HK1200170B

HK1200170B - (hetero)aryl cyclopropylamine compounds as lsd1 inhibitors

Info

Publication number: HK1200170B
Application number: HK15100672.8A
Authority: HK
Inventors: Alberto ORTEGA MUÑOZ; Matthew Colin Thor Fyfe; Marc Martinell Pedemonte; María de los Ángeles ESTIARTE MARTÍNEZ; Nuria Valls Vidal; Guido Kurz; Julio Cesar Castro Palomino Laria
Original assignee: Oryzon Genomics, S.A.
Priority date: 2011-10-20
Filing date: 2012-10-22
Publication date: 2018-04-13

Description

(hetero) arylcyclopropylamine compounds as LSD1 inhibitors

The present invention relates to (hetero) arylcyclopropylamine compounds, particularly compounds of formulae I, Ia-1, Ib and Ic, more particularly compounds of formulae I and Ia as described and defined herein and their use in therapy, including for example in the treatment or prevention of cancer, a neurological disease or a viral infection.

Abnormal gene expression in affected tissues compared to normal tissues is a common feature of many human diseases. This is true for cancers and many neurological diseases characterized by altered gene expression patterns. Gene expression patterns are controlled at various levels in cells. Controlling gene expression can be carried out by modifying the DNA: DNA promoter methylation is associated with suppression of gene expression. Several DNA methylation inhibitors are approved for clinical use, including heavy pound bombs (blockbuster) Vidaza^TM. Another type of modification involves histones, which form the protein backbone to which DNA is normally bound (coiled around) within eukaryotic cells. Histones play a crucial role in DNA organization, and the regulated helix and uncoiling of DNA around histones is a key in controlling gene expression-helical DNA is typically not amenable to gene transcription. A number of histone modifications have been found, including histone acetylation, histone lysine methylation, histone arginine methylation, histone ubiquitination, and histone threonination, many of which alter the operability of the relevant DNA by the cellular transcriber. These histone marks are used to complement various protein complexes involved in transcription and repression. An increasing number of studies are directed to complex drawings depicting how various combinations of histone markers control gene expression in a cell-type specific manner, and new terms are created to capture this concept: the histone code.

A typical histone mark is histone acetylation. Histone acetyltransferases and histone deacetylases are catalysts involved in the regulation of histone marks, however, typically these enzymes are part of a multi-protein complex containing other proteins involved in reading and modifying histone marks. The components of these protein complexes are typically cell type specific and typically comprise transcriptional regulators, repressors, co-repressors, receptors associated with the regulation of gene expression (e.g., estrogen or androgen receptors). Histone deacetylase inhibitors alter the histone acetylation properties of chromatin. Thus, histone deacetylase inhibitors such as Volinostat (SAHA), trichostatin A (TSA), and the like have been shown to alter gene expression in different in vitro and in vivo animal models. Clinically, histone deacetylase inhibitors have shown activity in the cancer setting and are being investigated for oncologic indications as well as neurological disorders and other diseases.

Another modification involved in regulating gene expression is histone methylation, including lysine and arginine methylation. The methylation status of histone lysines has recently been shown to be important in dynamically regulating gene expression.

A group of enzymes called histone lysine methyltransferase and histone lysine demethylase are involved in histone lysine modification. A specific human histone lysine demethylase called lysine-specific demethylase-1 (LSD1) (Shi et al (2004) Cell 119: 941), has recently been discovered and is involved in this key histone modification. LSD1 shares considerable structural similarity and amino acid identity/homology with polyamine oxidases and monoamine oxidases, all of which (i.e., MAO-A, MAO-B and LSD1) are flavin-dependent amine oxidases that catalyze the oxidation of nitrogen-hydrogen bonds and/or nitrogen-carbon bonds. LSD1 is considered to be a meaningful target for developing new drugs for the treatment of cancer, neurological diseases, and other disorders.

Cyclopropylamine-containing compounds are known to inhibit A number of medically important targets, including amine oxidases such as monoamine oxidase A (MAO-A; or MAOA), monoamine oxidase B (MAO-B; or MAOB), and lysine-specific demethylase-1 (LSD 1). Is known asTranylcypromine (also known as 2-phenylcyclopropylamine), an active ingredient and one of the best known examples of cyclopropylamines, inhibits all of these enzymes. Since MAO-A inhibition may lead to undesired side effects, it is desirable to identify cyclopropylamine derivatives that exhibit potent LSD1 inhibitory activity while avoiding or substantially reducing MAO-A inhibitory activity.

In view of the lack of adequate methods for treating conditions such as cancer and neurodegeneration, there is an urgent need for drugs that alter disease and drugs that act by inhibiting new targets. Therefore, there is a need to develop LSD1 inhibitors, particularly those that selectively inhibit LSD 1.

Summary of The Invention

The present invention relates to the identification of compounds and their use in the treatment or prevention of disease. The present invention provides (hetero) arylcyclopropylamine compounds as described and defined herein, including compounds of formulae I, Ia-1, Ib and Ic, particularly compounds I, Ia and Ia-1. The invention provides, inter alia, compounds of formula I, Ia-1, Ib and Ic, in particular compounds of formula I, Ia and Ia-1, pharmaceutical compositions comprising a compound of formula I, Ia-1, Ib or Ic, and in particular a compound of formula I, Ia or Ia-1, and a pharmaceutically acceptable carrier, and their use in the treatment of disease. One use of the compounds of formulae I, Ia-1, Ib and Ic is in the treatment or prevention of cancer. Another use of compounds of formula I, Ia-1, Ib and Ic is the inhibition of LSD 1. The invention thus relates to compounds of formula I, Ia-1, Ib or Ic, and in particular compounds of formula I, Ia or Ia-1, for use in the treatment or prophylaxis of a disease in a human. The invention also relates to compounds of formula I, Ia-1, Ib or Ic, and in particular compounds of formulae I, Ia and Ia-1, for use in the treatment or prevention of cancer. The invention also relates to compounds of formula I, Ia-1, Ib or Ic, and in particular compounds of formulae I, Ia and Ia-1, for use in the treatment or prevention of a neurological disease. The invention also relates to compounds of formula I, Ia-1, Ib or Ic, and in particular compounds of formulae I, Ia and Ia-1, for use in the treatment or prevention of a viral infection.

Accordingly, the present invention provides a compound of formula I:

wherein:

a is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R¹Substitution;

b is hydrogen, R¹or-L-E;

e is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R²Substitution;

l is a bond, -O-, -NH-, -N (C)_1-4Alkyl) -, C_1-4Alkylene or hetero C_1-4An alkylene group;

d is cycloalkyl having 4 to 7C atoms, wherein the cycloalkyl has one or two substituents;

R³and further optionally substituted with one or more R⁴And wherein cycloalkyl is optionally:

(a) fused with phenyl or a 5-or 6-membered aromatic heterocycle comprising 1-3 heteroatoms independently selected from N, O and S, wherein said fused phenyl or said fused aromatic heterocycle is optionally substituted with one or more R⁵Substitution; or

(b) To any two non-adjacent ring carbon atoms which together link a cycloalkyl group- (C (R)^a)₂)_p-bonding, wherein p is 1 or 2 and R^aEach independently is hydrogen or C_1-4An alkyl group; or

(c) Is linked to a second ring which is a 3-to 7-membered saturated carbocyclic ring or a 3-to 7-membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein the second ring and cycloalkyl are linked to each other through a single carbon atom common to both rings, and wherein the second ring is optionally substituted with one or more R⁶Substitution;

R¹each independently selected from C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, cyclic group, amino, amido, hydroxy, nitro, halogen, halo C_1-8Alkyl, halo C_1-8Alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C_1-8Alkoxy, acyl, carboxyl, O-carboxyl, C-carboxyl, carbamate, and urea;

R²each independently selected from C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, cyclic group, amino, amido, hydroxy, nitro, halogen, halo C_1-8Alkyl, halo C_1-8Alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C_1-8Alkoxy, acyl, carboxyl, O-carboxyl, C-carboxyl, carbamate, and urea;

R³each independently selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸、-OH、-CONR⁷R⁸Oxo, -C_1-4alkylene-NR⁷R⁸、-C_1-4alkylene-NHOH, -C_1-4alkylene-NR⁹COR¹⁰、-C_1-4alkylene-NR⁹SO₂R¹⁰、-C_1-4alkylene-NR⁹COOR¹⁰、-C_1-4alkylene-NR⁹CONR⁷R⁸、-C_1-4alkylene-NR⁹SO₂NR⁷R⁸、-C_1-4alkylene-OH and-C_1-4alkylene-CONR⁷R⁸；

R⁴Each and R⁶Each independently selected from C_1-8Alkyl, halogen, halogeno C_1-8Alkyl, halo C_1-8Alkoxy and C_1-8An alkoxy group;

R⁵each independently selected from C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, cyclic group, amino, amido, hydroxy, nitro, halogen, halo C_1-8Alkyl, halo C_1-8Alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C_1-8Alkoxy, acyl, carboxyl, O-carboxyl, C-carboxyl, carbamate, and urea;

R⁷each and R⁸Each independently selected from hydrogen and C_1-8Alkyl radical, R¹²R¹³N-C_1-8Alkyl and hydroxy C_1-8Alkyl, or R⁷And R⁸Is a saturated 3-to 7-membered heterocyclic ring, optionally containing another heteroatom selected from N, O and S, combined with the N atom to which it is attached, wherein one or more C atoms on the heterocyclic ring are optionally oxidized to a CO group, wherein if present, thenOne or more S atoms of the heterocyclic ring are optionally oxidized to form independently SO groups or SO₂And wherein said heterocycle is optionally substituted with one or more R¹¹Substitution;

R⁹each independently selected from hydrogen and C_1-4An alkyl group;

R¹⁰each independently selected from C_1-8Alkyl, halo C_1-8Alkyl, cyclic group and cyclic group C_1-8Alkyl, wherein the cyclic group is contained in the cyclic group C_1-8The cyclic moiety of the alkyl group is optionally substituted with one or more R¹⁴Substitution;

R¹¹each independently selected from C_1-8Alkyl, halogen, C_1-8Alkoxy, hydroxy and-NR¹²R¹³；

R¹²Each and R¹³Each independently selected from hydrogen and C_1-8An alkyl group;

R¹⁴each independently selected from C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, amino, amido, hydroxy, nitro, halogen, haloC_1-8Alkyl, halo C_1-8Alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C_1-8Alkoxy, acyl, carboxyl, O-carboxyl, C-carboxyl, carbamate, and urea; and is

R^w、R^x、R^yAnd R^zEach independently selected from hydrogen, halogen and C_1-4An alkyl group;

with the proviso that the following compounds are excluded:

2- ((2-phenylcyclopropyl) amino) cycloheptanol, and

2- ((2-phenylcyclopropyl) amino) cyclopentanol.

In addition, the compound 2- ((2-phenylcyclopropyl) amino) cyclohexanol is more preferably excluded.

In another embodiment, the invention provides a compound of formula I wherein R is^w、R^x、R^yAnd R^zEach is hydrogen, i.e. a compound of formula Ia:

wherein:

b is hydrogen, R¹or-L-E;

R³and further optionally substituted with one or more R⁴And wherein said cycloalkyl is optionally:

(c) Is linked to a second ring which is a 3-to 7-membered saturated carbocyclic ring or contains 1 to 3 substituents independently selected from N, N,A 3-to 7-membered saturated heterocyclic ring of heteroatoms of O and S, wherein said second ring and cycloalkyl are connected to each other through a single carbon atom common to both rings, and wherein said second ring is optionally substituted with one or more R⁶Substitution;

R⁷each and R⁸Each independently selected from hydrogen and C_1-8Alkyl radical, R¹²R¹³N-C_1-8Alkyl and hydroxy C_1-8Alkyl, or R⁷And R⁸Is a saturated 3-to 7-membered heterocyclic ring, optionally containing another heteroatom selected from N, O and S, combined with the N atom to which it is attached, wherein one or more C atoms on the heterocyclic ring are optionally oxidized to a CO group, wherein if present, one or more S atoms on the heterocyclic ring are optionally oxidized to independently a SO group or SO₂And wherein said heterocycle is optionally substituted with one or more R¹¹Substitution;

R⁹each independently selected from hydrogen and C_1-4An alkyl group;

R¹²Each and R¹³Each independently selected from hydrogen andC_1-8an alkyl group; and is

R¹⁴Each independently selected from C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, amino, amido, hydroxy, nitro, halogen, haloC_1-8Alkyl, halo C_1-8Alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C_1-8Alkoxy, acyl, carboxyl, O-carboxyl, C-carboxyl, carbamate, and urea;

with the proviso that the following compounds are excluded:

2- ((2-phenylcyclopropyl) amino) cycloheptanol, and

2- ((2-phenylcyclopropyl) amino) cyclopentanol.

In another embodiment, the present invention provides a compound of formula Ia as defined above wherein the substituents of the cyclopropyl moieties-a-B and-NH-D are in the trans-configuration, i.e. a compound of formula Ia-1:

wherein the groups and variables of formula Ia-1 include A, B, D, E, L, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³And R¹⁴As defined above for the compounds of formula Ia, provided that the following compounds are excluded:

2- ((2-phenylcyclopropyl) amino) cycloheptanol, and

2- ((2-phenylcyclopropyl) amino) cyclopentanol.

The chemical representation of the compounds of formula Ia-1 above is not intended to represent the absolute stereochemistry of the two chiral centers on the cyclopropyl ring, but rather only the relative stereochemistry (which is trans). Thus, the compounds of formula Ia-1 may likewise be represented by

The compounds of the formula Ia-1 are therefore each optically active trans isomer and any desired mixtures thereof.

In another embodiment, the present invention provides a compound of formula I as defined above, wherein R is^w、R^x、R^yAnd R^zEach independently selected from hydrogen, halogen and C_1-4Alkyl, provided that at least one R is^w、R^x、R^yAnd R^zIs not hydrogen; this compound is hereinafter referred to as compound of formula Ib. In a more preferred embodiment, R^wSelected from halogen and C_1-4Alkyl, preferably selected from fluoro and methyl, R^x、R^yAnd R^zEach is hydrogen. The compounds of formula I are hereinafter referred to as compounds of formula Ic, wherein R^wSelected from halogen and C_1-4Alkyl, preferably selected from fluoro and methyl, R^x、R^yAnd R^zEach is hydrogen.

Also included within the scope of the present invention are all isomers of the compounds of formulae I, Ia-1, Ib and Ic (as defined herein), including all stereoisomers and mixtures thereof. Also included within the scope of the present invention are all salts and all solvates, preferably pharmaceutically acceptable salts and solvates, of the compounds of formulae I, Ia-1, Ib and Ic. In addition, all physical forms (including amorphous and crystalline forms) of any such compound are also included within the scope of the present invention. Unless otherwise indicated, any reference to a compound of formula I, Ia-1, Ib or Ic shall be construed as referring to a compound of formula I, Ia-1, Ib or Ic (respectively), any isomer thereof (including any stereoisomer thereof or any mixture thereof), any salt thereof (including any pharmaceutically acceptable salt thereof), any solvate thereof (including any pharmaceutically acceptable solvate) and any physical form thereof, respectively.

Compounds of formula Ia, including compounds of formula Ia-1 as well, are particularly preferred compounds of the invention. The most preferred compounds of the present invention are compounds of formula Ia-1.

Any chemical diagram or formula given herein is intended to represent the unlabeled form as well as the isotopically labeled form of the compounds of the present invention. Isotopically-labeled compounds have the structures depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, for example each²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F、³⁶Cl and¹²⁵I. such isotopically-labelled compounds are useful in metabolic studies (preferably using¹⁴C) Reaction kinetics study (e.g., use of²H or³H) Detection or imaging techniques [ e.g. Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT)]Including drug or substrate tissue distribution assays or radiation therapy for patients. In particular, it is possible to use, for example,¹⁸f or¹¹C-labeled compounds may be particularly preferred for PET or SPECT studies. In addition, heavy isotopes such as deuterium (i.e., deuterium) are used²H) Substitution may provide some therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Particular preference is given to deuterated forms of the compounds of the invention, i.e. of the above-mentioned compounds of the formulae I, Ia-1, Ib and Ic in which one or more hydrogen atoms are replaced by deuterium. Isotopically-labeled compounds of the present invention can generally be prepared by the procedures disclosed in the schemes or in the examples and preparations below, by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagentAnd (4) preparation. All isotopically labeled forms of the compounds of formulae I, Ia-1, Ib and Ic are intended to be encompassed within the scope of the present invention, except for the unlabeled form.

In the compounds of formula I, Ia, Ib or Ic, the substituents-A-B and-NH-D on the cyclopropyl moiety are preferably in the trans-configuration.

The compounds of formula I, Ia-1, Ib or Ic are potent LSD1 inhibitors and thus may be used for the treatment or prevention of any disease associated with LSD 1.

The invention thus provides a pharmaceutical composition comprising a compound of formula I, Ia-1, Ib or Ic and a pharmaceutically acceptable carrier.

In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I

Wherein the groups and variables in formula I include A, B, D, R^w、R^x、R^yAnd R^zAs defined above, provided that the following compounds are excluded:

2- ((2-phenylcyclopropyl) amino) cycloheptanol, and

2- ((2-phenylcyclopropyl) amino) cyclopentanol;

and a pharmaceutically acceptable carrier.

In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia

Wherein the groups and variables in formula Ia include A, B and D are as defined above, with the proviso that the following compounds are excluded:

2- ((2-phenylcyclopropyl) amino) cycloheptanol, and

2- ((2-phenylcyclopropyl) amino) cyclopentanol;

and a pharmaceutically acceptable carrier.

In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia-1

Wherein the groups and variables in formula Ia-1 include A, B and D are as defined above, with the proviso that the following compounds are excluded:

2- ((2-phenylcyclopropyl) amino) cycloheptanol, and

2- ((2-phenylcyclopropyl) amino) cyclopentanol;

and a pharmaceutically acceptable carrier.

For example, preferred embodiments of the compounds of formula I, Ia-1, Ib and Ic for use in the compositions of the invention are defined below and described in more detail below.

In another aspect, the invention provides a method of treating or preventing a disease comprising administering to a patient (preferably a human) in need of such treatment or prevention an amount of a compound of formula I, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) effective to treat or prevent the disease. In one embodiment, the disease is a disease associated with LSD 1.

In a related aspect, the invention provides a compound of formula I, Ia-1, Ib or Ic (as defined in the embodiments described above or in the more detailed description herein) for use as a medicament. In a more specific embodiment, the present invention provides compounds of formula I, Ia-1, Ib or Ic for use in the treatment or prevention of a disease associated with LSD 1.

Thus, in one embodiment, the present invention provides a compound of formula I

2- ((2-phenylcyclopropyl) amino) cycloheptanol, and

2- ((2-phenylcyclopropyl) amino) cyclopentanol;

it is used as a medicament.

In another embodiment, the present invention provides a compound of formula Ia

2- ((2-phenylcyclopropyl) amino) cycloheptanol, and

2- ((2-phenylcyclopropyl) amino) cyclopentanol;

it is used as a medicament.

In another embodiment, the present invention provides a compound of formula Ia-1

2- ((2-phenylcyclopropyl) amino) cycloheptanol, and

2- ((2-phenylcyclopropyl) amino) cyclopentanol;

it is used as a medicament.

In another aspect, the invention provides a method of inhibiting LSD1 activity comprising administering to a patient in need of such treatment or prevention an amount of a compound of formula I, Ia-1, Ib, or Ic sufficient to inhibit LSD1 activity. Preferably the patient is a human. In a related aspect, the invention provides compounds of formula I, Ia-1, Ib or Ic as defined herein for use as LSD1 inhibitors. Preferred embodiments of the compounds of formula I, Ia-1, Ib or Ic for use herein are described in more detail below.

In another aspect, the invention provides a method of treating or preventing cancer, comprising administering to a patient (preferably a human) in need of such treatment or prevention an amount of a compound of formula I, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) sufficient to treat or prevent such cancer. In a related aspect, the invention provides a method of treating or preventing a cancer, wherein the cancer is selected from breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, skin cancer, blood cancer (e.g., leukemias, including, for example, Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL), or hairy cell leukemia), lymphoma and myeloma, the method comprising administering to a patient (preferably a human) having such treatment or prevention a compound of formula I, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) in an amount sufficient to treat or prevent such cancer. In an even more particular aspect, the cancer is selected from the group consisting of prostate cancer, brain cancer, colorectal cancer, lung cancer, breast cancer, skin cancer, and blood cancer. In a particular aspect, the cancer is prostate cancer. In a particular aspect, the cancer is lung cancer. In a particular aspect, the cancer is brain cancer. In a particular aspect, the cancer is a blood cancer (e.g., leukemia, including, for example, Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL), or hairy cell leukemia). In a particular aspect, the cancer is breast cancer. In a particular aspect, the cancer is colorectal cancer. In a particular aspect, the cancer is lymphoma. In a particular aspect, the cancer is myeloma. In a preferred embodiment, the method comprises administering a therapeutically effective amount of a compound of formula I, Ia-1, Ib or Ic sufficient to treat or prevent the cancer. In a preferred aspect, a therapeutically effective amount of a compound of formula I, Ia-1, Ib, or Ic is an amount sufficient to inhibit LSD 1. In another preferred aspect, a therapeutically effective amount is an amount sufficient to modulate the level of histone methylation. In another preferred aspect, a therapeutically effective amount is an amount sufficient to modulate the level of histone-3 lysine-4 methylation. In another preferred aspect, a therapeutically effective amount is an amount sufficient to modulate the level of histone-3 lysine-9 methylation. Although the present invention relates to the treatment and prevention of cancer, the treatment of cancer is particularly preferred.

Thus, in one embodiment, the present invention provides a method of treating or preventing cancer comprising administering to a patient (preferably a human) in need of such treatment or prevention an amount of a compound of formula I

2- ((2-phenylcyclopropyl) amino) cycloheptanol, and

2- ((2-phenylcyclopropyl) amino) cyclopentanol.

In another embodiment, the present invention provides a method of treating or preventing cancer comprising administering to a patient (preferably a human) in need of such treatment or prevention an amount of a compound of formula Ia

2- ((2-phenylcyclopropyl) amino) cycloheptanol, and

2- ((2-phenylcyclopropyl) amino) cyclopentanol.

In another embodiment, the present invention provides a method of treating or preventing cancer comprising administering to a patient (preferably a human) in need of such treatment or prevention an amount of a compound of formula Ia-1

2- ((2-phenylcyclopropyl) amino) cycloheptanol, and

2- ((2-phenylcyclopropyl) amino) cyclopentanol.

In a related aspect, the invention provides a compound of formula I, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) for use in the treatment or prevention of cancer. In another related aspect, the invention provides a compound of formula I, Ia-1, Ib or Ic for use in the treatment or prevention of cancer, wherein the cancer is selected from breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, skin cancer, blood cancer (e.g., leukemias, including, e.g., Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL) or hairy cell leukemia), lymphoma and myeloma. In a more specific aspect, the cancer is selected from the group consisting of prostate cancer, brain cancer, colorectal cancer, lung cancer, breast cancer, skin cancer, and blood cancer. In a particular aspect, the cancer is prostate cancer. In a particular aspect, the cancer is lung cancer. In a particular aspect, the cancer is brain cancer. In a particular aspect, the cancer is a blood cancer (e.g., leukemia, including, for example, Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL), or hairy cell leukemia). In a particular aspect, the cancer is breast cancer. In a particular aspect, the cancer is colorectal cancer. In a particular aspect, the cancer is lymphoma. In a particular aspect, the cancer is myeloma. In a preferred embodiment, a therapeutically effective amount of formula I, Ia-1, Ib or Ic sufficient to treat or prevent the cancer is administered. In a preferred aspect, a therapeutically effective amount of formula I, Ia-1, Ib, or Ic is an amount sufficient to inhibit LSD 1. In another preferred aspect, a therapeutically effective amount is an amount sufficient to modulate the level of histone methylation. In another preferred aspect, a therapeutically effective amount is an amount sufficient to modulate the level of histone-3 lysine-4 methylation. In another preferred aspect, a therapeutically effective amount is an amount sufficient to modulate the level of histone-3 lysine-9 methylation.

Thus, in one embodiment, the present invention provides a compound of formula I

2- ((2-phenylcyclopropyl) amino) cycloheptanol, and

2- ((2-phenylcyclopropyl) amino) cyclopentanol;

it is used for treating or preventing cancer.

In another embodiment, the present invention provides a compound of formula Ia

2- ((2-phenylcyclopropyl) amino) cycloheptanol, and

2- ((2-phenylcyclopropyl) amino) cyclopentanol;

it is used for treating or preventing cancer.

2- ((2-phenylcyclopropyl) amino) cycloheptanol, and

2- ((2-phenylcyclopropyl) amino) cyclopentanol;

it is used for treating or preventing cancer.

In another aspect, the invention provides a method of treating or preventing a neurological disease (e.g. a neurodegenerative disease) comprising administering to a patient in need of such treatment or prevention a compound of formula I, Ia-1, Ib or Ic (as defined in the embodiments above or described in more detail herein) in an amount sufficient to treat or prevent said neurological disease. In a related aspect, the invention provides a method of treatment or prevention of a neurological disease selected from depression, alzheimer's disease, huntington's disease, parkinson's disease, amyotrophic lateral sclerosis, dementia with lewy bodies or frontotemporal dementia, in particular selected from depression, alzheimer's disease, huntington's disease, parkinson's disease or dementia with lewy bodies, comprising administering to a patient (preferably a human) with such treatment or prevention a compound of formula I, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) in an amount sufficient to treat or prevent such neurological disease. In a preferred embodiment, the method comprises administering a therapeutically effective amount of a compound of formula I, Ia-1, Ib or Ic sufficient to treat or prevent such a neurological disorder. In a preferred aspect, a therapeutically effective amount of formula I, Ia-1, Ib, or Ic is an amount sufficient to inhibit LSD 1. In another preferred aspect, a therapeutically effective amount is an amount sufficient to modulate the level of histone methylation. In another preferred aspect, a therapeutically effective amount is an amount sufficient to modulate the level of histone-3 lysine-4 methylation. In another preferred aspect, a therapeutically effective amount is an amount sufficient to modulate the level of histone-3 lysine-9 methylation.

In another related aspect, the invention provides a compound of formula I, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) for use in the treatment or prevention of a neurological disease (e.g. a neurodegenerative disease). In one embodiment, the neurological disease is selected from depression, alzheimer's disease, huntington's disease, parkinson's disease, amyotrophic lateral sclerosis, dementia with lewy bodies and frontotemporal dementia, in particular from depression, alzheimer's disease, huntington's disease, parkinson's disease and dementia with lewy bodies. In a preferred embodiment, a therapeutically effective amount of a compound of formula I, Ia-1, Ib or Ic sufficient to treat or prevent the neurological disease is administered. In a preferred aspect, a therapeutically effective amount of a compound of formula I, Ia-1, Ib, or Ic is an amount sufficient to inhibit LSD 1. In another preferred aspect, a therapeutically effective amount is an amount sufficient to modulate the level of histone methylation. In another preferred aspect, a therapeutically effective amount is an amount sufficient to modulate the level of histone-3 lysine-4 methylation. In another preferred aspect, a therapeutically effective amount is an amount sufficient to modulate the level of histone-3 lysine-9 methylation.

In another aspect, the invention provides a method of treating or preventing a viral infection, comprising administering to a patient (preferably a human) in need thereof an amount of a compound of formula I, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) sufficient to treat or prevent the viral infection. In a related aspect, the invention also provides a compound of formula I, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) for use in the treatment or prevention of a viral infection. In a specific embodiment, the viral infection is a herpes viral infection. In a more specific embodiment, the herpes viral infection is caused by and/or associated with a herpes virus selected from the group consisting of HSV-1, HSV-2, and EB virus. In another embodiment, the viral infection is caused by and/or associated with HIV. In another embodiment, the viral infection is caused by and/or associated with a hepadnavirus (i.e., a virus of the hepadnaviridae family), particularly a Hepatitis B Virus (HBV). In another embodiment, the viral infection is caused by and/or associated with a flavivirus genus (i.e., a virus of the flaviviridae family), in particular Hepatitis C Virus (HCV), yellow fever virus, west nile virus, dengue virus, or japanese encephalitis virus, and more preferably HCV. In an even more specific embodiment, the present invention provides a method of treating or preventing post-incubation viral reactivation, the method comprising administering to a subject (preferably a human) a compound of formula I, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein). Accordingly, the present invention also provides a compound of formula I, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) for use in the treatment or prevention of viral reactivation after incubation. In a specific embodiment, the reactivated virus is a herpes virus. In a more specific embodiment, the reactivated herpesvirus is selected from the group consisting of HSV-1, HSV-2 and EB virus. In an even more specific embodiment, the reactivated virus is HSV. In another specific embodiment, the reactivated virus is HIV.

In another aspect, the invention provides the use of a compound of formula I, Ia-1, Ib or Ic (as defined in the embodiments described above or in the more detailed description herein) in the manufacture of a medicament for the treatment or prevention of cancer. In a preferred embodiment, the cancer is selected from breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, skin cancer, blood cancer (e.g., leukemia, including, for example, Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL), or hairy cell leukemia), lymphoma, and myeloma.

In another aspect, the invention provides the use of a compound of formula I, Ia-1, Ib or Ic (as defined in the embodiments described above or in the more detailed description herein) in the manufacture of a medicament for the treatment or prevention of a neurological disease (e.g. a neurodegenerative disease). In a preferred embodiment, the neurological disease is selected from depression, alzheimer's disease, huntington's disease, parkinson's disease, amyotrophic lateral sclerosis, dementia with lewy bodies or frontotemporal dementia, in particular from depression, alzheimer's disease, huntington's disease, parkinson's disease and dementia with lewy bodies.

In another aspect, the invention provides the use of a compound of formula I, Ia-1, Ib or Ic (as defined in the embodiments described above or in the more detailed description herein) in the manufacture of a medicament for the treatment or prevention of a viral infection. In a preferred embodiment, the viral infection is a herpes virus infection (e.g., a herpes virus infection caused by and/or associated with a herpes virus selected from the group consisting of HSV-1, HSV-2, and EB virus) or a viral infection caused by and/or associated with HIV. In another preferred embodiment, the viral infection is caused by and/or associated with a hepadnavirus, in particular Hepatitis B Virus (HBV). In another embodiment, the viral infection is caused by and/or associated with a flavivirus, in particular a Hepatitis C Virus (HCV), yellow fever virus, west nile virus, dengue virus or japanese encephalitis virus, and more preferably HCV.

In another aspect, the invention provides the use of a compound of formula I, Ia-1, Ib or Ic (as defined in the embodiments described above or in the more detailed description herein) in the manufacture of a medicament for the treatment or prevention of viral reactivation after incubation. In a preferred embodiment, the reactivated virus is a herpes virus (e.g., HSV-1, HSV-2, or EB virus), HSV, or HIV.

In another aspect, the invention provides A method of identifying A compound as A selective inhibitor of LSD1, the method comprising selecting or providing A compound of formulA I, IA-1, Ib, or Ic as defined herein and determining the ability of the compound to inhibit LSD1 and MAO-A and/or MAO-B, wherein A compound that inhibits LSD1 to A greater extent than MAO-A and/or MAO-B is identified as A selective inhibitor of LSD 1. In this regard, compounds that are LSD1 inhibitors may be useful in the treatment of diseases, particularly in vivo diseases.

In another aspect, the invention provides a process for the preparation of a compound of formula I or a salt thereof, which process comprises reacting a compound of formula II

A, B, R therein^w、R^x、R^y、R^zHaving the meanings disclosed above in connection with the compounds of the formula I, with compounds of the formula III in the presence of reducing agents,

wherein D has the meaning disclosed above in connection with the compounds of the formula I, and wherein the radical R on the ring D³Optionally protected by a protecting group, and optionally protected by a protecting group,

any protecting groups that may be present are then removed. The reducing agent may be, for example, a borohydride, such as sodium borohydride or sodium triacetoxyborohydride.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the present specification, including definitions, will control. Furthermore, the method is simple. The materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.

Detailed Description

The present invention relates to the identification of compounds and their use in the treatment and prevention of disease. The invention provides compounds of formula I, Ia-1, Ib and Ic, pharmaceutical compositions comprising a compound of formula I, Ia-1, Ib or Ic and a pharmaceutically acceptable carrier and the use thereof in the treatment of disease. One use of the compounds of formula I, Ia-1, Ib and Ic is in the treatment of cancer.

The present invention provides compounds of formula I

In the compounds of formula I, R^w、R^x、R^yAnd R^zEach independently selected from hydrogen, halogen and c_1-4An alkyl group. In one embodiment, R^w、R^x、R^yAnd R^zEach independently selected from hydrogen, fluorine and C_1-4Alkyl, preferably selected from hydrogen, fluorine and methyl. In another embodiment, R^w、R^x、R^yAnd R^zEach independently selected from hydrogen and fluorine. In another embodiment, R^wIs fluorine, R^x、R^yAnd R^zEach independently selected from hydrogen, halogen and C_1-4An alkyl group; preferably, R^wIs fluorine, R^x、R^yAnd R^zEach is hydrogen. In another embodiment, R^zIs fluorine, and R^w、R^xAnd R^yEach independently selected from hydrogen, halogen and C_1-4An alkyl group; preferably, R^zIs fluorine, and R^w、R^xAnd R^yEach is hydrogen. In another embodiment, R^wAnd R^zIs fluorine, and R^xAnd R^yEach independently selected from hydrogen, halogen and C_1-4An alkyl group; preferably, R^wAnd R^zIs fluorine, and R^xAnd R^yEach is hydrogen. In a preferred embodiment, R^wSelected from hydrogen, halogen and C_1-4Alkyl, preferably selected from hydrogen, fluoro and methyl, and R^x、R^yAnd R^zEach is hydrogen. In a more preferred embodiment, R^w、R^x、R^yAnd R^zEach is hydrogen. Wherein R is^w、R^x、R^yAnd R^zThe compounds of formula I, each being hydrogen, are compounds of formula Ia, as shown below:

in another embodiment, in the compounds of formula I, R^w、R^x、R^yAnd R^zEach independently selected from hydrogen, halogen and C_1-4Alkyl, provided that at least one is not hydrogen, which is a compound of formula Ib. In a more preferred embodiment, R^wSelected from halogen and C_1-4Alkyl, preferably fluoro and methyl, and R^x、R^yAnd R^zEach is hydrogen. The compound of formula I is a compound of formula Ic wherein R^wSelected from halogen and C_1-4Alkyl, preferably fluoro and methyl, and R^x、R^yAnd R^zEach is hydrogen. Preferably, in the compound of formula Ic, R^wIs methyl.

In the compounds of formula I, Ia-1, Ib or Ic, the group A is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted by one or more R¹And (4) substitution. In one embodiment, A is optionally substituted with one or more R¹Substituted aryl (preferably phenyl or naphthyl). In particular embodiments, A is optionally substituted with one or more R¹A substituted phenyl group. In another specific embodiment, A is optionally substituted with one or more R¹Substituted naphthyl. In another embodiment, a is heteroaryl (preferably monocyclic heteroaryl), optionally substituted with one or more R¹And (4) substitution. In a preferred embodiment, a is phenyl, naphthyl or monocyclic heteroaryl, wherein said phenyl, naphthyl or monocyclic heteroaryl is optionally substituted with one or more R¹And (4) substitution. Preferably, A is monocyclic aryl (i.e., phenyl) or monocyclic heteroaryl, wherein said monocyclic aryl or said monocyclic heteroaryl is optionally substituted with one or more R¹And (4) substitution. More preferably, a is phenyl, pyridyl, thienyl, pyrrolyl, furyl or thiazolyl, wherein a (i.e. said phenyl, said pyridyl, said thienyl, said pyrrolyl, said furyl or said thiazolyl) is optionally substituted by one or more R¹And (4) substitution. More preferably, A is phenyl, pyridyl, thiazolyl or thienyl, wherein A (i.e. the phenyl, thiazolyl or thienyl group),Said pyridyl, said thiazolyl or said thienyl) optionally substituted by one or more R¹And (4) substitution. Still more preferably, A is phenyl, pyridyl or thiazolyl, wherein A is optionally substituted with one or more R¹And (4) substitution. Even more preferably, A is phenyl, 3-pyridyl or 5-thiazolyl, as shown below:

wherein A is optionally substituted with one or more R¹And (4) substitution. In one embodiment, A is phenyl or pyridyl, preferably phenyl or 3-pyridyl. In another embodiment, a is phenyl. In another embodiment, A is pyridyl, preferably 3-pyridyl. In another embodiment, A is thiazolyl, preferably 5-thiazolyl. In one embodiment, A has 0, 1 or 2 substituents R¹. In another embodiment, A has 0 or 1 substituent R¹. In another embodiment, A has a 0 substituent R¹. In another embodiment, A has 1 or 2 substituents R¹. In another embodiment, A has 1 substituent R¹. In the above-mentioned embodiments, wherein A has 0, 1 or 2 substituents R¹Define substituent R¹Including B may be R¹The possibility of (a). Thus, if A has 0 substituents R¹Then B is not R¹。

In the compounds of the formula I, Ia-1, Ib or Ic, B is hydrogen, R¹or-L-E. In one embodiment, B is-L-E. In a preferred embodiment, B is hydrogen or R¹. In another preferred embodiment, B is hydrogen. In another embodiment, B is R¹。

In the compounds of formula I, Ia-1, Ib or Ic, E is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted by one or more R²And (4) substitution. In one embodiment, E is aryl (e.g., phenyl, naphthyl, orAnthracenyl) optionally substituted by one or more R²And (4) substitution. In another embodiment, E is heteroaryl (e.g., pyridyl, thienyl, pyrrolyl, furyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, indolyl, pyrazolyl, indazolyl, imidazolyl, or benzimidazolyl), optionally substituted with one or more R²And (4) substitution. Preferably, E is monocyclic aryl (i.e., phenyl) or monocyclic heteroaryl, wherein said monocyclic aryl or said monocyclic heteroaryl is optionally substituted with one or more R²And (4) substitution. In one embodiment, E has 0, 1, 2 or 3 substituents R². In another embodiment, E has 0, 1 or 2 substituents R². In another embodiment, E has 0 or 1 substituent R². In another embodiment, E has 0 substituents R². In another embodiment, E has 1 substituent R². Preferably, E is optionally substituted with one or more R²A substituted phenyl group. In one embodiment, E is optionally substituted with one, two or three R²A substituted phenyl group. In another embodiment, E is optionally substituted with one or two R²A substituted phenyl group. In another embodiment, E is optionally substituted with one R²A substituted phenyl group. In another embodiment, E is phenyl. In another embodiment, E is substituted with one, two or three, preferably one or two, R²A substituted phenyl group. In another preferred embodiment, E is heteroaryl, preferably monocyclic heteroaryl, optionally substituted with one or more (preferably one, two or three) R²And (4) substitution. In one embodiment, E is heteroaryl, preferably monocyclic heteroaryl. In another embodiment, E is heteroaryl (preferably monocyclic heteroaryl) interrupted by one, two or three, preferably one or two, R²And (4) substitution.

In the compounds of the formula I, Ia-1, Ib or Ic, L is a bond, -O-, -NH-, -N (C)_1-4Alkyl) -, C_1-4Alkylene or hetero C_1-4An alkylene group. Preferably said hetero C_1-4Alkylene oxideRadical is- (CH)₂)_x-NH-or- (CH)₂)_x-O-, wherein x is 1, 2, 3 or 4; still more preferably, the- (CH)₂)_x-NH-or- (CH)₂)_xthe-O-group connects ring A through the N or O atom and through- (CH)₂)_x-the group joining ring E. More preferably, said hetero C_1-4Alkylene is-CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-and-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group joining ring E.

In one embodiment, L is a bond, -O-, -NH-, -N (C)_1-4Alkyl) -, -CH₂-、CH₂-CH₂-、-CH₂-NH-or-CH₂-O-. In a preferred embodiment, L is a bond, -O-, -NH-, -N (C)_1-4Alkyl) -, -CH₂-NH-or-CH₂-O-. In preferred embodiments, L is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-. In a still more preferred embodiment, L is a bond or-CH₂-O-. In another preferred embodiment, L is a bond. In another embodiment, L is-O-, -NH-, -N (C)_1-4Alkyl) -, C_1-4Alkylene or hetero C_1-4An alkylene group; preferably, L is-O-, -NH-, -N (C)_1-4Alkyl) -, -CH₂-、CH₂-CH₂-、-CH₂-NH-or-CH₂-O-; more preferably, L is-O-, -NH-, -N (C)_1-4Alkyl) -, -CH₂-NH-or-CH₂-O-; even more preferably L is-O-, -NH-, -CH₂-NH-or-CH₂-O-; still more preferably L is-NH-, -CH₂-NH-or-CH₂-O-; it is particularly preferred that L is-CH₂-O-. Preferably, in all of these embodiments, the-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group joining ring E.

In one embodiment, B is-L-E; e is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R²Substitution; l is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein the group-CH₂-NH-and-CH₂-O-connects ring A through N or O atom and through-CH, respectively₂-the group joining ring E. In another embodiment, B is-L-E; e is optionally substituted with one or more R²Substituted phenyl; l is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein the group-CH₂-NH-and-CH₂-O-connects ring A through N or O atom and through-CH, respectively₂-the group joining ring E. In another embodiment, B is-L-E; e is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R²Substitution; l is a bond or-CH₂-O-, wherein the group-CH₂O-connects ring A through O atom and through-CH₂-the group joining ring E. In another embodiment, B is-L-E; e is optionally substituted with one or more R²Substituted phenyl; l is a bond or-CH₂-O-, wherein the group-CH₂O-connects ring A through O atom and through-CH₂-the group joining ring E. In another embodiment, B is-L-E; e is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R²Substitution; l is a bond. In another embodiment, B is-L-E; e is optionally substituted with one or more R²Substituted phenyl; l is a bond. In another embodiment, B is-L-E; e is optionally substituted with one or more R²Substituted heteroaryl; l is a bond. In another embodiment, B is-L-E; e is aryl or heteroaryl; l is a bond. In another embodiment, B is-L-E; e is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R²Substitution; l is-CH₂-O-, wherein the group-CH₂O-connects ring A through O atom and through-CH₂-the group joining ring E. In another embodiment, B is-L-E; e is optionally substituted with one or more R²Substituted phenyl; l is-CH₂-O-, wherein the group-CH₂O-connects ring A through O atom and through-CH₂-the group joining ring E. In another implementationIn the scheme, B is-L-E; e is heteroaryl (preferably monocyclic heteroaryl, more preferably pyridyl), wherein said heteroaryl is optionally substituted with one or more R²Substitution; l is-CH₂-O-, wherein the group-CH₂O-connects ring A through O atom and through-CH₂-the group joining ring E. In another embodiment, B is-L-E; e is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R²Substitution; l is-O-, -NH-, -N (C)_1-4Alkyl) -, C_1-4Alkylene or-CH₂-NH-, more preferably L is-O-, -NH-or-CH₂-NH-, wherein the radical-CH₂-NH-connects ring A through the N atom and through-CH₂-the group joining ring E. In another embodiment, B is-L-E; e is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R²Substitution; l is-NH-or-CH₂-NH-, wherein the radical-CH₂-NH-connects ring A through the N atom and through-CH₂-the group joining ring E.

