 920.7 [M + H] *. Example 33 2 - (((1H-pyrrolo [2,3-b] pyridin-S-yl) oxy) -4- (4 - ((2- (3- (difluoromethyl) bicyclo [1,1,1] pentan- 1- iI) -4 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) - N - (((3-nitro-4 - (((tetrahydro-2H-pyran-4- il)] methyl) amino) phenyl) sulfonyl) benzamide o. O THERE NON ” N O
[0406] [0406] Example 33 was prepared according to General Procedure A below, using Intermediate 30 and 3-nitro-4 - ((((tetrahydro-2H-pyran-4-iN) methyl) amino) benzenesulfonamide. NMR * H (400 MHz, CDCl3) 5 10.06 (br s, 1H), 8.94 (br s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.53 ( t, J = 5.6 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.18 (dd, J = 9.6, 2.0 Hz, 1H), 7, 98 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.45 (t, J = 3.2 Hz, 1H), 6.92 ( d, J = 9.6 Hz, 1H), 6.60-6.55 (m, 2H), 6.02 (d, J = 2.0 Hz,
[0407] [0407] Example 34 was prepared according to General Procedure A using Intermediate 30 and Intermediate 18. NMR * H (400 MHz, DMSO-ds) 5 11.70 (s, 1H), 11.40 (br s, 1H), 8.59-8.49 (m, 2H), 8.04 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.53-7.48 (m, 3H), 7.06 (d, J = 9.2 Hz, 1H), 6.72 (d, J = 7.2 Hz, 1H), 6.38 (s , 1H), 6.25 (s, 1H), 5.99 (t, J = 56.8 Hz, 1H), 4.25 (s, 1H), 3.33-3.25 (m, 2H) , 3.18-3.05 (m, 4H), 2.97 (s, 2H), 2.40-2.28 (m, 4H), 2.05-1.95 (m, 2H), 1 , 94 (s, 6H), 1.71-1.59 (m, 5H), 1.58-1.49 (m, 2H), 1.39-1.28 (m, 2H), 1.27 -1.20 (m, 2H), 1.18 - 1.09 (m, 2H), 1.10 (s, 3H), 0.83 (s, 6H); LC / MS (ESI) m / z 902.6 [M + H] *. Example 35 2 - (((1H-pyrrolo [2,3-b] pyridin-S5-yl) oxy) -4- (4 - ((2- (3- (difluoromethyl) bicyclo [1,1,1] pentan- 1- iI) -4,4-dimethylcyclohex-1-en-1-yl)] methyl) piperazin-1-yl) - N - ((4 - ((((4-fluorotetrahydro-2H-pyran-4- il)] methyl) amino) -3-nitrophenyl) sulfonyl) denzamide
[0408] [0408] Example 35 was prepared according to General Procedure A using Intermediate 30 and Intermediate 52. LC / MS (ESI) m / z 892.5 [M + H] *. Example 36 2 - ((1H-pyrrolo [2,3-b] pyridin-S-yl) oxy) -4- (4 - ((2- (3- (difluoromethyl) bicyclo [1,1,1] pentan- 1- iI) -4,4-dimethylcyclohex-1-en-1-yl)] methyl) piperazin-1-yl) -N - ((4 - ((4-fluorotetrahydro-2H-pyran-4-yl ) methoxy) -3-nitrophenyl) sulfonyl) benzamide
[0409] [0409] Example 36 was prepared according to General Procedure A using Intermediate 30 and Intermediate 53. LC / MS (ESI) m / z 893.5 [M + H] *. Example 37 2 - (((1H-pyrrolo [2,3-b] pyridin-S5-yl) oxy) -N - ((4 - (((7-oxaspiro [3,5] nonan-2-yl)] methyl ) amino) - 3-nitrophenyl) sulfonyl) -4- (4 - ((2- (3- (difluoromethyl) bicyclo [1,1, 1] pentan-1-i1) -4,4-dimethylcyclohex-1 -en-1-yl)] | methyl) piperazin-1-yl) benzamide o: from NO; Oo Ex BH
[0410] [0410] Example 37 was prepared according to General Procedure A using Intermediate 30 and Intermediate 6. LC / MS (ESI) m / z 914.5 [M + H] *. Example 38 2 - (((1H-pyrrolo [2,3-b] pyridin-S5-yl) oxy) -4- (4 - ((2- (3- (difluoromethyl) bicyclo [1,1,1] pentan- 1- i1) -4 4-dimethylcyclohex-1-en-1-yl)] methyl) piperazin-1-yl) - N - ((4 - ((((4-fluoro-1-methylpiperidin-4-yl) ) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide LS THE NONE O
[0411] [0411] Example 38 was prepared according to General Procedure A using Intermediate 30 and Intermediate 15. LC / MS (ESI) m / z 905.5 [M + H] *. Example 39 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((2- (3-isopropylbicyclo [1,1,1] pentan-1-yl ) - 4 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N - ((3-nitro-4 - (((tetrahydro-2H-pyran-4-yl)) methyl) amino) phenyl) sulfonyl) benzamide
[0412] [0412] Example 39 was prepared according to General Procedure A below, using Intermediate 32 and 3-nitro-4 - ((((tetrahydro-2H-pyran-4-iN) methyl) amino) benzenesulfonamide. NMR * H (400 MHz, CDCl3) 5 10.18 (br s, 1H), 8.92 (br s, 1H), 8.90 (d, J = 1.6 Hz, 1H), 8.53 ( t, J = 5.6 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H), 8.18 (dd, J = 9.0, 2.4 Hz, 1H), 7, 97 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.44 (t, J = 2.8 Hz, 1H), 6.91 ( d, J = 9.6 Hz, 1H), 6.59 (dd, J = 9.2, 2.4 Hz, 1H), 6.56 (dd, J = 3.4, 2.4 Hz, 1H ), 6.02 (d, J = 2.0 Hz, 1H), 4.03 (dd, J = 11.2, 4.0 Hz, 2H), 3.46-3.39 (m, 2H) , 3.27 (t, J = 6.4 Hz, 2H), 3.12-3.09 (m, 4H), 3.02 (s, 2H), 2.37-2.34 (m, 4H ), 2.05-1.95 (m, 3H), 1.78-1.71 (m, 2H), 1.66 (s, 2H), 1.65 (s, 6H), 1.62- 1.56 (m, 1H), 1.49-1.39 (m, 2H), 1.25 (t, J = 6.4 Hz, 2H), 0.83 (s, 6H), 0.78 (d, J = 6.8 Hz, 6H); LC / MS (ES!) M / z 866.4 [M + H] *. Example 40 2- (1H-pyrrolo [2,3-b] pyridin-S-yloxy) -4- (4 - ((2- (3- (1,1-difluoroethyl) bicyclo [1,1,1] pentan - 1-i1) -4 4-dimethylcyclohex-1-enyl)] methyl) piperazin-1-yl) -N- (3-nitro-4 - ((tetrahydro-2H-pyran-4-yl)] methylamino ) phenylsulfonyl) benzamide O. oo NONAN N.