In the compounds of formula I, Ia-1, Ib or Ic, R¹Each independently selected from C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, cyclic group, amino, amido, hydroxy, nitro, halogen, halo C_1-8Alkyl, halo C_1-8Alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C_1-8Alkoxy, acyl, carboxyl, O-carboxyl, C-carboxyl, carbamate, and urea. When more than one R is present¹As the substituents on the ring A, they may be the same or different. In one embodiment, R¹Each independently selected from C_1-8Alkyl, cyclic group, amino, amido, hydroxy, halogen, haloC_1-8Alkyl, halo C_1-8Alkoxy, cyano, sulfonamide, C_1-8Alkoxy, acyl, carboxyl, carbamate, and urea. In another embodiment, R¹Each independently selected from C_1-8Alkyl, amino, amido, hydroxy, halogen, haloC_1-8Alkyl, halo C_1-8Alkoxy, cyano, sulfonamide, C_1-8Alkoxy, acyl, carboxyl, carbamate, and urea. In another embodiment, R¹Each independently selected from C_1-8Alkyl, amino, amido, halogen, halo C_1-8Alkyl, halo C_1-8Alkoxy, cyano, sulfonamide, C_1-8Alkoxy, acyl, carboxyl, carbamate, and urea. In another embodiment, R¹Each independently selected from halogen, C_1-4Alkyl (e.g. methyl), halo C_1-4Alkyl (e.g. trifluoromethyl), C_1-4Alkoxy (e.g. methoxy) and C_3-6Cycloalkyl (e.g. cyclopropyl), preferably R¹Each independently selected from halogen, C_1-4Alkyl (e.g. methyl) and C_1-4Alkoxy (e.g., methoxy). In another embodiment, R¹Each independently selected from halogen, C_1-4Alkyl and C_3-6A cycloalkyl group.

In the compounds of formula I, Ia-1, Ib or Ic, R²Each independently selected from C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, cyclic group, amino, amido, hydroxy, nitro, halogen, halo C_1-8Alkyl, halo C_1-8Alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C_1-8Alkoxy, acyl, carboxyl, O-carboxyl, C-carboxyl, carbamate, and urea. When more than one R is present²As the substituents on the ring E, they may be the same or different. In one embodiment, R²Each independently selected from C_1-8Alkyl, cyclic group, hydroxy, halogen, halogeno C_1-8Alkyl, halo C_1-8Alkoxy, cyano, sulfonamide and C_1-8An alkoxy group. Preferably, R²Each independently selected from C_1-8Alkyl, cyclic group, hydroxy, halogen, halogeno C_1-8Alkyl, halo C_1-8Alkoxy, cyano, N-sulfonylamino and C_1-8An alkoxy group; more preferably R²Each independently selected from C_1-8Alkyl, hydroxy, halogen, halogeno C_1-8Alkyl, halo C_1-8Alkoxy, cyano, N-sulfonylamino and C_1-8An alkoxy group. In another embodiment, R²Each independently selected from hydroxy, halogen (e.g. fluorine or chlorine), halo C_1-8Alkyl (e.g., trifluoromethyl) and sulfonamide (preferably N-sulfonamido). In another embodiment, R²Each independently selected from hydroxy, halogen, halo C_1-8Alkyl and N-sulfonylamino. In another embodiment, R²Each independently selected from hydroxy, halogen, halo C_1-8Alkyl and-NR' SO₂R (wherein R and R 'are as defined below; preferably R' is H and R is C_1-8Alkyl (e.g., methyl, ethyl, or isopropyl), or R' is H and R is optionally substituted phenyl). In another embodiment, R²Each independently selected from hydroxy, halogen, halo C_1-8Alkyl and-NHSO₂R (wherein R is C_1-8Alkyl (e.g., methyl, ethyl or isopropyl), optionally substituted phenyl (e.g., phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-aminophenyl, 3-aminophenyl or 4-aminophenyl), optionally substituted heterocycloalkyl (e.g., piperazin-1-yl), or optionally substituted heteroaryl (e.g., 3-pyridyl or 6-amino-3-pyridyl)). In another embodiment, R²Each independently selected from hydroxy, halogen and halo C_1-8An alkyl group. In another embodiment, R²Each independently selected from hydroxy, halogen and halo C_1-4An alkyl group. In another embodiment, R²Each independently selected from hydroxy, chloro, fluoro or trifluoromethyl. In another embodiment, ring E is substituted with one R²Substituted, said R²is-NHSO₂R, wherein R is C_1-8Alkyl (e.g. methyl, ethyl or isopropyl), optionally substituted phenyl (e.g. phenyl or 2-cyanophenyl), optionally substituted heterocycloalkyl (e.g. piperazin-1-yl) or optionally substituted heteroaryl (e.g. 3-pyridyl or 6-amino-3-pyridyl).

In the compounds of the formula I, Ia-1, Ib or Ic D is cycloalkyl having 4 to 7C atoms, where the cycloalkyl has one or two substituents R³And further optionally substituted with one or more R⁴Substituted, wherein cycloalkyl isSelecting land:

(b) To any two nonadjacent ring carbon atoms which together are a ring carbon atom of (C) (R)^a)₂)_pBonding (i.e. forming a bridged structure), wherein p is 1 or 2 and R^aEach independently is hydrogen or C_1-4An alkyl group; or

(c) Is linked to a second ring, said second ring being a 3-to 7-membered saturated carbocyclic ring or a 3-to 7-membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein said second ring and cycloalkyl are linked to each other through a single carbon atom common to both rings (i.e. forming a spirocyclic ring), and wherein said second ring is optionally substituted with one or more R⁶And (4) substitution.

The cycloalkyl radicals on D are thus always substituted by one or two radicals R which may be identical or different³And may be substituted at any available position on the cycloalkyl group, preferably at a different ring C atom, but preferably not at the ring C atom connecting the cycloalkyl group to the rest of the molecule. Preferably, R³Radical (or two R)³One of the radicals, provided that there are two R³Groups) are located on most of the C atoms opposite the C atoms connecting the cycloalkyl group to the rest of the compound of formula I, which means a "1, 4" -like or "p" -like arrangement of the cyclobutyl and cyclohexyl rings and a "1, 3" -like or "m" -like arrangement of the cyclopentyl and cycloheptyl rings. In a preferred embodiment, there is only one R on the cycloalkyl group³A group. The cycloalkyl group may have one or more additional substituents R⁴Which may be the same or different and may be located at any available position of the cycloalkyl group. In addition. The cycloalkyl group may be fused to a second ring or form a bridged or spiro structure as defined in more detail above.

At one isIn an embodiment, D is cycloalkyl having 4 to 7C atoms, preferably cyclohexyl, wherein the cycloalkyl (preferably cyclohexyl) has one or two substituents R³And further optionally substituted with one or more R⁴And wherein cycloalkyl (preferably cyclohexyl) is optionally fused to phenyl or a 5-or 6-membered aromatic heterocycle containing 1-3 heteroatoms independently selected from N, O and S, wherein said fused phenyl or said fused aromatic heterocycle is optionally substituted with one or more R⁵And (4) substitution.

In a preferred embodiment, D is cycloalkyl having 4 to 7C atoms, preferably cyclohexyl, wherein the cycloalkyl (preferably cyclohexyl) has one or two substituents R³And further optionally substituted with one or more R⁴And (4) substitution.

In a more preferred embodiment, D is cycloalkyl having 4 to 7C atoms, preferably cyclohexyl, wherein said cycloalkyl (preferably cyclohexyl) has one substituent R³And further optionally substituted with one or more R⁴And (4) substitution.

In a still more preferred embodiment, D is cycloalkyl having 4 to 7C atoms, preferably cyclohexyl, wherein said cycloalkyl (preferably cyclohexyl) has one substituent R³。

In another embodiment, D is cycloalkyl having 4 to 7C atoms, preferably cyclohexyl, wherein the cycloalkyl (preferably cyclohexyl) has one or two substituents R³And further optionally substituted with one or more R⁴Substituted, and wherein cycloalkyl (preferably cyclohexyl) is fused to phenyl or a 5-or 6-membered aromatic heterocycle containing 1-3 heteroatoms independently selected from N, O and S, wherein said fused phenyl or said fused aromatic heterocycle is optionally substituted with one or more R⁵And (4) substitution.

In another embodiment, D is cycloalkyl having 4 to 7C atoms, preferably cyclohexyl, wherein said cycloalkyl has one or two substituents R³And further optionally substituted with one or more R⁴Is substituted, andwherein the cycloalkyl group is attached to a linking group- (C (R) wherein the cycloalkyl group is attached together to any two nonadjacent ring carbon atoms of the cycloalkyl group^a)₂)_p-bonding, wherein p is 1 or 2 and R^aEach independently is hydrogen or C_1-4An alkyl group.

In another embodiment, D is cycloalkyl having 4 to 7C atoms, preferably cyclohexyl, wherein said cycloalkyl has one or two substituents R³And further optionally substituted with one or more R⁴Substituted, and wherein cycloalkyl is attached to a second ring, said second ring being a 3-to 7-membered saturated carbocyclic ring or a 3-to 7-membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein said second ring and cycloalkyl are attached to each other through a single carbon atom common to both rings, and wherein said second ring is optionally substituted with one or more R⁶And (4) substitution.

In a preferred embodiment, D is selected from D1, D2, D3 and D4:

wherein the cyclobutyl ring comprised in D1, the cyclopentyl ring comprised in D2, the cyclohexyl ring comprised in D3 and the cycloheptyl ring comprised in D4 are optionally substituted by another R³Substituted and optionally substituted with one or more R⁴The substitution is carried out by the following steps,

wherein the cyclobutyl ring contained in D1 optionally:

(a) a linking group- (C (R) together with any two nonadjacent ring carbon atoms of the cyclobutyl ring contained in D1^a)₂)_p-bonding, wherein p is 1 or 2 and R^aEach independently is hydrogen or C_1-4An alkyl group; or

(b) Is linked to a second ring which is a 3-to 7-membered saturated carbocyclic ring or a 3-to 7-membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein the second ring is linked to a cyclobutyl group contained in D1The rings are linked to each other through a single carbon atom common to both rings, and wherein the second ring is optionally substituted with one or more R⁶Substitution;

and wherein the cyclopentyl ring comprised in D2, the cyclohexyl ring comprised in D3, and the cycloheptyl ring comprised in D4 are optionally:

(b) A linking group- (C (R) together with any two nonadjacent ring carbon atoms to which a cycloalkyl group (i.e. the cyclopentyl ring contained in D2, the cyclohexyl ring contained in D3 or the cycloheptyl ring contained in D4) is attached)^a)₂)_p-bonding, wherein p is 1 or 2 and R^aEach independently is hydrogen or C_1-4An alkyl group; or

(c) Is linked to a second ring which is a 3-to 7-membered saturated carbocyclic ring or a 3-to 7-membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein said second ring and cycloalkyl (i.e. the cyclopentyl ring contained in D2, the cyclohexyl ring contained in D3 or the cycloheptyl ring contained in D4) are linked to each other through a single carbon atom common to both rings, and wherein said second ring is optionally substituted with one or more R⁶And (4) substitution.

It is understood that R is the same as shown in the above formulae D1, D2, D3 and D4³Represents the point of attachment of the remainder of the compound of the corresponding group D1, D2, D3 or D4-formula I, Ia-1, Ib or Ic.

In another preferred embodiment, D is selected from D1, D2, D3 and D4:

wherein the cyclobutyl group in D1 is containedThe rings, the cyclopentyl ring comprised in D2, the cyclohexyl ring comprised in D3 and the cycloheptyl ring comprised in D4 are optionally substituted with another R³Substituted and optionally substituted with one or more R⁴And (4) substitution.

In another preferred embodiment, D is selected from D1, D2, D3 and D4:

wherein the cyclobutyl ring comprised in D1, the cyclopentyl ring comprised in D2, the cyclohexyl ring comprised in D3 and the cycloheptyl ring comprised in D4 are optionally substituted by one or more R⁴And (4) substitution.

In a more preferred embodiment, D is

Wherein the cyclohexyl ring comprised in D is optionally substituted by another R³Substituted and optionally substituted with one or more R⁴Substituted, and wherein the cyclohexyl ring comprised in D is optionally:

(b) To a linking group- (C (R) together with any two nonadjacent ring carbon atoms to which a cycloalkyl (i.e. cyclohexyl ring) is attached^a)₂)_p-bonding, wherein p is 1 or 2 and R^aEach independently is hydrogen or C_1-4An alkyl group; or

(c) Is linked to a second ring which is a 3-to 7-membered saturated carbocyclic ring or a 3-to 7-membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein the second ring is fused to a cycloalkaneThe radicals (i.e. cyclohexyl rings) being linked to each other via a single carbon atom common to both rings, and wherein said second ring is optionally substituted by one or more R⁶And (4) substitution.

In a still more preferred embodiment, D is

Wherein the cyclohexyl ring is optionally substituted with one or more R⁴And wherein the cyclohexyl ring is optionally:

(c) Is linked to a second ring which is a 3-to 7-membered saturated carbocyclic ring or a 3-to 7-membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein the second ring and cycloalkyl (i.e. cyclohexyl ring) are linked to each other through a single carbon atom common to both rings, and wherein the second ring is optionally substituted with one or more R⁶And (4) substitution.

In an even more preferred embodiment, D is

Wherein the cyclohexyl ring is optionally substituted with one or more R⁴And (4) substitution.

In a particularly preferred embodiment, D is

In another embodiment, D is a group of the formula

In the compounds of formula I, Ia-1, Ib or Ic, R³Each independently selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸、-OH、-CONR⁷R⁸Oxo, -C_1-4alkylene-NR⁷R⁸、-C_1-4alkylene-NHOH, -C_1-4alkylene-NR⁹COR¹⁰、-C_1-4alkylene-NR⁹SO₂R¹⁰、-C_1-4alkylene-NR⁹COOR¹⁰、-C_1-4alkylene-NR⁹CONR⁷R⁸、-C_1-4alkylene-NR⁹SO₂NR⁷R⁸、-C_1-4alkylene-OH and-C_1-4alkylene-CONR⁷R⁸. When R is³In the case of oxo (i.e. a group of formula ═ O), no further substituents (R) are present at this position, i.e. on the C atom on which the oxo group is located³Provided that there is aTwo R³(ii) a Or R⁴). It is also understood that if R is on any of the above formulas D1, D2, D3, or D4³Is oxo (i.e., ═ O), then the oxo group is bonded to the corresponding cycloalkyl ring through a carbon-carbon double bond. In a preferred embodiment, only one R is present on the compound of formula I, Ia-1, Ib or Ic³。

In one embodiment, R³Each independently selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸、-CONR⁷R⁸Oxo, -C_1-4alkylene-NR⁷R⁸、-C_1-4alkylene-NHOH, -C_1-4alkylene-NR⁹COR¹⁰、-C_1-4alkylene-NR⁹SO₂R¹⁰、-C_1-4alkylene-NR⁹COOR¹⁰、-C_1-4alkylene-NR⁹CONR⁷R⁸、-C_1-4alkylene-NR⁹SO₂NR⁷R⁸、-C_1-4alkylene-OH and-C_1-4alkylene-CONR⁷R⁸. In a preferred embodiment, there is only one R present³。

In another embodiment, R³Each independently selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸-OH, oxo, -C_1-4alkylene-NR⁷R⁸、-C_1-4alkylene-NHOH, -C_1-4alkylene-NR⁹COR¹⁰、-C_1-4alkylene-NR⁹SO₂R¹⁰、-C_1-4alkylene-NR⁹COOR¹⁰、-C_1-4alkylene-NR⁹CONR⁷R⁸、-C_1-4alkylene-NR⁹SO₂NR⁷R⁸and-C_1-4alkylene-OH. In a preferred embodiment, there is only one R present³。

In another embodiment, R³Each independently selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸Oxo, -C_1-4alkylene-NR⁷R⁸、-C_1-4alkylene-NHOH, -C_1-4alkylene-NR⁹COR¹⁰、-C_1-4alkylene-NR⁹SO₂R¹⁰、-C_1-4alkylene-NR⁹COOR¹⁰、-C_1-4alkylene-NR⁹CONR⁷R⁸、-C_1-4alkylene-NR⁹SO₂NR⁷R⁸and-C_1-4alkylene-OH. In a preferred embodiment, there is only one R present³。

In another embodiment, R³Each independently selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸、-OH、-CONR⁷R⁸And oxo. In a preferred embodiment, there is only one R present³。

In another embodiment, R³Each independently selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸、-CONR⁷R⁸And oxo. In alternative embodiments, onlyThere is one R³。

In another embodiment, R³Each independently selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸-OH and oxo. In a preferred embodiment, there is only one R present³。

In another embodiment, R³Each independently selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸And oxo. In a preferred embodiment, there is only one R present³。

In another embodiment, R³Each independently selected from-NR⁷R⁸、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-OH、-CONR⁷R⁸And oxo. In a preferred embodiment, there is only one R present³。

In another embodiment, R³Each independently selected from-NR⁷R⁸、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-CONR⁷R⁸And oxo. In a preferred embodiment, there is only one R present³。

In another embodiment, R³Each independently selected from-NR⁷R⁸、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸-OH and oxo. In a preferred embodiment, there is only one R present³。

In another embodiment, R³Each independently selected from-NR⁷R⁸、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸And oxo. In a preferred embodiment, there is only one R present³。

In another embodiment, R³Each independently selected from-NR⁷R⁸、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰-OH and oxo. In a preferred embodiment, there is only one R present³。

In another embodiment, R³Each independently selected from-NR⁷R⁸、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰And oxo. In a preferred embodiment, there is only one R present³。

In another embodiment, R³Each independently selected from-NR⁷R⁸-OH, oxo, -C_1-4alkylene-NR⁷R⁸and-C_1-4alkylene-OH. In a preferred embodiment, there is only one R present³。

In another embodiment, R³Each independently selected from-NR⁷R⁸Oxo, -C_1-4alkylene-NR⁷R⁸and-C_1-4alkylene-OH. In a preferred embodiment, there is only one R present³。

In another embodiment, R³Each independently selected from-NR⁷R⁸-OH and oxo. In a preferred embodiment, there is only one R present³。

In another embodiment，R³Each independently selected from-NR⁷R⁸and-OH. In a preferred embodiment, there is only one R present³。

In a preferred embodiment, R³Each independently selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸. Preferably, said-C_1-4alkylene-NR⁷R⁸is-C_1-2alkylene-NR⁷R⁸. In a preferred embodiment, there is only one R present³。

In a more preferred embodiment, R³Each independently selected from-NR⁷R⁸. In a preferred embodiment, there is only one R present³。

In the compounds of formula I, Ia-1, Ib or Ic, R⁴Each and R⁶Each independently selected from C_1-8Alkyl, halogen, halogeno C_1-8Alkyl, halo C_1-8Alkoxy and C_1-8An alkoxy group. Preferably, R⁴Each and R⁶Each independently selected from C_1-8Alkyl, halogen and C_1-8An alkoxy group. More preferably, R⁴Each and R⁶Each independently selected from C_1-4Alkyl, halogen and C_1-4An alkoxy group.

In the compounds of formula I, Ia-1, Ib or Ic, R⁷Each and R⁸Each independently selected from hydrogen and C_1-8Alkyl radical, R¹²R¹³N-C_1-8Alkyl and hydroxy C_1-8Alkyl, or R⁷And R⁸Is a saturated 3-to 7-membered heterocyclic ring, optionally containing another heteroatom selected from N, O and S, combined with the N atom to which it is attached, wherein one or more C atoms on the heterocyclic ring are optionally oxidized to a CO group, wherein one or more S atoms (if present) on the heterocyclic ring are optionally oxidized to independently a SO group or SO₂And wherein said heterocycle is optionally substituted with one or more R¹¹And (4) substitution. Preferably, the above alkyl groups are shown as groups or moieties of groups (e.g.Such as R¹²R¹³N-C_1-8Alkyl or hydroxy C_1-8On alkyl) is C_1-4Alkyl, more preferably C_1-2An alkyl group. In one embodiment, R⁷Each and R⁸Each independently selected from hydrogen and C_1-8Alkyl radical, R¹²R¹³N-C_1-8Alkyl (preferably H)₂N-C_1-8Alkyl) and hydroxy C_1-8An alkyl group; preferably, R⁷Each and R⁸Each independently selected from hydrogen and C_1-4Alkyl radical, R¹²R¹³N-C_1-4Alkyl (preferably H)₂N-C_1-4Alkyl) and hydroxy C_1-4Alkyl, more preferably R⁷Each and R⁸Each independently selected from hydrogen and C_1-2Alkyl radical, R¹²R¹³N-C_1-2Alkyl (preferably H)₂N-C_1-2Alkyl) and hydroxy C_1-2An alkyl group. In a preferred embodiment, R⁷And R⁸Each is hydrogen.

In another embodiment, R⁷And R⁸Taken together with the attached N atom to form a saturated 3-to 7-membered heterocyclic ring optionally containing another heteroatom selected from N, O and S, wherein one or more C atoms on the heterocyclic ring are optionally oxidized to a CO group, wherein one or more S atoms (if present) on the heterocyclic ring are optionally oxidized to an independent SO group or SO₂And wherein said heterocycle is optionally substituted with one or more R¹¹And (4) substitution. In a particular embodiment, -NR⁷R⁸Is a group of the formula:

in the compounds of formula I, Ia-1, Ib or Ic, R⁹Each independently selected from hydrogen and C_1-4An alkyl group. In a preferred embodiment, R⁹Each is hydrogen.

In the compounds of formula I, Ia-1, Ib or Ic, R¹⁰Each is independentSelected from C_1-8Alkyl, halo C_1-8Alkyl, cyclic group and cyclic group C_1-8Alkyl, wherein the cyclic group is contained in the ring C_1-8The cyclic group moiety of the alkyl group (i.e., any of the cyclic groups mentioned above also includes the cyclic group constituting ring C_1-8Cyclic group of alkyl moiety) optionally substituted by one or more R¹⁴And (4) substitution. In one embodiment, R¹⁰Are each selected from C_1-8Alkyl and optionally substituted by one or more R¹⁴Substituted cyclic groups, preferably R¹⁰Are each selected from C_1-4Alkyl (e.g. methyl) and aryl (preferably phenyl) optionally substituted with one or more R¹⁴And (4) substitution. In another embodiment, R¹⁰Each is C_1-8Alkyl radicals, e.g. C_1-4An alkyl group. In another embodiment, R¹⁰Each is a cyclic group optionally substituted with one or more R¹⁴Substituted, e.g. optionally with one or more R¹⁴Substituted aryl, preferably optionally substituted with one or more R¹⁴A substituted phenyl group. Optionally substituted by one or more R¹⁴The substituted radicals may be substituted, for example, by one, two or three R¹⁴And (4) substitution.

In another embodiment, there is one R³And said R is³Is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸wherein-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸Moiety of (A) to (B-NR)⁷R⁸is-NH₂Or a group of the formula:

in particular aspects of the above embodiments, there is one R³And said R is³Is selected from-NH₂and-C_1-4alkylene-NH₂Preferably from-NH₂and-C_1-2alkylene-NH₂(e.g., -CH)₂-NH₂、-CH₂-CH₂-NH₂or-CH (CH)₃)-NH₂)。

In another embodiment, there is one R³And said R is³is-NR⁷R⁸wherein-NR⁷R⁸is-NH₂Or a group of the formula:

in another embodiment, there is one R³And said R is³is-NH₂。

In another embodiment, there is one R³And said R is³Is a group of the formula:

in the above embodiments and in all of the following embodiments of the compounds of the present invention, the following compounds are excluded:

2- ((2-phenylcyclopropyl) amino) cycloheptanol, and

2- ((2-phenylcyclopropyl) amino) cyclopentanol.

Preferably, in the above embodiments and in all embodiments of the compounds of the invention described below, the compound 2- ((2-phenylcyclopropyl) amino) cyclohexanol is also not included.

The substituents of the cyclopropyl moieties-A-B and-NH-D on the compounds of formula I, Ia-1, Ib or Ic are preferably in the trans-configuration. Thus, in one embodiment, the invention provides compounds of formula I (including compounds Ia, Ib or Ic) wherein the groups-A-B and-NH-D are in the trans configuration. In a preferred embodiment, the present invention provides a compound of formula Ia, wherein the groups-A-B and-NH-D are in the trans configuration, which is a compound of formula Ia-1:

wherein the groups and variables of formula Ia-1 include A, B, D, E, L, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³And R¹⁴As defined above in relation to the different preferred embodiments of the compounds of formulae I and Ia and in relation to the compounds of formulae I and Ia. The chemical representation of the compounds of formula Ia-1 above is not intended to represent the absolute stereochemistry of the two chiral centers on the cyclopropyl ring, but rather only the relative stereochemistry (being trans). The compounds of the formula Ia-1 are therefore each optically active trans isomer as well as mixtures of trans isomers.

In one embodiment, the present invention provides a compound of formula I, wherein R is^w、R^x、R^yAnd R^zEach independently selected from hydrogen, fluorine and C_1-4Alkyl, preferably selected from hydrogen, fluorine and methyl.

In another embodiment, the invention provides a compound of formula I wherein R is^w、R^x、R^yAnd R^zEach independently selected from hydrogen and fluorine.

In another embodiment, the invention provides a compound of formula I wherein R is^wIs fluorine and R^x、R^yAnd R^zEach independently selected from hydrogen, halogen and C_1-4An alkyl group; preferably, R^wIs fluorine and R^x、R^yAnd R^zEach is hydrogen.

In another embodiment, the invention provides a compound of formula I wherein R is^zIs fluorine and R^w、R^xAnd R^yEach independently selected from hydrogen, halogen and C_1-4An alkyl group; preferably, R^zIs fluorineAnd R is^w、R^xAnd R^yEach is hydrogen.

In another embodiment, the invention provides a compound of formula I wherein R is^wAnd R^zIs fluorine and R^xAnd R^yEach independently selected from hydrogen, halogen and C_1-4An alkyl group; preferably, R^wAnd R^zIs fluorine and R^xAnd R^yEach is hydrogen.

In a preferred embodiment, the present invention provides a compound of formula I, wherein R is^wSelected from hydrogen, halogen and C_1-4Alkyl, preferably selected from hydrogen, fluoro and methyl, and R^x、R^yAnd R^zEach is hydrogen.

In a more preferred embodiment, the present invention provides a compound of formula I, wherein R is^w、R^x、R^yAnd R^zEach is hydrogen, i.e. a compound of formula Ia:

in another embodiment, the invention provides a compound of formula I wherein R is^w、R^x、R^yAnd R^zEach independently selected from hydrogen, halogen and C_1-4Alkyl, provided that at least one is not hydrogen, i.e. a compound of formula Ib.

In another embodiment, the invention provides a compound of formula I wherein R is^wSelected from halogen and C_1-4Alkyl, preferably selected from fluoro and methyl, R^x、R^yAnd R^zEach is hydrogen, i.e. a compound of formula Ic. Preferably, in the compound of formula Ic, R^wIs methyl.

In another embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1) wherein D is selected from D1, D2, D3 and D4:

wherein the cyclobutyl ring comprised in D1, the cyclopentyl ring comprised in D2, the cyclohexyl ring comprised in D3 and the cycloheptyl ring comprised in D4 are optionally substituted by another R³Substituted and optionally substituted with one or more R⁴And wherein the cyclobutyl ring contained in D1, the cyclopentyl ring contained in D2, the cyclohexyl ring contained in D3 and the cycloheptyl ring contained in D4 are optionally:

(a) fused with phenyl or a 5-or 6-membered aromatic heterocycle comprising 1-3 heteroatoms independently selected from N, O and S, wherein said fused phenyl or said fused aromatic heterocycle is optionally substituted with one or more R⁵Substitution (option (a) applies only to D2, D3, and D4, but not to D1); or

(b) A linking group- (C (R) together with any two non-adjacent ring carbon atoms linking a cycloalkyl group (i.e., the cyclobutyl ring contained in D1, the cyclopentyl ring contained in D2, the cyclohexyl ring contained in D3 and the cycloheptyl ring contained in D4))^a)₂)_p-bonding, wherein p is 1 or 2 and R^aEach independently is hydrogen or C_1-4An alkyl group; or

(c) Is linked to a second ring which is a 3-to 7-membered saturated carbocyclic ring or a 3-to 7-membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein said second ring is linked to a cycloalkyl group (i.e. the cyclobutyl ring contained in D1, the cyclopentyl ring contained in D2, the cyclohexyl ring contained in D3 and the cycloheptyl ring contained in D4) via a single carbon atom common to both rings, and wherein said second ring is optionally substituted with one or more R⁶And (4) substitution.

In a preferred embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1) wherein D is

In another preferred embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein D is

In a more preferred embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein D is

In a still more preferred embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1) wherein D is

In another embodiment, the invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1) wherein D is

In another embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein R is³Each independently selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸-OH, oxo, -C_1-4alkylene-NR⁷R⁸、-C_1-4alkylene-NHOH, -C_1-4alkylene-NR⁹COR¹⁰、-C_1-4alkylene-NR⁹SO₂R¹⁰、-C_1-4alkylene-NR⁹COOR¹⁰、-C_1-4alkylene-NR⁹CONR⁷R⁸、-C_1-4alkylene-NR⁹SO₂NR⁷R⁸and-C_1-4alkylene-OH.

In another embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein R is³Each independently selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸Oxo, -C_1-4alkylene-NR⁷R⁸、-C_1-4alkylene-NHOH, -C_1-4alkylene-NR⁹COR¹⁰、-C_1-4alkylene-NR⁹SO₂R¹⁰、-C_1-4alkylene-NR⁹COOR¹⁰、-C_1-4alkylene-NR⁹CONR⁷R⁸、-C_1-4alkylene-NR⁹SO₂NR⁷R⁸and-C_1-4alkylene-OH.

In another embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein R is³Each independently selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸-OH and oxo.

In another embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein R is³Each independently selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸And oxo.

In another embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein R is³Each independently selected from-NR⁷R⁸、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸-OH and oxo. In specific embodiments, R⁷Each and R⁸Each independently selected from hydrogen and C_1-8Alkyl radical, R¹²R¹³N-C_1-8Alkyl and hydroxy C_1-8An alkyl group; preferably, R⁷Each and R⁸Each independently selected from hydrogen and C_1-4Alkyl radical, R¹²R¹³N-C_1-4Alkyl and hydroxy C_1-4Alkyl, more preferably R⁷Each and R⁸Each independently selected from hydrogen and C_1-2Alkyl radical, R¹²R¹³N-C_1-2Alkyl and hydroxy C_1-2An alkyl group. Even more preferably R⁷And R⁸Each is hydrogen; r¹⁰Are each selected from C_1-8Alkyl and optionally substituted by one or more R¹⁴Substituted cyclic groups, preferably R¹⁰Are each selected from C_1-4Alkyl (e.g. methyl) and aryl (preferably phenyl) optionally substituted with one or more R¹⁴And (4) substitution. Optionally substituted by one or more R¹⁴May be substituted by one, two or three R¹⁴And (4) substitution.

In another embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein R is³Each independently selected from-NR⁷R⁸、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸And oxo. In specific embodiments, R⁷Each and R⁸Each independently selected from hydrogen and C_1-8Alkyl radical, R¹²R¹³N-C_1-8Alkyl and hydroxy C_1-8An alkyl group; preferably, R⁷Each and R⁸Each independently selected from hydrogen and C_1-4Alkyl radical, R¹²R¹³N-C_1-4Alkyl and hydroxy C_1-4Alkyl, more preferably R⁷Each and R⁸Each independently selected from hydrogen and C_1-2Alkyl radical, R¹²R¹³N-C_1-2Alkyl and hydroxy C_1-2Alkyl, even more preferably R⁷And R⁸Each is hydrogen; r¹⁰Are each selected from C_1-8Alkyl and optionally substituted by one or more R¹⁴Substituted cyclic groups, preferably R¹⁰Are each selected from C_1-4Alkyl (e.g. methyl) and aryl (preferably phenyl) optionally substituted with one or more R¹⁴And (4) substitution. Optionally substituted by one or more R¹⁴May be substituted by one, two or three R¹⁴And (4) substitution.

In another embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein R is³Each independently selected from-NR⁷R⁸、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰-OH and oxo. In more specific embodiments, R⁷Each and each R⁸Independently selected from hydrogen, C_1-8Alkyl radical, R¹²R¹³N-C_1-8Alkyl and hydroxy C_1-8An alkyl group; preferably, R⁷Each and R⁸Each independently selected from hydrogen and C_1-4Alkyl radical, R¹²R¹³N-C_1-4Alkyl and hydroxy C_1-4Alkyl, more preferably R⁷Each and R⁸Each independently selected from hydrogen and C_1-2Alkyl radical, R¹²R¹³N-C_1-2Alkyl and hydroxy C_1-2Alkyl, even more preferably R⁷And R⁸Each is hydrogen; r¹⁰Are each selected from C_1-8Alkyl and optionally substituted by one or more R¹⁴Substituted cyclic groups, preferably R¹⁰Are each selected from C_1-4Alkyl (e.g. methyl) and aryl (preferably phenyl) optionally substituted with one or more R¹⁴And (4) substitution. Optionally substituted by one or more R¹⁴The substituted radicals may be substituted, for example, by one, two or three R¹⁴And (4) substitution.

In another embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein R is³Each independently selected from-NR⁷R⁸、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰And oxo. In more specific embodiments, R⁷Each and R⁸Each independently selected from hydrogen and C_1-8Alkyl radical, R¹²R¹³N-C_1-8Alkyl and hydroxy C_1-8An alkyl group; preferably, R⁷Each and R⁸Each independently selected from hydrogen and C_1-4Alkyl radical, R¹²R¹³N-C_1-4Alkyl and hydroxy C_1-4Alkyl, more preferably R⁷Each and R⁸Each independently selected from hydrogen and C_1-2Alkyl radical, R¹²R¹³N-C_1-2Alkyl and hydroxy C_1-2Alkyl, even more preferably R⁷And R⁸Each is hydrogen; r¹⁰Are each selected from C_1-8Alkyl and optionally substituted by one or more R¹⁴Substituted cyclic groups, preferably R¹⁰Are each selected from C_1-4Alkyl (e.g. methyl) and aryl (preferably phenyl) optionally substituted with one or more R¹⁴And (4) substitution. Optionally substituted by one or more R¹⁴The substituted radicals may be substituted, for example, by one, two or three R¹⁴And (4) substitution.

In another embodiment, the invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1,most preferred are compounds of formula Ia-1), wherein R is³Each independently selected from-NR⁷R⁸-OH, oxo, -C_1-4alkylene-NR⁷R⁸and-C_1-4alkylene-OH. In specific embodiments, R⁷Each and R⁸Each independently selected from hydrogen and C_1-8Alkyl radical, R¹²R¹³N-C_1-8Alkyl and hydroxy C_1-8An alkyl group; preferably, R⁷Each and R⁸Each independently selected from hydrogen and C_1-4Alkyl radical, R¹²R¹³N-C_1-4Alkyl and hydroxy C_1-4Alkyl, more preferably R⁷Each and R⁸Each independently selected from hydrogen and C_1-2Alkyl radical, R¹²R¹³N-C_1-2Alkyl and hydroxy C_1-2Alkyl, even more preferably R⁷And R⁸Each is hydrogen. In another specific embodiment, R⁷And R⁸Taken together with the attached N atom to form a saturated 3-to 7-membered heterocyclic ring optionally containing another heteroatom selected from N, O and S, wherein one or more C atoms on the heterocyclic ring are optionally oxidized to a CO group, wherein one or more S atoms (if present) on the heterocyclic ring are optionally oxidized to an independent SO group or SO₂And wherein said heterocycle is optionally substituted with one or more (e.g., one, two or three) R¹¹Substituted, preferably-NR⁷R⁸Is a group of the formula:

in another embodiment, the invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-I, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein R is³Each independently selected from-NR⁷R⁸Oxo, -C_1-4alkylene-NR⁷R⁸and-C_1-4alkylene-OH. In more specific embodiments, R⁷Each and R⁸Each independently selected from hydrogen and C_1-8Alkyl radical, R¹²R¹³N-C_1-8Alkyl and hydroxy C_1-8An alkyl group; preferably, R⁷Each and R⁸Each independently selected from hydrogen and C_1-4Alkyl radical, R¹²R¹³N-C_1-4Alkyl and hydroxy C_1-4Alkyl, more preferably R⁷Each and R⁸Each independently selected from hydrogen and C_1-2Alkyl radical, R¹²R¹³N-C_1-2Alkyl and hydroxy C_1-2Alkyl, even more preferably R⁷And R⁸Each is hydrogen. In another specific embodiment, R⁷And R⁸Taken together with the attached N atom to form a saturated 3-to 7-membered heterocyclic ring optionally containing another heteroatom selected from N, O and S, wherein one or more C atoms on the heterocyclic ring are optionally oxidized to a CO group, wherein one or more S atoms (if present) on the heterocyclic ring are optionally oxidized to an independent SO group or SO₂And wherein said heterocycle is optionally substituted with one or more (e.g., one, two or three) R¹¹Substituted, preferably-NR⁷R⁸Is a group of the formula:

in another embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein R is³Each independently selected from-NR⁷R⁸and-OH. In more specific embodiments, R⁷Each and R⁸Each independently selected from hydrogen and C_1-8Alkyl radical, R¹²R¹³N-C_1-8Alkyl and hydroxy C_1-8An alkyl group; preferably, R⁷Each and R⁸Each independently selected from hydrogen and C_1-4Alkyl radical, R¹²R¹³N-C_1-4Alkyl and hydroxy C_1-4Alkyl, more preferably R⁷Each and R⁸Each independently selected from hydrogen and C_1-2Alkyl radical, R¹²R¹³N-C_1-2Alkyl and hydroxy C_1-2Alkyl, even more preferably R⁷And R⁸Each is hydrogen. In another specific embodiment, R⁷And R⁸Taken together with the attached N atom to form a saturated 3-to 7-membered heterocyclic ring optionally containing another heteroatom selected from N, O and S, wherein one or more C atoms on the heterocyclic ring are optionally oxidized to a CO group, wherein one or more S atoms (if present) on the heterocyclic ring are optionally oxidized to an independent SO group or SO₂And wherein said heterocycle is optionally substituted with one or more (e.g., one, two or three) R¹¹Substituted, preferably-NR⁷R⁸Is a group of the formula:

in another embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein R is³Each independently selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸Preferably from-NR⁷R⁸and-C_1-2alkylene-NR⁷R⁸. In more specific embodiments, R⁷Each and R⁸Each independently selected from hydrogen and C_1-8Alkyl radical, R¹²R¹³N-C_1-8Alkyl and hydroxy C_1-8An alkyl group; preferably, R⁷Each and R⁸Each independently selected from hydrogen and C_1-4Alkyl radical, R¹²R¹³N-C_1-4Alkyl and hydroxy C_1-4Alkyl, more preferably R⁷Each and R⁸Each independently selected from hydrogen and C_1-2Alkyl radical, R¹²R¹³N-C_1-2Alkyl and hydroxy C_1-2Alkyl, even more preferably R⁷And R⁸Each is hydrogen. In another embodimentIn an embodiment of (1), R⁷And R⁸Taken together with the attached N atom to form a saturated 3-to 7-membered heterocyclic ring optionally containing another heteroatom selected from N, O and S, wherein one or more C atoms on the heterocyclic ring are optionally oxidized to a CO group, wherein one or more S atoms (if present) on the heterocyclic ring are optionally oxidized to an independent SO group or SO₂And wherein said heterocycle is optionally substituted with one or more (e.g., one, two or three) R¹¹Substituted, preferably-NR⁷R⁸Is a group of the formula:

in another embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein R is³Each independently selected from-NR⁷R⁸. In more specific embodiments, R⁷Each and R⁸Each independently selected from hydrogen and C_1-8Alkyl radical, R¹²R¹³N-C_1-8Alkyl and hydroxy C_1-8An alkyl group; preferably, R⁷Each and R⁸Each independently selected from hydrogen and C_1-4Alkyl radical, R¹²R¹³N-C_1-4Alkyl and hydroxy C_1-4Alkyl, more preferably R⁷Each and R⁸Each independently selected from hydrogen and C_1-2Alkyl radical, R¹²R¹³N-C_1-2Alkyl and hydroxy C_1-2Alkyl, even more preferably R⁷And R⁸Each is hydrogen. In another specific embodiment, R⁷And R⁸Taken together with the attached N atom to form a saturated 3-to 7-membered heterocyclic ring optionally containing another heteroatom selected from N, O and S, wherein one or more C atoms on the heterocyclic ring are optionally oxidized to a CO group, wherein one or more S atoms (if present) on the heterocyclic ring are optionally oxidized to an independent SO group or SO₂Group (a) andwherein said heterocycle is optionally substituted with one or more (e.g., one, two or three) R¹¹Substituted, preferably-NR⁷R⁸Is a group of the formula:

in a preferred embodiment, the present invention provides compounds of formula I, Ia-1, Ib or Ic, including compounds I, Ia-1, Ib or Ic as defined in the specific embodiments disclosed herein, wherein only one substituent R is present on D³。

In one embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein:

d is selected from D1, D2, D3 and D4:

(b) Together with a cycloalkyl group (i.e. a cyclobutyl ring, as contained in D1, as contained in D)2, the cyclohexyl ring contained in D3, and the cycloheptyl ring contained in D4) to any two nonadjacent ring carbon atoms of a linker group of — (C (R)^a)₂)_p-bonding, wherein p is 1 or 2 and R^aEach independently is hydrogen or C_1-4An alkyl group; or

(c) Is linked to a second ring which is a 3-to 7-membered saturated carbocyclic ring or a 3-to 7-membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein said second ring is linked to a cycloalkyl group (i.e. the cyclobutyl ring contained in D1, the cyclopentyl ring contained in D2, the cyclohexyl ring contained in D3 and the cycloheptyl ring contained in D4) via a single carbon atom common to both rings, and wherein said second ring is optionally substituted with one or more R⁶Substitution; and is

R³Each independently selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸、-OH、-CONR⁷R⁸Oxo, -C_1-4alkylene-NR⁷R⁸、-C_1-4alkylene-NHOH, -C_1-4alkylene-NR⁹COR¹⁰、-C_1-4alkylene-NR⁹SO₂R¹⁰、-C_1-4alkylene-NR⁹COOR¹⁰、-C_1-4alkylene-NR⁹CONR⁷R⁸、-C_1-4alkylene-NR⁹SO₂NR⁷R⁸、-C_1-4alkylene-OH and-C_1-4alkylene-CONR⁷R⁸. More preferably, only one group R is present³。

d is selected from D1, D2, D3 and D4:

R³Each independently selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸. Furthermore, the utility modelPreferably, only one group R is present³. In a preferred embodiment, R⁷And R⁸Each is hydrogen.

In another embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein:

d is

Wherein the cyclohexyl ring comprised in D is optionally substituted by another R³Substituted and optionally substituted with one or more R⁴And wherein the cyclohexyl ring contained in D is optionally:

(c) Is linked to a second ring which is a 3-to 7-membered saturated carbocyclic ring or a 3-to 7-membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein the second ring and cycloalkyl (i.e. cyclohexyl ring) are linked to each other through a single carbon atom common to both rings, and wherein the second ring is optionally substituted with one or more R⁶Substitution; and is

d is

R³Each independently selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸-OH and oxo. More preferably, only one group R is present³。

d is

(b) To a linking group- (C (R) together with any two nonadjacent ring carbon atoms to which a cycloalkyl (i.e. cyclohexyl ring) is attached^a)₂)_p-bonding, wherein p is 1 or 2 and R^aEach independentlyIs hydrogen or C_1-4An alkyl group; or

R³Each independently selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸. More preferably, only one group R is present³. In a preferred embodiment, R⁷And R⁸Each is hydrogen.

d is

(c) To a second ring, said second ringIs a 3-to 7-membered saturated carbocyclic ring or a 3-to 7-membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein the second ring and cycloalkyl (i.e. cyclohexyl ring) are linked to each other through a single carbon atom common to both rings, and wherein the second ring is optionally substituted with one or more R⁶Substitution; and is

R³Is selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸、-OH、-CONR⁷R⁸Oxo, -C_1-4alkylene-NR⁷R⁸、-C_1-4alkylene-NHOH, -C_1-4alkylene-NR⁹COR¹⁰、-C_1-4alkylene-NR⁹SO₂R¹⁰、-C_1-4alkylene-NR⁹COOR¹⁰、-C_1-4alkylene-NR⁹CONR⁷R⁸、-C_1-4alkylene-NR⁹SO₂NR⁷R⁸、-C_1-4alkylene-OH and-C_1-4alkylene-CONR⁷R⁸。

d is

(a) fused with phenyl or a 5-or 6-membered aromatic heterocycle comprising 1-3 heteroatoms independently selected from N, O and S, wherein said fused phenyl orSaid fused aromatic heterocycle being optionally substituted by one or more R⁵Substitution; or

R³Is selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸-OH and oxo.

d is

R³Is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸. In a preferred embodiment, R⁷And R⁸Each is hydrogen.

d is

(b) To a linking group- (C (R) together with any two nonadjacent ring carbon atoms to which a cycloalkyl (i.e. cyclohexyl ring) is attached^a)₂)_p-bonding, wherein p is 1 or2 and R^aEach independently is hydrogen or C_1-4An alkyl group; or

R³is-NR⁷R^a。

In the above embodiments, R³Is preferably-NH₂. In another preferred embodiment, R³Is that

d is

Wherein the cyclohexyl ring is optionally substituted with one or more R⁴Substitution; and is

R³Is selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸、-OH、-CONR⁷R⁸Oxo, -C_1-4alkylene-NR⁷R⁸、-C_1-4alkylene-NHOH,-C_1-4alkylene-NR⁹COR¹⁰、-C_1-4alkylene-NR⁹SO₂R¹⁰、-C_1-4alkylene-NR⁹COOR¹⁰、-C_1-4alkylene-NR⁹CONR⁷R⁸、-C_1-4alkylene-NR⁹SO₂NR⁷R⁸、-C_1-4alkylene-OH and-C_1-4alkylene-CONR⁷R⁸。

d is

R³is-NR⁷R⁸。

d is

And is

d is

And is

In a preferred embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein:

d is

And is

In another preferred embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein:

d is

And is

R³is-NR⁷R⁸。

d is

Wherein the cyclobutyl ring is optionally substituted by one or more R⁴Substitution; and is

d is

R³is-NR⁷R⁸. In this embodiment, R³Is preferably-NH₂. In another preferred embodiment, R³Is that

d is

R³Is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸. In the preferred aspectsIn an embodiment of (1), R⁷And R⁸Each is hydrogen.

d is

In another embodiment, the invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1) wherein A is phenyl, naphthyl or monocyclic heteroaryl, wherein said phenyl, naphthyl or monocyclic heteroaryl is optionally substituted with one or more (e.g., one or two) R¹And (4) substitution. In a more preferred embodiment, a is phenyl, naphthyl, pyridyl, thienyl, pyrrolyl, furyl or thiazolyl, wherein a is optionally substituted with one or more R¹And (4) substitution. More preferably, A is phenyl, naphthyl, pyridyl or thiazolyl, wherein A is optionally substituted with one or more R¹And (4) substitution. Still more preferably, A is phenyl, 2-naphthyl, 3-pyridyl or 5-thiazolyl, wherein A is optionally substituted with one or more R¹And (4) substitution. In one embodiment, a is optionally substituted with one or more R¹A substituted phenyl group. In addition toIn one embodiment, A is naphthyl, preferably 2-naphthyl, optionally substituted with one or more R¹And (4) substitution. In another embodiment, a is pyridyl, preferably 3-pyridyl, optionally substituted with one or more R¹And (4) substitution. In another embodiment, A is thiazolyl, preferably 5-thiazolyl, optionally substituted with one or more R¹And (4) substitution.

In another embodiment, the invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1) wherein A is phenyl or monocyclic heteroaryl, wherein said phenyl or said monocyclic heteroaryl is optionally substituted with one or more (e.g., one or two) R¹And (4) substitution. In various preferred embodiments, A is phenyl, pyridyl, thienyl, pyrrolyl, furyl or thiazolyl, wherein A is optionally substituted with one or more R¹And (4) substitution. More preferably, A is phenyl, pyridyl or thiazolyl, wherein A is optionally substituted with one or more R¹And (4) substitution. In one embodiment, a is phenyl. In another embodiment, A is 3-pyridyl. In another embodiment, A is 5-thiazolyl.

In another embodiment, the invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein A is optionally substituted with one or more R¹A substituted phenyl group.

In another embodiment, the invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein A is optionally substituted with one or more R¹Substituted naphthyl (e.g., 2-naphthyl).

In another embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), which is a pharmaceutically acceptable salt thereof, pharmaceutically acceptable carrier thereof, pharmaceuticallyWherein A is optionally substituted with one or more R¹A substituted heteroaryl group. Preferably, A is optionally substituted with one or more R¹Substituted monocyclic heteroaryl.

a is phenyl or monocyclic heteroaryl (preferably phenyl, pyridyl or thiazolyl, more preferably phenyl, 3-pyridyl or 5-thiazolyl), wherein A is optionally substituted with one or more R¹Substitution;

b is hydrogen, R¹or-L-E;

e is optionally substituted with one or more R²Substituted phenyl; and is

L is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group connecting ring E; in a more specific embodiment, L is a bond or-CH₂-O-, wherein said-CH₂the-O-group connects ring A through the O atom and through the-CH₂-the group joining ring E.

a is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R¹Substitution; and is

B is hydrogen or R¹。

In the above embodiments, R is preferred¹Each independently selected from C_1-8Alkyl, amino, amido, hydroxy, halogen, haloC_1-8Alkyl, halo C_1-8Alkoxy radicals, cyanogenSulfonamide, C_1-8Alkoxy, acyl, carboxyl, carbamate, and urea. In another preferred embodiment, R¹Each independently selected from halogen, C_1-4Alkyl (e.g. methyl), halo C_1-4Alkyl (e.g. trifluoromethyl), C_1-4Alkoxy (e.g. methoxy) and C_3-6Cycloalkyl (e.g., cyclopropyl). In another preferred embodiment, R¹Each independently selected from halogen, C_1-4Alkyl and C_3-6A cycloalkyl group.

a is phenyl, naphthyl or monocyclic heteroaryl, wherein said phenyl, said naphthyl or said monocyclic heteroaryl is optionally substituted with one or more R¹Substitution; and is

B is hydrogen or R¹。

In the above embodiments, R is preferred¹Each independently selected from C_1-8Alkyl, amino, amido, hydroxy, halogen, haloC_1-8Alkyl, halo C_1-8Alkoxy, cyano, sulfonamide, C_1-8Alkoxy, acyl, carboxyl, carbamate, and urea. In another preferred embodiment, R¹Each independently selected from halogen, C_1-4Alkyl (e.g. methyl), halo C_1-4Alkyl (e.g. trifluoromethyl), C_1-4Alkoxy (e.g. methoxy) and C_3-6Cycloalkyl (e.g., cyclopropyl). In another preferred embodiment, R¹Each independently selected from halogen, C_1-4Alkyl and C_3-6A cycloalkyl group.

a is phenyl or monocyclic heteroaryl, wherein said phenyl or said monocyclic heteroaryl is optionally substituted with one or more R¹Substitution; and is

B is hydrogen or R¹。

a is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or 5-thiazolyl), wherein A is optionally substituted with one or more R¹Substitution; and is

B is hydrogen or R¹。

In the above embodiments, R is preferred¹Each independently selected from C_1-8Alkyl, amino, amido, hydroxy, halogen, haloC_1-8Alkyl, halo C_1-8Alkoxy, cyano, sulfonamide, C_1-8Alkoxy, acyl, carboxyl, carbamate, and urea. In another preferred embodiment, R¹Each independently selected from halogen, C_1-4Alkyl (e.g. methyl), halo C_1-4Alkyl (e.g. trifluoromethyl), C_1-4Alkoxy (e.g. methoxy)) And C_3-6Cycloalkyl (e.g., cyclopropyl). In another preferred embodiment, R¹Each independently selected from halogen, C_1-4Alkyl and C_3-6A cycloalkyl group.

a is optionally substituted by one or more R¹Substituted naphthyl; and is

B is hydrogen or R¹。

a is phenyl, naphthyl or monocyclic heteroaryl; and is

B is hydrogen.

a is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or 5-thiazolyl); and is

B is hydrogen.

a is phenyl; and is

B is hydrogen.

a is naphthyl; and is

B is hydrogen.

a is heteroaryl, preferably monocyclic heteroaryl; and is

B is hydrogen.

a is phenyl or monocyclic heteroaryl (preferably phenyl, pyridyl or thiazolyl, more preferably phenyl, 3-pyridyl or 5-thiazolyl), wherein said phenyl or said monocyclic heteroaryl is optionally substituted with one or more R¹Substitution; and is

B is-L-E. In the above embodimentsIn (B), L is preferably a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group joining ring E. In more particular embodiments, E is optionally substituted with one or more R²Substituted phenyl, L is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group connecting ring E; preferably, L is a bond or-CH₂-O-, wherein said-CH₂the-O-group connects ring A through the O atom and through the-CH₂-the group joining ring E.

a is phenyl or pyridyl (preferably phenyl or 3-pyridyl), wherein A is optionally substituted with one or more R¹Substitution; and is

B is-L-E. In the above embodiments, L is preferably a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group joining ring E. In more particular embodiments, E is optionally substituted with one or more R²Substituted phenyl, L is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group connecting ring E; preferably, L is a bond or-CH₂-O-, wherein said-CH₂the-O-group connects ring A through the O atom and through the-CH₂-the group joining ring E.

a is phenyl; and is

a is 3-pyridyl; and is

b is-L-E;

l is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein the group-CH₂-NH-and-CH₂-O-connects ring A through N or O atom and through-CH, respectively₂-the group connecting ring E; and is

E is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R²And (4) substitution. In specific embodiments, R²Each independently selected from hydroxy, halogen, halo C_1-8Alkyl and N-sulfonylamino.

d is

(b) To any two nonadjacent ring carbon atoms which together are a ring carbon atom of (C) (R)^a)₂)_p-bonding, wherein p is 1 or 2 and R^aEach independently is hydrogen or C_1-4An alkyl group; or

a is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or 5-thiazolyl), wherein A is optionally substituted with one or more R¹Substitution;

b is hydrogen, R¹or-L-E;

e is optionally substituted with one or more R²Substituted phenyl;

l is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group connecting ring E; preferably, L is a bond or-CH₂-O-, wherein said-CH₂the-O-group connects ring A through the O atom and through the-CH₂-the group joining ring E.

d is

(a) fused with phenyl or a 5-or 6-membered aromatic heterocycle comprising 1-3 heteroatoms independently selected from N, O and S, wherein said fused phenyl or said fused phenylThe aromatic heterocyclic ring being optionally substituted by one or more R⁵Substitution; or

a is aryl or heteroaryl, wherein A is optionally substituted with one or more R¹Substitution; and is

B is hydrogen or R¹。

d is

B is hydrogen or R¹。

In the above embodiments, R is preferred¹Each independently selected from C_1-8Alkyl, amino, amido, hydroxy, halogen, haloC_1-8Alkyl, halo C_1-8Alkoxy, cyano, sulfonamide, C_1-8Alkoxy, acyl, carboxyl, carbamate, and urea. In another preferred embodiment, R¹Each independently selected from halogen, C_1-4Alkyl (e.g. methyl), halo C_1-4Alkyl (e.g. trifluoromethyl), C_1-4Alkoxy (e.g. methoxy) and C_3-6Cycloalkyl radicals (e.g. rings)Propyl). In another preferred embodiment, R¹Each independently selected from halogen, C_1-4Alkyl and C_3-6A cycloalkyl group.

d is

a is optionally substituted by one or more R¹Substituted phenyl; and is

B is hydrogen or R¹。

d is

(c) Is linked to a second ring which is a 3-to 7-membered saturated carbocyclic ring or a 3-to 7-membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein the second ring and cycloalkyl are linked through twoA single carbon atom common to both rings being linked to each other and wherein said second ring is optionally substituted by one or more R⁶Substitution;

a is aryl or heteroaryl (preferably phenyl, naphthyl, pyridyl or thiazolyl); and is

B is hydrogen.

d is

a is phenyl; and is

B is hydrogen.

d is

B is-L-E. Preferably, L is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group joining ring E. In a more specific embodiment, E is optionallyBy one or more R²Substituted phenyl, and L is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group connecting ring E; preferably, L is a bond or-CH₂-O-, wherein said-CH₂the-O-group connects ring A through the O atom and through the-CH₂-the group joining ring E.

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

b is hydrogen, R¹or-L-E;

e is optionally substituted with one or more R²Substituted phenyl;

In a preferred embodiment of the above embodiments, R³is-NR⁷R⁸. More preferably R³is-NH₂. In another preferred embodiment, R³Is that

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

b is hydrogen, R¹or-L-E;

e is optionally substituted with one or more R²Substituted phenyl;

In a preferred embodiment of the above embodiments, R³is-NR⁷R⁸. More preferably R³is-NH₂。

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

B is hydrogen or R¹。

In the above embodimentIn a preferred embodiment of the invention, R³is-NR⁷R⁸. More preferably R³is-NH₂。

Preferably in the above embodiments, R¹Each independently selected from C_1-8Alkyl, amino, amido, hydroxy, halogen, haloC_1-8Alkyl, halo C_1-8Alkoxy, cyano, sulfonamide, C_1-8Alkoxy, acyl, carboxyl, carbamate, and urea. In another preferred embodiment, R¹Each independently selected from halogen, C_1-4Alkyl (e.g. methyl), halo C_1-4Alkyl (e.g. trifluoromethyl), C_1-4Alkoxy (e.g. methoxy) and C_3-6Cycloalkyl (e.g., cyclopropyl). In another preferred embodiment, R¹Each independently selected from halogen, C_1-4Alkyl and C_3-6A cycloalkyl group.

d is

(b) To any two nonadjacent ring carbon atoms which together are a ring carbon atom of (C) (R)^a)₂)_p-bonding, wherein p is 1 or 2 and R^aEach independently is hydrogen or C_1-4Alkyl radical(ii) a Or

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

B is hydrogen or R¹。

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

B is hydrogen or R¹。

Preferred in the above embodimentIn embodiments, R³is-NR⁷R⁸. More preferably R³is-NH₂。

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

A is optionally substituted by one or more R¹Substituted phenyl; and is

B is hydrogen or R¹。

In a preferred embodiment of the above embodiments, R ³is-NR⁷R⁸. More preferably R³is-NH₂。

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

A is phenyl; and is

B is hydrogen.

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

A is phenyl; and is

B is hydrogen.

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

B is-L-E. Preferably, L is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-or-CH₂The- -O- -groups being bound to the ring via the N or O atom, respectivelyA and through-CH₂-the group joining ring E. In more particular embodiments, E is optionally substituted with one or more R²Substituted phenyl, L is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group connecting ring E; preferably, L is a bond or-CH₂-O-, wherein said-CH₂the-O-group connects ring A through the O atom and through the-CH₂-the group joining ring E.

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

B is-L-E. Preferably, L is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group joining ring E. In more particular embodiments, E is optionally substituted with one or more R²Substituted phenyl, L is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group connecting ring E; preferably, L is a bond or-CH₂-O-, wherein said-CH₂the-O-group connects ring A through the O atom and through the-CH₂-the group joining ring E.

d is

Wherein the cyclohexyl ring is optionally substituted with one or more R⁴Substitution;

R³is selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸、-OH、-CONR⁷R⁸Oxo, -C_1-4alkylene-NR⁷R⁸、-C_1-4alkylene-NHOH, -C_1-4alkylene-NR⁹COR¹⁰、-C_1-4alkylene-NR⁹SO₂R¹⁰、-C_1-4alkylene-NR⁹COOR¹⁰、-C_1-4alkylene-NR⁹CONR⁷R⁸、-C_1-4alkylene-NR⁹SO₂NR⁷R⁸、-C_1-4alkylene-OH and-C_1-4alkylene-CONR⁷R⁸；

b is hydrogen, R¹or-L-E;

e is optionally substituted with one or more R²Substituted phenyl;

l is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group connecting ring E; preferably, L is a bond or-CH₂-O-, wherein said-CH₂the-O-group connects ring A through the O atom and through the-CH₂-group attachmentAnd (E) a ring E.

d is

B is hydrogen or R¹。

d is

A is phenyl; and is

B is hydrogen.

d is

WhereinThe cyclohexyl ring being optionally substituted by one or more R⁴Substitution;

d is

R³is selected from-NR⁷R⁸、-NHOH、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-NR⁹SO₂NR⁷R⁸-OH and oxo;

b is hydrogen, R¹or-L-E;

e is optionally substituted with one or more R²Substituted phenyl;

d is

B is hydrogen or R¹。

d is

a is phenyl; and is

B is hydrogen.

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

b is hydrogen, R¹or-L-E;

e is optionally substituted with one or more R²Substituted phenyl;

In more particular embodiments of the above embodiments, R³is-NH₂. In another specific embodiment, R³Is that

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

b is hydrogen, R¹or-L-E;

e is optionally substituted with one or more R²Substituted phenyl;

In more particular embodiments of the above embodiments, R³is-NH₂。

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

B is hydrogen or R¹。

In more particular embodiments of the above embodiments, R³is-NH₂。

In a more preferred embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein:

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

B is hydrogen or R¹。

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

B is hydrogen or R¹。

In more particular embodiments of the above embodiments, R³is-NH₂。

In a still more preferred embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein:

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

A is optionally substituted by one or more R¹Substituted phenyl; and is

B is hydrogen or R¹。

In more particular embodiments of the above embodiments, R³is-NH₂。

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

A is optionally substituted by one or more R¹Substituted naphthyl; and is

B is hydrogen or R¹。

In more particular embodiments of the above embodiments, R³is-NH₂。

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

A is heteroaryl, preferably monoA cyclic heteroaryl optionally substituted with one or more R¹Substitution; and is

B is hydrogen or R¹。

In more particular embodiments of the above embodiments, R³is-NH₂。

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

A is phenyl; and is

B is hydrogen.

In the above embodimentIn more specific embodiments of embodiments, R³is-NH₂. In another specific embodiment, R³Is that

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

A is phenyl; and is

B is hydrogen.

In more particular embodiments of the above embodiments, R³is-NH₂。

d is

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

In more particular embodiments of the above embodiments, R³is-NH₂。

d is

R³is-NR⁷R⁸；

A is aryl or heteroaryl(e.g., phenyl, naphthyl, or monocyclic heteroaryl), wherein said aryl or said heteroaryl is optionally substituted with one or more R¹Substitution; and is

B is hydrogen, R¹or-L-E.

In more particular embodiments of the above embodiments, R³is-NH₂。

d is

R³is-NR⁷R⁸；

B is hydrogen, R¹or-L-E.

In more particular embodiments of the above embodiments, R³is-NH₂。

d is

R³is-NR⁷R⁸；

b is hydrogen, R¹or-L-E;

e is optionally substituted with one or more R²Substituted phenyl;

l is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said_-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group connecting ring E; preferably, L is a bond or-CH₂-O-, wherein said-CH₂the-O-group connects ring A through the O atom and through the-CH₂-the group joining ring E.

d is

R³is-NR⁷R⁸；

b is hydrogen, R¹or-L-E;

e is optionally substituted with one or more R²Substituted phenyl;

In more particular embodiments of the above embodiments, R³is-NH₂。

d is

R³is-NR⁷R⁸；

A is aryl or heteroaryl (e.g., phenyl, naphthyl, or monocyclic heteroaryl), wherein said aryl or said heteroaryl is optionally substituted with one or morePlural R¹Substitution; and is

B is hydrogen or R¹。

In more particular embodiments of the above embodiments, R³is-NH₂。

d is

R³is-NR⁷R⁸；

A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl)Or 5-thiazolyl), wherein A is optionally substituted with one or more R¹Substitution; and is

B is hydrogen or R¹。

d is

R³is-NR⁷R⁸；

B is hydrogen or R¹。

In more particular embodiments of the above embodiments, R³is-NH₂。

d is

R³is-NR⁷R⁸；

A is optionally substituted by one or more R¹Substituted phenyl; and is

B is hydrogen or R¹。

In more particular embodiments of the above embodiments, R³is-NH₂。

In a very preferred embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic wherein:

d is

R³is-NR⁷R⁸；

A is phenyl, naphthyl or monocyclic heteroaryl; and is

B is hydrogen.

In more particular embodiments of the above embodiments, R³is-NH₂. In another very preferred embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic, wherein:

d is

R³is-NR⁷R⁸；

B is hydrogen.

In more particular embodiments of the above embodiments, R³is-NH₂. In another very preferred embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein:

d is

R³is-NR⁷R⁸；

A is phenyl; and is

B is hydrogen.

In another very preferred embodiment, the present invention provides a compound of formula I, Ia-1, Ib or Ic (preferably a compound of formula I, Ia or Ia-1, more preferably a compound of formula Ia or Ia-1, most preferably a compound of formula Ia-1), wherein:

d is

R³is-NR⁷R⁸；

A is phenyl; and is

B is hydrogen.

In more particular embodiments of the above embodiments, R³is-NH₂。

d is

R³is-NR⁷R⁸；

B is-L-E.

Preferably, L is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group connecting ring E; more preferably, L is a bond or-CH₂-O-, wherein said-CH₂the-O-group connects ring A through the O atom and through the-CH₂-the group joining ring E.

d is

R³is-NR⁷R⁸；

B is-L-E.

Preferably, L is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-group connecting ringE; more preferably, L is a bond or-CH₂-O-, wherein said-CH₂the-O-group connects ring A through the O atom and through the-CH₂-the group joining ring E.

In more particular embodiments of the above embodiments, R³is-NH₂。

d is

R³is-NR⁷R⁸；

A is phenyl or pyridyl (preferably phenyl or 3-pyridyl), wherein A is optionally substituted with one or more R¹Substitution;

b is-L-E;

e is optionally substituted with one or more R²Substituted phenyl; and is

L is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group joining ring E.

d is

R³is-NR⁷R⁸；

b is-L-E;

e is optionally substituted with one or more R²Substituted phenyl; and is

L is a bond, -O-, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-or-CH₂the-O-group connects ring A through N or O atom and through-CH, respectively₂-the group connecting ring E, preferably L is a bond or-CH₂-O-, wherein said-CH₂the-O-groups are each bound to ring A through the O atom and through the-CH₂-the group joining ring E.

In more particular embodiments of the above embodiments, R³is-NH₂。

In another embodiment, the present invention provides a compound of formula I, Ia or Ia-1 selected from:

n1- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1S,2R) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1S,2R) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1R,2S) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1R,2S) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (thiazol-5-yl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

4- (((trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropyl) amino) cyclohexanol;

4- (((trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropyl) amino) cyclohexanecarboxamide;

n- (4- (((trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropyl) amino) cyclohexyl) acetamide;

n- (4- (((trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropyl) amino) cyclohexyl) methanesulfonamide;

(R) -1- (4- (((trans) -2-phenylcyclopropyl) amino) cyclohexyl) pyrrolidin-3-amine;

n1- ((trans) -2- (4 '-chloro- [1, 1' -biphenyl ] -4-yl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (3 '-chloro- [1, 1' -biphenyl ] -4-yl) cyclopropyl) cyclohexane-1, 4-diamine;

4 '- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-ol;

n- (4 '- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) methanesulfonamide;

n1- ((trans) -2- (4- ((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4- ((3-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4- ((4-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

N1-methyl-N4- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

N1-methyl-N4- ((trans) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) -N4-methylcyclohexane-1, 4-diamine;

n1- ((trans) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine;

n1- ((trans) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) cyclobutane-1, 3-diamine;

n1- ((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) cyclobutane-1, 3-diamine;

n1- ((trans) -2-phenylcyclopropyl) -2, 3-dihydro-1H-indene-1, 3-diamine;

n1- ((trans) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) -2, 3-dihydro-1H-indene-1, 3-diamine;

n1- ((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) -2, 3-dihydro-1H-indene-1, 3-diamine;

n1- ((trans) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

n1- ((1S, 2S) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

n1- ((1R, 2R) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

1-methyl-N4- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

4- (aminomethyl) -N- ((trans) -2-phenylcyclopropyl) cyclohexylamine;

n1- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 3-diamine;

n1- ((cis) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(4- (((trans) -2-phenylcyclopropyl) amino) cyclohexyl) carbamic acid tert-butyl ester;

1-ethyl-3- (4- (((trans) -2-phenylcyclopropyl) amino) cyclohexyl) urea;

4-morpholino-N- ((trans) -2-phenylcyclopropyl) cyclohexylamine;

n1- ((trans) -2- (4-bromophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- (2- (o-tolyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- (2- (4- (trifluoromethyl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

N1- (2- (4-methoxyphenyl) cyclopropyl) cyclohexane-1, 4-diamine;

4- (2- ((4-aminocyclohexyl) amino) cyclopropyl) phenol;

n1- (2- (2-fluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- (2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- (2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- (2-methyl-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(R) -1- (4- (((trans) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) amino) cyclohexyl) pyrrolidin-3-amine;

(cis) -N1- ((1S,2R) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1S,2R) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclo-propyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1R,2S) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclo-propyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1R,2S) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclo-propyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4-cyclopropylphenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4- (pyridin-3-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4- (1H-indazol-6-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

3- (5- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) thiophen-2-yl) phenol;

3- (5- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) thiazol-2-yl) phenol;

3- (5- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) pyridin-2-yl) -5-methoxybenzonitrile;

5- (5- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) pyridin-2-yl) -2-methylphenol;

n- (4 '- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) -6-methoxy- [1, 1' -biphenyl ] -3-yl) methanesulfonamide;

n- (3- (5- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) thiazol-2-yl) phenyl) -2-cyanobenzenesulfonamide;

n- (4 '- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) -2-cyanobenzenesulfonamide;

6-amino-N- (4 '- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) pyridine-3-sulfonamide;

n- (4 '- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) piperazine-1-sulfonamide;

n1- ((cis) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4- ((3- (piperazin-1-yl) benzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4- (pyridin-3-ylmethoxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (6- ((3-methylbenzyl) amino) pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine;

3- ((5- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) pyridin-2-yl) amino) benzonitrile;

n1- ((trans) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (o-tolyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4- (trifluoromethyl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4-methoxyphenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (2-fluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2-methyl-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1S,2R) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1R,2S) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1R,2S) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1S,2R) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1S,2R) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine;

(trans) -N1- ((1R,2S) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine;

(cis) -N1- ((1R,2S) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine;

(trans) -N1- ((1S,2R) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine;

(cis) -N1- ((1S,2R) -2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1R,2S) -2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1R,2S) -2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1S,2R) -2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1S,2R) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1R,2S) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1R,2S) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1S,2R) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1S,2R) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1R,2S) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1R,2S) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1S,2R) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n- (4 '- ((1R,2S) -2- (((cis) -4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) piperazine-1-sulfonamide;

n- (4 '- ((1S,2R) -2- (((trans) -4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) piperazine-1-sulfonamide;

n- (4 '- ((1S,2R) -2- (((cis) -4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) piperazine-1-sulfonamide;

n- (4 '- ((1R,2S) -2- (((trans) -4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) piperazine-1-sulfonamide;

(cis) -N1- ((1S,2R) -2- (4- ((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1R,2S) -2- (4- ((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1R,2S) -2- (4- ((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1S,2R) -2- (4- ((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

and salts and solvates thereof (including pharmaceutically acceptable salts and solvates thereof).

The invention also relates to any one or any subgroup of the compounds listed above. The invention likewise relates to pharmaceutically acceptable salts, preferably hydrochlorides (e.g. monohydrochloride, dihydrochloride or, if appropriate, trihydrochloride), of any of the compounds listed above.

Preferred embodiments of the compounds of formula I, Ia-1, Ib and Ic for use in the compositions and methods of the invention are as defined above.

In another aspect, the invention provides A method of identifying A compound as A selective inhibitor of LSD1, the method comprising selecting or providing A compound of formulA I, IA-1, Ib, or Ic and determining the ability of the compound to inhibit LSD1 and MAO-A and/or MAO-B using, for example, an assay disclosed in the more detailed description below, wherein A compound that inhibits LSD1 to A greater extent than MAO-A and/or MAO-B is identified as A selective inhibitor of LSD 1. The LSD1 selective inhibitor has an IC50 value of LSD1 that is lower than the IC50 value of MAO-A and/or MAO-B. Preferably, LSD1 has an IC50 value that is less than MAO-A and/or MAO-B2-fold. In one aspect of this embodiment, the LSD1IC50 value is at least 5-fold lower than the IC50 value of MAO-A and/or MAO-B. In one aspect of this embodiment, the LSD1IC50 value is at least 10-fold lower than the IC50 value of MAO-A and/or MAO-B. Preferably, selective LSD1 inhibitors exhibit LSD1IC50 values > 50-fold, preferably > 100-fold lower than the IC50 values of MAO-A and/or MAO-B.

Asymmetric centers are present in the compounds of formula I, Ia-1, Ib and Ic disclosed herein. It is to be understood that the present invention encompasses all individual stereochemically isomeric forms, including diastereoisomers, enantiomers and epimeric forms and d-and 1-isomers ((+) -and (-) -isomers) of the compounds of formulae I, Ia-1, Ib and Ic and any mixtures thereof, including fully or partially equilibrated mixtures. The individual stereoisomers of the compounds of the invention can be prepared synthetically from commercially available chiral starting materials or by separation from mixtures of stereoisomers, as is also shown in the examples. Methods for separating enantiomeric and diastereomeric mixtures are well known to those skilled in the art. For example, diastereomeric mixtures can be separated by conventional separation techniques such as recrystallization or chromatography. Diastereomeric mixtures can be separated by conversion to a mixture of diastereomers, followed by separation using recrystallization or chromatographic techniques, direct separation of the enantiomers using a chiral chromatographic column, or any other suitable chiral resolution method known in the art. Specific stereochemical starting materials are either commercially available or may be prepared and resolved by methods well known in the art.

In addition, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, cis (syn), trans (anti), entgegen (e) and zusammen (z) isomers and mixtures thereof.

In addition, the compounds may exist as tautomers; the present invention provides all tautomers.

The compounds of the present invention contain one or more basic nitrogen atoms and thus can be salified with organic or inorganic acids. The compounds of the invention may also contain one or more acidic protons and may thus also form salts with bases. There is no limitation on the type of salts used, provided they are pharmaceutically acceptable for therapeutic purposes. The compounds of formulae I, Ia-1, Ib and Ic may be obtained during the final isolation and purification of the compounds of the invention or the corresponding salts may be obtained in a conventional manner by treating the compounds of formulae I, Ia-1, Ib and Ic with a sufficient amount of the desired acid or base to obtain the corresponding salts. All salts, including pharmaceutically acceptable salts, of the compounds of formulas I, Ia-1, Ib and Ic are included within the scope of the invention. In one embodiment, compounds of formula I, Ia-1, Ib and Ic are provided in salt form. In a more preferred embodiment, compounds of formula I, Ia-1, Ib and Ic are provided in the form of pharmaceutically acceptable salts. In one embodiment, such pharmaceutically acceptable salts are hydrochlorides, such as the monohydrochloride, dihydrochloride, or trihydrochloride.

In addition, the compounds disclosed herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated form with water is known as a hydrate. In general, the solvated forms are considered equivalent to unsolvated forms. The present invention thus relates to unsolvated and solvated forms of the compounds of formulae I, Ia-1, Ib, and Ic (or any salt thereof).

The compounds of formula I, Ia-1, Ib and Ic may exist in different physical forms, i.e. amorphous and crystalline forms. Furthermore, the compounds of the invention may have the ability to crystallize in more than one form, a feature known as polymorphism. Polymorphs can be distinguished by different material properties well known in the art, such as X-ray diffraction pattern, melting point or solubility. All physical forms of the compounds of the present invention, including all polymorphs (referred to as polymorphs) thereof, are included within the scope of the present invention.

The invention also covers all unlabeled and isotopically labeled forms of the compounds of formulae I, Ia-1, Ib and Ic. In one embodiment, the invention relates to deuterated forms of the compounds of formulas I, Ia-1, Ib, and Ic.

The present invention also relates to compounds of formulae I, Ia-1, Ib and Ic (preferably compounds of formula I, Ia or Ia-1, more preferably compounds of formula Ia or Ia-1, most preferably compounds of formula Ia-1) as described and defined herein, wherein the substituents-A-B and-NH-D on the cyclopropyl moiety are in the trans-configuration, and further wherein the compounds are optically active. The term "optically active" as used herein refers to the ability of a compound to rotate around plane polarized light.

In another aspect, the present invention relates to substantially pure optical stereoisomers of the compounds of formulae I, Ia-1, Ib and Ic as described and defined herein, wherein the substituents-a-B and-NH-D on the cyclopropyl moiety are in the trans-configuration, or pharmaceutically acceptable salts or solvates and their use as pharmaceuticals. As used herein, "substantially pure" means that 90 mole-% or more of the desired stereoisomer and 10 mole-% or less of any other stereoisomer are present, preferably 95 mole-% or more of the desired stereoisomer and 5 mole-% or less of any other stereoisomer are present, more preferably 98 mole-% or more of the desired stereoisomer and 2 mole-% or less of any other stereoisomer are present, still more preferably 99 mole-% or more of the desired stereoisomer and 1 mole-% or less of any other stereoisomer are present, even more preferably 99.5 mole-% or more of the desired stereoisomer and 0.5 mole-% or less of any other stereoisomer are present. Substantially pure optically active stereoisomers of the compounds of formulae I, Ia-1, Ib and Ic as described and defined herein, wherein the substituents-a-B and-NH-D on the cyclopropyl moiety are in the trans-configuration, are useful for the treatment or prevention of diseases or disorders, in particular cancer, neurological diseases or viral infections.

Definition of：

Any of the definitions herein may be used in combination with any other definition describing a complex structural group. As a definition, any such defined element is linked to the parent moiety. For example, the complex group cyclic group C_1-8Alkyl may be represented by C_1-8The alkyl group is attached to the cyclic group of the parent molecule.

The term "acyl" as used herein refers to a carbonyl group attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, or any other moiety, wherein the atom attached to the carbonyl group is carbon. Preferably, the term "acyl" refers to a group of formula-C (═ O) R ", wherein R" represents alkenyl, alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl. "acetyl" means-C (═ O) CH₃A group. "alkylcarbonyl" or "alkanoyl" refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include, but are not limited to, methylcarbonyl or ethylcarbonyl. Examples of acyl groups include, but are not limited to, formyl, alkanoyl, or aroyl.

As used hereinThe term "alkenyl" is used to indicate a straight or branched chain hydrocarbon group having one or more double bonds and comprising 2 to 20 carbon atoms. C_2-8Alkenyl is alkenyl having 2 to 8 carbon atoms.

The term "alkoxy" as used herein refers to an alkyl ether group (i.e., a group of the formula alkyl-O-), wherein the term alkyl is as defined below. Examples of suitable alkyl ether groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy or n-pentoxy. Term C_1-zAlkoxy means alkoxy wherein the alkyl moiety has 1 to z carbon atoms; e.g. C_1-8Alkoxy is alkoxy wherein the alkyl moiety is C_1-8Alkyl, i.e. of the formula C_1-8alkyl-O-groups.

The term "alkyl" as used herein refers to straight or branched chain alkyl groups containing from 1 to 20 carbon atoms. C_1-zAlkyl is alkyl of 1 to z carbon atoms; thus, C_1-8Alkyl having 1 to 8 carbon atoms, C_1-4Alkyl having 1 to 4 carbon atoms, C_1-2The alkyl group has 1 to 2 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neo-pentyl, iso-pentyl, hexyl, heptyl, octyl, or nonyl.

The term "C" as used herein_1-4Alkylene "means C attached at two positions_1-4Alkyl, i.e. alkanediyl. Examples include, but are not limited to, methylene (i.e., formula-CH)₂-groups), ethylene (including ethane-1, 2-diyl and ethane-1, 1-diyl), propylene (e.g. propane-1, 3-diyl, propane-1, 2-diyl and propane-1, 1-diyl) and butylene (e.g. butane-1, 4-diyl, butane-1, 3-diyl or butane-1, 1-diyl). Thus, the term "C_1-4Alkylene "may refer to straight or branched chain alkylene groups having 1 to 4 carbon atoms.

The term "alkynyl" as used herein refers to a straight or branched chain having one or more triple bonds and comprising 2 to 20 carbon atomsA hydrocarbyl group. C_2-8Alkynyl groups have 2 to 8 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, or hexyn-2-yl.

The term "acylamino" as used herein, means an amino group (e.g., -C (═ O) NRR ') or vice versa (-N (R) C (═ O) R') attached to the parent molecular moiety through a carbonyl group as described below, and "acylamino" includes "C-acylamino" and "N-acylamino" as defined herein. R and R' are as defined herein.

The term "C-acylamino" as used herein refers to the group-C (═ O) NRR ', where R and R' are as defined herein.

The term "N-acylamino" as used herein refers to the group-N (R) C (═ O) R ', where R and R' are as defined herein.

The term "amino" as used herein refers to-NRR 'wherein R and R' are independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, carbocyclyl and heterocyclyl. In addition, R and R' may be combined to form a heterocyclic group. Typical "amino" groups include-NH₂、-NH(C_1-4Alkyl) and-N (C)_1-4Alkyl) (C_1-4Alkyl), but is not limited thereto.

The term "aryl" as used herein refers to a carbocyclic aromatic system comprising one ring or two or three rings fused to each other, wherein all of the ring atoms are carbon. The term "aryl" includes, but is not limited to, groups such as phenyl, naphthyl, or anthracenyl. The term "monocyclic aryl" refers to phenyl.

The term "aryloxy", as used herein, refers to an aryl group attached to the parent molecular moiety through an oxy (-O-).

The term "carbamate" as used herein refers to an O-carbamoyl or N-carbamoyl group as defined herein. N-carbamoyl refers to-NR-COOR ', wherein R and R' are as defined herein. O-carbamoyl refers to-OCO-NRR ', wherein R and R' are as defined herein.

The term "carbonyl" as used herein includes formyl-C (═ O) H, alone and in combination, is a-C (═ O) -group.

The term "carboxy" or "carboxy" as used herein refers to-C (═ O) OH or the corresponding "carboxylate" anion, e.g., carboxylate salt form.

"O-carboxy" refers to an RC (═ O) O-group, where R is as defined herein.

"C-carboxy" refers to the group — C (═ O) OR, where R is as defined herein.

The term "cyano" as used herein refers to-CN.

The term "carbocyclyl" as used herein, refers to a saturated or partially saturated monocyclic or fused bicyclic or tricyclic group in which the ring atoms of the ring system are all carbon and in which each cyclic moiety contains from 3 to 12 carbon atom ring members. "carbocyclyl" includes ring systems benzo-fused to a carbocyclyl. One group of carbocyclic groups has 5 to 7 carbon atoms. Examples of carbocyclyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl. 2, 3-dihydro-1H-indenyl or adamantyl.

The term "cycloalkyl" as used herein, unless otherwise specified (e.g., as defined in ring D), refers to a saturated monocyclic, bicyclic, or tricyclic group in which the ring atoms of the ring system are all carbon, and in which each cyclic moiety contains from 3 to 12 carbon atom ring members. C_3-6Cycloalkyl is cycloalkyl having 3 to 6 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl groups containing 4 to 7C atoms include cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl.

The term "cyclic group" as used herein refers to an aryl, heterocyclic or carbocyclic group as defined herein.

The term "cyclic group C" as used herein_1-8Alkyl "means C as defined above_1-8Alkyl radical, wherein C_1-8One hydrogen atom of the alkyl group is replaced by a cyclic group as defined above.