[0413] [0413] Example 40 was prepared according to General Procedure B below, using Intermediate 33 and 3-nitro-4 - (((tetrahydro-2H-pyran-4-iNmethyl) amino) benzenesulfonamide. 1H NMR (400 MHz, DMSO-ds) 5 11.70 (s, 1H), 11.50 (br s, 1H), 8.61-8.49 (m, 2H), 8.03 (s, 1H), 7, 80-7.70 (m, 1H), 7.54-7.45 (m, 3H), 7.04 (br s, 1H), 6.71 (d, J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.25 (s, 1H), 3.87-3.83 (m, 2H), 3.33-3.21 (m, 4H), 3.15-3, 05 (m, 4H), 2.97 (s, 2H), 2.40-2.25 (m, 4H), 2.04 - 1.97 (m, 2H), 1.94 (s, 6H) , 1.93-1.82 (m, 1H), 1.67-1.57 (m, 4H), 1.53 (t, J = 18.8 Hz, 3H), 1.30-1.15 (m, 4H), 0.83 (s, 6H); LC / MS (ESI) m / z 888.7 [M + H] *. Example 41 (S) -N - ((4 - (((1 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2 - ((1H-pyrrolo [2,3-blpiridin-5-yl) oxy) -4- (4 - ((2- (3- (difluoromethyl |) bicyclo [1,1 1] pentan-1-i1) -4,4-dimethylcyclohex-1-en-1-yl)] methyl) piperazin-1-yl) benzamide iz 8 * O
[0414] [0414] Example 41 was prepared according to General Procedure B using Intermediate 30 and Intermediate 34. LC / MS (ESI) m / z 876.5 [M + H] *. Example 42 2 - ((1H-pyrrolo [2,3-b] pyridin-5-i /) oxy) -4- (4 - ((6- (3- (difluoromethyl) bicyclo [1,1,1] pentan -1- iespiro [3,5] non-6-en-7-yl)] methyl) piperazin-1-yl) -N - ((3-nitro-4 - (((tetrahydro-2H-pyran-4- i) methyl)> amino) pheni |) sulfonyl) benzamide
[0415] [0415] Example 42 was prepared according to General Procedure B below, using Intermediate 50 and 3-nitro-4 - (((tetrahydro-2H-pirand-iNmethyl) amino) benzenesulfonamide. NMR * H (400 MHz , DMSO-ds) 5 11.63 (s, 1H), 11.38 (br s, 1H), 8.61-8.54 (m, 2H), 8.04 (d, J = 2.8 Hz , 1H), 7.78 (dd, J = 9.6, 1.6 Hz, 1H), 7.53-7.50 (m, 3H), 7.10 (d, J = 9.2 Hz, 1H), 6.71 (dd, J = 9.2, 1.6 Hz, 1H), 6.39-6.38 (m, 1H), 6.25-6.24 (m, 1H), 5 , 99 (t, J = 56.4 Hz, 1H), 3.84 (dd, J = 11.2, 3.2 Hz, 2H), 3.32 - 3.23 (m, 4H), 3, 11 (br s, 4H), 2.94 (s, 2H), 2.33 (br s, 4H), 2.09-1.73 (m, 13H), 1.71 1.60 (m, 6H), 1.46 (t, J = 5.6 Hz, 2H), 1.30-1.20 (m, 2H); LC / MS (ESI) m / z 886.3 [M + H] * Example 43 2 - (((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -N - ((4 - (((4-fluorotetrahydro-2H-pyran-4-iNmethyl)> amino) -3-nitrophenyl) sulfonyl) -4- (4 - ((6- (3-methylbicyclo [1,1,1] pentan-1-iN) spiro [3,5] non-6-en-7-yl) ] Methyl) piperazin-1-yl) benzamide NO, LO O. oo THERE NONÃ
[0416] [0416] Example 43 was prepared according to General Procedure B neasanda is Interstate E1 4 A Interstate EO DMN 14 / ADND MH NMCOCO NANK
[0417] [0417] Example 44 was prepared according to General Procedure B using Intermediate 50 and Intermediate 18. LC / MS (ESI) m / z 914.5 [M + H] *. Example 45 (R) -4- (4 - ((2- (3-Chlorobicyclo [1,1,1] pentan-1-i1) -5,5-dimethylcyclohex-1-en-1- i) methyl ) piperazin-1-yl) - N - ((4 - ((4-morpholino-1- (phenylthio) butan-2-yl) amino) -3- (trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide Cl FA o SOzCF ; 3 In & EO o 2 N ONLY
[0418] [0418] To a stirred solution of Intermediate 36 (45 mg, 8.51 mmol) in DCM (5 mL) was added EDC-HCI (21 mg, 0.0252 mmol) followed by DMAP (26 mg, 0.21 mmol) ) to O ºC. After 10 minutes, (R) -4 - ((4-morpholino-1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) benzenesulfonamide (70 mg, 0.126 mmol) was added and the reaction was warmed to room temperature. After 48 h, water (10 ml) was added and the reaction mixture was extracted with DCM (3 x 20 ml). The combined organic layers were dried over Na2SO4 ;, filtered and concentrated. The product was purified by HPLC (45:55 to 1:99 NH4CO3H (aq.) 10 MM / CH3CN) to provide Example 45 (4 mg, 4% yield) as a white solid. LC / MS (ESI) m / z 964.4 [M + H] *. Example 46 (R) -4- (4 - ((2- (3-chlorobicyclo [1,1,1] pentan-1-i1) -5,5-dimethylcyclohex-1-enyl)] methyl) piperazin- 1-yl) -N- (4- (4- (4-hydroxypiperidin-1-iI) -1- (phenylthio) butan-2-ylamino) -3- (trifluoromethylsulfonyl) phenylsulfonyl) benzamide cl o SO, 2CF; HS OD O AND
[0419] [0419] Example 46 was prepared following the procedure described for Example 45, using Intermediate 37 instead of (R) -4 - ((4-morpholino-1- (phenylthio) butan-2-yl) amino) - 3 - ((trifluoromethyl) sulfonyl) Denzenesulfonamide. LC-MS (ESI) m / z 978.4 [M + H] ". Example 47 (R) -4- (4 - ((5.5-Dimethyl-2- (3-methylbicyclo [1,1,1 ] pentan-1-yl) cyclohex-1-enyl)] methyl) piperazin- 1-yl) -N- (4- (4-morpholino-1- (phenylthio) butan-2-ylamino) -3- ( triluoromethylsulfonyl) phenylsulfoni) benzamide
[0420] [0420] Example 47 was prepared following the procedure described for Example 45, using Intermediate 38 instead of Intermediate 36. NMR '* H (400 MHz, CDCI3) 5 8.36 (d, J = 2.4 Hz , 1H), 8.11 (dd, J = 9.4, 1.6 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 6, 8 Hz, 2H), 7.33-7.26 (m, 3H), 7.05 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.8 Hz, 2H) , 6.59 (d, J = 10.0 Hz, 1H), 3.95-3.85 (m, 1H), 3.71-3.60 (m, 4H), 3.36-3.24 (m, 4H), 3.14 (s, 2H), 3.13-2.98 (m, 2H), 2.61-2.50 (m, 4H), 2.49-2.28 (m , 6H), 2.19-2.08 (m, 1H), 1.99-1.92 (m, 2H), 1.86 (s, 2H), 1.81 (s, 6H), 1, 71 - 1.61 (m, 1H), 1.30 (t, J = 6.4 Hz, 2H), 1.13 (s, 3H), 0.86 (s, 6H). A -NH proton was not observed; LC / MS (ESI) m / z 944.6 [M + H] *. Example 48 (R) -4- (4 - ((5,5-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-enyl)] methyl) piperazin -1-yl) -N- (4- (4- (4-hydroxypiperidin-1-i1) -1- (phenylthio) butan-2-ylamino) -3- (trifluoromethylsulfoniD) phenylsulfonyl) benzamide OO ONLY P
[0421] [0421] Example 48 was prepared following the procedure described for Example 46, using Intermediate 38 instead of Intermediate 36. LC / MS (ESI) m / z 958.3 [M + H] *.
[0422] [0422] Step 1: (R) -N - ((4 - ((4 - ((2 - ((tert-butyldiphenylsilyl) oxy) ethyl) (methyl) amino) -1- (phenylthio) butan-2-yl ) amino) -3 - ((trifluoromethyl) | sulfonyl) phenyl) sulfoni! |) -4- (4 - ((4,4-dimethyl- 2- (3-methylbicyclo [1,1,1] pentan-1- il) cyclohex-1-en-1-yl)] methyl) piperazin-1-ibenzamide (Example 49-1) was prepared following General Procedure B using Intermediate 39 and Intermediate 35. LC / MS (ESI) m / z 1170.9 [M + H] *.
[0423] [0423] Step 2: To a stirred solution of Example 49-1 (375 mg, 0.32 mmol) in THF (15 mL) at 0 ° C, TBAF (1 M in THF, 0.48 mL) was added. After 5 min, the reaction was warmed to room temperature. After 2 h, the reaction was quenched with water (25 ml) and extracted with DCM / MeOH 9: 1 (3 x 35 ml) and concentrated. The crude product was purified by HPLC (50:50 to 0: 100 of NH.CO3H (aq.) 10 mMM / CH3CN) to obtain Example 49 as a white solid. LC-MS (ESI) m / z 932.6 [M + H] * Example 50 (R) -4- (4 - ((2- (3-Ethylbicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex-1-en-1-iNmethyl) piperazin-1-yl) - N - ((4 - ((4 - ((2-hydroxyethyl) (methyl) amino) -1- (phenylthio ) butan-2- i) amino) -3 - ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide o SOzCF;
[04241] [04241] Step 1: (R) N ((4 ((4 - ((2 - ((tert-Butyldiphenylsilyl) oxy) ethyl) (methyl) amino) -1- (phenylthio) butan-2-yl) amino) -3 - ((trifluoromethyl) sulfonyl) 'phenyl) sulfonyl) -4- (4 - ((2- (3-ethylbicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex- 1-en-1-yl)] methyl) piperazin-1- i) benzamide (Example 50-1) was prepared following General Procedure B using Intermediate 40 and Intermediate 35. LC-MS (ESI) m / z 1186 , 0 [M + H] *.