The term "halo" or "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.

The term "haloalkoxy," as used herein, refers to a haloalkyl group (as defined below) attached to the parent molecular moiety through an oxygen atom. Halogen substituted C_1-8Alkoxy means haloalkoxy wherein the haloalkyl moiety has 1 to 8C atoms. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2-fluoroethoxy, pentafluoroethoxy, or 3-chloropropoxy.

The term "haloalkyl" as used herein refers to an alkyl group having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Halogen substituted C_1-8Alkyl refers to haloalkyl wherein the alkyl portion has 1-8C atoms. In particular, a monohaloalkyl, dihaloalkyl or polyhaloalkyl group is included. As an example, a monohaloalkyl group can have one iodine, bromine, chlorine, or fluorine atom within the group. The dihalo-or polyhaloalkyl groups may have two or more of the same halogen atoms or a combination of different halogen atoms. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, or dichloropropyl.

The term "heteroalkyl" as used herein refers to a straight or branched alkyl chain wherein one, two or three carbons forming the alkyl chain are each replaced with a heteroatom independently selected from O, N and S, and wherein the nitrogen and/or sulfur heteroatoms (if present) may optionally be oxidized and the nitrogen heteroatoms (if present) may optionally be quaternized. For example, the heteroatoms O, N and S may be located at the terminus of or within the heteroalkyl group, i.e., the heteroalkyl group may be attached to the remainder of the molecule through a heteroatom or carbon atom.Up to two heteroatoms may be adjacent, e.g. -CH₂-NH-OCH₃. Thus, another example of a "heteroalkyl" group is a straight or branched chain alkyl group in which two adjacent carbon atoms are replaced by heteroatoms S and N, respectively, and the sulfur heteroatom is also oxidized, yielding, for example, -S (═ O)₂-NH₂、-S(＝O)₂-NH (alkyl) or-S (═ O)₂-N (alkyl) such moieties.

The term "hetero C" as used herein_1-4Alkylene "means a straight or branched chain C to which is attached a heteroatom selected from O, N and S_1-4Alkylene (i.e. straight or branched C)_1-4Alkanediyl) and also refers to such straight-chain or branched C_1-4Alkylene, wherein one or more (e.g., 1, 2 (if present) or 3 (if present)) of the carbon atoms of the alkylene are each replaced by a heteroatom independently selected from O, N or S. The nitrogen and/or sulfur heteroatoms (if present) may optionally be oxidized, and the nitrogen heteroatoms (if present) may optionally be quaternized. The heteroatoms O, N and S may be located at hetero C_1-4Terminal to the alkylene group and/or located at an internal position. It is understood that the presence of a hydrogen atom depends on the valence of the heteroatom replacing the corresponding carbon atom. For example, if-CH₂-the carbon atom on the group is replaced by O or S, the resulting group is-O-or-S-, respectively, and-N (H) -when the carbon atom is replaced by N. Likewise, if the radical-CH₂-CH(-CH₃)-CH₂The central carbon atom on-is replaced by N. The resulting group is then-CH₂-N(-CH₃)-CH₂-. "hetero C_1-4Examples of alkylene "are straight-chain or branched C_1-4Alkylene in which two adjacent carbon atoms are replaced by heteroatoms S and N, respectively, and the sulfur heteroatom is also oxidized to give, for example, -S (═ O)₂-n (h) -or-S (═ O)₂-N(CH₃) Such a portion.

The term "heteroaryl" as used herein refers to a 5-6 membered unsaturated monocyclic or fused bicyclic or tricyclic ring system, wherein said rings are aromatic and wherein at least one ring contains at least one heteroatom selected from O, S and N. Preferred heteroaryl groups are 5-to 6-membered monocyclic or 9-to 10-membered bicyclic heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, imidazopyridyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or furopyridyl.

The term "heterocyclyl" or "heterocyclic" as used herein, each refers to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently selected from nitrogen, oxygen, and sulfur, wherein the nitrogen, oxygen, and sulfur atoms may be oxidized (e.g., -N ═ O, -S (═ O) -or-S (═ O)₂-). In addition, 1, 2 or 3 of the carbon atoms of the heterocyclyl group may be optionally oxidized (e.g., to give an oxo group or ═ O). One group of heterocyclic groups has 1-4 heteroatoms as ring members. Another group of heterocyclyl groups has 1-2 hetero-azines as ring members. One group of heterocyclic groups has 3-8 ring members on each ring. Another group of heterocyclic groups has 3-7 ring members on each ring. Another group of heterocyclic groups has 5-6 ring members on each ring. "Heterocyclyl" is intended to include heterocyclyl groups fused to carbocyclic or benzo ring systems. Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thiaxalkyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepinyl, thiepinyl, diazepinyl, thiazepinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, dihydropyranyl, and the like,1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiopentanoyl, dihydropyranyl, dihydrothienyl, dihydrofuryl, pyrazolylimidazolinyl or imidazolidinyl. Examples of heteroaryl groups that are heterocyclyl groups include, but are not limited to, pyridyl, imidazolyl, imidazopyridyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or furopyridyl.

The term "heterocycloalkyl" as used herein refers to a heterocyclic group that is not fully unsaturated, e.g., one or more ring systems of the heterocycloalkyl group is not aromatic. Examples of heterocycloalkyl groups include piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl.

The term "hydroxy" as used herein refers to-OH.

The term "hydroxy C" as used herein_1-8Alkyl "means C_1-8Alkyl in which one or more hydrogen atoms (preferably one or two) are replaced by hydroxyl groups.

The term "R" as used herein¹²R¹³N-C_1-8Alkyl "means C_1-8Alkyl in which one or more hydrogen atoms (preferably one or two, more preferably one) are replaced by-NR¹²R¹³And (4) replacing.

The term "lower" as used herein, unless otherwise specifically defined, is meant to encompass from 1 to 6 carbon atoms, and includes 6 carbon atoms.

The term "nitro" as used herein means-NO₂。

In this contextThe term "sulfonic acid" as used herein refers to-SO₃H group and the anion thereof is a sulfonic acid for salt formation.

The term "sulfinyl", as used herein, refers to-S (═ O) (R), where R is as defined herein.

The term "sulfonyl" as used herein means-S (═ O)₂R, wherein R is as defined herein.

The term "sulfonamide" as used herein refers to an N-or S-sulfonamido group, as defined herein.

The term "N-sulfonylamino" as used herein refers to RS (═ O)₂A N (R ') -group, wherein R and R' are as defined herein. A preferred N-sulfonylamino group is-NHSO₂R, wherein R is as defined herein, preferably R is alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, or heterocycloalkyl, more preferably R is alkyl, aryl, heteroaryl, or heterocycloalkyl, wherein said alkyl, said cycloalkyl, said heteroalkyl, said aryl, said heteroaryl, and said heterocycloalkyl are each optionally substituted. Optional substituents on said alkyl, said cycloalkyl, said heteroalkyl, said aryl, said heteroaryl and said heterocycloalkyl may be independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower cycloalkyl, phenyl, aryl, heteroaryl, pyridyl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyl ester, lower carboxamido, cyano, halogen, hydroxy, amino, amido, nitro, sulfhydryl, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N₃、SH、SCH₃、C(O)CH₃、CO₂CH₃、CO₂H. Carbamates and ureas. Preferably, the optional substituents are independently selected from hydroxy, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -N (C)_1-3Alkyl radical)₂、-NH(C_1-3Alkyl), -NHC (═ O) (C)_1-3Alkyl), -C (═ O) OH, -C (═ O) O (C)_1-3Alkyl), -C (═ O) (C)_1-3Alkyl), -C (═ O) NH₂、-C(＝O)NH(C_1-3Alkyl), -C (═ O) NH (cycloalkyl), -C (═ O) N (C) C_1-3Alkyl radical)₂、-S(＝O)₂(C_1-3Alkyl), -S (═ O)₂NH₂、-S(＝O)₂N(C_1-3Alkyl radical)₂、-S(＝O)₂NH(C_1-3Alkyl), -CHF₂、-OCF₃、-OCHF₂、-SCF₃、-CF₃、-CN、-NH₂、-NO₂Or a tetrazolyl group. A particularly preferred N-sulfonylamino group is-NHSO₂R, wherein R is alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl or heterocycloalkyl, preferably R is alkyl, aryl, heteroaryl or heterocycloalkyl, and-NHSO₂(optionally substituted aryl). Still more preferably, the N-sulfonamido group is-NHSO₂Alkyl and-NHSO₂(optionally substituted aryl). A typical non-limiting N-sulfonylamino group is-NHSO₂Alkyl radicals, e.g. -NHSO₂CH₃、-NHSO₂CH₂CH₃or-NHSO₂(isopropyl) and-NHSO₂(optionally substituted aryl), e.g. -NHSO₂-phenyl, -NHSO₂- (2-cyanophenyl), -NHSO₂- (3-cyanophenyl), -NHSO₂- (4-cyanophenyl), -NHSO₂- (2-aminophenyl), -NHSO₂- (3-aminophenyl) or-NHSO₂- (4-aminophenyl). Another typical N-sulfonylamino group is-NHSO₂(optionally substituted heterocycloalkyl) such as-NHSO₂- (piperazin-1-yl) and-NHSO₂(optionally substituted heteroaryl), e.g. -NHSO₂- (optionally substituted pyridyl), e.g. NHSO₂- (3-pyridyl) or-NHSO₂- (6-amino-3-pyridyl).

The term "S-sulfonamido" as used herein means-S (═ O)₂NRR 'groups wherein R and R' are as defined herein.

The term "urea" as used herein refers to the group-n (R) C (═ O) n (R) (R '), wherein R and R' are as defined herein.

Unless otherwise defined, the term R or the term R', which is present by itself and without numerical designation, refers to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl. Including unsubstituted and substituted versions of the above groups. Preferably, the groups are unsubstituted.

Whether or not the R groups have numerical designations, each R group includes R, R' and R^zWherein z ═ 1, 2,3,. z), each substituent and each term are understood to be independent of each other in terms of group selection. Any variable, substituent or term (e.g., aryl, heterocycle, R, etc.) shall occur more than one time in a formula or general structure, and its definition at each occurrence is independent of its definition at every other occurrence. It is further recognized by those skilled in the art that some groups may be attached to the parent molecule or may occupy positions on the chain of elements starting from either written end. Thus, by way of example only, an asymmetric group, such as — C (═ O) n (r) -may be attached to the parent moiety on carbon or nitrogen.

The term "optionally substituted" as used herein means that the preceding or preceding group may or may not be substituted. When substituted and unless otherwise specified, "optionally substituted" substituents may include, but are not limited to, one or more substituents independently selected from the following groups, alone or in combination, or specifically specified: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower cycloalkyl, phenyl, aryl, heteroaryl, pyridyl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxy, lower alkylcarbonyl, lower carboxy ester, lower carboxamido, cyano, halogen, hydroxy, amino, amido, nitro, sulfhydryl, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N₃、SH、SCH₃、C(O)CH₃、CO₂CH₃、CO₂H. Carbamates and ureas. The two substituents may be joined to one another to form a fused 5-, 6-or 7-membered carbocyclic ring or a heterocyclic ring consisting of 0 to 3 heteroatoms, for example to form a methylenedioxy or ethylenedioxy group. Optionally substituted groups may be unsubstituted (e.g., -CH)₂CH₃) Fully substituted (e.g. -CF)₂CF₃) Monosubstituted (e.g. -CH)₂CH₂F) Or such levels of substitution between fully and mono-substitution (e.g. -CH)₂CF₃). If a substituent is described as substituted without limitation, both substituted and unsubstituted forms are included. If a substituent is designated as "substituted," it is specifically designated as a substituted form. In addition, different groups of optional substituents for a particular moiety may be defined as desired; in these cases, optional substitution is generally defined directly as the term "optionally substituted. In a particular definition, the optional substituents are selected from hydroxy, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -N (C)_1-3Alkyl radical)₂、-NH(C_1-3Alkyl), -NHC (═ O) (C)_1-3Alkyl), -C (═ O) OH, -C (═ O) O (C)_1-3Alkyl), -C (═ O) (C)_1-3Alkyl), -C (═ O) NH₂、-C(＝O)NH(C_1-3Alkyl), -C (═ O) NH (cycloalkyl), -C (═ O) N (C) C_1-3Alkyl radical)₂、-S(＝O)₂(C_1-3Alkyl), -S (═ O)₂NH₂、-S(＝O)₂N(C_1-3Alkyl radical)₂、-S(＝O)₂NH(C_1-3Alkyl), -CHF₂、-OCF₃、-OCHF₂、-SCF₃、-CF₃、-CN、-NH₂、-NO₂Or a tetrazolyl group.

The term "optional substituent" as used herein means that the corresponding substituent may or may not be present. Thus, a compound having 1, 2 or 3 optional substituents may be unsubstituted or may be substituted with 1, 2 or 3 substituents.

The term "treating a disease" as used herein refers to slowing or reversing the progression of the disease. Treating a disease includes treating and/or alleviating the symptoms of the disease.

The term "preventing a disease" as used herein refers to slowing the onset of a disease or disorder or symptoms thereof. Preventing the disease or disorder may include terminating the onset of the disease or its symptoms.

The term "unit dosage form" as used herein refers to physically discrete units such as capsules or tablets suitable for use as a unit dose for human patients. Each unit contains a predetermined amount of a compound of formula I, which is found or believed to produce the desired pharmacokinetic profile, which results in the desired therapeutic effect. The dosage unit is comprised of a compound of formula I together with at least one pharmaceutically acceptable carrier, salt, excipient, or combination thereof.

As used herein, the term "subject", "patient" or "individual", e.g., a subject in need of treatment or prevention, can be a eukaryote, an animal, a vertebrate, a mammal, a rodent (e.g., guinea pig, hamster, rat, mouse), a murine (e.g., mouse), a canine (e.g., dog), a feline (e.g., cat), an equine (e.g., horse), a primate, an ape (e.g., monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or a human. The meaning of the terms "eukaryote", "animal", "mammal", etc. are well known in the art and can be deduced, for example, from Wehner und Gehring (1995; Thieme Verlag). In the context of the present invention, economically, agriculturally or scientifically important animals to be treated are particularly envisaged. Scientifically important organisms include, but are not limited to, mice, rats and rabbits. Lower organisms such as fruit flies like Drosophila melagonaster and nematodes like beautiful Caenorhabditis elegans (Caenorhabditis elegans) can also be used in the scientific process. Non-limiting examples of agriculturally important animals include sheep, cattle and pigs, while, for example, cats and dogs can be considered economically important animals. Preferably, the subject/patient/individual is a mammal. More preferably, the subject/patient/individual is a human or non-human mammal (e.g., guinea pig, hamster, rat, mouse, rabbit, dog, cat, horse, monkey, ape, marmoset, baboon, gorilla, chimpanzee, orangutan, gibbon, sheep, cow, or pig); even more preferably, the subject/patient/individual is a human.

The term "dose" or "dose" as used herein refers to the amount of active ingredient taken or administered by an individual at one time. For example, a 40mg dose of a compound of formula I refers to a dose where the subject ingests 40mg of a compound of formula I twice a day, e.g., 40mg in the morning and 40mg in the evening, in a twice daily dosage regimen. A 40mg dose of a compound of formula I may be divided into two or more dosage units, for example, a 20mg dosage unit of a compound of formula I in a two-tablet dosage form or a 20mg dosage unit of a compound of formula I in a two-capsule dosage form.

The term "therapeutically effective amount," e.g., a therapeutically effective amount of a compound of the invention, as used herein, refers to an amount sufficient to produce a desired biological effect (e.g., therapeutic effect) in a subject. Thus, a therapeutically effective amount of a compound may be an amount sufficient to treat or prevent a disease or disorder and/or delay the onset or development of a disease or disorder and/or alleviate one or more symptoms of a disease or disorder when administered to a subject suffering from a disease or disorder or susceptible to such a disease or disorder.

As used herein, a "pharmaceutically acceptable prodrug" is a compound that can be converted under physiological conditions or by solvolysis to a specified compound or a pharmaceutically acceptable salt of such a compound.

As used herein, "pharmaceutically acceptable salt" is intended to refer to salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable. The compounds used in the present invention may have functional groups that are sufficiently acidic, sufficiently basic, or both, and thus react with any of several inorganic or organic bases, as well as organic and inorganic acids, to form pharmaceutically acceptable salts. Typical pharmaceutically acceptable salts include those salts prepared by the reaction of a compound of the invention with an inorganic or organic acid, for example, hydrobromide, sulphate, pyrosulphate, bisulphate, sulphite, bisulphite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, nitrate, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrate, hydroxybenzoate, methoxybenzoate, Phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, ethanesulfonate, propanesulfonate, benzenesulfonate, toluenesulfonate, trifluoromethanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, pyruvate, stearate, ascorbate or salicylate. When the compounds of the invention carry an acid moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts with suitable organic ligands such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine, and the like. Pharmaceutically acceptable salts are well known in the art.

As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to non-API (API refers to active pharmaceutical ingredient) substances such as disintegrants, binders, fillers, and lubricants used in formulating pharmaceutical products. They are generally safe for administration to humans in accordance with established government standards, including those promulgated by the U.S. food and drug administration and european medical institutions. Pharmaceutically acceptable carriers or excipients are well known in the art.

As will be understood by those skilled in the art, some of the variables in the substituent list are repeated (different names are used for the same substituent), are generic to others in the list and/or partially overlap in meaning with other terms. In the compounds of the invention, it is recognized by those skilled in the art that substituents may be attached to the rest of the molecule through a number of positions, preferred positions being as exemplified in the examples.

The compounds of the present invention are surprisingly potent and selective inhibitors of LSD 1. Avoiding inhibition of "off-target" may avoid unwanted or undesirable side effects, such as the cheese effect associated with MAO-A. The compounds of the present invention are therefore useful for the treatment or prevention of any disease or disorder associated with LSD 1. They include cancer, neurological diseases, viral infections, and the like.

Preferably, the compounds of formula I, including compounds of formulae Ia, Ia-1, Ib and Ic and any salts and solvates thereof are used for the treatment or prevention of cancer, most preferably for the treatment of cancer. Cancers that may be treated (or prevented) with the compounds of the invention include, but are not limited to, for example:

hematologic cancers (also referred to herein as hematologic cancers), including cancers of the blood, bone marrow, and lymph nodes, such as leukemias (e.g., Acute Myelogenous Leukemia (AML), Acute Promyelocytic Leukemia (APL), Chronic Myelogenous Leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL), or hairy cell leukemia), myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, and lymphomas (e.g., hodgkin's disease, non-hodgkin's lymphoma (malignant lymphoma));

breast cancer, including invasive ductal carcinoma, ductal carcinoma in situ, lobular carcinoma, and mixed ductal and lobular carcinoma;

lung cancer such as bronchogenic carcinoma (e.g., squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, hamartoma and mesothelioma;

gastrointestinal tract cancers, such as esophagus (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (e.g., carcinoma, lymphoma, leiomyosarcoma), pancreas (e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, pancreatic tumor), small intestine (e.g., adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), and large intestine (e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

genitourinary tract cancers, such as kidney (e.g., adenocarcinoma, Wilm's tumor (Wilm's tumor), lymphoma, leukemia), bladder and urethra (e.g., squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (e.g., adenocarcinoma, sarcoma), and testis (e.g., sperm cell tumor, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroadenoma, adenomatous tumors, lipoma);

liver cancers such as hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatoadenoma and hemangioma;

bone cancers, such as osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, chondrogenic condyloma (osteochronofroma) (osteochondral exostosis), benign chondroma, chondroblastoma, cartilage mucofibroma, osteogenic osteoma, and giant cell tumor;

cancers of the nervous system, such as the skull (e.g., osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (e.g., meningioma, meningiosarcoma, gliomas), brain (e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, and sarcoma;

gynecological cancers, such as the uterus (e.g., endometrial carcinoma), cervix (e.g., cervical carcinoma, pre-tumor cervical dysplasia), ovaries (e.g., ovarian cancer (serosa adenocarcinoma, myxocyst adenocarcinoma, nonmalignant carcinomas), granulosa-sheath cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), and fallopian tubes (carcinoma);

heart cancers such as sarcomas (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma;

skin cancers such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, and kaposi's sarcoma; and

adrenal cancer, such as neuroblastoma.

Thus, in one embodiment, the compounds of the invention are for use in the treatment or prevention of cancer, in particular for the treatment of cancer, wherein the cancer is selected from the group consisting of blood cancer, leukemia, lymphoma, breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, neuroblastoma, bladder cancer, liver cancer, sarcoma, myeloma and skin cancer. In another embodiment, the compounds of the invention are used for the treatment or prevention, in particular for the treatment, of blood cancers (also referred to as hematological cancers), including leukemias (e.g., Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL) or hairy cell leukemia), lymphomas and myelomas, prostate cancer, breast cancer, lung cancer, colorectal cancer, brain cancer or skin cancer. In a preferred embodiment, the compounds of formula I include compounds of formulae Ia, Ia-1, Ib and Ic for the treatment of leukemia. More preferably, compounds of formula I include compounds of formulae Ia, Ia-1, Ib, and Ic for the treatment of leukemia, including Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL), and hairy cell leukemia.

Typically, an effective amount of a compound of formula I, Ia-1, Ib or Ic can be about 0.01. mu.g/kg to about 100 mg/kg/day based on total body weight. The active ingredient may be administered once, or may be divided into several smaller doses that are administered at predetermined time intervals. A suitable dosage unit for each administration may be, for example, from about 1. mu.g to about 2000mg, preferably from about 5. mu.g to about 1000 mg. Even more preferably, the amount of active ingredient administered is from about 5 μ g to about 100mg per day. These dosages will depend on the pharmacokinetic parameters and other ADME properties of the particular compound and the potency of the compound in the particular disease setting.

It should be understood that the above-specified dosage ranges are exemplary only and are not intended to limit the scope of the invention. The therapeutically effective amount of each active compound may vary depending on a variety of factors, including, but not limited to, the activity of the compound employed, the stability of the active compound in the patient, the severity of the condition to be alleviated, the total weight of the patient to be treated, the route of administration, the ease of absorption, distribution, and excretion (through the body) of the active compound, the age and sensitivity of the patient to be treated, and the like, as will be apparent to those skilled in the art. The amount of application can be adjusted as various factors change over time.

Although the compounds of the present invention can be administered for direct therapy, as such, they are typically administered in the form of a pharmaceutical composition comprising the compound as an active pharmaceutical ingredient together with one or more pharmaceutically acceptable excipients or carriers.

The compounds of the present invention may be administered by any means that accomplishes their intended purpose. Examples include administration by oral, parenteral, intravenous, subcutaneous or topical routes.

For oral delivery, the active compound can be added to a formulation that includes pharmaceutically acceptable carriers such as binders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrants (e.g., alginates, Primogel, and corn starch), and sweetening or flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint). The above formulations can be delivered orally in the form of closed gelatin capsules or compressed tablets. Capsules and tablets may be prepared by any conventional technique. Capsules and tablets may also be coated with various coatings known in the art to improve the flavor, taste, color, and shape of the capsules and tablets. In addition, liquid carriers such as fatty oils may also be included in the capsules.

Suitable oral formulations may also be in the form of suspensions, syrups, chewing gums, wafers, elixirs and the like. Conventional agents for modifying the flavor, taste, color, and shape of particular forms may also be included, if desired. In addition, for convenient administration through the enteral feeding tube in patients who cannot be swallowed, the active compound can be dissolved in an acceptable lipophilic vegetable oil carrier such as olive oil, corn oil and safflower oil.

The active compounds can also be administered parenterally, in the form of solutions or suspensions, or in lyophilized form (which can be converted, before use, to the solution or suspension form). In such a formulation, a diluent or a pharmaceutically acceptable carrier such as sterile water and a physiological saline buffer may be used. Other conventional solvents, pH buffers, stabilizers, antimicrobials, surfactants, and antioxidants may be included. For example, useful ingredients include sodium chloride, acetate, citrate or phosphate buffers, glycerol, dextrose, fixed oils, methylparaben, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like. The parenteral preparation can be stored in any conventional container such as vials and ampoules.

The topical route of administration includes nasal, oral (bucal), mucosal, rectal, or vaginal routes. For topical administration, the active compounds may be formulated as lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols. Thus, one or more thickening agents, humectants, and stabilizers may be included in the dosage form. Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax, or mineral oil, lanolin, squalene, and the like. A particular form of topical application is delivery via a transdermal patch. Methods for making transdermal patches are disclosed, for example, in Brown et al (1988) ann.rev.med.39: 221-229, which is incorporated herein by reference, for example.

Subcutaneous implantation for sustained release of the active compound may also be a suitable route of administration. This requires surgery to implant the active compound in any suitable formulation into the subcutaneous space, for example, below the anterior abdominal wall. See, e.g., Wilson et al (1984) j.clin.psych.45: 242-247. Hydrogels can be used as carriers for the sustained release of active compounds. Hydrogels are generally known in the art. They are typically made as follows: high molecular weight biocompatible polymers are crosslinked into a network that swells in water to form a gel-like material. Preferably, the hydrogel is biodegradable or bioabsorbable. For the purpose of the present invention, a hydrogel composed of polyethylene glycol, collagen, or a (glycolic acid-L-lactic acid) copolymer can be useful. See, e.g., Phillips et al (1984) j.pharmaceut.sci., 73: 1718-1720.

The active compounds can also be conjugated to water-soluble, non-immunogenic, non-peptidic, high molecular weight polymers to form polymer conjugates. For example, the active compound is covalently attached to polyethylene glycol to form a conjugate. Typically, such conjugates exhibit improved solubility, stability, and reduced toxicity and immunogenicity. Thus, the active compound in the conjugate may have a longer half-life in vivo and exhibit better therapeutic efficacy when administered to a patient. See generally, Burnham (1994) am.j.hosp.pharm.15: 210-218. Pegylated proteins are currently being used in protein replacement therapy and for othersThe application in therapy. For example, pegylated interferon (PEG-INTRON)) It is used clinically in treating hepatitis B. Pegylated adenosine deaminase (A)) Is being used to treat Severe Combined Immunodeficiency Disease (SCIDS). Pegylated L-asparaginase () Is being used to treat Acute Lymphoblastic Leukemia (ALL). Preferably, the covalent bonds between the polymer and the active compound and/or the polymer itself are hydrolytically degradable under physiological conditions. Such conjugates (referred to as "prodrugs") can readily release the active compound in vivo. Controlled release of the active compound can also be achieved by incorporating the active ingredient into microcapsules, nanocapsules, or hydrogels (generally known in the art). Other pharmaceutically acceptable prodrugs of the compounds of the present invention include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphates, metal salts, and sulfonates.

Liposomes may also be used as carriers for the active compounds of the invention. Liposomes are micelles made of various lipids, such as cholesterol, phospholipids, fatty acids, and their derivatives. Various modified lipids can also be used. Liposomes can reduce the toxicity of the active compounds and increase their stability. Methods for preparing liposomal suspensions having active ingredients contained therein are generally known in the art. See, for example, U.S. Pat. nos. 4,522,811; prescott, ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976).

The active compounds may also be administered in conjunction with another active agent, where the above active agents synergistically treat or prevent the same condition or are effective for another disease or condition in the patient being treated, provided that the above other active agents do not interfere with or adversely affect the effects of the active compounds of the present invention. Such other active agents include, but are not limited to, anti-inflammatory agents, antiviral agents, antibiotics, antifungal agents, antithrombotic agents, cardiovascular agents, cholesterol lowering agents, anticancer agents, hypertension agents, and the like.

Combination therapy includes administration of a single pharmaceutical dosage form comprising a compound of the invention and one or more additional active agents as well as administration of the compound of the invention and each additional active agent in separate pharmaceutical dosage forms per se. If administered separately, administration may be simultaneous, sequential or separate and the compound of the invention and the additional therapeutic agent may be administered by the same route of administration or using different routes of administration, e.g., one compound may be administered orally while the other compound is administered intravenously.

In particular, when a compound of formula I, Ia-1, Ib, or Ic is used to treat or prevent cancer, the compound can be administered in combination with one or more additional active agents known to be useful in treating or preventing cancer, including chemotherapy or radiation therapy.

Typically, any anti-neoplastic agent that is active against cancer treated or prevented with a compound of the present invention can be used with a compound of the present invention for use in the combination therapy of the present invention. Examples of antineoplastic agents that may be used in conjunction with the compounds and methods of the present invention include, generally, and as the case may be, alkylating agents, antimetabolites, podophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and hematopoietic growth factors. Typical types of antineoplastic agents include anthracyclines, vinca drugs, mitomycins, bleomycin, cytotoxic nucleosides, epothilones, discodermolides, pteridines, enediynes (diynenes), and podophyllotoxins. Particularly useful members of these classes include, for example, carminomycin, daunorubicin, aminopterin, methotrexate, mitomycin C, porphyrinomycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytarabine, podophyllotoxin, or podophyllotoxin derivatives such as etoposide, etoposide phosphate, or teniposide, melphalan, vinblastine, vincristine, vinblastine, vindesine, vinblastine, paclitaxel, and the like. Other useful antineoplastic agents include estramustine, carboplatin, cyclophosphamide, bleomycin, gemcitabine, ifosfamide, melphalan, altretamine, thiotepa, cytarabine, itraconazole (idatrexate), trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, cytarabine, bicalutamide, flutamide, leuprolide, pyridobenzindole (pyridobenzindole) derivatives, interferons, and interleukins.

Thus, the compounds of formula I, Ia-1, Ib or Ic of the invention can be used for the treatment or prevention of cancer, wherein the compounds are administered together with one or more antineoplastic agents. If appropriate, the antineoplastic agents for administration in combination therapy may be selected from: tumor angiogenesis inhibitors (e.g., protease inhibitors, epidermal growth factor receptor kinase inhibitors, or vascular endothelial growth factor receptor kinase inhibitors); cytotoxic drugs (e.g., antimetabolites such as purine and pyrimidine analog antimetabolites); anti-mitotic drugs (e.g., microtubule stabilizing drugs or anti-mitotic alkaloids); a platinum complex; an anti-tumor antibiotic; alkylating agents (e.g., nitrogen mustards or nitrosoureas); endocrine active agents (e.g., adrenocorticosteroids, androgens, antiandrogens, estrogens, antiestrogens, aromatase inhibitors, gonadotropin releasing hormone agonists, or somatostatin analogues); or compounds that target specific metabolic pathways that are overexpressed and/or otherwise implicated in misregulation in tumor cells (e.g., ATP and GTP phosphodiesterase inhibitors, histone deacetylase inhibitors, protein kinase inhibitors (e.g., serine, threonine, and tyrosine kinase inhibitors (e.g., Abelson protein tyrosine kinase)), and various growth factors and their receptors and kinase inhibitors (e.g., epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, fibroblast growth factor inhibitors, insulin-like growth factor receptor inhibitors, and platelet-derived growth factor receptor kinase inhibitors)); an aminopeptidase inhibitor; a proteasome inhibitor; cyclooxygenase inhibitors (e.g., cyclooxygenase-1 or cyclooxygenase-2 inhibitors); a topoisomerase inhibitor (e.g., a topoisomerase I inhibitor or a topoisomerase II inhibitor); or a retinoid active agent.

Alkylating agents which may be used as anticancer agents in conjunction with the compounds of the present invention may be, for example, nitrogen mustards (such as cyclophosphamide, nitrogen mustard (methine chloride), uramustine, melphalan, chlorambucil, ifosfamide, bendamustine or trofosfamide), nitrosoureas (such as carmustine, streptozocin, fotemustine, lomustine, nimustine, prednimustine, ramustine or semustine), alkyl sulfonates (such as busulfan, mannosulfan or troosendan), aziridines (such as hexamethylmelamine (hexamethylmelamine), tritamin, ThioTEPA (N, N' -triethylenethiophosphoramide), carboquone or triimidyl quinone), hydrazines (such as procarbazine), triazenes (such as dacarbazine) or imidazotetrazine (such as temozolomide).

Platinum complexes which may be used as anticancer drugs together with the compounds of the present invention may be, for example, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin or triplatin tetranitrate.

Cytotoxic drugs which can be used as anticancer drugs together with the compound of the present invention may be, for example, antimetabolites including folic acid analog antimetabolites (e.g., aminopterin, methotrexate, pemetrexed or raltitrexed), purine analog antimetabolites (e.g., cladribine, clofarabine, fludarabine, 6-mercaptopurine (including its prodrug form azathioprine), pentostatin, or 6-thioguanine), and pyrimidine analog antimetabolites (e.g., cytarabine, decitabine, 5-fluorouracil (including its prodrug form capecitabine and tegafur), floxuridine, gemcitabine, enocitabine or sapatibine).

Antimitotic drugs which can be used as anticancer drugs in conjunction with the compounds of the present invention can be, for example, a taxane (such as docetaxel, larotaxel, otaxel, paclitaxel/taxol, or tesetaxel), a vinca alkaloid (such as vinblastine, vincristine, vinflunine, vindesine, vinzolidine, or vinorelbine), an epothilone (such as epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, or epothilone F), or an epothilone B analog (such as ixabepilone/azaepothilone B).

Antitumor antibiotics that can be used as anticancer drugs in conjunction with the compounds of the present invention can be, for example, anthracyclines (such as doxorubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin), anthracenediones (such as mitoxantrone or pixantrone), or antitumor antibiotics isolated from streptomyces (such as actinomycin (including actinomycin D), bleomycin, mitomycin (including mitomycin C), or plicamycin.

Tyrosine kinase inhibitors that may be used as anticancer drugs together with the compounds of the present invention may be, for example, axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semanib, sorafenib, sunitinib or vandetanib.

The topoisomerase inhibitor that can be used as an anticancer drug together with the compound of the present invention may be, for example, a topoisomerase I inhibitor (such as irinotecan, topotecan, camptothecin, belotecan, rubitecan, or lamellarin D) or a topoisomerase II inhibitor (such as amsacrine, etoposide phosphate, teniposide, or doxorubicin).

Additional anti-cancer drugs may be used in conjunction with the compounds of the present invention. The anti-cancer drug may include biological or chemical molecules such as TNF-related apoptosis-inducing ligand (TRAIL), tamoxifen, toremifene, floxymethyl sterol (nuoxymestrenol), raloxifene, diethylstilbestrol, bicalutamide, nilutamide, flutamide, aminoglutethimide, anastrozole, tetrazole, gonadotropin releasing hormone (LHRH) analogs, ketoconazole, capromorelin acetate, leuprolide, megestrol acetate, prednisone, mifepristone, amsacrine, bexarotene, estramustine, irovervine, trabectedin, cetuximab, palimumab, tositumomab, alemtuzumab, bevacizumab, ecumab, gemumumab, alxipide, celecoxib, trioxayl, methyl aminoacetonate, efloxan, porfimer sodium, talaporfin, temoporfin, vea, vex, arsenic disulfide, tamoxifen, doxorame, nalytical, fludarabine, fludartin, fludarabine, atrasentan, bortezomib, carmofur, celecoxib, colchicine, elisamol, elsamitrucin, etoglut, lonidamine, thioxanthone, maxol, dibromomannitol, mitoguazone, mitotane, olmerson, homoharringtonine (omacetaxine), sitimene, seimazemad, tegafur, testolactone, thiazolufrine, tipifarnib and vorinostat.

Examples of retinoid active agents include all natural, recombinant and synthetic derivatives or mimetics of vitamin A, for example, retinyl palmitate, retinyl- β -glucuronide (vitamin A1 β -glucuronide), retinyl phosphate (vitamin A1 phosphate), retinyl esters, 4-oxoretinol, 4-oxoretinyl, 3-dehydroretinol (vitamin A2), 11-cis-retinal (11-cis-retinal, 11-cis-or neo-b-vitamin A1 aldehyde), 5, 6-epoxyretinol (5, 6-epoxyretinol 1 alcohol), anhydrous retinol (anhydrous vitamin A1) and 4-ketoretinol (4-keto-vitamin A1 alcohol), all-trans-retinoic acid (ATRA; vitamin A acid; 3, 7-dimethyl-9- (2, 6, 6, -trimethyl-1-cyclohexene-1-yl) -2,4, 6-nonanoic acid [ 8, 8-nonanoic acid ] 302, 79-4-oxo-retinol]) Lipid formulations of all-trans retinoic acid (e.g., ATRA-IV), 9-cis retinoic acid (9-cis-RA; aliretin A acid; panretin^TM(ii) a LGD1057), 13-cis-tretinoin (isotretinoin), (E) -4- [2- (5, 5,8, 8-tetramethyl-5, 6,7, 8-tetrahydro-2-naphthyl) -1-propenyl]-benzoic acid, 3-methyl- (E) -4- [2- (5, 5,8, 8-tetramethyl-5, 6,7, 8-tetrahydro-2-naphthalenyl) -1-propenyl]Benzoic acid, fenretinamide (N- (4-hydroxyphenyl) retinamide; 4-HPR), abamectinEster A ((all-E) -9- (4-methoxy-2, 3, 6-trimethylphenyl) -3, 7-dimethyl-2, 4,6, 8-nonatetraenoic acid ethyl ester; Tegison), Averme ((all-E) -9- (4-methoxy-2, 3, 6-trimethylphenyl) -3, 7-dimethyl-2, 4,6, 8-nonatetraenoic acid; Ro 10-1670; Averme A; New Zealand pine), Tazarotene (6- [2- (4, 4-dimethylthio chroman-6-yl) -ethynyl acid; Tazarotene, Triazalide]Ethyl nicotinate; tazorac; avage; zorac), Tocoretinate (9-cis-vitamin a acid; torvata ester), adapalene (6- [3- (1-adamantyl) -4-methoxyphenyl]-2-naphthoic acid; davolvin), motretinide (trimethylmethoxyphenyl-N-ethyl retinoamide; trasmaderm), retinal (retinal), CD437(6- [3- (1-adamantyl) -4-hydroxyphenyl) -2-naphthalenecarboxylic acid; AHPN), CD2325, ST1926([ E-3- (4 '-hydroxy-3' -adamantyl biphenyl-4-yl) acrylic acid), ST1878(2- [3- [2- [3- (2-methoxy-1, 1-dimethyl-2-oxoethoxy) phenoxy]Ethoxy radical]Phenoxy radical]Methyl isobutyrate), ST2307, ST1898, ST2306, ST2474, MM11453, MM002(3-CI-AHPC), MX2870-1, MX3350-1, MX84 and MX90-1, docosahexaenoic acid (DHA), phytanic acid (3,7, 11, 15-tetramethylhexadecanoic acid), MS6682(methoprene acid), LG100268(LG268), LG100324, SR 11203 ([2- (4-carboxyphenyl) -2- (5, 6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-2-naphthyl) -1, 3-dithiane), SR11217(4- (2-methyl-1- (5, 6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-2-naphthyl) propenyl) benzoic acid), SR11234, SR 36(2- (4-carboxyphenyl) -2- (5, 6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-2-naphthyl) -1, 3-dioxane), SR11246, AGN194204, derivatives of 9-cis-RA, such as LGD1069 (3-methyl TTNEB; bexarotene;(ii) a 4- [1- (5, 6,7, 8-tetrahydro-3, 5,5,8, 8-pentamethyl-2-naphthyl) ethenyl]Benzoic acid).

Examples of histone deacetylase inhibitors include, but are not limited to, MS-275 (SNDX-275; entinostat), FK228(FR 901228; depsipeptide; romidepsin), CI-994 (Acetyldinaline; tadalaine), Apicidin (cyclo [ (2S) -2-amino-8-oxodecanoyl-1-methoxy-L-tryptophanyl-L-isoleucyl- (2R) -2-piperidinecarbonyl), A-161906(7- [4- (4-cyanophenyl) phenoxy ] -heptisohydroxamic acid), Scriptaid (6- (1, 3-dioxo-1H, 3H-benzo [ de ] isoquinolin-2-yl) -hexanoic acid hydroxyamide), PXD-101 (belinostat), CHAP (cyclo-isohydroxamic acid peptide), LAQ-824 (Dacistat), BML-EI319(Depudecin), O3139 (Oxamfltine), NSC 69685 (Pyroxamide), MW 2796; MW2996, T2580(Trapoxin A), AN-9(Pivanex), W222305 (tributyrin) trichostatin A, trichostatin C, butyric acid, valproic acid (VPA), suberoylanilide hydroxamic acid (SAHA; Vorinostat), m-carboxy cinnamic acid bishydroxamide (CBHA), salicylbishydroxamic acid (S607; SHA; SHAM); suberoyl Bis Hydroxamic Acid (SBHA); azelaic Acid Bis Hydroxamic Acid (ABHA); azelaic acid-1-hydroxamic acid-9-anilide (AAHA); 3CI-UCHA (6- (3-chlorophenylureido) hexanoic acid hydroxamic acid); and sodium butyrate, sodium 4-phenylbutyrate, sodium phenylacetate, sodium valerate, sodium isovalerate, isobutyramide, sodium 3-bromopropionate, and sodium valproate.

In addition, biopharmaceuticals such as antibodies, antibody fragments, antibody constructs (e.g., single chain constructs) and/or modified antibodies (e.g., CDR-grafted antibodies, humanized antibodies, "fully humanized" antibodies, etc.) directed against cancer or tumor markers/factors/cytokines involved in cancer may be used in co-therapy with the compounds of the present invention. Examples of such biomolecules are alemtuzumab, aprezumab, aselizumab, atlizumab, bapirozumab, bevacizumab, bivatuzumab, melilizumab, sidaclizumab, pezilizumab, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efuzumab, epratuzumab, eprazizumab, eprazilizumab, novavizumab, aryltuzumab, gemuzumab olanzemin, ibruzumab, ipiuzumab, labuzumab, rituzumab, matuzumab, maclizumab, motuzumab, motozuzumab, natalizumab, nimuzumab, nolovizumab, numazumab, aurizumab, oclizumab, pamezumab, pacuzumab, cfuzumab, cfucilizumab, rituximab, rituzumab, rituximab, and rituximab, Celizumab, matuzumab, tacatuzumab tetraxetan, taduzumab, talilizumab, tefralizumab, tollizumab, trastuzumab, simon interleukin mab, tucusituzumab, umavivizumab, Uuzumab, and Vilizumab.

Other biological agents include, but are not limited to, immunomodulatory proteins such as cytokines (e.g., interleukin-2 (IL-2, aldesleukin), Epoietin-alpha; EPO), granulocyte-CSF (G-CSF; filgrastim) and granulocyte-macrophage-CSF (GM-CSF; sargrastim) and interferons (e.g., interferon-alpha, interferon-beta and interferon-gamma), BCG, levamisole and octreotide, endostatin, tumor suppressor genes (e.g., DPC4, NF-1, NF-2, RB, p53, WT1, BRCA1 and BRCA2) and cancer vaccines (e.g., tumor associated antigens such as gangliosides (GM2), Prostate Specific Antigen (PSA), Alpha Fetoprotein (AFP), cancer antigen (CEA) (produced by colon cancer and other adenocarcinomas such as breast cancer, and others, Lung, gastric, and pancreatic cancers), melanoma-associated antigens (MART-1, gap100, MAGE 1,3 tyrosinase), papillomavirus E6 and E7 fragments, autologous tumor cells, and whole cells or portions/lysates of allograft tumor cells.

General synthetic pathway description

The compounds of formula I can be synthesized according to the general synthetic route described below or according to methods analogous thereto. Unless otherwise indicated, in the following processes, the meanings of the various substituents on the individual synthesis intermediates and the individual compounds of the formula I are as described above for the compounds of the formula I. Other routes and other reactants and intermediates known to those skilled in the art may also be used to obtain compounds of formula I. The following reaction schemes are meant only to represent examples of the present invention and are in no way meant to limit the present invention. In some of the methods described below, it may be necessary or desirable to protect the reactive or labile groups with conventional functional groups. The nature of these Protecting Groups and methods for their introduction and removal are well known in the art (see, e.g., Greene TW and Wuts PGM, "Greene's Protecting Groups in Organic Synthesis", 4 th edition, Wiley, 2006). Whether or not a protecting group is present, a subsequent deprotection step is required, which can be carried out under standard conditions well known in the art, such as those described in the above references.

In general, compounds of formula I can be prepared by reductive alkylation of cyclopropylamino derivatives of formula II with ketones of formula III, as shown in scheme 1:

scheme 1

A, B, D, R therein^w、R^x、R^y、R^zHave the meanings disclosed above in connection with the compounds of formula I.

The reductive alkylation may be carried out under standard conditions for reductive alkylation well known in the art. For example, a suitable set of conditions consists in reacting II with III using a reducing agent such as a borohydride (e.g. sodium triacetoxyborohydride or sodium borohydride), in a suitable solvent such as dichloroethane or methanol, optionally in the presence of an acid such as acetic acid. In order to carry out this reaction, any further amino groups which may be present on II or III must be protected using conventional amino protecting groups to avoid any side reactions; if such an amino protecting group is present, a subsequent deprotection step is required to give the compound of formula I. Any suitable amino protecting group may be used, for example, tert-butyloxycarbonyl (Boc). If Boc is used, deprotection can be carried out under standard conditions, for example under acidic conditions using HCl in an organic solvent such as diethyl ether or 1, 4-dioxane or trifluoroacetic acid (TFA) in dichloromethane. When HCl is used in the final step of the synthesis, the compound of formula I is obtained as the hydrochloride salt. Likewise, if TFA is used, the compound is obtained as the trifluoroacetate salt.

Cyclopropylamino derivatives of formula II and ketones of formula III are commercially available or can be prepared according to methods disclosed in the literature.

More detailed methods for obtaining compounds of formula I are described below.

For example, compounds of formula I, wherein R is^w、R^x、R^y、R^zAnd (H). This route is particularly suitable for compounds in which B = H or R¹Since the corresponding aldehyde (1) is commercially available or readily available. In scheme 2 below, "B" is omitted for illustration purposes.

Scheme 2: DCE (dichloroethane), DMSO (dimethyl sulfoxide), THF (tetrahydrofuran), aq = aqueous solution

The aldehydes of formula (1) are subjected to Horner-Wadsworth-Emmons reaction using triethylphosphoryl acetate and a base, preferably potassium tert-butoxide, in a suitable solvent such as tetrahydrofuran to give ethyl acrylate derivatives of formula (2), which are then subjected to cyclopropanation using trimethylsulfoxonium iodide and sodium hydride in dimethylsulfoxide as a solvent to give (trans) -cyclopropanecarboxylic acid ethyl ester derivatives of formula (3) as a trans ((1S,2R) and (1R, 2S)) racemic mixture. The corresponding (trans) -cyclopropanecarboxylic acid derivative of formula (4) can be hydrolyzed under basic conditions, for example using NaOH in a suitable solvent, for example MeOH. Compound (4) is then reacted first with ethyl chloroformate and triethylamine in acetone, and then with sodium azide in water to give a (trans) -cyclopropanecarbonyl azide derivative of formula (5). Reaction with tert-butanol leads to the formation of the (trans) -cyclopropylcarbamic acid tert-butyl ester derivative of formula (6). Deprotection of the Boc-group under acidic conditions, e.g. using HCl2M in ether in a suitable solvent, e.g. ether, or using HCI in 1, 4-dioxane, results in the formation of the (trans) -cyclopropylamine derivative of formula (7).

Alternatively, (trans) -cyclopropylamine derivatives of formula (7) can be synthesized by reacting aldehydes of formula (1) with nitromethane and ammonium acetate using tetrahydrofuran as solvent, leading to the formation of nitrostyrene of formula (10), followed by cyclopropanation using trimethylsulfoxonium iodide and potassium tert-butoxide, leading to the formation of trans-nitrocyclopropyl derivatives of formula (11) (obtained as a trans ((1S,2R), (1R, 2S)) racemic mixture), finally reduced using zinc in hydrochloric acid, leading to (trans) -cyclopropylamine derivatives of formula (7).

Reductive alkylation of a derivative of formula (7) with a ketone of formula (8) under standard conditions, for example using sodium triacetoxyborohydride or sodium borohydride as reducing agent in a suitable solvent such as dichloroethane or methanol, results in the formation of a (trans) -cyclopropylamino derivative of formula (9), which corresponds to a compound of formula I, in particular Ia, wherein R is^w、R^x、R^y、R^zAnd (H). In the case that the ketone of formula (8) contains a protected amino group, for example a Boc-protected amine (Boc: t-butyloxycarbonyl), an additional deprotection reaction step is required to give compound (9) which is carried out under acidic conditions, for example using HCl2M in diethyl ether in a suitable solvent such as diethyl ether or HCl in 1, 4-dioxane.

The aldehydes of formula (1) and ketones of formula (8) are commercially available or can be prepared starting from readily available starting materials using well-known synthetic methods.

For example, compounds of formula I, wherein B = -L-E, R, may be synthesized by the general route described in scheme 3^w、R^x、R^y、R^zH and L = - (CH)₂)_x-O- (wherein x is as defined above):

scheme 3: DCE (dichloroethane), DMF (N, N-dimethylformamide), DMSO (dimethyl sulfoxide), THF (tetrahydrofuran)

Use ofA bromine derivative of formula (12) (where R is formula 1) and a base, preferably potassium carbonate, in a suitable solvent such as N, N-dimethylformamide¹-OH) leads to the formation of the aldehyde derivative of formula (13). They were subjected to Horner-Wadsworth-Emmons reaction under the same conditions as disclosed in scheme 2 to give an ethyl acrylate derivative of formula (14), and then subjected to cyclopropanation reaction under the same conditions as disclosed in scheme 2 to give an ethyl (trans) -cyclopropanecarboxylate derivative of formula (15). Compound (15) is then converted to the (trans) -cyclopropylamine derivative of formula (19) under the same conditions as disclosed for the conversion of compound (3) to compound (7) in scheme 2.

Alternatively, (trans) -cyclopropylamine derivatives of formula (19) can be synthesized from aldehydes of formula (13) by the following steps: conversion to nitrostyrene (21), followed by cyclopropanation, gives compound (22), and reduction of the nitro group is carried out under the same conditions as disclosed in scheme 2 for the conversion of compound (1) to compound (7) by compounds (10) and (11).

Reductive alkylation of a derivative of formula (19) with a ketone of formula (8) under the conditions disclosed in scheme 1 or 2 gives compound (20), which corresponds to a compound of formula I, wherein B ═ L-E, R^w、R^x、R^y、R^z＝H，L＝-(CH₂)_x-O-. In the case that the ketone of formula (8) contains a protected amino group, for example a Boc-protected amine (Boc: t-butyloxycarbonyl), an additional deprotection step is required to give compound (20) which is carried out under acidic conditions, for example using HCl2M in diethyl ether in a suitable solvent such as diethyl ether or HCl in 1, 4-dioxane.

Formula (1, wherein R¹Aldehydes of ═ OH), bromine derivatives of formula (12) and ketones of formula (8) are commercially available or can be prepared starting from readily available starting materials using well-known synthetic methods.

For example, compounds of formula I, wherein B ═ L-E, R^w、R^x、R^y、R^z＝H，L＝-O-：

Scheme 4: DCE (dichloroethane), DMSO (dimethyl sulfoxide), Pd₂(dba)₃(tris (dibenzylideneacetone) dipalladium (0)), THF (tetrahydrofuran), Xantphos (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene).

Reacting a compound of formula (1, wherein R is¹Br) to give the aldehyde of the formula (2, wherein R is¹Br) followed by cyclopropanation under the same conditions as disclosed for the conversion of compound (2) to (3) in scheme 2, to give (3) of formula (3) wherein R¹Br) -ethyl (trans) -cyclopropanecarboxylate derivatives. Reacting a compound of formula (3) (wherein R is¹Br) to the corresponding formula (4, wherein R¹(trans) -cyclopropanecarboxylic acid derivatives of ═ Br), then converted to formula (5, where R is¹Br) -of (trans) -cyclopropanecarbonyl azide, which is then converted to formula (6, wherein R is as disclosed in scheme 2, according to the same conditions as disclosed in scheme 2¹Br) -tert-butyl (trans) -cyclopropylcarbamate derivative. Reaction of a compound (6, wherein R1 ═ Br) with a hydroxy-derivative of formula (23) using a palladium catalyst such as (tris (dibenzylideneacetone) dipalladium (0)), Xantphos and a base such as sodium tert-butoxide in a suitable solvent such as dioxane, results in the formation of a (trans) -cyclopropyl carbamic acid tert-butyl ester derivative of formula (24). Deprotection of the Boc-group under acidic conditions, for example using HCl2M in ether in a suitable solvent, for example ether, results in the formation of the (trans) -cyclopropylamine derivative of formula (25). Reductive alkylation using ketones of formula (8) under the same conditions as disclosed in scheme 1 or 2 results in the formation of (trans) -cyclopropylamino derivatives of formula (26), which correspond to compounds of formula I, wherein B ═ L-E, R^w、R^x、R^y、R^zH, L is O. The ketone package of the formula (8)For protected amino groups containing, for example, Boc-protected amine (Boc: t-butyloxycarbonyl), an additional deprotection step is required to afford compound (26) which is carried out under acidic conditions, for example using HCl2M in diethyl ether in a suitable solvent such as diethyl ether or HCl in 1, 4-dioxane.

Formula (1, wherein R¹Br), the hydroxy-derivatives of formula (25) and the ketones of formula (8) are commercially available or can be prepared starting from readily available starting materials using well-known synthetic methods.

For example, compounds of formula I, wherein B ═ L-E, R^w、R^x、R^y、R^zH, L-NH-or- (CH)₂)_x-NH-。

Scheme 5: boc₂O (di-tert-butyl dicarbonate), DCE (dichloroethane), DMSO (dimethyl sulfoxide), Pd₂(dba)₃(tris (dibenzylideneacetone) dipalladium (0)), THF (tetrahydrofuran), Xantphos (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene).

The compound of formula (6, wherein R is obtained according to the same method as disclosed in scheme 4¹(trans) -cyclopropyl carbamic acid tert-butyl ester derivatives of Br) to formula (7, wherein R is¹Br) by deprotection of the Boc-group under acidic conditions, e.g. using HCl2M in ether in a suitable solvent, e.g. ether, or using HCl in 1, 4-dioxane. The ketone of formula (8) is used to compound (7, R) under the same conditions as disclosed above, for example using sodium triacetoxyborohydride or sodium borohydride as a reducing agent in a suitable solvent such as dichloroethane or methanol¹Br) leads to the formation of formula (9, wherein R is¹Br) -is used as a substituent. Make (9, R)¹Br) and twoDi-tert-butyl carbonate is reacted under basic conditions using, for example, triethylamine in a suitable solvent, for example tetrahydrofuran, to give the Boc-protected derivative of formula (27), which is then reacted with an amino-derivative of formula (28) using a palladium catalyst, for example, tris (dibenzylideneacetone) dipalladium (0)), Xantphos and a base, for example sodium tert-butoxide, in a suitable solvent, for example dioxane, to give the (trans) -cyclopropyl carbamic acid tert-butyl ester derivative of formula (29). Deprotection of the Boc-group of compound (29) under acidic conditions, e.g. using HCl2M in a suitable solvent such as diethyl ether, results in the formation of a (trans) -cyclopropylamine derivative of formula (30), which corresponds to a compound of formula I, wherein B ═ L-E, R ═ L-E^w、R^x、R^y、R^zH, L is-NH-or- (CH)₂)_x-NH-。

Formula (1, wherein R¹Br), amines of formula (28) and ketones of formula (8) are commercially available or can be prepared using well-known synthetic methods starting from readily available starting materials.

For example, compounds of formula I, wherein R is^wF. This process is used to obtain compounds having trans-or cis-configuration (i.e. where the B-a-and-NH-D groups are trans or cis configuration) on the cyclopropyl ring or mixtures thereof, since the cyclopropanation reaction used gives a mixture of cis/trans isomers, as indicated by the wavy lines in scheme 6, which can be used as such to obtain the compounds of the invention as a cis/trans mixture, or which can be separated at the end of the synthesis, if desired, to give the desired cis or trans product.

Scheme 6: boc₂O (di-tert-butyl dicarbonate), DCE (dichloroethane), DPPA (diphenylphosphoryl azide), Cu (acac)₂(copper (II) acetylacetonate)), NBS (N-bromosuccinimide).

Bromofluorination of the derivative of formula (31) using N-bromosuccinimide and triethylamine trihydrofluoride in a suitable solvent such as dichloromethane results in the formation of the fluoro-derivative of formula (32). Elimination using a base such as potassium tert-butoxide in a suitable solvent such as pentane affords the fluoro-derivative of formula (33). Cyclopropanation using ethyl diazoacetate and copper (II) acetylacetonate as catalysts in a suitable solvent such as dichloromethane gives a 1: 1 mixture of cis-and trans-derivatives of formula (34). The diastereoisomers may be isolated by recrystallisation of the corresponding carboxylic acids of formula (35) either as chromatography or after saponification (carried out under basic conditions, e.g. using NaOH in a suitable solvent, e.g. MeOH). Curtius degradation of Boc-protected cyclopropylamines of formula (36) can be carried out using bases such as triethylamine, diphenylphosphoryl azide and di-tert-butyl dicarbonate in a suitable solvent such as tert-butanol. Deprotection of the Boc-group under acidic conditions, for example using HCl2M in ether in a suitable solvent such as ether or using HCl in 1, 4-dioxane, results in the formation of the cyclopropylamine derivative of formula (37). Reductive alkylation using ketones of formula (8) under the same conditions as disclosed in scheme 1 or 2 results in the formation of cyclopropylamino derivatives of formula (38), which correspond to compounds of formula I, wherein R is^wF. For ketones of formula (8) containing a protected amino group, e.g. a Boc-protected amine (Boc: t-butyloxycarbonyl), an additional deprotection step is required to give compound (38) which is carried out under acidic conditions, e.g. using HCl2M in ether in a suitable solvent, e.g. ether, or using HCl in 1, 4-dioxane.

The compounds of formula (31) and ketones of formula (8) are commercially available or can be prepared starting from readily available starting materials using well-known synthetic methods.

For example, compounds of formula I, wherein R is^wIs H, fluorine or C_1-4Alkyl radical, R^x、R^y、R^zH. The method is used to obtain a compound having trans-or cis-configuration on the cyclopropyl ring (i.e., wherein the B-A-and-NH-D groupsIn the trans or cis configuration) in which R is^wOther than hydrogen, and compounds of formula I having the cis configuration, wherein R^w、R^x、R^y、R^zBecause the cyclopropanation reaction used gives a mixture of cis/trans isomers, as represented by the wavy lines in scheme 7, it can be isolated to give the desired cis or trans compounds of the invention.

Scheme 7: DCE (dichloroethane)

Cyclopropanation of the derivative of formula (39) using ethyl diazoacetate and copper (I) chloride as catalysts in a suitable solvent such as chloroform gives a 1: 1 mixture of cis-and trans-derivatives of formula (40). Alternatively, copper catalysis as disclosed in scheme 6 can be used. The diastereoisomers may be isolated by recrystallisation of the corresponding carboxylic acids of formula (41) either as chromatography or after saponification (carried out under basic conditions, e.g. using NaOH in a suitable solvent, e.g. MeOH). The cyclopropanecarbonyl azide derivative of formula (42) can be obtained by first Curtius degradation of Boc-protected cyclopropylamines of formula (43) using ethyl chloroformate and a base such as triethylamine in a suitable solvent such as acetone, followed by reaction with sodium azide in water. Reaction with tert-butanol results in the formation of Boc-protected cyclopropylamines of formula (43).

Under acidic conditions, e.g. using HCl in 1, 4-dioxane in a suitable solvent, e.g. 1, 4-dioxane or HCl in Et₂Et was used as O solution₂Deprotection of the Boc-group using O as a solvent results in the formation of the cyclopropylamine derivative of formula (44). Reductive alkylation with ketones of formula (8) under the same conditions as disclosed in scheme 1 results in the formation of the cyclopropylamino derivative of the invention, designated compound of formula (45) in the above scheme. To the extent that the ketone of formula (8) contains a protected amino group, for example, a Boc-protected amine (Boc:t-butyloxycarbonyl) group, requiring an additional deprotection step, compound (45) is obtained which can be used under acidic conditions, e.g. using HCl in 1, 4-dioxane in a suitable solvent, e.g. 1, 4-dioxane or HCl in Et₂Et was used as O solution₂O is carried out as a solvent.

The compounds of formula (39) and ketones of formula (8) are commercially available or can be prepared starting from readily available starting materials using well known synthetic methods.

For example, compounds of formula I, wherein B ═ L-E, R^w、R^x、R^y、R^zH, L is a bond.

Scheme 8: ACN (acetonitrile), DCE (dichloroethane), DMSO (dimethyl sulfoxide), THF (tetrahydrofuran)

The (trans) -cyclopropylcarbamic acid tert-butyl ester derivative of formula (6) obtained by the same method as disclosed in scheme 4 is converted into the (trans) -cyclopropylamine derivative of formula (47) by reacting the boronic acid or ester derivative of formula (46) with a suitable solvent such as acetonitrile and water, a base such as potassium carbonate and a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0). Deprotection of the Boc-group under acidic conditions, for example using HCl in 1, 4-dioxane in a suitable solvent, for example 1, 4-dioxane, results in the formation of the (trans) -cyclopropylamine derivative of formula (48). Reductive alkylation with ketones of formula (8) under the same conditions as disclosed in scheme 1 leads to the formation of (trans) -cyclopropylamino derivatives of formula (49), which correspond to compounds of formula I, wherein B ═ L-E, R^w、R^x、R^y、R^zH, L is a bond. When the ketone of formula (8) contains a protected amino group, such as a Boc-protected amine (Boc: t-butyloxycarbonyl), an additional deprotection step is required to afford compound (49). This deprotection can be carried out under acidic conditions, e.g. 1, 4-dioxan using HClAlkane solutions in a suitable solvent such as 1, 4-dioxane or HCl Et₂Et was used as O solution₂O is carried out as a solvent.

Alternatively, (trans) -cyclopropylamino derivatives of formula (49) may be synthesized by removing the Boc-group of the (trans) -cyclopropylcarbamic acid tert-butyrate ester derivatives of formula (6) under acidic conditions, e.g. using HCl in a suitable solvent such as 1, 4-dioxane, to give (trans) -cyclopropylamine derivatives of formula (7). Reductive alkylation with ketones of formula (8) in a suitable solvent such as dichloroethane or methanol using, for example, sodium triacetoxyborohydride or sodium borohydride as reducing agent under the same conditions as disclosed in scheme 1 or 2 results in the formation of (trans) -cyclopropylamino derivatives of formula (9). Reaction of (9) with di-tert-butyl dicarbonate under basic conditions, e.g., using triethylamine, in a suitable solvent, e.g., tetrahydrofuran, affords the Boc-protected derivative of formula (27). They are converted to (trans) -cyclopropylamine derivatives of formula (50) by reaction with a commercially available boronic acid or ester derivative of formula (46) using a suitable solvent such as acetonitrile and water, a base such as potassium carbonate and a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0). Under acidic conditions, e.g. using HCl in 1, 4-dioxane in a suitable solvent, e.g. 1, 4-dioxane or HCl in Et₂Et was used as O solution₂O as a solvent to remove the Boc-group, resulting in the formation of the (trans) -cyclopropylamine derivative of formula (49).

The aldehydes of formula (1), boronic acids or ester derivatives of (46) and ketones of formula (8) are commercially available or can be prepared starting from readily available starting materials using well-known synthetic methods.

In addition, some compounds of the invention can be obtained from other compounds of formula I by appropriate interconversion of functional groups present on the compounds of formula I in one or several steps using reactions well known in organic synthesis under standard experimental conditions. The transformation may be to R¹、R²Or R³And include, for example, conversion of amines to amides, sulfonates, by reduction of nitro groups to amines by treatment of substituted primary or secondary amines or alcohols with alkylating agentsAmides, sulfonamides, carbamates, or ureas, palladium-catalyzed cross-coupling of amines with aryl halides, and the like. This interconversion reaction may be carried out on the compound of formula I and any suitable synthetic intermediate described in the schemes above.

Salts of the compounds of formula I may be obtained during the final isolation and purification of the compounds of the invention or may be prepared by treating the compounds of formula I with a sufficient amount of the desired acid (or base) to obtain the salts in a conventional manner.

In schemes 2-5 and 8 above, cyclopropanation under the disclosed conditions consistently yielded racemic mixtures of the trans-isomers of compounds (3), (11), (15) and (22). If the synthesis is carried out continuously using the trans-racemic mixture thus obtained, the corresponding compound of the formula I is obtained as a mixture of trans-isomers. Likewise, in schemes 6 and 7, cyclopropanation under the disclosed conditions yielded a mixture of cis/trans isomers of compounds (34) and (40). If the synthesis process is continued using said mixture of isomers, the corresponding compound of formula I is obtained as a mixture of cis/trans isomers, cis and trans as used herein referring to the arrangement of the group-A-B relative to-NH-D on the cyclopropyl ring.

If the process for the preparation of the compounds of the invention gives mixtures of stereoisomers, the individual stereoisomers of the compounds of the formula I can be isolated from the compounds of the formula I obtained as mixtures of stereoisomers by using well-known methods, for example by salt formation with optically active acids, followed by fractional crystallization and regeneration of the free base or by chiral preparative chromatography to form diastereomeric pairs. Alternatively, optically pure or enantiomerically enriched synthetic intermediates can be obtained, which can then be used as such for the subsequent steps of the different stages of the above synthetic methods using any known method for chiral resolution. Preferably, the trans-cyclopropylamines of formula (7), (19), (25), (37) or (48) are subjected to chiral separation. For example, isolation may also be carried out on a compound of formula (34) or (40) at a further stage of the process. To obtain(7) Suitable methods for the enantiomers of trans-cyclopropylamines of (19), (25), (37) and (48) include contacting trans-substituted cyclopropylamine with a chiral recrystallization reagent in a solvent, particularly under conditions sufficient to crystallize the chiral recrystallization reagent and the salt of trans-substituted cyclopropylamine; and separating the chiral recrystallization reagent and the crystalline salt of the trans-substituted cyclopropylamine, thereby preparing an enantiomer of the trans-N-substituted cyclopropylamine. Suitable chiral recrystallization reagents are S (+) mandelic acid, D (-) tartaric acid, L (+) tartaric acid, L (-) di-p-toluoyltartaric acid or R (-) mandelic acid. Suitable solvents are tetrahydrofuran, ethanol or their reaction with H₂A mixture of O.

Alternatively, one skilled in the art can obtain optically pure or enantiomerically enriched final compounds (or synthetic intermediates) by using chiral chromatography.

Examples

Unless otherwise indicated, in the compounds of all examples in this specification, stereochemical configuration is defined by the chemical names indicated for the respective compounds, however, the structures drawn may represent a plurality of specific configurations. However, the present invention relates to all stereoisomers of the compounds described and defined herein. The invention therefore includes the compounds defined in the examples by their chemical name and, in addition, also compounds having the absolute configuration shown in the corresponding drawn structure.

The following abbreviations are used:

ACN: acetonitrile, AcOH: acetic acid, aq: aqueous solution, Boc: tert-butyloxycarbonyl, (Boc)₂O: di-tert-butyl dicarbonate, brm: broad multiplet, brs: broad singlet, Cu (acac)₂: copper acetylacetonate (II), d: bimodal, DCE: 1, 2-dichloroethane, DCM: dichloromethane, DMF: n, N-dimethylformamide, DMSO: dimethylsulfoxide, DPPA: diphenylphosphoryl azide, Et₂O: ether, EtOAc: ethyl acetate, HPLC: high performance liquid chromatography, m:multiplet, MEM: methoxymethyl ether, MeOH: methanol, NBS: n-bromosuccinimide, NMR: nuclear magnetic resonance, Pd₂(dba)₃: tris (dibenzylideneacetone) dipalladium (O), petother: petroleum ether, q: quartet, Rf: retention factor, RT: room temperature, s: singlet, sat.: saturation, t: triplet, TEA: triethylamine, THF: tetrahydrofuran, TLC: thin layer chromatography, Xantphos: 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene.

An intermediate A: 1- (benzyloxy) -4- [ (trans) -2-nitrocyclopropyl ] benzene

Trimethylsulfoxonium iodide (0.62g, 2.82mmol) was added portionwise to a solution of t-BuOK (0.32g, 2.82mmol) in dry DMSO (5 mL). After 10min, the 1- (benzyloxy) -4- [ (E) -2-nitrovinyl group was transferred through cannula]A solution of benzene (0.60g, 2.35mmol) in DMSO (5mL) was stirred at room temperature for 6 h. The reaction was poured into water (10mL) and treated with Et₂O (3 × 10 mL); the organic layer was washed with brine (2 × 15mL) and anhydrous Na₂SO₄Drying and filtering. After removal of the solvent, the residual orange oil was purified by silica gel column chromatography (5% EtOAc/hexane) to give 0.16g of 1- (benzyloxy) -4- [ (trans) -2-nitrocyclopropyl]Benzene [ Rf ═ 0.5 (20% EtOAc/hexanes), white solid, 26% yield]。

An intermediate B: trans-2- [4- (benzyloxy) phenyl ] cyclopropylamines

Zn powder (1.97g, 30mmol) was added in small portions over a period of 30min to a vigorously stirred 1- (benzyloxy) -4- [ (trans) -2-nitrocyclopropyl]Benzene (intermediate A, 0.81g, 3.0mmol) in a solution of i-PrOH (25mL) and HCl (11mL aq, 2.7N, 30 mmol). After 17h, the mixture was passedThe filter was washed with 10mL of methanol and then filtered through a pad of Celite. The filtrate was concentrated, 10mL of water was added, and CH was used₂Cl₂(3 × 15mL) washing. With anhydrous Na₂SO₄The organic layer was dried and filtered. After removal of the solvent, the crude product was purified by silica gel column chromatography (10% MeOH/CH)₂Cl₂) To give 0.50g of (trans) -2- [4- (benzyloxy) phenyl]Cyclopropylamine [ Rf ═ 0.2 (10% MeOH/CH)₂Cl₂) White solid, 70% yield]。

¹H-NMR(MeOH，250MHz，)：7.45-7.27(m，5H，ArH)；6.96(d，J＝8.5Hz，2H，ArH)；6.86(d，J＝8.5Hz，2H，ArH)；5.03(s，2H，CH2)；2.41-2.34(m，1H，CH)；1.86-1.76(m，1H，CH)；0.98-0.85(m，2H，CH2)。

An intermediate C: 4- (benzyloxy) benzaldehyde

Potassium carbonate (678g, 4.91mol) was added to a solution of 4-hydroxybenzaldehyde (200g, 1.63mol) in DMF (2L), followed by benzyl bromide (214mL, 1.80mol) at 0 ℃ and stirring at RT for 18 h. After completion, the reaction mixture was poured into ice water (3L), the solid was filtered and dried to give 4- (benzyloxy) benzaldehyde (230g, 66%).

An intermediate D: (E) -ethyl 3- (4- (benzyloxy) phenyl) acrylate

Triethyl phosphonoacetate (259mL, 1.3mol) was slowly added dropwise to a solution of potassium tert-butoxide (145g, 1.29mol) in dry THF (2L) at-5 deg.C, stirring for 30-45 mins. A solution of 4- (benzyloxy) benzaldehyde (intermediate C, 230g, 1.08mol) in dry THF (1.5L) was then slowly added dropwise over a period of 15mins at-10 ℃ and stirred for 30 mins. After completion, the reaction mixture was poured into ice water (1L) and washed with EtOAc (2X)1.5L) of the extract. With saturated NaHCO₃The combined organic extracts were washed with solution (1L), water (1L), brine (1L), and anhydrous Na₂SO₄Drying, filtration and evaporation gave crude (E) -ethyl 3- (4- (benzyloxy) phenyl) acrylate (290g, 95%). The crude product was used in the next step without further purification.

Intermediate E: 2- (4- (benzyloxy) phenyl) cyclopropanecarboxylic acid (trans) -ethyl ester

Trimethylsulfoxonium iodide (224g, 1.02mol) was added portionwise over a 20min period at RT to a suspension of NaH (40.8g, 1.02mol) in dry DMSO (2L) and stirred for 1h until a clear solution formed. A solution of (E) -ethyl 3- (4- (benzyloxy) phenyl) acrylate (intermediate D, 240g, 0.85mol) in dry DMSO (2L) was added dropwise and stirred at RT for 30 mins. After completion, the reaction mixture was poured into ice water (2L) and extracted with EtOAc (2 × 1L). The combined organic extracts were washed with ice water (1L), brine (1L), and anhydrous Na₂SO₄Drying, filtration and evaporation gave (trans) -ethyl 2- (4- (benzyloxy) phenyl) cyclopropanecarboxylate (142g, 58.6%) as an off-white solid. The crude product was used in the next step without further purification.

An intermediate F: (trans) -2- (4- (benzyloxy) phenyl) cyclopropanecarboxylic acid

4N NaOH (4L) was added to a solution of 2- (4- (benzyloxy) phenyl) cyclopropanecarboxylic acid (trans) -ethyl ester (intermediate E, 250g, 0.844mol) in methanol (1.2L) at 0 ℃ and stirred at RT for 4 h. Upon completion, the solvent was evaporated, the residue diluted with water (1L), acidified with 4N HCl solution and extracted with EtOAc (2 × 2L). The combined organic extracts were washed with water (1L), brine (1L), and anhydrous Na₂SO₄Drying, filtration and evaporation gave (trans) -2- (4- (benzyloxy) phenyl) cyclopropanecarboxylic acid (190g, 84%) as an off-white solid. The crude product was used in the next step without further purification.

Intermediate G: (trans) -2- (4- (benzyloxy) phenyl) cyclopropanecarbonyl azide

Ethyl chloroformate (143mL, 1.48mol) was added to a solution of (trans) -2- (4- (benzyloxy) phenyl) cyclopropanecarboxylic acid (intermediate F, 190g, 0.70mol), triethylamine (229mL, 1.63mol) in acetone (2.8L) at-20 deg.C and stirred for 1h, followed by a solution of NaN3(138g, 2.1mol) in water (200mL) and stirred at RT for 30 mins. After completion, the solvent was evaporated and the residue was dissolved in EtOAc (2L), washed with water (2L), brine (1L) and dried over anhydrous Na₂SO₄Drying, filtration and evaporation gave (trans) -2- (4- (benzyloxy) phenyl) cyclopropanecarbonyl azide (178g, 85.9%).

Intermediate H: ((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) carbamic acid tert-butyl ester

A solution of (trans) -2- (4- (benzyloxy) phenyl) cyclopropanecarbonyl azide (intermediate G, 178G, 0.64mol) in tert-butanol (2.6L) was heated at 90 ℃ for 16 h. After completion, the solvent was evaporated by using (SiO)₂) EtOAc: the crude residue was purified by column chromatography on petroleum ether (4: 96) to give tert-butyl ((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) carbamate (78g, 37.8%) as an off-white solid.

Intermediate I: 3- (6-Bromopyridin-3-yl) acrylic acid (E) -ethyl ester

Triethyl phosphonoacetate (26.6g, 118.8mmol) was slowly added dropwise to a mixture of potassium tert-butoxide (14.5g, 129.6mmol) in dry THF (200mL) at-5 deg.C with stirring for 20min, followed by a solution of 6-bromopyridine-3-carbaldehyde (20g, 108mmol) in dry THF (100mL) slowly added dropwise at-5 deg.C with stirring for 30 min. After completion, the reaction mixture was poured into ice water (350mL) and extracted with EtOAc (2 × 300 mL). With saturated NaHCO₃The combined organic extracts were washed with Na, water (250mL), and brine (250mL)₂SO₄Dried anhydrous, filtered and evaporated to give (E) -ethyl 3- (6-bromopyridin-3-yl) acrylate (20g, 72.9%) as a brown liquid. It was used in the next step without further purification.

Intermediate J: (trans) -ethyl-2- (6-bromopyridin-3-yl) cyclopropanecarboxylate

Trimethylsulfoxonium iodide (20.8g, 94.7mmol) was added in small portions to a solution of sodium hydride (4g, 170.6mmol) in dry DMSO (400mL) at rt. and stirred for 1h until a clear solution was obtained. A solution of (E) -ethyl 3- (6-bromopyridin-3-yl) acrylate (intermediate I, 20g, 78.7mmol) in dry DMSO (20mL) was added and stirred for 4 h. After completion, the reaction mixture was poured into ice water (700mL) and extracted with EtOAc (2 × 350 mL). The combined organic extracts were washed with water (250mL), brine (250mL), and anhydrous Na₂SO₄Drying, filtration and evaporation gave (trans) -ethyl-2- (6-bromopyridin-3-yl) cyclopropanecarboxylate (10g, 47%) as a brown liquid.

An intermediate K: (trans) -2- (6-bromopyridin-3-yl) cyclopropane formate salt

NaOH4N solution (60mL) was added to a solution of (trans) -ethyl-2- (6-bromopyridin-3-yl) cyclopropanecarboxylate (intermediate J, 10g, 37.1mmol) in methanol (100mL) and the reaction mixture was stirred at RT for 4 h. Upon completion, the solvent was evaporated, the residue diluted with ice water (250mL), acidified with 4N HCl solution, and the aqueous layer extracted with EtOAc (2 × 350 mL). The combined organic extracts were washed with water (250mL), brine (250mL), and anhydrous Na₂SO₄Drying, filtration and evaporation gave (trans) -2- (6-bromopyridin-3-yl) cyclopropane formate (5g, 55.8%) as a light brown solid.

Intermediate L: (trans) -2- (6-bromopyridin-3-yl) cyclopropanecarbonyl azide

Ethyl chloroformate (5.8mL, 62mmol) was added to (trans) -2- (6-bromopyridin-3-yl) cyclopropane formate salt (intermediate K, 5g, 20.7mmol) and Et at-5 deg.C₃N (14,2mL, 103.7mmol) in acetone (100mL), then the reaction mixture was stirred at-5 ℃ for 1h, then NaN was added₃A solution of (2.7g, 41.4mmol) in water (10mL) was stirred at RT for 30 mins. After evaporation of the solvent in vacuo, the crude residue was dissolved in ethyl acetate (200mL), washed with water (80mL), brine (80mL), and dried over anhydrous Na₂SO₄Drying, filtration and evaporation gave (trans) -2- (6-bromopyridin-3-yl) cyclopropanecarbonyl azide (2.5g, 45.5%) as a brown gummy liquid.

An intermediate M: (trans) -2- (6-Bromopyridin-3-yl) cyclopropylcarbamic acid tert-butyl ester

Reacting (trans) -2- (6-bromopyridin-3-yl) cyclopropanecarbonyl azideA solution of the compound (intermediate L, 2.5g, 9.36mmol) in t-butanol (80mL) was heated at 90 ℃ for 16 h. Upon completion, the solvent was evaporated in vacuo and the residue was dissolved in water (100mL) and extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with water (100mL), brine (100mL), and anhydrous Na₂SO₄Drying, filtering and evaporating. The crude residue (SiO) was purified by flash column chromatography₂) The reaction was performed with EtOAc: hexane (2: 8) gave tert-butyl (trans) -2- (6-bromopyridin-3-yl) cyclopropylcarbamate (1.1g, 37.5%) as a pale yellow solid.

¹H-NMR(CDCl₃)(ppm)：1.16(q，1H)，1.23(quin，1H)，1.45(s，9H)，2.01(m，1H)，2.69(m，1H)，4.88(br，1H)，7.36(s，2H)，8.20(s，1H)。

An intermediate N: 3- (4-bromophenyl) acrylic acid (E) -ethyl ester

Triethyl phosphonoacetate (13.1g, 0.0589mol) was added slowly (dropwise) to a solution of potassium tert-butoxide (6.59g, 0.0589mol) in dry THF (150mL) at-5 deg.C, stirred at the same temperature for 30-45mins, then a solution of 4-bromobenzaldehyde (10g, 0.054mol) in dry THF (50mL) was added slowly dropwise over a 15mins period at-5 deg.C, and the reaction mixture stirred at the same temperature for 30 mins. After completion of the reaction by TLC, the reaction mixture was poured into ice water (300mL) and extracted with EtOAc (2 × 200 mL). With saturated NaHCO₃The combined organic extracts were washed with solution (200mL), water (200mL), brine (200mL), and anhydrous Na₂SO₄Drying, filtration and evaporation gave crude (E) -ethyl 3- (4-bromophenyl) acrylate (10g, 72%) as a pale green liquid. It was used in the next step without further purification.

Intermediate O: 2- (4-bromophenyl) cyclopropanecarboxylic acid (trans) -ethyl ester

Trimethylsulfoxonium iodide (5.19g, 0.0236mol) was slowly added in small portions to a suspension of sodium hydride (0.44g, 0.0236mol) in dry DMSO (80mL) at rt over a 20min. A solution of (E) -ethyl 3- (4-bromophenyl) acrylate (intermediate N, 5g, 0.01968) in dry DMSO (20mL) was then slowly added dropwise with stirring at RT for 30 mins. After completion of the reaction was checked by TLC, the reaction mixture was poured into ice water (200mL) and extracted with EtOAc (2 × 150 mL). The combined organic extracts were washed with ice water (2X150mL), brine (150mL), anhydrous Na₂SO₄Drying, filtration and evaporation gave (trans) -ethyl 2- (4-bromophenyl) cyclopropanecarboxylate (4g, 75.9%) as a green liquid. The crude product was used in the next step without further purification.

An intermediate P: (trans) -2- (4-bromophenyl) cyclopropanecarboxylic acid

NaOH4N (20mL) was added to a solution of 2- (4-bromophenyl) cyclopropanecarboxylic acid (trans) -ethyl ester (intermediate O, 4g, 0.0149mol) in methanol (40mL) and stirred at RT for 2 h. After completion of the reaction by TLC, the solvent was evaporated, the residue was diluted with water (50mL), acidified with HCl4N solution, and the solid formed was filtered and dried to give (trans) -2- (4-bromophenyl) cyclopropanecarboxylic acid (2.59g, 72%) as a white solid.

Intermediate Q: (trans) -2- (4-bromophenyl) cyclopropanecarbonyl azide

Ethyl chloroformate (1.9mL) was added to (trans) -2- (4-bromophenyl) cyclopropanecarboxylic acid (intermediate P, 4g,0.0165mol) and Et₃N (2.51mL, 0.0199mol) in acetone (60mL) was stirred at the same temperature for 1h, then NaN was added₃A solution of (1.3g, 0.0199mol) in water (5mL) was stirred at rt for 30 mins. After completion of the reaction by TLC detection, the solvent was evaporated, the crude residue was dissolved in ethyl acetate (100mL), washed with water (40mL), and dried over anhydrous Na₂SO₄Drying, filtration and evaporation gave (trans) -2- (4-bromophenyl) cyclopropanecarbonyl azide (4 g). The crude residue was used in the next step without further purification.

Intermediate R: (trans) -2- (4-bromophenyl) cyclopropylcarbamic acid tert-butyl ester

A solution of (trans) -2- (4-bromophenyl) cyclopropanecarbonyl azide (intermediate Q, 4g) in t-butanol (40mL) was heated at 90 ℃ for 16 h. After completion of the reaction was checked by TLC, the solvent was evaporated and the residue was poured into water (50mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with water (50mL), brine (50mL), and anhydrous Na₂SO₄Drying, filtering and evaporating. By column chromatography (SiO)₂) The crude residue was purified with EtOAc: petroleum ether (2: 98) gave tert-butyl (trans) -2- (4-bromophenyl) cyclopropylcarbamate (2.5g, 48%, over 2 steps) as a white solid.

¹H-NMR(CDCl₃，250MHz)：1.07-1.19(m，2H)，1.44(s，9H)；2.05-1.94(m，1H)；2.72-2.62(m，1H)；4.85(br，1H，)；7.09-6.96(m，2H)；7.44-7.33(m，2H)。

An intermediate S: (E) -ethyl 3- (pyridin-3-yl) acrylate

Phosphonyl is carried out at-5 ℃ within a period of 10minsA triethyl acetate solution (66.75mL, 336.44mmol) was added dropwise to a solution of potassium tert-butoxide (37.7g, 280.37mmol) in dry THF (300mL) and stirred at 0 deg.C for 30 mins. A solution of nicotinaldehyde (30g, 280.37mmol) in dry THF (50mL) was then added dropwise over a 15mins period at 0 ℃ and stirred at RT for 2 h. After completion, the reaction mixture was poured into ice water (150ml) and extracted with EtOAc (2 × 300 mL). With saturated NaHCO₃The combined extracts were washed with solution (200mL), water (200mL), brine (200mL), and anhydrous Na₂SO₄Drying, filtration and evaporation gave crude liquid (E) -ethyl 3- (pyridin-3-yl) acrylate (42g, 84.67%). The crude product was used in the next step without further purification.