[0425] [0425] Step 2: Example 50 was prepared following the procedure described in Step 2 for Example 49 using Example 50-1 in place of Example 49-
[0426] [0426] Step 1: (R) -N - ((4 - ((4 - ((2 - ((tert-Butyldiphenylsilyl) oxy) ethyl) (methyl) amino) -1- (phenylthio) butan-2-yl ) amino) -3 - ((trifluoromethyl) sulfonyl) phenyl) sulfoni!) - 4- (4 - ((2- (3-ethylbicyclo [1,1,1] pentan-1-yl) -4,4-dimethylcyclo -hex-1-en-1-yl) methyl) piperazin-1- i) benzamide (Example 51-1) was prepared following General Procedure B using Intermediate 41 and Intermediate 35. LC-MS (ES!) m / z 1225.9 [M + 2H] *
[0427] [0427] Step 2: To a stirred solution of Example 51-1 (500 mg, 0.4 mmol) in THF at 0 ° C, TBAF (1 M in THF, 0.49 mL) was added. After 5 min, the reaction was warmed to room temperature. After 5 h, the reaction was quenched with water (25 ml) and 9: 1 DCM / MeOH (3 x 50 ml). The combined organic layers were washed with brine (2 x 15 ml), dried over Na2SO :,
[0428] [0428] Example 52 was prepared following General Procedure B using Intermediate 39 and (R) -4 - ((4-morpholino-1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) benzenesulfonamide. LC / MS (ESI) m / z 944.9 [M + H] *. Example 53 (R) -4- (4 - ((2- (3-Ethylbicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex-1-en-1- i) methyl ) piperazin-1-yl) -N - ((4 - ((4-morpholino-1- (phenylthio) butan-2-yl) amino) -3- ((triluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide SONS SINK ONLY
[0429] [0429] Example 53 was prepared following General Procedure B using Intermediate 40 and (R) -4 - ((4-morpholino-1- (phenylthio) butan-2-yl) amino) -3- ((triluoromethyl) sulfonyl) benzenesulfonamide. LC / MS (ESI) m / z 958.8 [M + H] *.
[0430] [0430] Example 54 was prepared following General Procedure B using Intermediate 41 and (R) -4 - ((4-morpholino-1- (phenylthio) butan-2-yl) amino) -3- ((triluoromethyl) sulfonyl) Denzenesulfonamide. LC / MS (ESI) m / z 998.9 [M + H] *. Example 55 (R) -4- (4 - ((2- (3- (difluoromethyl |) bicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex-1-en-1 - i) methyl) piperazin-1-yl) - N - (((4 - ((4-morpholino-1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) pheni) sulfonyl) benzamide HF2C qo SOzCF; 3 No ÇY EO o Hx N ONLY
[0431] [0431] Example 55 was prepared following General Procedure B using Intermediate 42 and (R) -4 - ((4-morpholino-1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) benzenesulfonamide. LC / MS (ESI) m / z 980.9 [M + H] *.
[0432] [0432] Example 56 was prepared according to General Procedure B using Intermediate 39 and Intermediate 43. LC / MS (ESI) m / z 857.8 [M + H] *. Example 57. (R) -4- (4 - ((2- (3-ethylbicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex-1-en-1- i) methyl) piperazin-1-yl) -N - ((4 - ((4-morpholino-1- (phenylthio) butan-2-yl) amino) -3-nitrophenyl) sulfonyl) benzamide NO, I AM OD ONLY
[0433] [0433] Example 57 was prepared according to General Procedure B using Intermediate 40 and Intermediate 43. LC / MS (ESI) m / z 871.8 [M + H] *. Example 58 (R) -4- (4 - ((2- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex-1-en-1- i) methyl) piperazin-1-yl) -N - (((4 - ((4-morpholino-1- (phenylthio) butan-2-yl) amino) -3-nitrophenyl) sulfonyl) benzamide
[0434] [0434] Example 58 was prepared according to General Procedure B using Intermediate 42 and Intermediate 43. NMR * H (400 MHz, DMSO-d6s) 5 8.48 (s, 1H), 8.40-8 , 30 (m, 1H), 7.78 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.31- 7.28 (m, 2H), 7.25-7.20 (m, 2H), 7.17-7.13 (m, 1H), 7.05-6.95 (m, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.01 (t, J = 56.0 Hz, 1H), 4.19-4.09 (m, 1H), 3.60-3.45 (m, 4H), 3.30 - 3.15 (m, 6H), 3.10-2.90 (m, 2H), 2.55-2.10 (m, 10H), 2.10-2.01 (m, 3H ), 1.99 (s, 6H), 1.90-1.80 (m, 1H), 1.71 (s, 2H), 1.30-1.21 (m, 2H), 0.86 ( s, 6H). An NH proton was not observed; LC / MS (ESI) m / z 893.6 [M + H] *. Example 59 (R) -4- (4 - ((4,4-dimethyl-2- (3-methylbicyclo [1,1,1] pentan-1-yl) cyclohex-1-en-1-methyl) piperazin-1-yl) -N - ((4 - ((4- (dimethylamino) -1- (phenylthio) butan-2-yl) amino) -3-LUtrifluoromethi) sulfoni) phenyl) sulfoni) benzamide o SOzCF; FO Y O
[0435] [0435] Example 59 was prepared according to General Procedure B using Intermediate 39 and Intermediate 44. LC / MS (ESI) m / z 902.6 [M + H] *. Example 60 (R) -4- (4 - ((2- (3- (difluoromethyl |) bicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex-1-en-1 - iNmethyl) piperazin-1-yl) -N - ((4 - ((4 - ((2-hydroxyethyl) (methyl) amino) -1- (phenylthio) butan-2- i) amino) -3 - (( trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide
[0436] [0436] Step 1: (R) -N - ((4 - ((4 - ((2 - ((tert-butyldiphenylsilyl) oxy) ethyl) (methyl) amino) -1- (phenylthio) butan-2-yl ) amino) -3 - ((trifluoromethyl) sulfoni!) 'phenyl) sulfonyl) -4- (4 - ((2- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1-i1) -4 , 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide (Example 60-1) was prepared following General Procedure B using Intermediate 42 and Intermediate 35. LC-MS ( ESI) m / z 1206.5 [M + H] *.
[0437] [0437] Step 2: To a stirred solution of Intermediate 60-1 (130 mg, 0.10 mmol) in 1,4-dioxane (5 mL) was added HCI (4 M in 1,4-dioxane, 1 mL) followed by 3 drops of water at O “C. The mixture was warmed to room temperature for 16 h and then concentrated. The crude reaction mixture was diluted with saturated aqueous NaHCO solution; and extracted with EtOAc (3 x 25 ml). The combined organic layers were dried over Na> zSO:, filtered and concentrated. The crude product was purified by column chromatography (SiO2, MeOH / DCM) to produce Example 60 (30 mg, 29% yield) as an off-white solid. LC / MS (ESI) m / z 968.2 [M + H] *. Example 61 (R) -4- (4 - ((2- (3- (Difluoromethyl) bicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex-1-en-1- iNmethyl) piperazin-1-yl) - N - (((4 - ((4- (4-hydroxypiperidin-1-yl) -1- (phenylthio) butan-2- i)> amino) -3 - ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) Denzamide HF2C Fx o SO, ZCF; ANA & ESSE o AX OO HO
[0438] [0438] Example 61 was prepared according to General Procedure B
[0439] [0439] Example 62 was prepared according to General Procedure B using Intermediate 42 and Intermediate 45. LC / MS (ESI) m / z 1021.2 [M + H] ". Example 63 (R) -4 - (4 - ((2- (3- (Difluoromethyl) bicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex-1-en-1-iNmethyl) piperazin-1-yl ) -N - ((4 - ((4- (dimethylamino) -1- (phenylthio) butan-2-yl) amino) -3- LUtrifluoromethi) sulfoni) phenyl) sulfonyl) benzamide HEZG YOU, - Õ
[0440] [0440] Example 63 was prepared according to General Procedure B using Intermediate 42 and Intermediate 44. LC / MS (ESI) m / z 938.4 [M + H] *. Example 64 (R) -4- (4 - ((2- (3- (difluoromethyl |) bicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex-1-en-1 - i) methyl) piperazin-1-yl) -N - (((4 - ((1- (phenylthio) -4- (piperazin-1-yl) butan-2-i) amino) -3- ((triluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide
[0441] [0441] Step 1: 4- (3 - ((4- (N- (4- (4 - ((2- (3- (Difluoromethyl) bicycles [1,1,1] pentan-1-i1) -4 , 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoyl) sulfamoyl) -2 - ((trifluoromethyl) sulfonyl) phenyl) amino) -4- (phenylthio) butyl) (R) -tert-butyl piperazine-1-carboxylate (Example 64-1) was prepared following General Procedure B using Intermediate 42 and Intermediate 46. LC-MS (ESI) m / z 1079.3 [M + H]*
[0442] [0442] Step 2: To a stirred solution of Example 64-1 (350 mg, 0.32 mmol) in Et2O (5 mL) at 0 ° C, HCI (2 M in Et2O, 2.0 mL) was added. The reaction was warmed to room temperature and stirred for 16 h. The reaction was concentrated, diluted with ice water, basified with saturated aqueous NaHCO solution; (10 mL) and extracted with 10% MeOH in DCM (3 x 30 mL). The combined organic layers were dried over Na2SO, anhydrous, filtered and concentrated. The crude product was purified by HPLC (30:70 to 1:99 NH.CO3H (aq.) 10 MM / CH3CN) to provide Example 64 (14 mg, 4% yield) as an off-white solid. NMR * H (400 MHz, DMSO-ds) 5 8.32 (br s, 2H), 8.02 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.34- 7.23 (m, 4H), 7.19-7.15 (m, 1H), 6.83-6.75 (m, 3H ), 6.66 (d, J = 8.8 Hz, 1H), 5.97 (t, J = 56.8 Hz, 1H), 3.97 (br s, 1H), 3.26-3, 23 (m, 2H), 3.15-3.10 (m, 4H), 3.02-2.90 (m, 6H), 2.52-2.50 (m, 2H), 2.40- 2.23 (m, 8H), 2.10-1.83 (m, 9H), 1.67 (s, 3H), 1.23 (t, J = 6.4 Hz, 2H), 0.82 (s, 6H); LC / MS (ESI) m / z 979.4 [M + H] *. Example 65 (R) -4- (4 - ((2- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1-i1) -5,5-dimethylcyclohex-1-en-1- iNmethyl) piperazin-1-yl) - N - (((4 - ((4- (4-hydroxypiperidin-1-i1) -1- (phenylthio) butan-2-iNamino) -3 - ((trifluoromethyl) sulfonyl) phenyl ) sulfonyl) benzamide
[0443] [0443] Example 65 was prepared according to General Procedure B using Intermediate 56 and Intermediate 37. LC / MS (ESI) m / z 994.4 [M + H] *. Example 66 (R) -4- (4 - ((2- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1-yl) -4 4-dimethylcyclohex-1-en-1- iNmethyl ) piperazin-1-yl) -N - ((4 - ((4- (3-hydroxyazetidin-1-yl) -1- (phenylthio) butan-2-yl) amino) - 3 - ((trifluoromethyl) sulfonyl) Yfenyl) sulfonyl) benzamide HF3C Fx o SOCF;
[0444] [0444] Example 66 was prepared according to General Procedure B using Intermediate 42 and Intermediate 57. LC / MS (ESI) m / z 966.5 [M + H] *. Example 67 (R) -4- (4 - ((6- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1-yl) spiro [3,5] non-6-en-7- i ) methyl) piperazin-1-yl) -N - ((4 - ((4- (4-hydroxypiperidin-1-yl) -1- (phenylthio) outan-2- i)> amino) -3 - ((trifluoromethyl ) sulfonyl) phenyl) sulfonyl) Denzamide
[0445] [0445] Example 67 was prepared according to General Procedure B
[0446] [0446] Example 68 was prepared according to General Procedure B using Intermediate 37 and Intermediate 39. LC / MS (ESI) m / z 958.2 [M + H] *. Example 69 (R) -4- (4 - ((2- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1-i1) -4,4-dimethylcyclohex-1-en-1- i) methyl) piperazin-1-yl) -N - ((4 - ((4- (4- (2-hydroxyethyl) piperazin-1-i1) -1- (phenylthio) butan-2- i) amino) - 3 - ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide
[0447] [0447] Step 1: (R) -N - ((4 - ((4- (4- (2 - ((tert-butyldiphenylsilyl) oxy) ethyl) piperazin-1-i1) -1- (phenylthio) butan- 2-yl) amino) -3 - ((trifluoromethyl) sulfonyl) phenyl) sulfoni!) - 4- (4 - ((2- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1-yl) -4,4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide (Example 69-1) was prepared following General Procedure B using Intermediate 42 and Intermediate 59. LC / MS (ESI) m / z 631.6 [M + 2H] *.
[0448] [0448] Step 2: To a stirred solution of Intermediate 69-1 (250 mg, 0.198 mmol) in 1,4-dioxane was added HCI (4 M in 1,4-dioxane, 1.5 mL) followed by
[0449] [0449] Step 1: (R) N - ((4 - ((4 - ((2 - ((tert-butyldiphenylsilyl) oxy) ethyl) (ethyl) amino) -1- (phenylthio) butan-2-yl) amino) -3 - ((trifluoromethyl) sulfoni!) phenyl) sulfonyl) -4- (4 - ((2- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1-yl) -4,4 -dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide (Example 70-1) was prepared following General Procedure B using Intermediate 42 and Intermediate 60. LC / MS (ESI) m / z 611.3 [M + 2H] *.
[0450] [0450] Step 2: Example 70 was prepared following the procedure described in Example 69 using Example 70-1 in place of Example 69-1. LC / MS (ESI) m / z 982.5 [M + H] *. Example 71 (R) -N - ((4 - ((4 - ((2 - ((tert-butyldiphenylsily) oxy) ethyl) (ethyl) amino) -1- (phenylthio) butan-2-yl) amino) - 3 - (((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4 - ((2- (3- (difluoromethyl) bicyclo [1,1,1] pentan-1- i1) -4 4-dimethylcyclohex- 1-en-1-yl)] methyl) piperazin-1-yl) benzamide
[0451] [0451] Example 71 was prepared according to General Procedure B using Intermediate 42 and Intermediate 61. LC / MS (ESI) m / z 980.4 [M + H] *. Example 72 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxide) -4- (4 - ((2- (3-chlorobicyclo [1,1,1] pentan-1-yl ) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) - N - (((3-nitro-4 - ((((tetrahydro-2H-pyran-4-methyl)> amino) phenyl) sulfonyl) benzamide 3rd ota
[0452] [0452] Example 72 was prepared according to General Procedure A below, using Intermediate 62 and 3-nitro4 ((((tetrahydro-2H-pyran4-i) methyl) amino) benzenesulfonamide. LC / MS (ESI) m / z 830.8 [M + H] *. Example 73 (R) -2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((2- (3- (difluoromethyl) bicycles [1,1, 1] pentan-1- i) -4,4-dimethylcyclohex-1-en-1-yl)] methyl) piperazin-1-yl) -N - ((4 - ((((4-methylmorpholin-2- i) methyl)> amino) -3-nitrophenyl) sulfonyl) benzamide
[0453] [0453] Example 73 was prepared according to General Procedure B using Intermediate 30 and Intermediate 17A. Absolute stereochemistry was assigned arbitrarily. LOC-MS (ESI) m / z 445.5 [M + 2H] *. Examples 74 to 97
[0454] [0454] Examples 74 to 97, with the chemical names and structures shown in Figures 3, 4A and 4B, are prepared according to the methods described herein. Similar results are obtained. Example A Bcl-2 protein binding assay
[0455] [0455] Binding to Bcl-2 and Bcl-X proteins. was evaluated using the Bcl2scanTY platform: The T7 phage types exhibiting BCL2 proteins were grown in parallel in 24-well blocks in an E. coli host derived from the BL21 strain. E. coli were cultured to the logarithmic stage and infected with T7 phage from a frozen stock (multiplicity of infection = 0.4) and incubated under agitation at 32 ºC until lysis (90 to 150 minutes). The lysates were centrifuged (5,000 x g) and filtered (0.2 µm) to remove cell debris. Streptavidin-coated magnetic beads were treated with biotinylated BIM peptide ligand for 30 minutes at room temperature to generate affinity resins for the BCL2 assays. Bound beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20 and 1 mM DTT) to remove unbound ligand and to reduce non-specific phage binding . The binding reactions were assembled by combining the BCL2 proteins, the linked affinity beads and the test compounds in 1x binding buffer (SeaBlock 20% 0 17xPBS
[0456] [0456] The curves were fitted using a nonlinear least squares fit with the Levenberg-Marquardt algorithm. The results are shown in Table 1. Table 1 Pa Ae | Le dA e | EX rr n ar A "
[0457] [0457] Binding to Bcl-2 and Bcl-X1 proteins was also assessed using the HTRF assay. Background: FAM-Bak / Bad binds to the surface pocket of the Bcl-2 protein family. This linkage can be monitored by HTRF signals between the anti-GST-Tb and the Fam-peptide using the Gcl-labeled Bcl proteins. Assay Conditions: Bcl-2: Bcl-2 4 nM, FAM-Bak 100 nM peptide, Bel-X1: Bcl-X1 3 nM, peptide
[0458] [0458] Cell proliferation was measured using the CellTiter-Glo € luminescent cell viability assay. The test involved adding a single reagent (CellTiter-Glo & Reagent) directly to cells cultured in medium supplemented with serum. RS4; 11 cells (ATC, CRL-1873) were cultured according to the ATCC recommendations and were seeded at 50,000 cells per well. NCI-H1963 cells (ATCC, CRL-5982) were cultured according to ATCC recommendations and seeded at 12,000 cells per well.