An intermediate T: 2- (pyridin-3-yl) cyclopropanecarboxylic acid (trans) -ethyl ester

Trimethylsulfoxonium iodide (14.90g, 67.76mmol) was added portionwise to a suspension of NaH (2.71g, 67.76mmol) in dry DMSO (100mL) at RT over a 20min. A solution of (E) -ethyl 3- (pyridin-3-yl) acrylate (intermediate S, 10g, 56.47mmol) in dry DMSO (50mL) was added dropwise and stirred at RT for 20min. After completion, the reaction mixture was poured into ice water (200mL) and extracted with EtOAc (2 × 200 mL). The combined organic extracts were washed with ice water (150mL), brine (150mL), and anhydrous Na₂SO₄Drying, filtration and evaporation gave (trans) -ethyl 2- (pyridin-3-yl) cyclopropanecarboxylate (4g, 37.07%) as a light brown liquid. The crude product was used in the next step without further purification.

An intermediate U: (trans) -2- (pyridin-3-yl) cyclopropanecarboxylic acid

NaOH (7.116g in 45mL H at 0 deg.C₂O, 177.92mmol) was added to a solution of 2- (pyridin-3-yl) cyclopropanecarboxylic acid (trans) -ethyl ester (intermediate T, 17g, 88.96mmol) in methanol (170mL) and stirred at RT for 16 h. Upon completion, the solvent was evaporated, the residue diluted with water (50mL), neutralized with acetic acid, and extracted with EtOAc (4 × 100 mL). The combined organic extracts were washed with water (100mL), brine (100mL), and anhydrous Na₂SO₄Drying, filtration and evaporation gave (trans) -2- (pyridin-3-yl) cyclopropanecarboxylic acid (9g, 62.06%) as an off-white solid. The crude product was used in the next step without further purification.

An intermediate V: (trans) -2- (pyridin-3-yl) cyclopropanecarbonyl azides

Ethyl chloroformate (6.89mL, 71.15mmol) was added to a solution of (trans) -2- (pyridin-3-yl) cyclopropanecarboxylic acid (intermediate U, 9g, 55.194mmol) and triethylamine (11.03mL, 82.79mmol) in acetone (90mL) at-20 deg.C, stirred for 1h, then NaN was added₃A solution of (5.38g, 82.79mmol) in water (25mL) was stirred at RT for 30 mins. After completion, the solvent was evaporated and the residue was dissolved in EtOAc (100mL), washed with water (2 × 50mL), brine (50mL), and dried over anhydrous Na₂SO₄Drying, filtration and evaporation gave (trans) -2- (pyridin-3-yl) cyclopropanecarbonyl azide (8.4g, 81%). The crude product was used in the next step without further purification.

Intermediate W: ((trans) -2- (pyridin-3-Yl) cyclopropyl) carbamic acid tert-butyl ester

A solution of (trans) -2- (pyridin-3-yl) cyclopropanecarbonyl azide (intermediate V, 8.4g, 44.66mmol) in t-butanol (85mL) was heated at 90 ℃ for 16 h. After completion, the solvent was evaporated and purified by column chromatography (Si)O₂) Using EtOAc: the crude residue was purified with petroleum ether (25: 75) to give tert-butyl (trans) -2- (pyridin-3-yl) cyclopropylcarbamate (3.9g, 37.32%) as a colorless liquid.

An intermediate X: (trans) -2- (pyridin-3-yl) cyclopropylamine hydrochloride

Reacting HCl at 0 deg.CAn alkane solution (10mL) was added to (trans) -tert-butyl 2- (pyridin-3-yl) cyclopropylcarbamate (intermediate W, 2g, 8.541mmol) in 1, 4-bisA solution in alkane (10mL) was stirred at RT for 12 h. Upon completion, the solvent was evaporated and the residue was triturated with ether (20mL) then hexanes (20mL) to give (trans) -2- (pyridin-3-yl) cyclopropylamine hydrochloride (1.2g, 82.7%).

Intermediate Y: 3- (Thiazol-5-yl) acrylic acid (E) -ethyl ester

A triethyl phosphonoacetate solution (11.88g, 53.03mmol) was added dropwise to a solution of potassium tert-butoxide (5.94g, 53.03mmol) in dry THF (100mL) at-5 deg.C and stirred for 30 mins. A solution of thiazole-5-carbaldehyde (5g, 44.19mmol) in dry THF (25mL) was then added dropwise over a 15mins period at-5 ℃ and stirred for 30 mins. After completion, the reaction mixture was poured into ice water (150mL) and extracted with EtOAc (2 × 100 mL). With saturated NaHCO₃The combined extracts were washed with solution (100mL), water (100mL), brine (100mL), and anhydrous Na₂SO₄Drying, filtration and evaporation gave crude (E) -ethyl 3- (thiazol-5-yl) acrylate (10g,82.3%) as a white solid. The crude product was used in the next step without further purification.

An intermediate Z: 2- (Thiazol-5-Yl) cyclopropanecarboxylic acid (trans) -ethyl ester

Trimethylsulfoxonium iodide (14.40g, 65.49mmol) was added dropwise over a 20min period at RT to a suspension of NaH (2.61g, 108.75mmol) in dry DMSO (200mL) and stirred for 1h until a clear solution formed. A solution of (E) -ethyl 3- (thiazol-5-yl) acrylate (intermediate Y, 10g, 54.57mmol) in dry DMSO (50mL) was then added dropwise and stirred at RT for 30 mins. After completion, the reaction mixture was poured into ice water (100mL) and extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with water (2 × 50mL), brine (50mL), and anhydrous Na₂SO₄Drying, filtration and evaporation gave 2- (thiazol-5-yl) cyclopropanecarboxylic acid trans-ethyl ester (8g, 61.9%) as a tan liquid. The crude product was used in the next step without further purification.

Intermediate AA: (trans) -2- (thiazol-5-yl) cyclopropanecarboxylic acid

A4N NaOH solution (40mL) was added to a solution of 2- (thiazol-5-yl) cyclopropanecarboxylic acid trans-ethyl ester (intermediate Z, 8g, 40.55mmol) in methanol (80mL) and stirred at RT for 4 h. Upon completion, the solvent was evaporated, the residue diluted with water (50mL), acidified with acetic acid and extracted with EtOAc (2 × 75 mL). The combined extracts were washed with water (50mL), brine (50mL), and anhydrous Na₂SO₄Drying, filtration and evaporation gave trans-2- (thiazol-5-yl) cyclopropanecarboxylic acid (4g, 58.30%). The crude product was used in the next step without further purification.

An intermediate AB: (trans) -2- (thiazol-5-yl) cyclopropanecarbonyl azide

Ethyl chloroformate (3-34g, 30-76mmol) was added to a solution of trans-2- (thiazol-5-yl) cyclopropanecarboxylic acid (intermediate AA, 4g, 26.3mmol) and triethylamine (3.62g, 35.50mmol) in acetone (40mL) at-20 deg.C and stirred at the same temperature for 1 h. Then adding NaN₃A solution of (2.84g, 47.33mmol) in water (10mL) was stirred at RT for 30 mins. After completion, the solvent was evaporated, the crude residue was dissolved in EtOAc (100mL), washed with water (50mL), brine (50mL), and dried over anhydrous Na₂SO₄Drying, filtration and evaporation gave trans-2- (thiazol-5-yl) cyclopropanecarbonyl azide (3g, 58.7%) as a brown liquid. The crude product was used in the next step without further purification.

An intermediate AC: ((trans) -2- (Thiazol-5-Yl) cyclopropyl) carbamic acid tert-butyl ester

A solution of trans-2- (thiazol-5-yl) cyclopropanecarbonyl azide (intermediate AB, 3g, 15.44mmol) in t-butanol (60mL) was heated at 90 ℃ for 16 h. Upon completion, the solvent was evaporated, the residue was dissolved in water (50mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with water (50mL), brine (50mL), and anhydrous Na₂SO₄Drying, filtering and evaporating. By using EtOAc: column chromatography (SiO) of petroleum ether (20: 80)₂) The crude residue was purified to give tert-butyl trans-2- (thiazol-5-yl) cyclopropylcarbamate (1.1g, 29.64%) as a light yellow liquid.

Intermediate AD: (trans) -2- (thiazol-5-yl) cyclopropylamine hydrochloride

Reacting HCl at 15 deg.CAn alkane solution (10mL) was added to trans-2- (thiazol-5-yl) cyclopropylcarbamic acid tert-butyl ester (intermediate AC, 1.1g, 45.83mmol) in bisTo a solution in alkane solution (10mL) was stirred at RT for 3 h. Upon completion, the solvent was evaporated and the residue triturated with EtOAc to give trans-2- (thiazol-5-yl) cyclopropylamine hydrochloride (600mg, 74.8%) as a light yellow solid.

Intermediate AE: ((trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropyl) carbamic acid tert-butyl ester

(trans) -tert-butyl 2- (6-bromopyridin-3-yl) cyclopropylcarbamate (intermediate M, 100mg, 0.32mmol), potassium carbonate (132mg, 0.96mmol) and 3-trifluoromethylphenylboronic acid (72mg, 0.38mmol) in CH₃CN：H₂The solution in O (4: 1) (10mL) was degassed for 30 mins. Tetratriphenylphosphine palladium (37mg, 0.032mmol) was added, degassed 10mins and the reaction mixture heated at reflux temperature for 2 h. After completion, the reaction mixture was poured into ice water (100mL) and extracted with ethyl acetate (5 × 40 mL). The combined extracts were washed with water (70mL), brine (70mL), and anhydrous Na₂SO₄Drying, filtering and evaporating. By using EtOAc: column chromatography (SiO) of petroleum ether (1: 9)₂) The crude residue was purified to give tert-butyl (trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropylcarbamate (70mg, 58.3%) as a white solid.

¹H-NMR(CDCl₃)(ppm)：1.26(m，2H)，1.46(s，9H)，2.10(m，1H)，2.78(m，1H)，4.86(br，1H)，7.55(m，2H)，7.65(t，2H)，8.14(d，1H)，8.24(s，1H)，8.54(s，1H)。MS(M+H)：379.1。

Intermediate AF: (trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropylamine dihydrochloride

A solution of HCl in ether (5Ml) was added slowly dropwise over a 10mins period at 0 deg.C to a solution of tert-butyl (trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropylcarbamate (intermediate AE, 70mg, 0.185mmol) in ether (10mL) and stirred for 2 h. Upon completion, the reaction mixture was filtered under an inert gas atmosphere, washed with hexane (10mL), EtOAC (5mL), and dried under reduced pressure to give (trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropylamine dihydrochloride (50mg, 86.2%) as a pale yellow powder.

¹H-NMR(D₂O)(ppm)：1.52(q，1H)，1.63(quin，1H)，2.66(m，1H)，3.08(m，1H)，7.72(t，1H)，7.89(d，1H)，7.98(d，1H)，8.09(s，1H)，8.14(d，1H)，8.27(d，1H)，8.61(s，1H)。MS(M+H)：279.1。

Intermediate AG: ((trans) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) carbamic acid tert-butyl ester

Tert-butyl (trans) -2- (4-bromophenyl) cyclopropylcarbamate (intermediate R, 1g, 3.2mmol), potassium carbonate (1.31g, 9.6mmol) and 3- (trifluoromethyl) phenylboronic acid (0.73g, 3.8mmol) in acetonitrile: the solution in water (4: 1) was degassed for 30 mins. Tetratriphenylphosphine palladium (36mg, 0.032mmol) was then added, degassed again for 10mins, and the reaction mixture heated at reflux temperature for 5 h. After completion, the reaction mixture was poured into ice water (50mL), extracted with ethyl acetate (2X50 mL). The combined extracts were washed with water (70mL), brine (70mL), and anhydrous Na₂SO₄Dried, then filtered and evaporated. By using EtOAc: column chromatography (SiO) of petroleum ether (2: 8)₂) Purifying the crude residue to obtain ((trans) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl)]-4-yl) cyclopropyl) carbamic acid tert-butyl ester (0.8g, 66%) as a white solid.

Intermediate AH: (trans) -2- (3, - (trifluoromethyl) - [1,1, -biphenyl ] -4-yl) cyclopropylamine hydrochloride

A solution of HCl in diethyl ether (3mL) was added slowly dropwise over a 10min period to a solution of tert-butyl ((trans) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) carbamate (intermediate AG, 200mg, 0.53mmol) in diethyl ether (5mL) at 10 deg.C, then stirred for 4 h. Upon completion, the solvent was evaporated and the residue triturated with hexane (5mL), diethyl ether (5mL) and dried under reduced pressure to give (trans) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropylamine hydrochloride (140mg, 77.8%) as a white solid.

¹H-NMR (DMSO-d6) (ppm): 1.27(q, 1H), 1.46 (quintuple, 1H), 2.41(m, 1H), 2.86(m, 1H), 7.29(d, 2H), 7.69(m, 4H), 7.96(m, 2H), 8.53(s, 1H), 8.61(br, 2H). MS (M + H): 278.3.

intermediate AI: 4, 4-Dimethoxycyclohexanecarboxamide

A solution of HCl in methanol (2mL) was added to a solution of ethyl 4-oxocyclohexanecarboxylate (5g, 29.41mmol) in methanol (2mL) at RT, stirred at RT for 3h, then aqueous ammonia (30mL) was added, heated at 90 ℃ in a sealed tubeAnd (5) 48 h. After completion, the solvent was evaporated. By column chromatography (SiO)₂) The crude product was purified to give 4, 4-dimethoxycyclohexanecarboxamide (1.2g, 31.8%) as a white solid.

Intermediate AJ: 4-oxocyclohexanecarboxamides

P-toluenesulfonic acid (500mg, 2.90mmol) was added to a solution of 4, 4-dimethoxycyclohexanecarboxamide (intermediate AI, 1.2g, 7.36mmol) in acetone-water (1: 1) (20mL) and heated to 60 ℃ for 3 h. After completion, the reaction mixture was poured into ice water (20mL) and extracted with 40% isopropanol in chloroform (3X30 mL). The combined extracts were washed with water, brine, and anhydrous Na₂SO₄Drying, filtering and evaporating. The crude product was washed with 10% dichloromethane in petroleum ether to give 4-oxocyclohexanecarboxamide (410mg, 45.55%) as a white solid.

Intermediate AK: 4-aminocyclohexanone hydrochloride

Reacting HCl at 5 deg.CThe alkane solution (1mL) was added dropwise to a solution of tert-butyl 4-oxocyclohexylcarbamate (200mg, 0.938mmol) in waterA solution in alkane (2mL) was stirred at RT for 6 h. After completion, the solvent was evaporated and the solid residue was taken up with Et₂O (10mL) was triturated together and dried to give 4-aminocyclohexanone hydrochloride (150mg, 100%) as an off-white solid. The crude product was used in the next step without further purification.

Intermediate AL: n- (4-oxocyclohexyl) methanesulfonamides

Methanesulfonyl chloride (1.83g, 16.07mmol) was added dropwise to 4-aminocyclohexanone hydrochloride (intermediate AK, 1.5g, 13.39mmol) and K₂CO₃(6.46g, 46.87mmol) in ACN-THF (1: 1) (30mL) and then stirred at RT for 16 h. Upon completion, the solvent was evaporated, the crude residue diluted with water (50mL) and extracted with EtOAc (2X50 mL). The combined organic extracts were washed with water (50mL), brine (50mL), and anhydrous Na₂SO₄Drying, filtration and evaporation gave N- (4-oxocyclohexyl) methanesulfonamide (990mg, 38.6%) as a white solid.

Intermediate AM: (1- (1, 4-dioxaspiro [ 4.5 ] decan-8-yl) pyrrolidin-3-yl) carbamic acid (R) -tert-butyl ester

1, 4-dioxaspiro [ 4.5 ] decan-8-one (0.76g, 4.88mmol) was added to a solution of pyrrolidin-3-ylcarbamic acid (R) -tert-butyl ester (1.0g, 5.36mmol) in DCE (65mL) and stirred for 15 mins. Sodium triacetoxyborohydride (1.55g, 7.32mmol) was then added at 0 ℃ and stirred at RT for 16 h. Upon completion, the reaction mixture was diluted with DCM (50mL) and saturated NaHCO₃The solution (50mL), water (50mL), brine (50mL) was washed with anhydrous Na₂SO₄Drying, filtering and evaporating. By SiO₂The crude residue was purified by column chromatography using hexane: methyl tert-butyl ether (80: 20) was eluted to give (1- (1, 4-dioxaspiro [ 4.5 ] decan-8-yl) pyrrolidin-3-yl) carbamic acid (R) -tert-butyl ester (1.53g, 96.8%).

Intermediate AN: (R) -4- (3-Aminopyrrolidin-1-yl) Cyclohexanone

1,4 bis HCl at 15 deg.CAn alkane solution (5mL) was added to (1- (1, 4-dioxaspiro [ 4.5 ] decan-8-yl) pyrrolidin-3-yl) carbamic acid (R) -tert-butyl ester (intermediate AM, 1.53g, 8.39mmol) in bisA solution in alkane (25mL) was stirred at RT for 16 h. After completion, saturated Na was added₂CO₃Solution (50mL), evaporate solvent and combine the residue with Et₂O was triturated together and dried to give (R) -4- (3-aminopyrrolidin-1-yl) cyclohexanone (0.61g, 71.5%).

Intermediate AO: (1- (4-Oxocyclohexyl) pyrrolidin-3-yl) carbamic acid (R) -tert-butyl ester

Di-tert-butyl dicarbonate (1.77g, 9.98mmol) was added to a solution of (R) -4- (3-aminopyrrolidin-1-yl) cyclohexanone (0.61g, 3.34mmol) in water (6mL) and stirred at RT for 2 h. Upon completion, the reaction mixture was washed with DCM (50mL) and AcOEt (50 mL). The organic layer was washed with H2O (50mL) and brine (50mL), and dried over anhydrous Na₂SO₄Drying, filtering and evaporating. By SiO₂The crude residue was purified by column chromatography using hexane: methyl tert-butyl ether (80: 20) was eluted to give (1- (4-oxocyclohexyl) pyrrolidin-3-yl) carbamic acid (R) -tert-butyl ester (0.23g, 23.9%).

An intermediate AP: 1-ethyl-3- (4-oxocyclohexyl) urea

Isocyanatoethane (237mg,3.34mmol) and triethylamine (0.85mL, 6.68mmol) were added to a solution of 4-aminocyclohexanone hydrochloride (intermediate AK, 500mg, 3.34mmol) in toluene (5mL) and stirred at 110 ℃ for 16 h. After completion, the solvent was evaporated, and the reaction mixture was purified by using EtOAc: of petroleum ether (3: 7) (SiO)₂) The crude residue was purified by column chromatography to give 1-ethyl-3- (4-oxocyclohexyl) urea (600mg, 98%) as a brown solid.

Intermediate AQ: 4- ((2-methoxyethoxy) methoxy) benzaldehyde

A solution of 4-hydroxybenzaldehyde (50g, 409mmol) in THF (50mL) was slowly added dropwise over a period of 30min at 0 deg.C to a suspension of sodium hydride (19.6g, 817mmol) in THF (750mL), stirred for 15min, then 1- (chloromethoxy) -2-methoxyethane (MEM chloride, 61.10g, 490mmol) was added at 0 deg.C. The reaction mixture was stirred at RT for 30min, after completion, poured into ice water (500mL) and extracted with EtOAc (2 × 750 mL). The combined organic extracts were washed with ice water (500mL), brine (500mL), and anhydrous Na₂SO₄Drying, filtration and concentration gave 4- ((2-methoxyethoxy) methoxy) benzaldehyde (52g, 50%) as a pale yellow liquid. The crude product was used in the next step without further purification.

An intermediate AR: (trans) -2- (4-bromophenyl) cyclopropylamines

To a solution of tert-butyl trans-2- (4-bromophenyl) cyclopropylcarbamate (intermediate R, 10g, 32.05mmol) in 1, 4-dioxane (100mL) was added HCl in dioxane (50mL) at 10 ℃ and stirred at RT for 20 h. After completion, the solvent was evaporated, the residue was dissolved in ice water,with saturated NaHCO₃Basification of the aqueous solution, extraction with EtOAc (2 × 100mL), washing of the combined extracts with water, brine, and anhydrous Na₂SO₄Drying, filtration and concentration gave (trans) -2- (4-bromophenyl) cyclopropylamine (6.2g, 91%). The crude product was used in the next step without further purification.

Intermediate AS: (4- (((trans) -2- (4-bromophenyl) cyclopropyl) amino) cyclohexyl) carbamic acid tert-butyl ester

Tert-butyl 4-oxocyclohexylcarbamate (5g, 23.58mmol) was added to a solution of (trans) -2- (4-bromophenyl) cyclopropylamine (intermediate AR, 5g, 23.58mmol) in DCE (100mL), followed by AcOH (1.41g, 23.58 mmol). The mixture was stirred for 5min, then cooled to 0 ℃ after which sodium triacetoxyborohydride (8.9g, 42.45mmol) was added. The reaction mixture was stirred at RT for 16h, after completion, poured into saturated NaHCO₃Aqueous solution, extracted with DCM (2 × 100 mL). The combined organic extracts were washed with water (100mL), brine (100mL), and anhydrous Na₂SO₄Drying, filtering and concentrating. The crude residue was purified by column chromatography (SiO)₂Petroleum ether/EtOAc 7: 3) to give tert-butyl (4- (((trans) -2- (4-bromophenyl) cyclopropyl) amino) cyclohexyl) carbamate (6.2g, 64%).

Intermediate AT: ((trans) -2- (4-bromophenyl) cyclopropyl) (4- ((tert-butoxycarbonyl) amino) cyclohexyl) carbamic acid tert-butyl ester

NaOH solution (1.96g, 49mmol) was added to tert-butyl (4- (((trans) -2- (4-bromophenyl) cyclopropyl) amino) cyclohexyl) carbamate (intermediate AS, 5g, 12.25mmol) in 1, 4-dioxane/H₂O9: 1(100mL), howeverBoc anhydride (4g, 18.37mmol) was added. The reaction mixture was stirred at RT for 16h, after completion, water (50mL) was poured in and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with water (50mL), brine (50mL), and anhydrous Na₂SO₄Drying, filtering and concentrating. The crude residue was purified by column chromatography (SiO)₂EtOAc/petroleum ether 2: 8) to give tert-butyl ((trans) -2- (4-bromophenyl) cyclopropyl) (4- ((tert-butoxycarbonyl) amino) cyclohexyl) carbamate (5.2g, 83%) as a colorless liquid.

Intermediate AU: (trans) -2- (6-bromopyridin-3-yl) cyclopropylamines

This compound was synthesized by the method described in intermediate AR and using the corresponding starting material, ((trans) -2- (6-bromopyridin-3-yl) cyclopropyl) carbamic acid tert-butyl ester, to give 1.2g of the title compound.

Intermediate AV: (2-bromo-1-fluoroethyl) benzene

Triethylamine trihydrofluoride (36.3mL, 216.01mmol) and N-bromosuccinimide (30.75g, 172.8mmol) were added to a solution of styrene (15g, 144.0mmol) in DCM (150mL) at 0 deg.C and stirred at RT for 16 h. After completion, with NH₄The reaction mixture was neutralized with aqueous OH (150mL) and extracted with DCM (2 × 200 mL). With 0.1N HCl solution (100mL), 5% NaHCO₃The combined extracts were washed with solution (100mL), brine (100mL), and anhydrous Na₂SO₄Drying, filtration and concentration gave (2-bromo-1-fluoroethyl) benzene (25g, 85%) as a brown liquid.

Intermediate AW: (1-fluorovinyl) benzene

Adding KO at 0 deg.C^tBu (27.77g, 247.54mmol) was added stepwise to a solution of (2-bromo-1-fluoroethyl) benzene (intermediate AV, 25g, 123.7) in pentane (250 mL). The reaction mixture was stirred at reflux temperature for 1h, after completion, cooled to RT, then poured into ice water (150mL) and extracted with hexane (2 × 200 mL). With 5% NaHCO₃The combined extracts were washed with solution (150mL), 0.05M HCl solution (150mL), water (150mL), brine (150mL), and anhydrous Na₂SO₄Drying, filtration and concentration gave (1-fluorovinyl) benzene (13g, 86%) as a pale yellow liquid.

Intermediate AX: 2-fluoro-2-phenylcyclopropanecarboxylic acid ethyl ester (cis/trans)

Copper (II) acetylacetonate (321mg, 1.23mmol) was dissolved in dry DCM (10mL), stirred for a few minutes, and then a few drops of phenylhydrazine were added. The solution was stirred at RT for 10min, then a solution of (1-fluorovinyl) benzene (intermediate AW, 5g, 40.98mmol) in dry DCM (50mL) was added. The mixture was heated to reflux and ethyl diazoacetate (6.46ml, 61.47mmol) was added dropwise over CH₂Cl₂The solution in (1) was slowly stirred for 60 min. The reaction mixture was stirred at reflux temperature for 14h, after completion, cooled to room temperature, diluted with DCM (50ml) and Na₂CO₃The solution (25mL), water (25mL) and brine (25mL) were washed with anhydrous Na₂SO₄Drying, filtering and concentrating. By using DCM: hexane (10: 90) of (SiO)₂) The crude residue was purified by column chromatography to give ethyl 2-fluoro-2-phenylcyclopropanecarboxylate (cis) (540mg, 6.3%) and ethyl 2-fluoro-2-phenylcyclopropanecarboxylate (trans) (480mg, 5.6%).

Intermediate AY: 2-Phenylcyclopropanecarboxylic acid (cis) -ethyl ester

Ethyl diazoacetate (10.09mL, 96.01mmol) was added to a solution of styrene (10g, 96.01mmol) in dry chloroform (200mL) followed by addition of cu (i) Cl (catalyzed) and stirring at 60 ℃ for 4 h. After completion, the solvent was evaporated and the crude residue (SiO) was purified by column chromatography₂EtOAc/petroleum ether 1: 9) to give 2-phenylcyclopropanecarboxylic acid (cis) -ethyl ester (1.7g, 9.3%) as a colorless liquid.

An intermediate AZ: n- (3-bromo-4-methoxyphenyl) methanesulfonamide

Methanesulfonyl chloride (55.82mL, 0.494mmol) was added to a solution of 3-bromo-4-methoxyaniline (100mg, 0.494mmol) in pyridine (1mL) at 0 deg.C and stirred at RT for 2 h. After completion, the reaction mixture was poured into ice water (10mL) and extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with water (3 × 10mL), brine (15mL), and anhydrous Na₂SO₄Drying, filtering and evaporating. By using EtOAc: hexane (3: 7) (SiO)₂) The crude residue was purified by column chromatography to give N- (3-bromo-4-methoxyphenyl) methanesulfonamide (137mg, 99%) as a white solid.

Intermediate BA: n- (4-methoxy-3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanesulfonamide

A solution of N- (3-bromo-4-methoxyphenyl) methanesulfonamide (intermediate AZ, 136mg, 0.485mmol), bis (pinacolato) diboron (147mg, 0.58mmol) and KOAc (87.3mg, 0.888mmol) in dioxane (5.5mL) was degassed for 30minThen adding PdCl₂(dppf)₂(17.7mg, 0.020mmol) and the reaction mixture was heated at 100 ℃ for 3 h. After completion, the reaction mixture was poured into water (10mL) and extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with water (10mL), brine (50mL), and anhydrous Na₂SO₄Drying, filtering and evaporating. The crude residue was purified by column chromatography (SiO)₂EtOAc: petroleum ether 1: 9) to yield N- (4-methoxy-3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanesulfonamide (100mg, 63%) as a white solid.

Intermediate BB: 3-methoxy-5- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile

This compound was synthesized by the method described in intermediate BA and using the corresponding starting material (3-bromo-5-methoxybenzonitrile) to give 1.4g of the title compound as a white solid.

Intermediates BC (2- (5-bromothien-2-yl) cyclopropanecarboxylic acid (trans) -ethyl ester), BD (2- (2-bromothiazol-5-yl) cyclopropanecarboxylic acid (trans) -ethyl ester) and BE (2- (4- ((2-methoxyethoxy) methoxy) phenyl) cyclopropanecarboxylic acid (trans) -ethyl ester):

these intermediates were synthesized by the same method as for intermediate T (Horner-Wadsworth-Emmons reaction on nicotinaldehyde to give intermediate S, followed by cyclopropanation to give intermediate T), starting with the corresponding commercially available aldehydes as listed below:

intermediates BF ((trans) -2- (5-bromothien-2-yl) cyclopropylamine), BG ((trans) -2- (2-bromothiazol-5-yl) cyclopropylamine), BH (4- ((trans) -2-aminocyclopropyl) phenol), BI ((cis) -2-fluoro-2-phenylcyclopropylamine), BJ ((trans) -2-fluoro-2-phenylcyclopropylamine)) and BK ((cis) -2-phenylcyclopropylamine)

These intermediates were synthesized from intermediate T using the corresponding intermediates by the same method as for intermediate X (hydrolysis of 2- (pyridin-3-yl) cyclopropanecarboxylic acid (trans) -ethyl ester to give intermediate U, followed by Curtius reaction to give intermediate V first, then intermediate W, and finally Boc-deprotection to give intermediate X).

The hydrochloride salt gives the intermediates BF, BH and BK.

The intermediates BG, BI and BJ were basified with saturated aqueous NaHCO3 solution after acid treatment at the Boc-deprotection step to give the free base.

Intermediate BL: ((trans) -2- (4-hydroxyphenyl) cyclopropyl) carbamic acid tert-butyl ester

Will K₂CO₃(20.36g, 147.56mmol) and (Boc)₂O (16.8mL, 70.27mmol) was added to a solution of 4- ((trans) -2-aminocyclopropyl) phenol hydrochloride (intermediate BI, 13g, 70.27mmol) in 1, 4-dioxane (78mL) and water (195mL) and stirred at RT for 16 h. Upon completion, the reaction mixture was poured into water (300mL) and extracted with EtOAc (2 × 200 mL). The combined organic extracts were washed with water (75mL), brine (75mL), and anhydrous Na₂SO₄Drying, filtering and concentrating. The crude residue was purified by column chromatography (SiO)₂EtOAc/petroleum ether 3: 7) to give tert-butyl ((trans) -2- (4-hydroxyphenyl) cyclopropyl) carbamate (14g, 80%) as a brown thick viscous liquid.

Intermediate BM ((4- (((trans) -2- (6-bromopyridin-3-yl) cyclopropyl) amino) cyclohexyl) carbamic acid tert-butyl ester) BN ((4- (((trans) -2- (5-bromothiophen-2-yl) cyclopropyl) amino) cyclohexyl) carbamic acid tert-butyl ester) and BO ((4- (((trans) -2- (2-bromothiazol-5-yl) cyclopropyl) amino) cyclohexyl) carbamic acid tert-butyl ester)

These intermediates are synthesized from intermediate AR (reductive alkylation) by the same method AS described for obtaining intermediate AS, using the corresponding starting intermediates.

Intermediate BP (((trans) -2- (6-bromopyridin-3-yl) cyclopropyl) (4- ((tert-butoxycarbonyl) amino) cyclohexyl) carbamic acid tert-butyl ester) and

BQ (((trans) -2- (2-bromothiazol-5-yl) cyclopropyl) (4- ((tert-butoxycarbonyl) amino) cyclohexyl) carbamic acid tert-butyl ester)

These intermediates were synthesized from intermediate AS (Boc-protected) by the same method AS described for obtaining intermediate AT, using the corresponding starting intermediates.

Intermediate BR: ((trans) -2- (3 '-amino- [1, 1' -biphenyl ] -4-yl) cyclopropyl) (4- ((tert-butoxycarbonyl) amino) cyclohexyl) carbamic acid tert-butyl ester

((trans) -2- (4-bromophenyl) cyclopropyl) (4- ((tert-butoxycarbonyl) amino) cyclohexyl) carbamate (intermediate AT, 1.5g, 3.32mmol), (3-aminophenyl) boronic acid (484mg, 2.35mmol) and K₂CO₃(805mg, 5.88mmol) in ACN-H₂Degassing of the solution in O8: 2(20vol)15min, then Pd (PPh) is added₃)₄(68mg, 0.06 mmol). The reaction mixture was stirred at 90 ℃ for 16h, after completion, poured into ice water and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with water (50mL), brine (50mL), and anhydrous Na₂SO₄Drying, filtering and concentrating. The crude residue was purified by column chromatography (SiO)₂EtOAc: petroleum ether 3: 7) to give ((trans) -2- (3 '-amino- [1, 1' -biphenyl)]-4-yl) cyclopropyl) (tert-butyl 4- ((tert-butoxycarbonyl) amino) cyclohexyl) carbamate (1.23g, 71%) as a gummy solid.

Intermediates BS (N- (4 '- ((trans) -2-aminocyclopropyl) -6-methoxy- [1, 1' -biphenyl ] -3-yl) methanesulfonamide), BT (3- (5- ((trans) -2-aminocyclopropyl) pyridin-2-yl) -5-methoxybenzonitrile) and BU (5- (5- ((trans) -2-aminocyclopropyl) pyridin-2-yl) -2-methylphenol)

These intermediates were synthesized by using the corresponding starting intermediates and commercially available or below named boronic acid or ester derivatives, following the same procedure described to give intermediate R, from intermediate AH, which was Suzuki coupled with 3- (trifluoromethyl) phenylboronic acid to give intermediate AG, followed by Boc-deprotection to give intermediate R.

These intermediates are obtained as the hydrochloride salt.

Example 1: n1- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine dihydrochloride

Step 1:

acetic acid (586mg, 9.77mmol) was added to trans-2-phenylA solution of cyclopropylamine (1.3g, 9.77mmol) and tert-butyl 4-oxocyclohexylcarbamate (2.08g, 9.77mmol) in DCE (26mL) was stirred for 5mins. Sodium triacetoxyborohydride (3.72g, 17.5mmol) was then added at 0 ℃ and stirred at RT for 5 h. After completion, the reaction mixture was diluted with DCM (50mL), water (50mL), brine (50mL), anhydrous Na₂SO₄Drying, filtering and evaporating. By column chromatography using SiO₂The crude residue was purified by elution with EtOAc: petroleum ether (1: 9) to give tert-butyl 4- (trans-2-phenylcyclopropylamino) cyclohexylcarbamate (2.5g, 77.6%) as a pale yellow liquid.

Step 2:

a solution of HCl in 1,4 dioxane (10mL) was added to a solution of tert-butyl 4- (trans-2-phenylcyclopropylamino) cyclohexylcarbamate (2.45g, 7.57mmol) in dioxane (25mL) at 15 ℃ and stirred at RT for 16 h. After completion, the solvent was evaporated and the residue was taken up with Et₂O were triturated together and dried to give N1- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine dihydrochloride (1.5g, 67.5%) as an off-white solid.

¹HNMR (400MHz, DMSO-d6) (ppm): 9.66-9.56(brd, 2H), 8.15-8.11(d, 3H), 7.32-7.16(m, 5H), 3.33(brs, 1H), 3.24-3.16(m, 1H), 2.99(brs, 1H), 2.91(brs, 1H), 2.55(brs, 1H), 2.17(brs, 1H), 2.0(m, 1H), 1.96-1.75(m, 4H), 1.63-1.43(m, 2H), 1.4-1.3(m, 1H), 1.29-1.26(m, 1H); mass (M + H): 231.34.

the N1- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine obtained above is a mixture of 4 isomers, corresponding to 2 different combinations of (trans) conformations (1R,2S) and (1S,2R) respectively) with respect to the cyclopropyl ring and cis and trans conformations with respect to the cyclohexane ring. Each of these single isomers was synthesized as follows:

example 2: (cis) -N1- ((1S,2R) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine hydrochloride

Step 1:

to a solution of trans-2-phenylcyclopropylamine (1.1g, 8.2mmol) in EtOH (6mL) was added D (-) tartaric acid (1.24g, 8.2mmol) at 0 deg.C and stirred at RT for 1 h. After completion, the solid was filtered and dried to give trans-2-phenylcyclopropylamine as the tartrate salt (2.15g, 91.8%). The salt was dissolved in Isopropanol (IPA) to water (3: 1) (20mL) and stirred at 70 deg.C for 2 h. The clear solution was cooled to RT. The isolated solid was collected by filtration, dissolved in water (50mL), basified with NaOH solution, and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with water (50mL), brine (50mL), and anhydrous Na₂SO₄Drying, filtration and evaporation gave (1S,2R) -2-phenylcyclopropylamine (510mg, 46.3%).

Step 2:

to a solution of (1S,2R) -2-phenylcyclopropylamine (450mg, 3.38mmol), tert-butyl 4-oxocyclohexylcarbamate (792mg, 3.72mmol) and acetic acid (202mg, 3.38mmol) in DCE (10mL) was added sodium triacetoxyborohydride (1.29g, 6.09mmol) at 0 deg.C and stirred at RT for 3 h. After completion, the solvent was evaporated, the crude residue was dissolved in water (25mL) and NaHCO was used₃Basified and extracted with EtOAc (2 × 25 mL). The combined organic extracts were washed with water (25mL), brine (25mL), and anhydrous Na₂SO₄Drying, filtering and evaporating. By column chromatography using SiO₂The crude product was purified by elution with EtOAc: petroleum ether (3: 7) to give tert-butyl ((trans) -4- (((1S,2R) -2-phenylcyclopropyl) amino) cyclohexyl) carbamate (210mg, 18.8%) and tert-butyl ((cis) -4- (((1S,2R) -2-phenylcyclopropyl) amino) cyclohexyl) carbamate (280mg, 25.1%).

And step 3:

to a solution of tert-butyl ((cis) -4- (((1S,2R) -2-phenylcyclopropyl) amino) cyclohexyl) carbamate (190mg, 0.57mmol) in 1,4 dioxane (2mL) was added dropwise a solution of HCl in 1,4 dioxane (2mL) at 10 ℃ and stirred at RT for 16 h. After completion, the solvent was evaporated, and the solid was taken up with Et₂Stirring O together, filtering and drying to obtain (cis-form)) -N1- ((1S,2R) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine hydrochloride (110mg, 71.89%) as an off-white solid.

¹HNMR (400MHz, DMSO-d 6): 9.5(brs, 2H), 8.12(brs, 3H), 7.17-7.32(M, 5H), 3.24(brs, 2H), 2.98(brs, 1H), 2.57(brs, 1H), 1.98-1.74(M, 8H), 1.61(brs, 1H), 1.28(M, 1H); mass (M + H): 231.27; [ α 26H ]]_D ²⁸: +57.50(C ═ 0.54% in DMSO).

Example 3: (trans) -N1- ((1S,2R) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine hydrochloride

This compound was synthesized according to the same method as described in example 2, except that tert-butyl ((trans) -4- (((1S,2R) -2-phenylcyclopropyl) amino) cyclohexyl) carbamate as an intermediate in step 3 was subjected to Boc-deprotection reaction to obtain 120mg (yield: 59.4%) as an off-white solid.

¹H-NMR (400MHz, DMSO-d6) (ppm): 9.52(brs, 2H), 8.03(brs, 3H), 7.33-7.16(M, 5H), 3.17(brs, 1H), 2.9(brm, 2H), 2.16(brs, 2H), 2.03(brd, 2H), 1.54-1.25(M, 6H); mass (M + H): 231.28; [ α; ], [ α; (M + H); (M, 2H)]^28.1 _D: +67.04 ° (C ═ 0.53% in DMSO).

Example 4: (cis) -N1- ((1R,2S) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine hydrochloride

Step 1:

to a solution of trans-2-phenylcyclopropylamine (crude recovered from the reaction mother liquor in step 1 of example 2) (0.8g, 6.01mmol) in EtOH (5.4mL) was added L (+) tartaric acid (0.90g, 6.01mmol) at 0 deg.C and stirred at RT for 1 h. After completion, the solid was filtered and dried to give trans-2-phenylcyclopropylamine as the tartrate salt (1.5g, 88.2%). The salt was dissolved In (IPA) to water (3: 1) (15mL) and stirred at 70 ℃ for 2 h. The clear solution was cooled to RT. By passingThe isolated solid was collected by filtration, dissolved in water (50mL), basified with NaOH solution, and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with water (50mL), brine (50mL), and anhydrous Na₂SO₄Drying, filtration and evaporation gave (1R,2S) -2-phenylcyclopropylamine (320 mg).

Step 2:

to a solution of (1R,2S) -2-phenylcyclopropylamine (280mg, 1.21mmol), tert-butyl 4-oxocyclohexylcarbamate (309mg, 1.45mmol) and acetic acid (72mg, 1.21mmol) in DCE (8mL) was added sodium triacetoxyborohydride (461mg, 2.17mmol) at 0 deg.C and stirred at RT for 3 h. After completion, the solvent was evaporated, the crude residue was dissolved in water (25mL) and NaHCO was used₃Work up and extract with EtOAc (2 × 25 mL). The combined organic extracts were washed with water (25mL), brine (25mL), and anhydrous Na₂SO₄Drying, filtering and evaporating. By column chromatography using SiO₂The crude product was purified by elution with EtOAc: petroleum ether (3: 7) to give tert-butyl ((cis) -4- (((1R,2S) -2-phenylcyclopropyl) amino) cyclohexyl) carbamate (180mg, 25.35%) and tert-butyl ((trans) -4- (((1R,2S) -2-phenylcyclopropyl) amino) cyclohexyl) carbamate (210mg, 29.5%).

And step 3:

to a solution of tert-butyl ((cis) -4- (((1R,2S) -2-phenylcyclopropyl) amino) cyclohexyl) carbamate (160mg, 0.48mmol) in 1,4 dioxane (2mL) was added dropwise a solution of HCl in 1,4 dioxane (2mL) at 10 ℃ and stirred at RT for 16 h. After completion, the solvent was evaporated, and the solid was taken up with Et₂O were stirred together, filtered and dried to give (cis) -N1- ((1R,2S) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine hydrochloride (80mg, 58.3%) as an off-white solid.

¹HNMR (400MHz, DMSO-d 6): 9.54(brs, 2H), 8.14(brs, 3H), 7.35-7.15(M, 5H), 3.33(brs, 1H), 3.25(brs, 2H), 2.62-2.55(M, 1H), 2.03-1.67(M, 8H), 1.63-1.57(M, 1H), 1.28(q, 1H); mass (M + H): 231.27; [ α, 2H, 3.4H, 3H, 2H, 1H,3H, 2H]_D ^28.5: -65.70 ° (C ═ 0.5%, in DMSO)。

Example 5: (trans) -N1- ((1R,2S) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine hydrochloride

This compound was synthesized according to the same method as described in example 4, except that tert-butyl ((trans) -4- (((1R,2S) -2-phenylcyclopropyl) amino) cyclohexyl) carbamate was subjected to Boc-deprotection reaction in step 3 to obtain 95mg (yield ═ 50.8%) as an off-white solid.