[0459] [0459] Each evaluated compound was prepared as a stock solution of DMSO (10 mM). The compounds were tested in duplicate on each plate, with a 10-point serial dilution curve (1: 3 dilution). Compound treatment (1.0 µl) was added from the compound dilution plate to the cell plate. The highest compound concentration was 10 µM (final), with a final DMSO concentration of 0.1%. The plates were then incubated at 37 ºC, 5% CO ». After 48 h of treatment of the compound for RS4; 11 or 72 h for NCI-H1963, the cell plates were equilibrated at room temperature for approximately 30 minutes. An equivalent volume amount of CellTiter-Glo & reagent (40 µL) was added to each well. The plates were mixed for 2 minutes on an orbital shaker to induce cell lysis and then incubated at room temperature for 10 minutes to stabilize the luminescent signal. Luminescence was recorded using an Envision plate reader according to the CellTiter-Glo protocol. The Clso of each compound was calculated using the GraphPad Prism software by non-linear regression analysis. Clso values are given in Table 3.
[0460] [0460] Primary CDA4 T cells were purified by negative selection, using the RosetteSep human CD4 * T cell enrichment cocktail (Stemcell Technologies) or an EasySep human CD4 * T cell isolation kit (Stemcell Technologies), according to the manufacturer's protocol. Primary CD4 T cells were isolated and activated with IL-2 at 50 IU / mL and phytohemagglutinin (PHA) at 1 µg / mL for 48 hours. Then, the cells were infected with a stock of HIV-1m "virus (NIH AIDS Reagent Program) for 3 to 6 hours with 6 ug / mL of Polybrene (Sigma Aldrich), washed and resuspended with complete RPMI and IL-2 for 48 hours. The cells were treated with the compounds as 100 µM and 300 µM DMSO stock solutions, or DMSO. Cell death was measured using an IncuCyte system (Essen Bioscience) and the IncuCyte Caspase green apoptosis assay reagent. 3/7 (catalog number 4440, from Essen Bioscience). Data analysis was performed using the IncuCyte Zoom software (2018A). The statistical analysis was performed using the GraphPad Prism software. The results are represented as the standard error (SE The changes in times for the analysis of the area under the curve were compared by multiple t-tests. P values less than 0.05 were considered statistically significant. The results of this test are summarized in Figure 5 and indicate that Examples 34 and 36 exhibit selectiv age when killing infected cells vs. not infected with HIV.
[0461] [0461] Furthermore, although the aforementioned has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those skilled in the art that various modifications can be made without departing from the character of the present description. Therefore, it must be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present description, but also to cover all modifications and alternatives that come with the true scope and spirit of the invention.

权利要求:
Claims (126)
[1]
1. Compound of formula (1), or a pharmaceutically acceptable salt thereof, characterized by having the structure: Rº R5 Ne) o N. Co pe R (1) where: R 'is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-Cs alkyl, substituted or unsubstituted C1-Cs haloalkyl, substituted or unsubstituted C3-C6s cycloalkyl, substituted or unsubstituted C1-Cs alkoxy, unsubstituted and C1-Cs monoalkylamine an unsubstituted C1-Cs dialkylamine; each R is independently selected from the group consisting of halogen, a substituted or unsubstituted C1-Cs alkyl, a substituted or unsubstituted C1-Cs haloalkyl and a substituted or unsubstituted C3-C6 cycloalkyl; or when m is 2 or 3, each R is independently selected from the group consisting of halogen, a substituted or unsubstituted C1-Cs alkyl, a substituted or unsubstituted C1-Cs haloalkyl and a substituted or unsubstituted C3-Cs cycloalkyl, or two R groups, together with ( s) atom (s) to which
they are attached, form a substituted or unsubstituted C3-Cs cycloalkyl or a 3- to 6-membered, substituted or unsubstituted heterocyclyl;
R it is hydrogen or halogen;
Rº is selected from the group consisting of NO>, S (O) Rô, SO2R $, halogen, cyan and an unsubstituted C1-Cs haloalkyl «;
Rº is selected from the group consisting of —X '- (Alk')) - R ”and -Xº (CHR $) - (AIk ), - X -Rº;
AIkK 'and AIkK are independently selected from unsubstituted C1-C4 alkylene and C1-Ca1 alkylene substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, unsubstituted C1-C3 alkyl and unsubstituted C1-C3 haloalkyl;
Rô is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-Cs haloalkyl and substituted or unsubstituted C3-Cs cycloalkyl;
R 'is selected from a substituted or unsubstituted C1-Cs alkoxy, a substituted or unsubstituted C3a-C1io cycloalkyl, a substituted or unsubstituted 3 to 10 membered heterocyclic, hydroxy, amino, a substituted or unsubstituted monosubstituted amino group a substituted or unsubstituted amino group, a substituted or unsubstituted N-carbamyl, a substituted or unsubstituted C-starch and a substituted or unsubstituted N-starch;
Rº is selected from a substituted or unsubstituted 3- to 10-membered heterocyclyl (C1-Cs alkyl), a substituted or unsubstituted alkylamino (C1-Cs alkyl) and a substituted or unsubstituted C1-Cs monoalkylamino ;
Rº is selected from a substituted or unsubstituted 5 to 10 membered heteroarla and a substituted or unsubstituted Cg-C1o aryl;
n and p are independently selected from 0 and 1; and XI, X º and X are independently selected from the group consisting of -—- O-, —-S— and -NH-.
[2]
A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R 'is halogen.
[3]
A compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, characterized in that R * is fluoro.
[4]
Compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, characterized in that R 'is chlorine.
[5]
Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R 'is substituted or unsubstituted C 1- C alkyl.
[6]
A compound according to claim 1 or 5, or a pharmaceutically acceptable salt thereof, characterized in that R 'is unsubstituted C 1- C alkyl.
[7]
A compound according to any one of claims 1 or 5 to 6, or a pharmaceutically acceptable salt thereof, characterized by R; be unsubstituted methyl or unsubstituted ethyl.
[8]
A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R 'is a substituted or unsubstituted C 1 -Cs haloalkyl.
[9]
Compound according to claim 1 or 8, or a pharmaceutically acceptable salt thereof, characterized in that R 'is an unsubstituted - CHF> 2, -CF3, -CH2C0F3 or -CF2CH;
[10]
A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R * is hydrogen.
[11]
Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R 'is a substituted or unsubstituted C3-Cs cycloalkyl.
[12]
Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R 'is an unsubstituted C3-Cs6 cycloalkyl.
[13]
Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R 'is a substituted or unsubstituted C1-C6 alkoxy.