¹HNMR (400MHz, DMSO-D6, D2O exchange) (ppm): 7.32(t, J ═ 7.2Hz, 2H), 7.24(t, J ═ 7.2Hz, 1H), 7.17(D, J ═ 8Hz, 2H), 3.26-3.18(M, 1H), 3.05-2.89(M, 2H), 2.51-2.42(M, 1H), 2.22-2.10(M, 2H), 2.08-1.98(M, 2H), 1.57-1.28(M, 6H), mass (M + H): 231.25; [ α H; (M + H); (M, 6H)]_D ^28.5: -60.19 ° (C ═ 0.54% in DMSO).

(trans) -N1- ((1R,2S) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine was obtained using the following alternative procedure:

to a well stirred solution of (1R,2S) -2-phenylcyclopropylamine (0.752g5.64mmol) in methanol (10ml) at room temperature (22-25 deg.C) was added molecular sieve (1.0g) followed by tert-butyl-4-oxocyclohexylcarbamate (1.07g, 5.0mmol) at 10 deg.C and stirred for 5min. To the reaction mixture was added acetic acid (0.028ml, 0.5mmol) at 0-5 ℃ and stirred at room temperature for 3 h. The reaction mixture was cooled to-25-to-30 ℃ and sodium borohydride (0.229g, 6.02mmol) was added stepwise at the same temperature. The reaction mixture was stirred for 3h and the reaction temperature was allowed to rise to room temperature.

The progress of the reaction was monitored by TLC (EtOAc/hexane 8: 2). After completion of the reaction, the inorganic matter was filtered off with celite. The filtrate was evaporated and the crude residue was dissolved in a mixture of water (20ml) and DCM (20ml) and basified with 5% aqueous NaOH (to pH 10). The DCM layer was separated and the aqueous layer was extracted with DCM (20 ml). The combined organic extracts were washed with water (20ml) and 10% aqueous brine (20ml), dried over anhydrous sodium sulfate, filtered and evaporated completely. The crude product was purified by stirring at room temperature for 2h in 2% EtOAc in hexanes to give tert-butyl-4- ((1R,2S) -2-phenylcyclopropylamino) cyclohexylcarbamate as an off-white solid (0.90g, 54%).

To a well stirred solution of tert-butyl-4- ((1R,2S) -2-phenylcyclopropylamino) cyclohexylcarbamate (0.8g, 2.42mmol) in 1, 4-dioxane (10ml) was slowly added 15% HCl in dioxane (8ml) at 10-15 ℃ and stirred at room temperature for 20 h. The progress of the reaction was monitored by HPLC. After completion of the reaction, the solvent was removed under reduced pressure. The residue was suspended in diisopropyl ether (15ml), stirred at room temperature for 1h, filtered and dried in vacuo. The crude product was further purified by stirring at room temperature in diisopropyl ether (15ml) for 2 h. The solid was filtered off to give (trans) -N1- ((1R,2S) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine dihydrochloride (0.57g, 77%) (dihydrochloride salt form present as determined by silver titration) as a yellowish white solid.

¹HNMR (400MHz, DMSO-d6) (ppm): 9.74(bs, 2H), 8.18(bs, 3H), 7.30(m, 2H), 7.24(m, 1H), 7.18(m, 2H), 3.15(bs, 1H), 2.94(m, 2H), 2.56(m, 1H), 2.18(m, 2H), 2.04(m, 2H), 1.58(m, 3H), 1.44(m, 2H), 1.26(m, 1H); mass (M + H): 231.5.

the following compounds were synthesized according to the procedure described for example 1, by using the corresponding intermediates. Step 2 was only performed in the case of the intermediate comprising the Boc (tert-butyloxycarbonyl) protecting group used for the reductive amination (step 1).

Example 6: n1- ((Trans) -2- (Thiazol-5-Yl) cyclopropyl) cyclohexane-1, 4-diamine hydrochloride

¹HNMR(400MHz，DMSO-d6-D₂O exchange) (ppm): 8.95(s, 1H), 7.75(s, 1H),3.3-3.18(m, 1H), 3.1-2.9(m, 2H), 2.85-2.72(m, 1H), 2.25-1.98(brm, 3H), 1.7-1.35(brm, 5H); mass (M + H): 238.19.

example 7: n1- ((Trans) -2- (pyridin-3-Yl) cyclopropyl) cyclohexane-1, 4-diamine hydrochloride

¹HNMR(400MHz，D₂O) (ppm): 8.64(2H, d), 8.32(1H, d), 7.98(1H, t), 3.37(2H, M), 3.22(2H, M), 2.77-2.72(1H, M), 2.25-2.12(3H, M), 1.92-1.46(7H, M), mass (M + H): 232.34.

example 8: n1- ((trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine hydrochloride

¹HNMR(400MHz，D₂O) (ppm): 8.60(s, 1H), 8.20-8.00(m, 3H), 7.90(d, J ═ 12Hz, 1H), 7.76-7.72(t, J ═ 8Hz, 1H), 7.60-7.40(br, 1H), 3.60-3.40(m, 2H), 3.20(m, 1H), 2.70(m, 1H), 2.30(m, 1H), 2.20-2.00(m, 2H), 1.97-1.67(m, 5H), 1.65(m, 1H), 1.60-1.40(m, 1H); mass (M + H): 376.3.

example 9: n1- ((trans) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) cyclohexane-1, 4-diamine hydrochloride

¹HNMR (400MHz, DMSO d 6): 9.65-9.48(brd, 2H), 8.1(s, 3H), 7.95(m, 2H), 7.7(m, 4H), 7.3(d, 2H), 3.2(brd, 1H), 2.9(brd, 2H), 2.52(m, 1H), 2.2(brd, 2H), 2.05(brd, 2H), 1.86-1.76(m, 2H), 1.6-1.25(m, 5H); mass (M + H): 375.29.

example 10: n1- ((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine hydrochloride

¹HNMR (400MHz, DMSO d 6): 9.64-9.45(brd, 2H), 8.2-8.05(brd, 3H), 7.48-7.3(m, 5H), 7.15(d, 2H), 6.95(d, 2H), 5.08(s, 2H), 3.2-3.15(brs, 1H), 2.9(brs, 1H), 2.82(brs, 1H), 2.45(brs, 1H), 2.18(brd, 2H), 2.05(brd, 2H), 1.9(brs, 1H), 1.58-1.27(m, 4H), 1.22(m, 1H); mass (M + H): 337.31.

example 11: 4- (((trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropyl) amino) cyclohexanol

¹HNMR(400MHz，D₂O) (ppm): 8.76(s, 1H), 8.37(brs, 1H), 8.32-8.26(m, 2H), 8.16(m, 1H), 8.06(m, 1H), 7.91(t, J ═ 8Hz, 1H), 4.11(brs, 1H), 3.84-3.65(m, 1H), 3.60-3.40(m, 1H), 3.33(brs, 1H), 2.87(brs, 1H), 2.28-2.03(m, 3H), 1.90-1.70(m, 4H), 1.68-1.57(m, 1H), 1.55-1.40(m, 1H); mass (M + H): 377.2.

example 12: 4- (((trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropyl) amino) cyclohexanecarboxamide hydrochloride

¹HNMR(400MHz，D₂O) (ppm): 8.80(brs, 1H), 8.50-8.40(brs, 1H), 8.38-8.26(m, 2H), 8.20-8.00(m, 2H), 7.95-7.83(m, 1H), 3.65-3.25(m, 3H), 2.96-2.82(m, 1H), 2.75-2.54(m, 1H), 2.47-2.30(m, 1H), 2.20-1.80(m, 7H), 1.70-1.50(m, 1H); mass (M + H): 404.3.

example 13: n- (4- (((trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropyl) amino) cyclohexyl) acetamide hydrochloride

¹HNMR(400MHz，D₂O) (ppm): 8.79(s, 1H), 8.39(m, 1H), 8.30(m, 1H), 8.24(s, 1H), 8.13(m, 1H), 8.11(m, 1H), 7.88(t, J ═ 8Hz, 1H), 3.70-3.62(m, 1H), 3.50-3.40(m, 1H), 3.38-3.24(m, 1H), 2.92-2.80(m, 1H), 2.34-2.24(m, 2H), 2.17-2.03(m, 3H), 1.98(s, 1H), 1.94-1.72(m, 4H), 1.70-1.57(m, 1H), 1.50-1.35(m, 2H). Mass (M + H): 418.2.

example 14: n- (4- (((trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropyl) amino) cyclohexyl) methanesulfonamide hydrochloride

¹HNMR(400MHz，D₂O) (ppm): 8.73(s, 1H), 8.41-8.32(m, 1H), 8.28-8.22(m, 2H), 8.12(d, J =8Hz, 1H), 8.03(d, J =8Hz, 1H), 7.88(t, J =8Hz, 1H), 3.3.52-3.26(m, 3H), 3.14(s, 3H), 2.91-2.80(m, 1H), 2.36-1.96(m, 4H), 1.88-1.58(m, 4H), 1.56-1.42(m, 2H). Mass (M + H): 454.1.

example 15: (R) -1- (4- (((trans) -2-phenylcyclopropyl) amino) cyclohexyl) pyrrolidin-3-amine trihydrochloride

¹HNMR (400MHz, DMSO-d6) (ppm)10.71-10.45(m, 1H), 9.61-9.50(brs, 1H), 9.49-9.34(brs, 1H), 8.09(t, J =6Hz, 3H), 7.98(quin, 2H), 4.85-4.20(m, 7H), 4.08-3.92(m, 1H), 3.82-3.65(m, 1H), 3.47-3.38(m, 1H), 3.10-2.32(m, 11H), 2.07(q, 1H). Mass (M + H): 300.1.

the following compounds were synthesized according to the procedure described for example 1, by using the corresponding intermediates and commercially available reagents. Step 2 applies only to those intermediates used in the reductive amination (step 1) that contain a Boc (tert-butyloxycarbonyl) protecting group.

Example 16: 1-methyl-N4- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine

¹HNMR(400MHz，D₂O)：7.45-7.30(m，3H)，7.24(d，J=8Hz，2H)，3.55-3.42(m，1H)，3.05-2.98(m，1H)，2.62-2.52(m，1H)，2.28-2.20(m，2H)，2.18-1.98(m，2H)，1.87-1.64(m，4H)，1.62-1.44(m，2H)，1.41(s, 3H); mass (M + H): 245.33. the hydrochloride salt compound is obtained.

Example 17: 4- (aminomethyl) -N- ((trans) -2-phenylcyclopropyl) cyclohexylamine

¹HNMR(400MHz，CD₃OD): 7.33-7.25(m, 2H), 7.21-7.17(m, 3H), 3.45(brs, 1H), 2.98(d, J =8Hz, 1H), 2.95-2.92(m, 1H), 2.82(d, J =7Hz, 1H), 2.57-2.55(m, 1H), 2.28-2.26(m, 1H), 1.95-1.90(m, 4H), 1.73-1.70(m, 3H), 1.62-1.58(m, 2H), 1.45-1.39(m, 1H); mass (M + H): 245.29. the compound was obtained as the hydrochloride salt.

Example 18: n1- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 3-diamine

¹HNMR(400MHz，DMSO-d6-D₂O exchange) (ppm): 7.33(t, J =7.4Hz, 2H), 7.26(d, J =7.2Hz, 1H), 7.23(t, J =8Hz, 2H), 4.1-4.0(m, 1H), 4.0-3.9(m, 1H), 2.96-2.86(m, 1H), 2.5-2.43(m, 1H), 2.10-1.90(m, 2H), 1.88-1.76(m, 2H), 1.75-1.63(m, 3H), 1.62-1.48(m, 2H), 1.40-1.30(m, 1H); mass (M + H): 231.29. the compound was obtained as the hydrochloride salt.

Example 19: n1- ((trans) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine

¹HNMR(400Mz，DMSO-d6-D₂O exchange) (ppm): 7.33(t, J =8Hz, 2H), 7.25(t, J =8Hz, 1H), 7.17(d, J =8Hz, 2H), 4.1-4.0(m, 1H), 2.95-2.85(m, 1H), 2.74-2.60(m, 2H), 2.5-2.42(m, 3H), 1.48 (quintuple, 1H), 1.33(q, 1H); mass (M + H): 203.0. the compound was obtained as the hydrochloride salt.

Example 20: n1- ((trans) -2-phenylcyclopropyl) -2, 3-dihydro-1H-indene-1, 3-diamine

¹HNMR(400MHz，D₂O): 7.70-7.53(m, 4H), 7.46-7.30(m, 3H), 7.17(d, J =8Hz, 1H), 7.03(d, J =8Hz, 1H), 5.40-5.30(m, 1H), 5.14-5.04(m,1H), 3.05-2.93(m, 2H), 2.78-2.64(m, 1H), 2.54-2.32(m, 1H), 1.62-1.42(m, 2H); mass (M + H): 265.3. the compound was obtained as the hydrochloride salt.

Example 21: n1- ((cis) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine

¹HNMR(400MHz，DMSO-d6-D₂O exchange): 7.46-7.30(m, 5H), 3.03-2.88(m, 2H), 2.52-2.45(m, 1H), 2.27-2.20(m, 1H), 2.08-1.94(m, 2H), 1.94-1.58(m, 3H), 1.54-1.20(m, 5H); mass (M + H): 231.18. the compound was obtained as the hydrochloride salt.

Example 22: N1-methyl-N4- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine

¹HNMR(400MHz，D₂O): 7.61-7.34(m, 3H), 7.30-7.20(m, 2H), 3.70-3.58(brs, 1H), 3.53-3.33(m, 1H), 3.22-2.95(m, 1H), 2.82-2.70(m, 3H), 2.63-2.47(brs, 1H), 2.42-2.22(m, 2H), 2.18-1.85(m, 5H), 1.45-1.65(m, 3H); mass (M + H): 245.1. the compound was obtained as the hydrochloride salt.

Example 23: (4- (((trans) -2-phenylcyclopropyl) amino) cyclohexyl) carbamic acid tert-butyl ester

¹HNMR(400MHz，CDCl₃) (rotamer 1: 1): 7.28-7.23(m, 2H), 7.17-7.13(m, 1H), 7.02(d, J =8Hz, 2H), 4.62(brs, 0.5H), 4.35(brs, 0.5H), 3.63(brs, 0.5H), 3.39(brs, 0.5H), 2.79(brs, 0.5H), 2.69-2.57(m, 0.5H), 2.38-2.22(m, 1H), 1.98-1.94(m, 3H), 1.87-1.82(m, 1H), 1.75-1.60(m, 2H), 1.43(s, 9H), 1.33-1.00(m, 5H); mass (M + H): 331.27. this compound was obtained as the free amine.

Example 24: 1-ethyl-3- (4- ((9 trans) -2-phenylcyclopropyl) amino) cyclohexyl) urea

¹HNM[R(400MHz，DMSO-d6-D₂O exchange): 7.33(t, J =7.6Hz, 2H), 7.24(t, J =7.2Hz, 1H), 7.18(d, J =8Hz, 2H), 3.36-314(m, 1H), 3.04-2.92(m, 3H), 2.50-2.40(m, 2H), 2.12-2.04(m, 1H), 1.93-1.81(m, 2H), 1.75-1.61(m, 2H), 1.60-1.40(m, 3H), 1.39-1.30(m, 1H), 1.20-1.13(m, 1H), 1.03-0.94(m, 3H); mass (M + H): 302.26. the compound was obtained as the hydrochloride salt.

Example 25: 4-morpholino-N- ((trans) -2-phenylcyclopropyl) cyclohexylamine

¹HNMR(400MHz，CDCl₃): 7.28-7.22(m, 2H), 7.14(t, J =8Hz, 1H), 7.02(d, J =8Hz, 2H), 3.78-3.68(m, 4H), 2.94-2.85(m, 1H), 2.53(brs, 4H), 2.30-2.23(m, 1H), 2.22-2.16(m, 1H), 1.92-1.84(m, 1H), 1.70-1.62(m, 2H), 1.61-1.47(m, 5H), 1.10-1.02(m, 1H), 1.01-0.96(m, 1H); mass (M + H): 301.2. this compound was obtained as the free amine.

Example 26: n1- ((trans) -2- (4-bromophenyl) cyclopropyl) cyclohexane-1, 4-diamine

¹HNMR(400MHz，D₂O): 7.56(d, J =8Hz, 2H), 7.14(d, J =8Hz, 2H), 3.64-3.50(m, 1H), 3.48-3.38(m, 1H), 2.35-2.24(m, 1H), 3.05-2.97(m, 1H), 2.60-2.48(m, 1H), 2.40-2.19(m, 2H), 2.18-1.84(m, 3H), 1.70-1.44(m, 4H); mass (M + H): 309.06. the compound was obtained as the hydrochloride salt.

Example 27: n1- (2- (o-tolyl) cyclopropyl) cyclohexane-1, 4-diamine

¹HNMR(400MHz，CD₃OD): 7.22-7.12(m, 3H), 7.04-6.98(m, 1H), 3.60-3.40(m, 1H), 3.22-3.08(m, 2H), 2.72-2.49(m, 1H), 2.44(s, 3H), 2.42-2.34(m, 1H), 2.25-2.16(m, 1H), 2.15-1.92(m, 4H), 1.70-1.50(m, 3H), 1.32-1.24(m, 1H); mass (M + H): 245.22. the compound was obtained as the hydrochloride salt.

Example 28: n1- (2- (4- (trifluoromethyl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

¹HNMR(400MHz，DMSO-d6-D₂O exchange): 7.73-7.63(m, 2H), 7.50-7.36(m, 2H), 3.26-3.10(m, 1H), 3.07-2.92(m, 1H), 2.48-2.41(m, 1H), 2.20-2.09(m, 2H), 2.08-1.98(m, 1H), 1.90-1.67(m, 5H), 1.60-1.32(m, 4H); mass (M + H): 299.24. the compound was obtained as the hydrochloride salt.

Example 29: n1- (2- (4-methoxyphenyl) cyclopropyl) cyclohexane-1, 4-diamine

¹HNMR(400MHz，CD₃OD)：7.16-7.08(m，2H)，6.87(d，J=8.8Hz，4H)，3.76(s，3H)，3.44-3.38(m，1H)，3.22-3.12(m，0.5H)，2.94-2.85(m，1H)，2.52-2.44(m，0.5H)，2.43-2.30(m，2H)，2.24-2.14(m，1H)，2.10-1.90(m，3H)，1.62-1.51(m，3H)，1.50-1.42(m，1H)，1.37(q, 1H); mass (M + H): 261.26. the compound was obtained as the hydrochloride salt.

Example 30: 4- (2- ((4-aminocyclohexyl) amino) cyclopropyl) phenol

¹HNMR(400MHz，DMSO-d6-D₂O exchange): 6.98(d, J =8.4Hz, 2H), 6.71(d, J =8.4Hz, 2H), 3.24-3.15(m, 1H), 3.07-2.95(m, 1H), 2.87-2.78(m, 1H), 2.45-2.36(m, 1H), 2.22-2.11(m, 2H), 2.09-1.98(m, 2H), 1.94-1.75(m, 1H), 1.58-1.34(m, 4H), 1.26-1.18(m, 1H); mass (M + H): 247.22. this compound was obtained as the hydrochloride salt.

Example 31: n1- (2- (2-fluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine

¹HNMR(400MHz，CD₃OD): 7.33-7.31(m, 1H), 7.29-7.26(m, 3H), 3.52-3.30(m, 2H), 3.17-3.06(m, 2H), 2.73-2.61(m, 1H), 2.36-2.33(m, 1H), 2.17-2.20(m, 1H), 2.05-1.95(m, 4H), 1.58-1.45(m, 4H); mass (M + H): 249.23. this compound was obtained as the hydrochloride salt.

Example 32: n1- (2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine

¹HNMR(400MHz，CD₃OD): 7.27-7.12(m, 2H), 7.08-7.00(m, 1H), 3.56-3.46(m, 1H), 3.46-3.34(m, 1H), 3.24-3.14(m, 1H), 3.05-2.97(m, 1H), 2.68-2.60(m, 1H), 2.58-2.48(m, 1H), 2.38-2.25(m, 1H), 2.38-2.25(m, 1H), 2.23-2.15(m, 1H), 2.14-1.90(m, 4H), 1.70-1.50(m, 3H), 1.43(q, 1H); mass (M + H): 267.21. this compound was obtained as the hydrochloride salt.

Example 33: n1- (2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine

¹HNMR(400MHz，DMSO-d6-D₂O exchange): 7.93-7.83(m, 3H), 7.71(s, 1H), 7.50(quin, 2H), 7.34(d, J =8.4Hz, 1H), 3.28-3.19(m, 1H), 3.10-2.97(m, 2H), 2.68-2.60(m, 1H), 2.24-2.15(m, 2H), 2.08-1.98(m, 2H), 1.62-1.35(m, 6H); mass (M + H): 281.14. this compound was obtained as the hydrochloride salt.

Example 34: n1- (2-methyl-2-phenylcyclopropyl) cyclohexane-1, 4-diamine

¹HNMR(400MHz，CD₃OD): 7.40-7.30(m, 4H), 7.27-7.21(m, 1H), 3.58-3.46(m, 1H), 2.95-2.85(m, 1H), 2.54-2.28(m, 1H), 2.25-2.18(m, 1H), 2.16-1.92(m, 5H), 1.67(s, 3H), 1.62-1.52(m, 2H), 1.35-1.25(m, 1H); mass (M + H): 245.22. this compound was obtained as the hydrochloride salt.

Example 35: (R) -1- (4- (((trans) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) amino) cyclohexyl) pyrrolidin-3-amine

¹HNMR(400MHz，D₂O): 7.98(s, 1H), 7.89(d, J =8Hz, 2H), 7.76-7.62(m, 3H), 7.2(d, J =8Hz, 2H), 4.2(brs, 2H), 4.06-3.96(m, 2H), 3.72-3.62(m, 2H), 3.10-3.01(m, 1H), 2.70-2.56(m, 2H), 2.34-2.20(m, 2H), 2.18-2.02(m, 3H), 2.00-1.86(m, 2H), 1.65-1.55(m, 2H); mass (M + H): 444.3. the compound was obtained as the hydrochloride salt.

Example 36: (cis) -N1- ((1S,2R) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) cyclohexane-1, 4-diamine

Step 1:

l (+) mandelic acid (2.7g, 18.05mmol) was added to (trans) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl)]-4-yl) cyclopropylamine (free amine derived from intermediate AH, 5g, 18.05mmol) in EtOH/H₂In a solution of O1: 9(25vols) at reflux for 2 h. After a clear solution had formed, the reaction mixture was cooled to RT (16 h). The precipitated solid was filtered off, dissolved in water (100mL) and washed with NaHCO₃The aqueous solution was basified and extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with water (100mL), brine (100mL), and anhydrous Na₂SO₄Drying, filtering and evaporating to obtain (1S,2R) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl]-4-yl) cyclopropylamine (1.3g) as a pale yellow solid.

Step 2:

4-Oxocyclohexylcarbamic acid tert-butyl ester at 0 DEG C(999mg, 4.69mm0l), acetic acid (280mg, 4.69mmol) and sodium triacetoxyborohydride (1.78g, 8.44mmol) were added to (1S,2R) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl)]A solution of-4-yl) cyclopropylamine (1.3g, 4.69mmol) in DCE (10mL) was stirred at RT for 3 h. After completion of the reaction, the solvent was evaporated, the crude residue was dissolved in water (25mL) and NaHCO was used₃Washed and extracted with EtOAc (2 × 25 mL). The combined organic extracts were washed with water (25mL), brine (25mL), and anhydrous Na₂SO₄Drying, filtering and evaporating.

By flash column chromatography using SiO₂The diastereoisomers were separated by elution with EtOAc: petroleum ether (3: 7). The less polar isomer ((cis) -4- (((1S,2R) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl) is first isolated]-4-Yl) cyclopropyl) amino) cyclohexyl) carbamic acid tert-butyl ester (460mg) and the more polar isomer ((trans) -4- (((1S,2R) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl) was then isolated]-4-yl) cyclopropyl) amino) cyclohexyl) carbamic acid tert-butyl ester (490 mg).

And step 3:

a solution of HCl in 1, 4-dioxane (5mL) was added to ((cis) -4- (((1S,2R) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl) at 15 ℃]-4-yl) cyclopropyl) amino) cyclohexyl) carbamic acid tert-butyl ester (440mg, 0.93mmol) in 1, 4-dioxane (9mL) was stirred at RT for 16 h. After completion, the solvent was evaporated. The residue is taken up in Et₂Grinding O together, filtering and drying to obtain (cis) -N1- ((1S,2R) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl)]-4-yl) cyclopropyl) cyclohexane-1, 4-diamine as the hydrochloride salt (320mg) as a yellow-white solid.

¹HNMR(400MHz，DMSO-d6-D₂O-exchange) 8.02-7.92(M, 2H), 7.71(d, J =8Hz, 4H), 7.32(d, J =8Hz, 2H), 3.38(brs, 1H), 3.27(brs, 1H), 3.06(brs, 1H), 2.60(brs, 1H), 2.0-1.73(M, 8H), 1.62(brs, 1H), 1.44-1.35(M, 1H), mass (M + H) 375.23; [ α; ], [ M + H ]; (M + H); 375.23; ]]_D ^25.1: +53.93 ° (C = 0.53% in DMSO).

Example 37: (trans) -N1- ((1S,2R) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) cyclohexane-1, 4-diamine

This compound was synthesized according to the same procedure as described in example 36 to give tert-butyl Boc-intermediate ((trans) -4- (((1S,2R) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) amino) cyclohexyl) carbamate as the second product in the reductive amination step to finally give 328mg of the title compound as the hydrochloride salt as a light purple brown solid.

¹HNMR(400MHz，DMSO-d6-D₂O exchange) 8.02-7.92(M, 2H), 7.71(d, J =8Hz, 4H), 7.32(d, J =8Hz, 2H), 3.30-3.20(M, 1H), 3.06-2.96(M, 2H), 2.62-2.54(M, 1H), 2.25-2.15(M, 2H), 2.10-2.00(M, 2H), 1.62-1.35(M, 6H), mass (M + H): 375.25; [ α H ]; (M, H); 2]_D ^25.5: +52.83 ° (C = 0.53% in DMSO).

Example 38: (cis) -N1- ((1R,2S) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclo-propyl) cyclohexane-1, 4-diamine

Step 1:

d (-) mandelic acid (2.7g, 18.05mmol) was added to (trans) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl)]-4-yl) cyclopropylamine (free amine derived from intermediate AH, 5g, 18.05mmol) in EtOH/H₂In a solution of O1: 9(25vols) at reflux for 2 h. After a clear solution had formed, the reaction mixture was cooled to RT (16 h). The precipitated solid was filtered off, dissolved in water (100mL) and washed with NaHCO₃The aqueous solution was basified and extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with water (100mL), brine (100mL), and anhydrous Na₂SO₄Drying, filtering and evaporating to obtain (1R,2S) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl]-4-yl) cyclopropylamine (900mg) as a pale yellow solid.

Step 2:

tert-butyl 4-oxocyclohexylcarbamate (692mg,3.2mmol), acetic acid (194mg, 3.2mmol) and sodium triacetoxyborohydride (1.2g, 5.76mmol) were added to (1R,2S) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl) at 0 deg.C]A solution of-4-yl) cyclopropylamine (900mg, 3.2mmol) in DCE (10mL) was stirred at RT for 3 h. After completion, the solvent was evaporated. The residue was dissolved in water (25mL) and NaHCO was used₃Washed and extracted with EtOAc (2 × 25 mL). The combined organic extracts were washed with water (25mL), brine (25mL), and anhydrous Na₂SO₄Drying, filtering and evaporating.

By flash column chromatography using SiO₂The diastereoisomers were separated by elution with EtOAc: petroleum ether (3: 7). The less polar isomer ((cis) -4- (((1R,2S) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl) is first isolated ]-4-Yl) cyclopropyl) amino) cyclohexyl) carbamic acid tert-butyl ester (390mg) and the more polar isomer ((trans) -4- (((1R,2S) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl) was then isolated]-4-yl) cyclopropyl) amino) cyclohexyl) carbamic acid tert-butyl ester (480 mg).

And step 3:

a solution of HCl in dioxane (4mL) was added to ((cis) -4- (((1R,2S) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl) at 15 ℃]-4-yl) cyclopropyl) amino) cyclohexyl) carbamic acid tert-butyl ester (380mg, 0.801mmol) in 1,4 dioxane (8mL) was stirred at RT for 16 h. After completion, the solvent was evaporated. The residue is taken up in Et₂Grinding O together, filtering and drying to obtain (cis) -N1- ((1R,2S) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl)]-4-yl) cyclopropyl) cyclo-hexane-1, 4-diamine as the hydrochloride salt (280mg) as a white solid.

¹HNMR(400MHz，DMSO-d6-D₂O exchange) 8.02-7.92(M, 2H), 7.71(d, J =8Hz, 4H), 7.33(d, J =8Hz, 2H), 3.39(brs, 1H), 3.28(brs, 1H), 3.05(brs, 1H), 2.60(brs, 1H), 2.0-1.75(M, 8H), 1.68-1.60(M, 1H), 1.46-1.38(M, 1H), Mass (M + H) 375.28; [ α H ]; (M + H); 375.28; (M, H)]_D ^28.1: -65.31 ° (C = 0.53% in DMSO).

Example 39: (trans) -N1- ((1R,2S) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) cyclohexane-1, 4-diamine

This compound was synthesized according to the same procedure as described in example 38 to give tert-butyl Boc-intermediate ((trans) -4- (((1R,2S) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) amino) cyclohexyl) carbamate as the second product in the reductive amination step to finally give 350mg of the title compound as the hydrochloride salt as a light brown solid.

¹HNMR(400MHz，DMSO-d6-D₂O exchange) 8.02-7.92(M, 2H), 7.71(d, J =8Hz, 4H), 7.32(d, J =8Hz, 2H), 3.30-3.20(M, 1H), 3.06-2.96(M, 2H), 2.62-2.54(M, 1H), 2.25-2.15(M, 2H), 2.10-2.00(M, 2H), 1.62-1.35(M, 6H), mass (M + H): 375.24; [ α H ]; (M, H); 2]_D ^25.848.30 ° (C = 0.52% in DMSO).

Example 40: n1- ((trans) -2- (4-cyclopropylphenyl) cyclopropyl) cyclohexane-1, 4-diamine

Step 1:

tert-butyl ((trans) -2- (4-bromophenyl) cyclopropyl) (4- ((tert-butoxycarbonyl) amino) cyclohexyl) carbamate (intermediate AT, 400mg,0.78mmol), cyclopropylboronic acid (81mg, 0.94mmol) and K₂CO₃(322mg, 2.34mmol) in ACN/H₂The solution in O4: 1(8mL) was degassed for 30min. Adding Pd (PPh)₃)₄(45mg, 0.039mmol) and the mixture was stirred at reflux temperature for 16 h. After completion, the reaction mixture was poured into water and extracted with EtOAc (2 × 25 mL). The combined organic extracts were washed with water (25mL), brine (25mL), and anhydrous Na₂SO₄Drying, filtering and evaporating. By column chromatography (SiO)₂) The crude material was purified using EtOAc: petroleum ether (3: 7) to give tert-butyl (4- ((tert-butoxycarbonyl) amino) cyclohexyl) ((trans) -2- (4-cyclopropylphenyl) cyclopropyl) carbamate (160mg) as a white solid.

Step 2:

a solution of HCl in dioxane (1mL) was added to a solution of tert-butyl (4- ((tert-butoxycarbonyl) amino) cyclohexyl) ((trans) -2- (4-cyclopropylphenyl) cyclopropyl) carbamate (160mg, 0.33mmol) in dioxane (3mL) at 10 ℃ and stirred at RT for 16 h. After completion, the solvent was evaporated. The solid is reacted with Et₂O were triturated together, filtered and dried to give N1- ((trans) -2- (4-cyclopropylphenyl) cyclopropyl) cyclohexane-1, 4-diamine as the hydrochloride salt (60mg) as a white solid.

¹HNMR (400MHz, DMSO d 6): 9.50-9.43(m, 2H), 8.03(brs, 3H), 7.02-6.98(m, 4H), 3.28-3.18(m, 1H), 2.97-2.80(m, 1H), 2.43(brs, 1H), 2.17(brs, 1H), 2.02-1.75(m, 6H), 1.58-1.20(m, 5H), 0.92-0.87(m, 2H), 0.61-0.57(m, 2H); mass (M + H): 271.24.

the following compounds were synthesized according to the general procedures disclosed in the general synthetic route description section, in particular according to the procedures described in example 40, using the corresponding intermediates or commercially available reagents.

Example 41: n1- ((trans) -2- (4- (pyridin-3-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

¹HNMR (400MHz, DMSO d 6): 9.82-9.69(m, 2H), 9.16(m, J =12.8Hz, 1H), 8.78(brs, 1H), 8.68-8.63(m, 1H), 8.19-8.15(m, 3H), 7.95-7.92(m, 1H), 7.81(s, 2H), 7.38(s, 2H), 3.28-3.08(m, 2H), 2.99(brs, 1H), 2.67(brs, 1H), 2.20(brs, 1H), 2.05-2.02(m, 1H), 1.98-1.89(m, 1H), 1.78-1.63(m, 5H), 1.44-1.36(m, 2H); mass (M + H): 308.2. this compound was obtained as the hydrochloride salt.

Example 42: n1- ((trans) -2- (4- (1H-indazol-6-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

¹HNMR(400MHz，DMSO-d6-D₂O exchange): 8.11(s, 1H), 7.86(d, J =8Hz, 1H), 7.75(s, 1H), 7.69(d, J =8Hz, 2H), 7.42(d, J =8Hz, 1H), 7.31(d, J =8Hz, 2H), 3.42(brs, 1H), 3.36-3.20(m, 1H), 3.10-2.98(m, 1H), 2.24-2.15(m, 1H), 2.10-2.00(m, 1H), 1.90(brs, 2H), 1.81(brs, 2H), 1.63-1.35(m, 4H); mass (M + H): 347.2. the compound was obtained as the hydrochloride salt.

Example 43: n1- ((trans) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

¹HNMR(400MHz，CD₃OD): 8.24-8.15(m, 1H), 7.80(d, J =7.6Hz, 2H), 7.43-7.37(m, 2H), 7.09-7.02(m, 1H), 3.58-3.50(m, 1H), 3.46-3.40(m, 1H), 3.22-3.08(m, 1H), 2.77-2.59(m, 1H), 2.40-2.29(m, 1H), 2.24-2.15(m, 1H), 2.13-1.93(m, 4H), 1.80-1.48(m, 4H); mass (M + H): 297.32. the compound was obtained as the hydrochloride salt.

Example 44: 3- (5- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) thiophen-2-yl) phenol

¹HNMR(400MHz，D₂O): 7.32-7.21(m, 2H), 7.20(d, J =8Hz, 1H), 7.11(s, 1H), 6.89-6.88(m, 1H), 6.84(d, J =7.6Hz, 1H), 3.42-3.38(m, 1H), 3.28-3.18(m, 1H), 3.03-2.98(m, 1H), 2.74-2.68(m, 1H), 2.38-2.30(m, 2H), 2.11-2.04(m, 3H), 2.00-1.78(m, 2H), 1.61-1.42(m, 5H); mass (M + H): 329.13. the compound was obtained as the hydrochloride salt.

Example 45: 3- (5- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) thiazol-2-yl) phenol

¹HNMR (400MHz, DMSO d 6): 9.79(brs, 1H), 9.70(brs, 1H), 8.10(brs, 2H), 7.72(s, 1H), 7.30(s, 2H), 6.86(s, 1H), 3.40-3.19(m, 2H), 3.18-2.95(m, 2H), 2.85(brs, 1H), 2.22-2.19(m, 1H), 2.08-1.62(m, 5H), 1.58-1.38(m, 3H); mass (M + H): 330.2. the compound was obtained as the hydrochloride salt.

Example 46: 3- (5- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) pyridin-2-yl) -5-methoxybenzonitrile

Step 1:

AcOH (12.9mg, 0.215mmol) was added to a solution of 3- (5- ((trans) -2-aminocyclopropyl) pyridin-2-yl) -5-methoxybenzonitrile (intermediate BT, 65mg, 0.245mmol) and tert-butyl 4-oxocyclohexylcarbamate (45.9mg, 0.215mmol) in DCE (2mL), stirred at RT for 15min, then sodium triacetoxyborohydride (82mg, 0.387mmol) was added at 0 ℃ and stirred at RT for 5 h. After completion, the solvent was evaporated. The crude residue was dissolved in water (10mL) and washed with NaHCO₃Basified (10mL) and extracted with DCM (2 × 10 mL). The combined organic extracts were washed with water (10mL), brine (10mL), and anhydrous Na₂SO₄Drying, filtration and evaporation gave tert-butyl (4- (((trans) -2- (6- (3-cyano-5-methoxyphenyl) pyridin-3-yl) cyclopropyl) amino) cyclohexyl) carbamate (110 mg). The crude product was used in the next step without further purification.

Step 2:

a solution of HCl in dioxane (1mL) was added to a solution of tert-butyl (4- (((trans) -2- (6- (3-cyano-5-methoxyphenyl) pyridin-3-yl) cyclopropyl) amino) cyclohexyl) carbamate (110mg, 0.238mmol) in dioxane (2mL) at 10 ℃ and stirred at RT for 16 h. After completion, the solvent was evaporated. The residue is taken up in Et₂O were triturated together, filtered and dried to give 3- (5- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) pyridin-2-yl) -5-methoxybenzonitrile as the hydrochloride salt (20mg) as an orange solid.

¹HNMR(400MHz，CD₃OD)：8,70(s，1H)，8.07(d，J=8.8Hz，1H)，7.96(d，J=7.2Hz，1H)，7.93-7.88(m，1H)，7.85-7.80(m，1H)，7.46(s，1H)，3.94(s3H), 3.26-3.16(m, 1H), 2.77-2.68(m, 1H), 2.42-2.25(m, 1H), 2.24-2.10(m, 1H), 2.08-1.90(m, 3H), 1.89-1.80(m, 1H), 1.78-1.27(m, 6H); mass (M + H): 363.30.

the following compounds were synthesized according to the general procedures disclosed in the general synthetic route description section, in particular according to the procedures described in example 46, using the corresponding intermediates.

Example 47: 5- (5- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) pyridin-2-yl) -2-methylphenol

¹HNMR(400MHz，CD₃OD): 8.74(s, 1H), 8.33(d, J =8.4Hz, 1H), 8.17(d, J =8.4Hz, 1H), 7.35(d, J =7.6Hz, 1H), 7.34-7.25(m, 2H), 3.50-3.42(m, 1H), 3.38-3.32(m, 1H), 3.24-3.10(m, 1H), 2.90-2.82(m, 1H), 2.43-2.31(m, 2H), 2.28(s, 3H), 2.23-2.12(m, 2H), 1.84-1.78(m, 1H), 1.76-1.50(m, 5H); mass (M + H): 338.32. the compound was obtained as the hydrochloride salt.

Example 48: n- (4 '- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) -6-methoxy- [1, 1' -biphenyl ] -3-yl) methanesulfonamide

¹HNMR(400MHz，CD₃OD): 7.45(d, J =8Hz, 2H), 7.27-7.19(m, 4H), 7.10-7.02(m, 1H), 3.78(s, 3H), 3.08-3.00(m, 1H), 2.91(s, 3H), 2.55-2.47(m, 1H), 2.40-2.30(m, 2H), 2.24-2.14(m, 2H), 2.05-1.93(m, 2H), 1.66-1.46(m, 6H); mass (M + H): 430.22. is obtained and changed intoCompound, hydrochloride.

Example 49: n- (3- (5- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) thiazol-2-yl) phenyl) -2-cyanobenzenesulfonamide

Step 1:

tert-butyl ((trans) -2- (2-bromothiazol-5-yl) cyclopropyl) (4- ((tert-butoxycarbonyl) amino) cyclohexyl) carbamate (intermediate BQ, 1.25g, 2.42mmol), 3-aminophenylboronic acid (364mg, 2.66mmol) and K₂CO₃(1g, 7.26mmol) in ACN-H₂The solution in O (4: 1) (12mL) was degassed for 30 minutes. Adding Pd (PPh)₃)₄(27.9mg, 0.024mmol), the mixture was stirred at reflux temperature for 16 h. After completion, the reaction mixture was poured into water and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with water (50mL), brine (50mL), and anhydrous Na₂SO₄Drying, filtering and evaporating. The crude product (SiO) was purified by column chromatography₂EtOAc/petroleum ether 3: 7) to give tert-butyl ((trans) -2- (2- (3-aminophenyl) thiazol-5-yl) cyclopropyl) (4- ((tert-butoxycarbonyl) amino) cyclohexyl) carbamate (950mg) as a yellow gummy liquid.

Step 2:

2-Cyanobenzene-1-sulfonyl chloride (361mg, 1.799mmol) was added to a solution of tert-butyl ((trans) -2- (2- (3-aminophenyl) thiazol-5-yl) cyclopropyl) (4- ((tert-butoxycarbonyl) amino) cyclohexyl) carbamate (950mg, 1.799mmol) in pyridine (5mL) at 0 ℃ and stirred at RT for 5 h. After completion, the reaction mixture was poured into water and extracted with EtOAc (2 × 25 mL). The combined organic extracts were washed with water (2 × 25mL), brine, and anhydrous Na₂SO₄Drying, filtering and evaporating. The crude product was purified by preparative HPLC to give (4- ((tert-butoxycarbonyl) amino) cyclohexyl) ((trans)Tert-butyl 2- (2- (3- (2-cyanophenylsulphonamido) phenyl) thiazol-5-yl) cyclopropyl) carbamate (240mg) as a white solid.

And step 3:

a solution of HCl in dioxane (1.2mL) was added to a solution of tert-butyl (4- ((tert-butoxycarbonyl) carbonyl) amino) cyclohexyl) ((trans) -2- (2- (3- (2-cyanophenylsulphonamido) phenyl) thiazol-5-yl) cyclopropyl) carbamate (240mg, 0.34mmol) in dioxane (2.4mL) at 10 ℃ and stirred at RT for 16 h. After completion, the solvent was evaporated and the residue was taken up with Et₂O were triturated together, filtered and dried to give N- (3- (5- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) thiazol-2-yl) phenyl) -2-cyanobenzenesulfonamide as the hydrochloride salt (110mg) as a light brown solid.