[14]
Compound according to claim 1 or 13, or a pharmaceutically acceptable salt thereof, characterized in that R 'is an unsubstituted C1-Cs alkoxy.
[15]
A compound according to any one of claims 1 or 13 to 14, or a pharmaceutically acceptable salt thereof, characterized in that R 'is an unsubstituted methoxy or an unsubstituted ethoxy.
[16]
A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R 'is an unsubstituted C 1 -Cs monoalkylamine.
[17]
A compound according to claim 1 or 16, or a pharmaceutically acceptable salt thereof, characterized in that R 'is methylamine or ethylamine.
[18]
A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R 'is an unsubstituted C1-Cs6 dialkylamine.
[19]
A compound according to claim 1 or 18, or a pharmaceutically acceptable salt thereof, characterized in that R 'is dimethylamine or diethylamine.
[20]
A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, characterized in that m is 1.
[21]
A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, characterized in that m is 2.
[22]
22. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, characterized in that m is 3.
[23]
A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, characterized by an R be unsubstituted C1-Cs alkyl and any other R , if present, be independently selected from the group consisting of halogen, substituted or unsubstituted C1-Cs alkyl, substituted or unsubstituted C1-Cs haloalkyl and cycloalkyl C3-Cs substituted or unsubstituted.
[24]
24. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, characterized by each R independently be unsubstituted C1-Cs alkyl.
[25]
25. A compound according to any one of claims 1 to 19, 23 or 24, or a pharmaceutically acceptable salt thereof, characterized in that m is 2; and each R be an unsubstituted methyl.
[26]
26. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, characterized in that it is O.
[27]
27. A compound according to any one of claims 1 to 19 or 21 to 22, or a pharmaceutically acceptable salt thereof, characterized by two groups R ', together with the atom (s) to which ( is) they are attached, form a substituted or unsubstituted C3-Cs cycloalkyl.
[28]
28. A compound according to any one of claims 1 to 19, 21 to 22 or 27, or a pharmaceutically acceptable salt thereof, characterized by two groups R ', together with the atom to which they are
[29]
A compound according to any one of claims 1 to 19 or 21 to 22, or a pharmaceutically acceptable salt thereof, characterized by two R 'groups, together with the atom (s) to which ( is) they are linked, form a 3- to 6-membered heterocyclic, substituted or unsubstituted.
[30]
Compound according to any one of claims 1 to 19, characterized in that it is also a compound of Formula (la), Formula (lb), Formula (lc) or Formula (ld): Ró Ró Ró Ró
N N N N QD Q * CD Rº R Y R J R (la) (lb) (lc) (1d) or pharmaceutically acceptable salts of any of the previously mentioned.
[31]
31. A compound according to any one of claims 1 to 30, characterized by R be hydrogen.
[32]
32. A compound according to any one of claims 1 to 30, characterized by R be halogen.
[33]
33. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, characterized in that R ° is NO ».
[34]
34. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, characterized in that R ° is cyan.
[35]
35. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, characterized in that R ° is halogen.
[36]
36. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, characterized in that R ° is an unsubstituted C1-Cs haloalkyl.
[37]
37. A compound according to any one of claims 1 to 32 or 36, or a pharmaceutically acceptable salt thereof, characterized in that R ° is -CF3.
[38]
38. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, characterized in that Rº is S (O) Rº.
[39]
39. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, characterized in that Rº is SO2Rº.
[40]
40. A compound according to any one of claims 1 to 32 or 38 to 39, or a pharmaceutically acceptable salt thereof, characterized in that R $ is substituted or unsubstituted C1-Cs alkyl.
[41]
41. A compound according to any one of claims 1 to 32 or 38 to 39, or a pharmaceutically acceptable salt thereof, characterized in that R $ is a substituted or unsubstituted C3-Cs cycloalkyl.
[42]
42. A compound according to any one of claims 1 to 32 or 38 to 39, or a pharmaceutically acceptable salt thereof, characterized in that R $ is a substituted or unsubstituted C1-Cs haloalkyl.
[43]
43. A compound according to any one of claims 38 to 39 or 42, or a pharmaceutically acceptable salt thereof, characterized in that Rô is -CF3.
[44]
44. A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, characterized in that R ° is "X * -
[45]
45. A compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, characterized in that X 'is -O-.
[46]
46. A compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, characterized in that X 'is -S-.
[47]
47. A compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, characterized in that X * is -NH-.
[48]
48. A compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, characterized in that AIlk 'is - (CH2): 14— * unsubstituted, for which "*" represents the point of attachment to R *.
[49]
49. A compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, characterized in that AIk 'is selected from among
[50]
50. A compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, characterized in that AIk 'is an alkylene-substituted Eres, for which "*" represents the point of attachment to R.
[51]
51. A compound according to any one of claims 1 to 47 or 50, or a pharmaceutically acceptable salt thereof, characterized by Alk ' be selected from:
THEY AAA
[52]
52. A compound according to any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, characterized in that n is 1.
[53]
53. A compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, characterized in that n is O.
[54]
54. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, characterized in that R 'is a substituted or unsubstituted monosubstituted amino group.
[55]
55. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, characterized in that R 'is a substituted or unsubstituted amino group.
[56]
56. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, characterized in that R 'is selected from a substituted or unsubstituted N-carbamyl, a substituted or unsubstituted C-amino and an N - substituted or unsubstituted starch.
[57]
57. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, characterized in that R 'is a substituted or unsubstituted C3-C10 cycloalkyl.
[58]
58. A compound according to any one of claims 1 to 53 or 57, or a pharmaceutically acceptable salt thereof, characterized in that R is a substituted or unsubstituted Cs-C10o spirocycloalkyl.
[59]
59. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, characterized in that R 'is a substituted or unsubstituted 3 to 10 membered heterocyclyl.
[60]
60. A compound according to any one of claims 1 to 53 or 59, or a pharmaceutically acceptable salt thereof, characterized by R be a substituted or unsubstituted 6 to 10 membered spiroheterocyclyl.
[61]
61. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, characterized in that R 'is hydroxy or amino.
[62]
62. A compound according to any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, characterized in that R 'is unsubstituted.
[63]
63. A compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof, characterized in that R 'is substituted.
[64]
64. A compound according to any one of claims 1 to 60 or 63, or a pharmaceutically acceptable salt thereof, characterized by R be substituted with 1 or 2 substituents independently selected from an unsubstituted C1-Cs alkyl, an unsubstituted C1-Cs alkoxy, fluoro, chloro, hydroxy and -SO2- (unsubstituted C1-C6 alkyl).
[65]
65. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, characterized in that R 'is selected from: INOO OCT EO IX pb ENOXO p O xOo ss / NON ss / VN 8 / NO 2 / N 8 / Nou
F FO HO EO: EO PO “06 EO» ', h' i O Va '
NH TN N— A> »N N NO O) HO), F ARO NEN No a 7 ee (O (NEN Ns NH O) no EN NH EN No 2 o POR; PO; o
CO e.
[66]
66. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, characterized in that R 'is selected from: O o / - oH
CEOXKKOD AO, NS, F; “The e:
[67]
67. A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, characterized in that Rº is X 2— (CHR $) - (Alk2), - X -Rº.
[68]
68. A compound according to any one of claims 1 to 43 or 67, or a pharmaceutically acceptable salt thereof, characterized in that X be -O-.
[69]
69. A compound according to any one of claims 1 to 43 or 67, or a pharmaceutically acceptable salt thereof, characterized in that X be —S-.
[70]
70. A compound according to any one of claims 1 to 43 or 67, or a pharmaceutically acceptable salt thereof, characterized in that X be -NH-.
[71]
71. A compound according to any one of claims 1 to 43 or 67 to 70, or a pharmaceutically acceptable salt thereof, characterized in that X be -O-.
[72]
72. A compound according to any one of claims 1 to 43 or 67 to 70, or a pharmaceutically acceptable salt thereof, characterized in that X is -S-.
[73]
73. A compound according to any one of claims 1 to 43 or 67 to 70, or a pharmaceutically acceptable salt thereof, characterized by X ° be -NH-.
[74]
74. A compound according to any one of claims 1 to 43 or 67 to 73, or a pharmaceutically acceptable salt thereof, characterized by AIk be - (CH2) 1 --— * unsubstituted, for which "*" represents the point of attachment to X * .
[75]
75. A compound according to any one of claims 1 to 43 or 67 to 73, or a pharmaceutically acceptable salt thereof, characterized by Alk be selected from among the DEF,
[76]
76. A compound according to any one of claims 1 to 43 or 67 to 73, or a pharmaceutically acceptable salt thereof, characterized by Alk be a $ —er-C, alhylene-—: substituted, for which "*" represents the point of attachment to the X .
[77]
77. A compound according to any one of claims 1 to 40, 67 to 73 or 76, or a pharmaceutically acceptable salt thereof, characterized by Alk be selected from:
DÉKLA AE DARÃO + É. +++ TT; e and CF;
[78]
78. A compound according to any one of claims 1 to 43 or 67 to 77, or a pharmaceutically acceptable salt thereof, characterized in that p is 1.
[79]
79. A compound according to any one of claims 1 to 43 or 67 to 73, or a pharmaceutically acceptable salt thereof, characterized in that p is O.
[80]
80. A compound according to any one of claims 1 to 43 or 67 to 78, or a pharmaceutically acceptable salt thereof, characterized in that Rô is a substituted or unsubstituted 3 to 10 membered heterocyclyl (C1-Cs alkyl).
[81]
81. A compound according to any one of claims 1 to 43, 67 to 78 or 80, or a pharmaceutically acceptable salt thereof, characterized in that R ° is a 6 to 10-membered spiroheterocyclyl (C1-Cs alkyl) or not replaced.
[82]
82. A compound according to any one of claims 1 to 43 or 67 to 78, or a pharmaceutically acceptable salt thereof, characterized in that R $ is a substituted or unsubstituted C1-Ce dialkylamino (C1-Cs alkyl).
[83]
83. A compound according to any one of claims 1 to 43, 667 to 77 or 82, or a pharmaceutically acceptable salt thereof, characterized in that R ° is a substituted or unsubstituted dimethylamino (C1-Cs alkyl).
[84]
84. A compound according to any one of claims 1 to 43 or 67 to 77, or a pharmaceutically acceptable salt thereof, characterized by Rº
[85]
85. A compound according to any one of claims 1 to 43, 67 to 78 or 80 to 84, or a pharmaceutically acceptable salt thereof, characterized in that R $ is substituted.
[86]
86. A compound according to any one of claims 1 to 43, 67 to 78 or 80 to 85, or a pharmaceutically acceptable salt thereof, characterized in that R $ is substituted with 1 or 2 substituents independently selected from a C1-Cs alkyl unsubstituted, an unsubstituted C1-Cs alkoxy, an unsubstituted C1-Cs dialkylamine, an unsubstituted acyl (C1-Cs alkyl), an unsubstituted C-carboxy, fluoro, chloro and hydroxy.
[87]
87. A compound according to any one of claims 1 to 43, 67 to 78 or 80 to 84, or a pharmaceutically acceptable salt thereof, characterized in that Rô is unsubstituted.
[88]
88. A compound according to any one of claims 1 to 43 or 67 to 78, or a pharmaceutically acceptable salt thereof, characterized in that R $ is selected from: AO Os Oo AC A NOx AO VAO AA,
NO OH,
[89]
89. A compound according to any one of claims 1 to 43 or 67 to 78, or a pharmaceutically acceptable salt thereof, characterized in that R $ is selected from:
NO NAC pr Ooh NO, NO6
AOL NS
[90]
90. A compound according to any one of claims 1 to 43 or 67 to 89, or a pharmaceutically acceptable salt thereof, characterized in that R ° is a substituted or unsubstituted Cs-C10 aryl.
[91]
91. A compound according to any one of claims 1 to 43 or 67 to 90, or a pharmaceutically acceptable salt thereof, characterized in that R ° is an unsubstituted Cg-C10 aryl.
[92]
92. A compound according to any one of claims 1 to 43 or 67 to 91, or a pharmaceutically acceptable salt thereof, characterized in that R ° is unsubstituted phenyl.
[93]
93. A compound according to any one of claims 1 to 43 or 67 to 89, or a pharmaceutically acceptable salt thereof, characterized in that R ° is a substituted or unsubstituted 5 to 10 membered heteroaryl.
[94]
94. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that it is the compound listed in Figure 3 of the present application.
[95]
95. A compound according to claim 94, characterized in that the compound is selected from the group consisting of:
the a
Q QD OS 2.
Q O
Q QD
AND
Q or a pharmaceutically acceptable salt of any of the above.
[96]
96. Pharmaceutical composition, characterized in that it comprises an effective amount of the compound as defined in any one of claims 1 to 95, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient or a combination thereof.
[97]
97. Method for treating a cancer or tumor, characterized in that it comprises administering an effective amount of a compound as defined in any one of claims 1 to 95, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 96, to an individual who has the cancer or tumor, the cancer or tumor being selected from a bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, cancer colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancy of T-cell or B-cell origin, melanoma, myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cancer head and neck (including oral cancer), ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, cell lung cancer s small, spleen cancer, polycythemia vera, thyroid cancer, endometrial cancer, stomach cancer, gallbladder cancer, bile duct cancer, testicular cancer, neuroblastoma, osteosarcoma, an Ewing's tumor and Wilms' tumor.
[98]
98. Method for inhibiting the replication of a malignant growth or tumor, characterized in that it comprises bringing the growth or tumor into contact with an effective amount of a compound, as defined in the same, or a pharmaceutical composition, as defined in the claim 96, where the malignant growth or tumor is selected from an Ewing's tumor and a Wilms tumor, or the malignant growth of the tumor is due to a cancer selected from a bladder cancer, a brain cancer, a breast cancer , bone marrow cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, T-cell or B-cell lymphoid malignancy, melanoma, myeloid leukemia , a Hodgkin's lymphoma, a non-Hodgkin's lymphoma, a head and neck cancer (including oral cancer), an ovarian cancer, a non-small cell lung cancer, a chronic lymphocytic leukemia, a myelo ma, prostate cancer, small cell lung cancer, spleen cancer, polycythemia vera, thyroid cancer, endometrial cancer, stomach cancer, gallbladder cancer, bile duct cancer, testicular cancer, neuroblastoma and osteosarcoma.
[99]
99. Method for treating a cancer, characterized in that it comprises contacting a malignant growth or a tumor with an effective amount of a compound as defined in any one of claims 1 to 95, or a pharmaceutically acceptable salt thereof, or a composition pharmaceutical as defined in claim 96, wherein the malignant growth or tumor is selected from an Ewing tumor and a Wilms tumor, or the malignant growth of the tumor is due to a cancer selected from a bladder cancer, a brain cancer , breast cancer, bone marrow cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancy originating in T cell or B cell, a melanoma, myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, head and small cell cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer, spleen cancer, polycythemia vera, thyroid cancer, endometrial cancer, stomach cancer, gallbladder cancer, bile duct cancer, testicular cancer, neuroblastoma or an osteosarcoma.
[100]
100. Method for inhibiting Bcl-2 activity, characterized in that it comprises providing an effective amount of a compound as defined in any one of claims 1 to 95, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 96 , to a cancer cell or tumor, the cancer cell or tumor being from a cancer selected from bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, cancer colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancy of T-cell or B-cell origin, melanoma, myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cancer head and neck cancer (including oral cancer), ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, cell lung cancer small, spleen cancer, polycythemia vera, thyroid cancer, endometrial cancer, stomach cancer, gallbladder cancer, bile duct cancer, testicular cancer, neuroblastoma, osteosarcoma, tumor Ewing's disease and Wilms' tumor.
[101]
101. Method for inhibiting Bcl-2 activity in an individual, characterized in that it comprises providing an effective amount of a compound as defined in any one of claims 1 to 95, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as appropriate. the cancer or tumor is selected from bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, a follicular lymphoma, a lymphoid malignancy of T-cell or B-cell origin, a melanoma, a myeloid leukemia, a Hodgkin's lymphoma, a non-Hodgkin's lymphoma, a head and neck cancer (including oral cancer), an ovarian cancer, a non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer, spleen cancer, polycythemia vera, thyroid cancer, u m endometrial cancer, stomach cancer, gallbladder cancer, bile duct cancer, testicular cancer, neuroblastoma, osteosarcoma, Ewing's tumor and Wilms' tumor.
[102]
102. Use of an effective amount of a compound as defined in any one of claims 1 to 95, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 96, characterized by referring to the manufacture of a medicament to treat a cancer or tumor, the cancer or tumor being selected from a bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, colorectal cancer, esophageal cancer, a hepatocellular cancer, a lymphoblastic leukemia, a follicular lymphoma, a lymphoid malignancy of T-cell or B-cell origin, a melanoma, a myeloid leukemia, a Hodgkin's lymphoma, a non-Hodgkin's lymphoma, a head and neck cancer (including cancer oral), ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer, spleen cancer, polycythemia vera, thyroid cancer, endometrial cancer, stomach cancer, gallbladder cancer, bile duct cancer, testicular cancer, a
[103]
103. Use of an effective amount of a compound as defined in any one of claims 1 to 95, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 96, characterized in that it is in the manufacture of a medicament to inhibit replication of a malignant growth or a tumor, the malignant growth or the tumor being due to a cancer selected from a bladder cancer, a brain cancer, a breast cancer, a bone marrow cancer, a cervical cancer, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, T-cell or B-cell lymphoid malignancy, melanoma, myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, a head and neck cancer (including oral cancer), ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, cancer small cell lung cancer, spleen cancer, polycythemia vera, thyroid cancer, endometrial cancer, stomach cancer, gallbladder cancer, bile duct cancer, testicular cancer, neuroblastoma, a osteosarcoma, an Ewing's tumor and a Wilms' tumor.
[104]
104. Use of an effective amount of a compound as defined in any one of claims 1 to 95, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 96, in the manufacture of a medicament to treat malignant growth or a tumor, characterized by malignant growth or the tumor is due to a cancer selected from bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, colorectal cancer, esophageal cancer , hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancy of T-cell or B-cell origin, melanoma, myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, non-small cell lung lymphoma, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer, spleen cancer, polycythemia vera, thyroid cancer, endome cancer trial, stomach cancer, gallbladder cancer, bile duct cancer, testicular cancer, neuroblastoma, osteosarcoma, Ewing's tumor and Wilms' tumor.
[105]
105. Method for improving or treating an infection caused by HIV, characterized in that it comprises administering to an individual suffering from HIV infection an effective amount of a compound, as defined in any one of claims 1 to 95, or a pharmaceutically acceptable salt thereof , or the pharmaceutical composition as defined in claim 96, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof.
[106]
106. Method for reducing the population of HIV-infected cells, characterized in that it comprises administering to an individual suffering from HIV infection an effective amount of a compound, as defined in any one of claims 1 to 95, or a pharmaceutically acceptable salt thereof , or the pharmaceutical composition as defined in claim 96, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof.
[107]
107. Method for improving or treating an infection caused by HIV, characterized in that it comprises contacting an HIV-infected cell with a compound, as defined in any one of claims 1 to 95, or a pharmaceutically acceptable salt thereof, or the composition pharmaceutical composition as defined in claim 96, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof.
[108]
108. Method for reducing the reoccurrence of an HIV-infected infection caused with a compound, as defined in any one of claims 1 to 95, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as defined in claim 96, and an amount effectiveness of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof.
[109]
109. Method for improving or treating an infection caused by HIV, characterized in that it comprises administering to an individual suffering from HIV infection an effective amount of a Becl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an agent HIV latency reverser, or a pharmaceutically acceptable salt thereof.
[110]
110. Method for reducing the population of HIV-infected cells, characterized in that it comprises administering to an individual suffering from HIV infection an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an agent HIV latency reverser, or a pharmaceutically acceptable salt thereof.
[111]
111. Method for improving or treating an infection caused by HIV, characterized by comprising contacting an HIV-infected cell with an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of a HIV latency reversing agent, or a pharmaceutically acceptable salt thereof.
[112]
112. Method for reducing the reoccurrence of an HIV infection, characterized by comprising contacting an HIV-infected cell with an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an agent HIV latency reverser, or a pharmaceutically acceptable salt thereof.
[113]
113. Method according to any one of claims 107 to 108 or 111 to 112, characterized in that the cells are CD4 + T cells.
[114]
114. The method of any one of claims 105 to 113, characterized in that the HIV latency reversing agent is selected from: a protein kinase C agonist, a PD-1 inhibitor, a PD-L1 inhibitor, a HDAC inhibitor, a phorbol ester and a bromodomain inhibitor.
[115]
115. Method according to claim 114, characterized in that the HIV latency reversing agent is selected from: ingenol, rostatin, nivolumab, pembrolizumab, pidilizumab, AMP-224, AMP-514, PDRO01, REGN2810, MEDIO680, durvalumab, atezolizumab, avelumab, BMS-936559, BGB-A317, vorinostat, panobinostat, valproic acid, romidepsin, prostratin, phorbol-12-myristate-13-acetate, briostatin-1, 2- (4- (4-chlorophenyl) - 2, 3,9-trimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-6-yl) (S) - tert- butyl, JQ1, I-BET762, OTX015, I-BET151, CPI203, PFI-1, MS436, CPI- 0610, RVX2135, FT-1101, BAY 1238097, INCBO54329, TEN-010, GSK2820151, ZENOO03694, BAY-299, BMS -986158, ABBV-075 and GS-5829.
[116]
116. Method according to any one of claims 105 to 115, characterized in that it further comprises the use of one or more agents selected from the group consisting of a non-nucleoside reverse transcriptase inhibitor (NNRTI), a nucleoside reverse transcriptase inhibitor ( NRTI), a protease inhibitor (PI), a fusion / entry inhibitor, a tape transfer integrase inhibitor (INSTI), an HIV vaccine, another HIV antiretroviral therapy compound and combinations thereof, or a pharmaceutically acceptable salt of any of the above.
[117]
117. Use of a compound, as defined in any of claims 1 to 95, or a pharmaceutically acceptable salt thereof, or of the pharmaceutical composition, as defined in claim 96, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, characterized in that it is for preparing a
[118]
118. Use of a compound, as defined in any of claims 1 to 95, or a pharmaceutically acceptable salt thereof, or of the pharmaceutical composition, as defined in claim 96, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, characterized in that it is for preparing a drug to reduce the reoccurrence of an infection caused by HIV.
[119]
119. Use of a compound, as defined in any of claims 1 to 95, or a pharmaceutically acceptable salt thereof, or of the pharmaceutical composition, as defined in claim 96, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, characterized in that it is for preparing a drug to reduce the population of HIV-infected cells.
[120]
120. Use of an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, characterized in that it is to prepare a medicine for the treatment of an HIV infection.
[121]
121. Use of an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, characterized in that it is to prepare a medicine to reduce the reoccurrence of an HIV infection.
[122]
122. Use of an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV latency reversing agent, or a pharmaceutically acceptable salt thereof, characterized in that it is to prepare a medicine to reduce the population of HIV-infected cells.
[123]
123. Use according to claim 119 or 122, characterized in that the cells are CD4 + T cells.
[124]
124. Use according to any of claims 117 to 123, characterized in that the HIV latency reversing agent is selected from: a protein kinase C agonist, a PD-1 inhibitor, a PD-L1 inhibitor, a HDAC inhibitor, a phorbol ester and a bromodomain inhibitor.
[125]
125. Use according to claim 124, characterized in that the HIV latency reversing agent is selected from: ingenol, rostatin, nivolumab, pembrolizumab, pidilizumab, AMP-224, AMP-514, PDRO01, REGN2810, MEDIO680, durvalumab, atezolizumab, avelumab, BMS-936559, BGB-A317, vorinostat, panobinostat, valproic acid, romidepsin, prostratin, phorbol-12-myristate-13-acetate, Dbriostatin-1, 2- (4- (4-chlorophenyl) - 2, 3,9-trimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-6-yl) (S) - tert- butyl, JQ1, I-BET762, OTX015, I-BET151, CPI203, PFI-1, MS436, CPI- 0610, RVX2135, FT-1101, BAY 1238097, INCBO54329, TEN-010, GSK2820151, ZENOO3694, BAY-299, BMS -986158, ABBV-075 and GS-5829.
[126]
126. Use according to any one of claims 117 to 125, characterized in that it further comprises the use of one or more agents selected from the group consisting of a non-nucleoside reverse transcriptase inhibitor (NNRTI), a nucleoside reverse transcriptase inhibitor ( NRTI), a protease inhibitor (PI), a fusion / entry inhibitor, a tape transfer integrase inhibitor (INSTI), an HIV vaccine, another HIV antiretroviral therapy compound and combinations thereof, or a pharmaceutically acceptable salt of any of the above.

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法律状态:
2021-12-07| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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