¹HNMR (400MHz, DMSO d 6): 11.11(s, 1H), 9.81-9.71(m, 2H), 8.24-8.08(brs, 2H), 8.08(dd, J =7.6 and 4.8Hz, 2H), 7.93(t, J =8Hz, 1H), 7.83(t, J =7.2Hz, 1H), 7.73(s, 1H), 7.66(s, 1H).7.56(d, J =7.2Hz, 1H), 7.38(t, J =8Hz, 1H), 7.18(d, J =8Hz, 1H), 3.4-3.18(m, 2H), 3.05-2.85(m, 2H), 2.2(m, 1H), 2.1-1.8(m, 4H), 1.75(brd, 2H), 1.42(m, 3H); mass (M + H): 494.1.

the following compounds were synthesized according to the general procedures disclosed in the general synthetic route description section, in particular according to the procedures described in example 49, using the corresponding intermediates or commercially available reagents.

Example 50: n- (4 '- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) -2-cyanobenzenesulfonamide

¹HNMR(400MHz，DMSO-d6-D₂O exchange): 8.11(d, J =8Hz, 1H), 8.06(d, J =8Hz, 1H), 7.93(t, J =8Hz,1H) 7.83(t, J =8Hz, 1H), 7.72-7.60(m, 1H), 7.48(d, J =8Hz, 2H), 7.40-7.31(m, 2H), 7.30-7.24(m, 2H), 7.07-7.01(m, 1H), 3.39(brs, 1H), 3.35-3.18(m, 1H), 3.08-2.94(m, 2H), 2.15(brs, 1H), 2.10-2.00(m, 1H), 1.88(brs, 2H), 1.80(brs, 2H), 1.62-1.35(m, 4H); mass (M + H): 487.27. the compound was obtained as the hydrochloride salt.

Example 51: 6-amino-N- (4 '- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) pyridine-3-sulfonamide

Step 1:

6-Nitropyridine-3-sulfonyl chloride (223mg, 1mmol) was added to ((trans) -2- (3 '-amino- [1, 1' -biphenyl) at 0 deg.C]-4-Yl) cyclopropyl) (4- ((tert-butoxycarbonyl) amino) cyclohexyl) carbamic acid tert-butyl ester (intermediate BR, 500mg, 0.95mmol) in pyridine (10mL) was stirred at RT for 16 h. After completion, the reaction mixture was poured into water (25mL) and extracted with EtOAc (2 × 25 mL). The combined organic extracts were washed with water (3 × 25mL), brine (25mL), and anhydrous Na₂SO₄Drying, filtering and evaporating to obtain (4- ((tert-butoxycarbonyl) amino) cyclohexyl) ((trans) -2- (3 '- (6-nitropyridine-3-sulfonylamino) - [1, 1' -biphenyl)]-4-yl) cyclopropyl) carbamic acid tert-butyl ester (580 mg). The crude product was used in the next step without further purification.

Step 2:

ammonium chloride (217mg, 4.1mmol) was added to (4- ((tert-butoxycarbonyl) amino) cyclohexyl) ((trans) -2- (3 '- (6-nitropyridine-3-sulfonylamino) - [1, 1' -biphenyl)]-4-Yl) cyclopropyl) carbamic acid tert-butyl ester (580mg, 0.82mmol) in EtOH (12mL) followed by addition of iron powder (229mg, 4.1mmol) and stirring of the reaction mixture at reflux temperature for 4 h. After completion, through siliconThe reaction mixture was filtered through a pad of celite, the filtrate was concentrated, and the residue was dissolved in water (25mL) and extracted with EtOAc (2 × 25 mL). The combined organic extracts were washed with water (25mL), brine (25mL), and anhydrous Na₂SO₄Drying, filtering and evaporating. The crude product was purified by preparative HPLC to give ((trans) -2- (3 '- (6-aminopyridine-3-sulfonylamino) - [1, 1' -biphenyl)]-4-yl) cyclopropyl) (4- ((tert-butoxycarbonyl) amino) cyclohexyl) carbamic acid tert-butyl ester (190mg) as an off-white solid.

And step 3:

a solution of HCl in dioxane (1mL) was added dropwise to ((trans) -2- (3 '- (6-aminopyridine-3-sulfonylamino) - [1, 1' -biphenyl) at 10 ℃]A solution of tert-butyl (4- ((tert-butoxycarbonyl) amino) cyclohexyl) carbamate (90mg, 0.13mmol) in dioxane (2mL) was stirred at RT for 16 h. After completion, the solvent was evaporated. The residue is taken up in Et₂Grinding together O, filtering and drying to obtain 6-amino-N- (4 '- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl]-3-yl) pyridine-3-sulfonamide as the hydrochloride salt (60mg) as a yellow-white solid.

¹HNMR(400MHz，DMSO-d6-D₂O exchange): 8.24(s, 1H), 7.72(dd, J =8Hz, 2.5Hz, 1H), 7.50(d, J =8Hz, 2H), 7.38-7.32(m, 3H), 7.28(d, J =8Hz, 1H), 7.10-7.05(m, 1H), 6.57(d, J =8Hz, 2H), 3.30-3.19(m, 1H), 3.05-2.98(m, 2H), 2.54-2.46(m, 1H), 2.23-2.13(m, 2H), 2.10-2.00(m, 2H), 1.59-1.36(m, 6H); mass (M + H): 478.06.

example 52: n- (4 '- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) piperazine-1-sulfonamide

This compound was synthesized according to the same method as described in example 51, using tert-butyl 4- (chlorosulfonyl) piperazine-1-carboxylate in step 1 and omitting step 2. Final deprotection (Boc removal, step 3) gave 80mg of the title compound as the hydrochloride salt as a white solid.

¹HNMR(400MHz，DMSO-d6-D₂O exchange): 7.57(d, J =8Hz, 2H), 7.50-7.38(m, 3H), 7.35-7.25(m, 2H), 7.24(d, J =8Hz, 1H), 3.37(brs, 4H), 3.36-3.20(m, 2H), 3.37(brs, 4H), 3.11(brs, 3H), 3.05-2.96(m, 2H), 2.23-2.15(m, 1H), 2.10-2.0(m, 1H), 1.90(brs, 2H), 1.81(brs, 2H), 1.63-1.35(m, 4H); mass (M + H): 470.33.

example 53: n1- ((trans) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine

Step 1:

tert-butyl 4-oxocyclohexylcarbamate (493mg, 2.31mmol) was added to a solution of (trans) -2-fluoro-2-phenylcyclopropylamine (intermediate BJ, 350mg, 2.31mmol) in DCE (7mL), the mixture was stirred at RT for 10min, then cooled to 0 ℃. Sodium triacetoxyborohydride (978mg, 4.62mmol) was added and stirring continued at RT for 15min. After completion, the reaction mixture was poured into ice water and extracted with DCM (2 × 25 mL). The combined organic extracts were washed with water (10mL), brine (10mL), and anhydrous Na₂SO₄And (5) drying. The filtrate was used for the next step without evaporation.

A solution of HCl in dioxane (1.6mL) was added to a solution of tert-butyl (4- (((trans) -2-fluoro-2-phenylcyclopropyl) amino) cyclohexyl) carbamate in DCM (3.2mL) and stirred at RT for 16 h. Upon completion, the solvent was evaporated and the crude residue was triturated with ether (10mL) and hexane (10mL) to give N1- ((trans) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine as the hydrochloride salt (300mg) as a yellow solid.

Step 2:

2N NaOH solutions (5.8mL) and (Boc) were added at 10 deg.C₂O (0.54mL, 2.26mmol) was added to a solution of N1- ((trans) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine (290mg, 0.906mmol) in 1,4 dioxane (10vols) and stirred at room temperature for 4 h. Upon completion, the reaction mixture was diluted with water (10mL) and extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with water (10mL), brine (10mL), and anhydrous Na₂SO₄Drying, filtering and evaporating. The crude product was purified by preparative HPLC to give tert-butyl (4- ((tert-butoxycarbonyl) amino) cyclohexyl) ((trans) -2-fluoro-2-phenylcyclopropyl) carbamate (140mg) as a white solid.

And step 3:

a solution of HCl in dioxane (0.7mL) was added to a solution of tert-butyl (4- ((tert-butoxycarbonyl) amino) cyclohexyl) ((trans) -2-fluoro-2-phenylcyclopropyl) carbamate (140mg, 0.312mmol) in dioxane (1.4mL) at 0 ℃ and stirred at RT for 6 h. Upon completion, the solvent was evaporated and the residue was triturated with ether (5mL) then N-pentane (5mL) to give N1- ((trans) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine as the hydrochloride salt (80mg) as an off-white solid.

¹HNMR(400MHz，D₂O): 7.49(s, 2H), 7.42(s, 3H), 3.60-3.43(M, 2H), 3.22-3.12(M, 2H), 2.33-2.18(M, 3H), 1.98-1.91(M, 3H), 1.68-1.45(M, 3H), mass (M + H): 249.17.

example 54: n1- ((cis) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine

This compound was synthesized according to the same method as described in example 53, starting from (cis) -2-fluoro-2-phenylcyclopropylamine (intermediate BI), to give 80mg as the hydrochloride salt as an off-white solid.

¹HNMR(400MHz，D₂O): 7.79(s, 2H), 7.62(s, 3H), 3.69-3.53(M, 2H), 3.4-3.18(M, 2H), 2.39(s, 1H), 2.28-2.08(M, 3H), 2.02-1.81(M, 4H), 1.68-1.45(M, 3H), mass (M + H): 249.17.

example 55: n1- ((trans) -2- (4- ((3- (piperazin-1-yl) benzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

Step 1:

adding K at 0 DEG C₂CO₃(1.1g, 8.0mmol) was added to a solution of tert-butyl ((trans) -2- (4-hydroxyphenyl) cyclopropyl) carbamate (intermediate BL, 1g, 4.0mmol) and 1-bromo-3- (bromomethyl) benzene (997mg, 4.0mmol) in DMF (10mL) and stirred at RT for 18 h. After completion, the reaction mixture was poured into ice water (20mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with water (20mL), brine (20mL), and anhydrous Na₂SO₄Drying, filtering and evaporating. The crude product (SiO) was purified by column chromatography₂EtOAc/petroleum ether 2: 8) to give tert-butyl ((trans) -2- (4- ((3-bromobenzyl) oxy) phenyl) cyclopropyl) carbamate (1.2g) as an off-white solid.

Step 2:

a solution of HCl in dioxane (10mL) was added dropwise to a solution of tert-butyl ((trans) -2- (4- ((3-bromobenzyl) oxy) phenyl) cyclopropyl) carbamate (1.2g, 2.8mmol) in dioxane (5mL) at 15 ℃ and stirred at RT for 2 h. After completion, the solvent was evaporated. The residue was dissolved in water (15mL) and NaHCO was used₃The solution (5mL) was basified and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with water (20mL), brine (20mL), and anhydrous Na₂SO₄Drying, filtration and evaporation gave (trans) -2- (4- ((3-bromobenzyl) oxy) phenyl) cyclopropylamine (800 mg). The crude product was used in the next step without further purification.

And step 3:

acetic acid (0.17mL, 2.515mmol) was added to a solution of (trans) -2- (4- ((3-bromobenzyl) oxy) phenyl) cyclopropylamine (800mg, 2.51mmol) and tert-butyl 4-oxocyclohexylcarbamate (537mg, 2.515mmol) in DCE (20 mL). Sodium triacetoxyborohydride (960mg, 4.52mmol) was added at 0 ℃ and the mixture was stirred at RT for 4 h. Upon completion, the reaction mixture was diluted with DCM (20mL) and NaHCO₃The aqueous solution was then washed with water (10mL), brine (10 mL). With anhydrous Na₂SO₄The organic phase was dried, filtered and evaporated. The crude product (SiO) was purified by column chromatography₂EtOAc/petroleum ether 6: 4) to give tert-butyl (4- (((trans) -2- (4- ((3-bromobenzyl) oxy) phenyl) cyclopropyl) amino) cyclohexyl) carbamate (900 mg).

And 4, step 4:

NaOH (310mg, 7.76mmol) was added to a solution of tert-butyl (4- (((trans) -2- (4- ((3-bromobenzyl) oxy) phenyl) cyclopropyl) amino) cyclohexyl) carbamate (1.0g, 1.94mmol) in 1, 4-dioxane/water (4: 1) at 10 ℃. Then adding Boc₂O (830mg, 3.88mmol), and the mixture is stirred at RT for 18 h. After completion, the reaction mixture was poured into ice water (20mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with water (20mL), brine (20mL), and anhydrous Na₂SO₄Drying, filtering and evaporating. The crude product (SiO) was purified by column chromatography₂EtOAc/petroleum ether 3: 7) to give tert-butyl ((trans) -2- (4- ((3-bromobenzyl) oxy) phenyl) cyclopropyl) (4- ((tert-butoxycarbonyl) amino) cyclohexyl) carbamate (600 mg).

And 5:

NaO at RT^tBu (141mg, 1.46mmol) was added to ((trans) -2- (4- ((3-bromobenzyl) oxy) phenyl) cyclopropyl) (4- ((tert-butoxycarbonyl)) Amino) cyclohexyl) carbamic acid tert-butyl ester (600mg, 0.975mmol) and piperazine-1-carboxylic acid tert-butyl ester (363mg, 1.95mmol) in dioxane solution (15mL) which was then degassed with argon for 15min. Adding Pd₂(dba)₃(44.6mg, 0.0487mmol) followed by xanthphos (169mg, 0.292mmol) and degassing repeated for 15min. The reaction mixture was stirred at reflux temperature for 18 h. After completion, the mixture was filtered through a pad of celite, and the filtrate was concentrated. The residue was dissolved in water (20mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with water (20mL), brine (20mL), and anhydrous Na₂SO₄Drying, filtering and evaporating. The crude product was purified by column chromatography (neutral alumina, EtOAc/petroleum ether 2: 8) to give tert-butyl 4- (3- ((4- ((trans) -2- ((tert-butoxycarbonyl) (4- ((tert-butoxycarbonyl) amino) cyclohexyl) amino) cyclopropyl) phenoxy) methyl) phenyl) piperazine-1-carboxylate (260mg) as a white solid.

Step 6:

a solution of HCl in dioxane (3mL) was added to a solution of tert-butyl 4- (3- ((4- ((trans) -2- ((tert-butoxycarbonyl) (4- ((tert-butoxycarbonyl) amino) cyclohexyl) amino) cyclopropyl) phenoxy) methyl) phenyl) piperazine-1-carboxylate (150mg, 0.208mmol) in 1, 4-dioxane solution (2mL) at 10 ℃ and stirred at RT for 6 h. Upon completion, the solvent was evaporated and the residue triturated with EtOAc (4mL) then N-hexane (2mL) to give N1- ((trans) -2- (4- ((3- (piperazin-1-yl) benzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine as the hydrochloride salt (80mg) as a light yellow solid.

¹HNMR(400MHz，D₂O): 7.40(t, J =8Hz, 1H), 7.19(s, 1H), 7.18-7.07(m, 4H), 7.01(d, J =8Hz, 2H), 5.11(s, 2H), 3.6-3.3(m, 9H), 3.28-3.18(m, 1H), 3.95-3.84(m, 1H), 2.50-2.39(m, 1H), 2.32-2.24(m, 1H), 2.19-2.11(m, 1H), 2.09-1.99(m, 1H), 1.98-1.77(m, 3H), 1.62-1.33(m, 4H); mass (M + H): 421.28.

the following compounds were synthesized according to the general procedures disclosed in the general synthetic route description section, in particular according to the procedure described in example 55, using the corresponding intermediates or commercially available reagents, but omitting steps 4 and 5.

Example 56: n1- ((trans) -2- (4- (pyridin-3-ylmethoxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

¹HNMR(400MHz，DMSO-d6-D₂O exchange): 8.79(s, 1H), 8.68(s, 1H), 8.31-8.24(m, 1H), 7.83-75(m, 1H), 7.20-7.10(m, 2H), 7.01(d, J =8.4Hz, 2H), 5.23(s, 2H), 3.42-3.17(m, 2H), 3.08-2.95(m, 1H), 2.94-2.83(m, 1H), 2.48-2.35(m, 1H), 2.22-2.10(m, 1H), 2.09-1.98(m, 1H), 1.97-1.72(m, 3H), 1.55-1.38(m, 3H), 1.37-1.25(m, 1H); mass (M + H): 338.19. the compound was obtained as the hydrochloride salt.

Example 57: n1- ((trans) -2- (4- ((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

¹HNMR (400MHz, DMSO d 6): 9.55(brd, 2H), 8.1(brs, 3H), 7.58(t, 1H), 7.62(d, 1H), 7.28(m, 2H), 7.18(d, 2H), 6.98(d, 2H), 5.1(s, 2H), 3.25-3.15(m, 2H), 2.88-2.81(m, 2H), 2.45(brs, 1H), 2.15(brs, 1H), 2.05-1.7(m, 5H), 1.6-1.3(m, 3H), 1.25(d, 1H); mass (M + H): 355.25. the compound was obtained as the hydrochloride salt.

Example 58: n1- ((trans) -2- (6- ((3-methylbenzyl) amino) pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine

Step 1:

a solution of tert-butyl ((trans) -2- (6-bromopyridin-3-yl) cyclopropyl) (4- ((tert-butoxycarbonyl) amino) cyclohexyl) carbamate (intermediate BP, 300mg, 0.58mmol), m-tolylmethylamine (78mg, 0.64mmol), sodium tert-butoxide (83mg, 0.87mmol) and BINAP (108mg, 0.17mmol) in 1, 4-dioxane solution (6mL) was degassed for 10min. Tris (dibenzylideneacetone) dipalladium (0) (26mg, 0.029mmol) was added and the reaction mixture was stirred at 100 ℃ for 16 h. Upon completion, the reaction mixture was poured into cold water (15mL) and extracted with EtOAc (2 × 10 mL). The combined organic extracts were washed with water (10mL), brine (10mL), and anhydrous Na₂SO₄Drying, filtering and evaporating. By column chromatography (SiO)₂) Using EtOAc: the crude residue was purified with petroleum ether (3: 7) to give tert-butyl (4- ((tert-butoxycarbonyl) amino) cyclohexyl) ((trans) -2- (6- ((3-methylbenzyl) amino) pyridin-3-yl) cyclopropyl) carbamate (100mg) as a white solid.

Step 2:

a solution of HCl in 1, 4-dioxane (1mL) was added to a solution of tert-butyl (4- ((tert-butoxycarbonyl) amino) cyclohexyl) ((trans) -2- (6- ((3-methylbenzyl) amino) pyridin-3-yl) cyclopropyl) carbamate (100mg, 0.181mmol) in dioxane solution (2mL) at 10 ℃ and the reaction mixture was stirred at RT for 16 h. After completion, the solvent was evaporated. The solid residue is taken up in Et₂Trituration of O with hexanes provided N1- ((trans) -2- (6- ((3-methylbenzyl) amino) pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine as the hydrochloride salt (60mg) as a brown solid.

¹HNMR(400MHz，D₂O)：7.68(d，J=9.6Hz，1H)，7.63(s，1H)，7.30(t，J=8Hz，1H)，7.24-7.16(m，3H)，6.99(d，J=9.4Hz，2H)，4.56(s，2H)，3.58-3.47(m，1H)，3.42-3.31(m，1H)，3.27-3.17(m, 1H), 3.05-2.95(m, 1H), 2.52-2.41(m, 1H), 2.30(s, 3H), 2.27-2.23(m, 1H), 2.20-2.12(m, 2H), 2.00-1.80(m, 2H), 1.64-1.39(m, 4H); mass (M + H): 351.41.

example 59: 3- ((5- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) pyridin-2-yl) amino) benzonitrile

Step 1:

to a solution of tert-butyl (trans) -2- (6-bromopyridin-3-yl) cyclopropylcarbamate (intermediate M, 250mg, 0.798mmol), 3-aminobenzonitrile (113mg, 0.957mmol) and sodium tert-butoxide (115mg, 1.197mmol) in 1, 4-dioxane solution (5mL) was degassed for 30min, then tris (dibenzylideneacetone) dipalladium (0) (36mg, 0.039mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (xanthphos) (138mg, 0.238mmol) were added and the reaction heated at 80 ℃ for 1 h. Upon completion, the solvent was evaporated, the residue was dissolved in water (10mL) and extracted with EtOAc (2 × 20 mL). The combined extracts were washed with water (10mL), brine (10mL), and anhydrous Na₂SO₄Drying, filtering and evaporating. By column chromatography (SiO)₂) The crude residue was purified using EtOAc: petroleum ether (2: 8) to give tert-butyl ((trans) -2- (6- ((3-cyanophenyl) amino) pyridin-3-yl) cyclopropyl) carbamate (100mg) as a yellow solid.

Step 2:

a solution of HCl in 1,4 dioxane (1mL) was added to a solution of tert-butyl ((trans) -2- (6- ((3-cyanophenyl) amino) pyridin-3-yl) cyclopropyl) carbamate (100mg, 0.285mmol) in 1, 4-dioxane solution (1mL) at 0 ℃ and stirred at RT for 4 h. Upon completion, the solvent was evaporated and the residue was triturated with ether (5mL) then n-pentane (5mL) to give 3- ((5- ((trans) -2-aminocyclopropyl) pyridin-2-yl) amino) benzonitrile as the hydrochloride salt (80mg) as a pale yellow solid.

And step 3:

AcOH (11.46mg, 0.191mmol) was added to a solution of 3- ((5- ((trans) -2-aminocyclopropyl) pyridin-2-yl) amino) benzonitrile (55mg, 0.191mmol) and tert-butyl 4-oxocyclohexylcarbamate (40.68mg, 0.191mmol) in DCE (1mL) and stirred at RT for 15min, then sodium triacetoxyborohydride (72.8mg, 0.343mmol) was added at 0 ℃ and stirred at RT for 5 h. After completion, the solvent was evaporated. The crude residue was dissolved in water (10mL) and washed with NaHCO₃Basified (10mL) and extracted with DCM (2 × 10 mL). The combined extracts were washed with water (10mL), brine (10mL), and anhydrous Na₂SO₄Drying, filtration and evaporation gave tert-butyl (4- (((trans) -2- (6- ((3-cyanophenyl) amino) pyridin-3-yl) cyclopropyl) amino) cyclohexyl) carbamate (75mg) as a pale yellow oil. The crude product was used in the next step without further purification.

And 4, step 4:

a solution of HCl in 1, 4-dioxane (1mL) was added to a solution of tert-butyl (4- (((trans) -2- (6- ((3-cyanophenyl) amino) pyridin-3-yl) cyclopropyl) amino) cyclohexyl) carbamate (75mg, 0.167mmol) in 1, 4-dioxane solution (2mL) at 10 ℃ and stirred at RT for 16 h. After completion, the solvent was evaporated. The solid is reacted with Et₂And grinding and drying the O together to obtain a crude product. The crude product was purified by preparative HPLC to give 3- ((5- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) pyridin-2-yl) amino) benzonitrile as the hydrochloride salt (28mg) as a yellow-white sticky solid.

¹HNMR(400MHz，DMSO-d6-D₂O exchange): 8.35(s, 1H), 8.15(s, 1H), 7.78(d, J =8Hz, 1H), 7.54-7.42(m, 2H), 7.31(d, J =8Hz, 1H), 6.85(d, J =8.8Hz, 1H), 3.45-3.17(m, 2H), 3.08-2.93(m, 2H), 2.44-2.34(m, 1H), 2.22-2.10(m, 1H), 2.09-1.98(m, 1H), 1.97-1.70(m, 3H), 1.55-1.32(m, 4H); mass (M + H): 348.20.

the following compounds may be synthesized according to the general methods disclosed in the general synthetic route descriptions section, including schemes 1, 2, 3, 4, 5, 6, 7, or 8 and the methods described in the examples above.

Example 60: n1- ((trans) -2- (4 '-chloro- [1, 1' -biphenyl ] -4-yl) cyclopropyl) cyclohexane-1, 4-diamine

Example 61: n1- ((trans) -2- (3 '-chloro- [1, 1' -biphenyl ] -4-yl) cyclopropyl) cyclohexane-1, 4-diamine

Example 62: 4 '- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-ol

Example 63: n- (4 '- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) methanesulfonamide

Example 64: n1- ((trans) -2- (4- ((3-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 65: n1- ((trans) -2- (4- ((4-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 66: N1-methyl-N4- ((trans) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) cyclohexane-1, 4-diamine

Example 67: n1- ((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) -N4-methylcyclohexane-1, 4-diamine

Example 68: n1- ((trans) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) cyclobutane-1, 3-diamine

Example 69: n1- ((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) cyclobutane-1, 3-diamine

Example 70: n1- ((trans) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) -2, 3-dihydro-1H-indene-1, 3-diamine

Example 71: n1- ((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) -2, 3-dihydro-1H-indene-1, 3-diamine

Example 72: n1- ((1S, 2S) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine

Example 73: n1- ((1R, 2R) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine

Example 74: n1- ((Trans) -2- (Naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine

Example 75: n1- ((trans) -2- (o-tolyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 76: n1- ((trans) -2- (4- (trifluoromethyl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 77: n1- ((trans) -2- (4-methoxyphenyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 78: n1- ((trans) -2- (2-fluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 79: n1- ((trans) -2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 80: n1- ((trans) -2-methyl-2-phenylcyclopropyl) cyclohexane-1, 4-diamine

Example 81: (cis) -N1- ((1S, 2R) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine

Example 82: (trans) -N1- ((1R,2S) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine

Example 83: (cis) -N1- ((1R,2S) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine

Example 84: (trans) -N1- ((1S, 2R) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine

Example 85: (cis) -N1- ((1S, 2R) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine

Example 86: (trans) -N1- ((1R,2S) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine

Example 87: (cis) -N1- ((1R,2S) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine

Example 88: (trans) -N1- ((1S, 2R) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine

Example 89: (cis) -N1- ((1S, 2R) -2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 90: (trans) -N1- ((1R,2S) -2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 91: (cis) -N1- ((1R,2S) -2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 92: (trans) -N1- ((1S, 2R) -2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 93: (cis) -N1- ((1S, 2R) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine

Example 94: (trans) -N1- ((1R,2S) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine

Example 95: (cis) -N1- ((1R,2S) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine

Example 96: (trans) -N1- ((1S, 2R) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine

Example 97: (cis) -N1- ((1S, 2R) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 98: (trans) -N1- ((1R,2S) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 99: (cis) -N1- ((1R,2S) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 100: (trans) -N1- ((1S, 2R) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 101: n- (4 '- ((1R,2S) -2- (((cis) -4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) piperazine-1-sulfonamide

Example 102: n- (4 '- ((1S, 2R) -2- (((trans) -4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) piperazine-1-sulfonamide

Example 103: n- (4 '- ((1S, 2R) -2- (((cis) -4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) piperazine-1-sulfonamide

Example 104: n- (4 '- ((1R,2S) -2- (((trans) -4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) piperazine-1-sulfonamide

Example 105: (cis) -N1- ((1S, 2R) -2- (4- ((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 106: (trans) -N1- ((1R,2S) -2- (4- ((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 107: (cis) -N1- ((1R,2S) -2- (4- ((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

Example 108: (trans) -NI- ((1S, 2R) -2- (4- ((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine

Biological assay

Example 109: bioassay-inhibition of LSD1

The compounds of the invention may be tested for their ability to inhibit LSD 1. The ability of the compounds of the invention to inhibit LSD1 can be tested as follows. Human recombinant LSD1 protein was purchased from BPS Bioscience Inc (catalog reference No. 50100: human recombinant LSD1, GenBank accession No. NM-015013, amino acid 158-terminal with N-terminal GST tag, MW: 103 kDa). To monitor the catalytic activity of LSD1 enzyme and/or its rate of inhibition by one or more inhibitors of interest, dimethylated H3-K4 peptide (Anaspec) was selected as a substrate. By usingRed Hydrogen peroxide/peroxidase assay kit (Invitrogen) measures H produced during the catalytic process₂O₂For evaluation of demethylase activity under aerobic conditions.

Briefly, a fixed amount of LSD1 was incubated on ice for 15 minutes in the absence and/or presence of at least 8 3-fold serial dilutions of various concentrations of inhibitor (e.g., 0-75 μ M, depending on inhibitor strength). Tranylcypromine (Biomol International) was used as a control for inhibition. In the experiments, inhibitors at each concentration were tested in duplicate. After the enzyme has interacted with the inhibitor, K is reacted_MThe dimethylated H3-K4 peptide was added to each reaction and the experiment was allowed to proceed in the dark at 37 ℃ for 30 minutes. The enzymatic reaction was set in 50mM sodium phosphate, pH7.4 buffer. At the end of the incubation, the recommendations provided by the supplier (Invitrogen) will be followedRed reagent and Horseradish Peroxidase (HPR) solution were added to the reaction and incubated at room temperature in the darkThe incubation was carried out for another 5 minutes. Mix 1 μ M H₂O₂The solution was used as a control for the efficiency of the kit. H was monitored by fluorescence (excitation at 540nm, emission at 590 nm) using a fully automated quantitative plotter microplate reader (Infinite200, Tecan) as a result of the assay₂O₂In the presence ofThe Red reagent is converted to resorufin. Using arbitrary units for measuring H produced in the absence and/or presence of inhibitors₂O₂The level of (c).

Maximum demethylase activity of LSD1 was obtained in the absence of inhibitor and background fluorescence was corrected in the absence of LSD 1. IC50 values for each inhibitor were calculated using GraphPad Prism software.

The results provided in table 1 below show the results of the LSD1 inhibition study for a number of example compounds. In table 2, IC50 values are shown for all examples tested in this trial. Parnate (tranylcyclopropylamine; i.e., 2-trans-phenylcyclopropylamine) was found to have an IC50 value of 35. + -.10 micromolar. Studies have shown that the compounds of the present invention have surprisingly effective LSD1 inhibition.

Example 110: bioassay-monoamine oxidase assay for determining the selectivity of the Compounds of the invention for LSD1

Human recombinant monoamine oxidase proteins MAO-A and MAO-B were purchased from sigmA Aldrich. MAOs catalyze the oxidative deamination of primary, secondary and tertiary amines. To monitor MAO enzyme activity and/or their rate of inhibition by the inhibitor of interest, a fluorescence-based (inhibitor) screening assay was set up. 3- (2-aminophenyl) -3-oxopropylamine (kynuramine dihydrobromic acid, Sigma Aldrich), a non-fluorescent compound, was selected as substrate. Kynuramine is A non-specific substrate for both MAO-A and MAO-B activity. Kynuramine is converted to 4-hydroxyquinoline (4-HQ), a fluorescent product obtained, while undergoing oxidative deamination due to MAO activity.

Monoamine oxidase activity was evaluated by measuring the conversion of kynuramine to 4-hydroxyquinoline. The assay was performed in a final volume of 100. mu.L in a 96-well black plate (Corning) with a clear bottom. The assay buffer was 100mM HEPES, pH 7.5. Each experiment was performed in duplicate in the same experiment.

Briefly, A fixed amount of MAO (0.25 μ g for MAO-A and 0.5 μ g for MAO-B) was incubated on ice for 15 minutes in the absence and/or presence of at least 8 3-fold serial dilutions. Clorgyline and selegiline (SigmA Aldrich) were used as controls for MAO-A and MAO-B inhibition, respectively.

After allowing to interact with the inhibitor, K is added_MKynuramine (D) was added to each reaction for MAO-B and MAO-A assays, respectively, and the reactions were allowed to proceed in the dark at 37 ℃ for 1 hour. Oxidative deamination of the substrate was stopped by adding 50 μ of L NaOH 2N. Conversion of kynuramine to 4-hydroxyquinoline was monitored by fluorescence (excitation at 320nm, emission at 360 nm) using a fully automated quantitative plotter microplate reader (Infinite200, Tecan). Any unit is used to measure the level of fluorescence produced in the absence and/or presence of the inhibitor.

Maximum oxidative deamination activity was obtained by determining the amount of 4-hydroxyquinoline formed by deamination of kynuramine in the absence of inhibitor and calibrating for background fluorescence in the absence of MAO enzyme. IC50 values for each inhibitor were calculated using GraphPad Prism software.

The results obtained in the bioassay of examples 109 and 110 using the compounds of the present invention are shown below.

Example numbering	MAO-A(Ki)	MAO-B(Ki)	LSD1(Ki)
				1	I	I	IV
2	I	I	III
				3	I	I	III
4	I	I	IV
				5	I	I	IV
8	I	II	III
				11	II	II	III
12	II	II	IV
				13	II	II	III
14	II	II	III
				15	II	II	IV

Table 1: summary of data from MAO-A, MAO-B and LSD1 inhibition studies

The range of Ki values reported in Table 1 for MAO-A, MAO-B and LSD1 are: i ═ 40 μ M; II is 1 μ M to 40 μ M; III-0.1 μ M-1 μ M; IV is 0.001 μ M to 0.1 μ M. The term Ki value as used herein designates the IC50 value, i.e. the concentration required for half-maximal (50%) inhibition of the corresponding target (MAO-A, MAO-B or LSD 1).

In general, the compounds of the present invention were found to have IC50 values, particularly for LSD1, lower than for MAO-A and MAO-B. For some of the compounds of the examples, the IC50 value of LSD1 was below 0.1 μ M.

When examples 109(LSD1 inhibition) and 110(MAO-A and B inhibition) were tested in the assay, the specific IC50 values obtained for the compounds disclosed in the examples are shown in table 2 below:

as the data in the above table show, the compounds of the invention are very potent LSD1 inhibitors with IC50 values in many cases below 100nM or even below 50 nM. In addition, the compounds show high selectivity compared to MAO-A and MAO-B, with IC50 values for LSD1 generally > 100-fold more effective than the corresponding IC50 values for MAO-A and MAO-B.

Example 111: cell assay-induction of THP-1 leukemia cell differentiation

Acute Myeloid Leukemia (AML) is characterized by the presence of rapidly dividing leukemia cells with a cessation of maturation. Due to the induction of terminal differentiation, AML cells lose proliferative capacity and die without direct cytotoxic effects.

By analyzing the ability to induce CD11b membrane expression on THP-1 cells, we evaluated LSD1 inhibitors for their ability to induce terminal monocyte differentiation of the MLL-AF9AML cell line.

The following tests were carried out:

THP-1 cells were established from peripheral blood of 1 year old boys with acute monocytic leukemia that relapsed in 1978. They carry t (9; 11) (p 21; q23), giving rise to the MLL-MLLT3(MLL-AF9) fusion gene. Such cell lines can undergo monocyte differentiation when treated with a suitable stimulus. THP-1 was purchased from DSMZ GmbH (Deutsche Sammlung von Mikroorganismen und Zellkulturen) and cultured in RPMI1640 medium containing 10% fetal bovine serum.

In this experiment, 150,000 THP-1 cells were seeded in 1ml of complete medium in 6-well tissue culture plates. Serial dilutions of the compounds were prepared in DMSO and then further diluted with complete medium to generate a solution at a concentration 2 times the final concentration at which the cells were exposed. 1ml of these 2 × concentration solutions was added to the cells. The final DMSO content must be the same in all wells and must be kept below 0.1% v/v (usually 0.01-0.02% v/v) because higher DMSO contents may induce THP-1 cell differentiation.

Cells were kept in the presence of test compound at 37 ℃ for 96h in a 5% C02 atmosphere. After this treatment period, cells were collected, washed 2 times with PBS buffer, and placed in a V-bottom 96-well plate. Each treated sample was divided into 2 portions. One was stained with phycoerythrin-labeled anti-CD 11b antibody (clone ICRF44, available from eBiosciences) and the other with a control antibody of one type (mouse IgG) labeled with the relevant phycoerythrin₁Purchased from eBiosciences). The samples were incubated in the dark at 4 ℃ for 30-60 minutes and washed 3 times with PBS buffer containing 1% fetal bovine serum.

Samples were analyzed by flow cytometry with a blue laser (488 nm). The emitted fluorescence was detected and quantified using an 575/30 nm filter. The percentage of CD11b positive cells compared to isotype control antibody stained cells was determined as an indicator of monocyte differentiation. EC50 values were calculated by nonlinear regression analysis.

The results obtained using the compounds of the invention in this test are shown in table 3 below.

These results show that the compounds of the invention have extremely potent activity in inducing differentiation of leukemic THP-1 cells, indicating that these compounds are particularly useful in the treatment or prevention of leukemia.

Previous reports of LSD1 have found that it is involved in cell differentiation and growth. Some studies have implicated LSD1 as a therapeutic target for cancer. Huang et al (2007) PNAS 104: 8023-8028 polyamine inhibitors of LSD1 were found to suitably induce the re-expression of genes that are aberrantly silenced in Cancer cells and in particular colorectal cancers (Huang et al Clin Cancer Res. (2009) Dec 1; 15 (23): 7217-28.Epub2009Nov24. PMID: 19934284). Scoumann et al ((2007) J.biol.chem.May25; 282 (21): 15471-5) found that defects in LSD1 resulted in partial cell cycle arrest in G2/M and sensitized cells to growth inhibition induced by DNA damage. Kahl et al ((2006) Cancer Res.66 (23): 11341-7.) found that LSD1 expression correlated with prostate Cancer invasion. Metzger et al ((2005) Nature,437(7057), 436-429) reported that siRNA and LSD1 of pargyline modulate Androgen Receptor (AR) and may have therapeutic potential in cancers where AR plays a role, such as prostate, testicular, and brain cancers. Lee et al ((2006) chem.Bi0l.13: 563-567) reported that tranylcypromine derepresses Egr-1 gene expression in some cancer lines. There is accumulating evidence that Egr-1 is a tumor suppressor gene in many contexts (see, e.g., Calogero et al (2004) Cancer Cell International 4: 1 exogenous expression leading to growth arrest and eventual Cell death in the original Cancer Cell lines; Lucerna et al (2006) Cancer research66(13), 6708-6713 show that sustained expression of Egr-1 causes anti-angiogenic effects and inhibits tumor growth in some models; Ferraro et al ((2005) j.clin.oncol.mar20; 23 (9): 1921-6) report that Egr-1 is down regulated and potentially more resistant to therapy in lung Cancer patients at higher risk of recurrence; thus, increasing Egr-1 expression by inhibition of LSD1 is a therapeutic approach for some cancers; recent studies also relate to LSD1 in brain Cancer (Schulte et al (2009) Cancer et al (Cancer) 69; 5. 2065: 206nom et al, (2010),31(3): 512-20, electronic edition, 30 months 12 in 2009 [ electronic edition before printing ] PMID: 20042638), lung, bladder and colorectal Cancer (Hayami et al (2011), Int J Cancer, 128 (3): 574-86, PMID: 20333681) and leukemia (Binda et al (2010), J Am Chem Soc, 132 (19): 6827-33, PMID: 20415477) of the LSD 1.

Thus, there is substantial evidence for LSD1 in many cancers, suggesting that LSD1 is a therapeutic target for cancer. The inventors of the present invention have discovered a class of LSD1 inhibitors that may be useful in the treatment of diseases in which LSD1 is implicated as a therapeutic target, e.g., cancer. Thus, the (hetero) arylcyclopropylamine compounds of the invention may be useful in the treatment of such diseases.

Recent studies have also implicated LSD1 in viral infection and reactivation. In particular, it was demonstrated that siRNA knockdown of pharmacological inhibitors of LSD1, such as tranylcypromine and LSD1, resulted in reduced viral infectivity and reduced reactivation after latency (Liang et al (2009) nat. Med.15 (11): 1312-1317). Thus, it is believed that the compounds of the present invention may be useful in the treatment or prevention of viral infections. In addition, it is believed that the compounds of the present invention may treat or prevent viral reactivation after incubation.

Thus, without being bound by theory, the inventors have identified a new class of cyclopropylamine-based LSD1 inhibitors with surprising potency and selectivity for the biologically relevant target LSD1 in tumors and other diseases.

All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The mere mentioning of publications and patent applications is not an admission that they are prior art to the present application.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims.

Claims

1. A compound of formula I

Wherein:

a is phenyl, naphthyl, pyridyl, thiazolyl or thienyl, wherein said phenyl, said naphthyl, said pyridyl, said thiazolyl or said thienyl is optionally substituted with one or more R¹Substitution;

b is hydrogen or-L-E;

e is phenyl, pyridyl, pyrazolyl or indazolyl, wherein said phenyl, said pyridyl, said pyrazolyl or said indazolyl are optionally substituted with one or more R²Substitution;

l is a bond, -NH-, -CH₂-NH-or-CH₂-O-, wherein said-CH₂-NH-and-CH₂the-O-group is bonded to ring A through the N or O atom, respectively, and through the-CH group₂-NH-and-CH₂-CH of the-O-group₂-the group connecting ring E;

d is selected from D1, D2, D3, D4 and D5

Wherein the cyclobutyl ring comprised in D1, the cyclopentyl ring comprised in D2, the cyclohexyl ring comprised in D3, the cycloheptyl ring comprised in D4 and the cyclohexyl ring comprised in D5 are optionally substituted by one or more R⁴Substitution;

R¹each independently selected from C_1-8Alkyl radical, C_3-6Cycloalkyl, hydroxy, halogen, halogeno C_1-8Alkyl, halo C_1-8Alkoxy and C_1-8An alkoxy group;

R²each independently selected from C_1-8Alkyl, 3-8 membered monocyclic heterocyclic group, hydroxy, halogen, halogeno C_1-8Alkyl, halo C_1-8Alkoxy, cyano, N-sulfonylamino and C_1-8An alkoxy group;

R³is selected from-NR⁷R⁸、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-OH、-CONR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

R⁴Each independently is C_1-8An alkyl group;

R⁷each and R⁸Each independently selected from hydrogen and C_1-8Alkyl, or R⁷And R⁸Together with the N atom to which it is attached form a saturated 3-to 7-membered heterocyclic ring optionally comprising another heteroatom selected from N, O and S, wherein one or more C atoms on the heterocyclic ring are optionally oxidized to a CO group, wherein if present, one or more S atoms on the heterocyclic ring are optionally independently oxidized to a SO group or SO₂And wherein said heterocycle is optionally substituted with one or more

R¹¹Substitution;

R⁹each is hydrogen;

R¹⁰each independently is C_1-8An alkyl group;

R¹¹each is-NR¹²R¹³；

R¹²Each and R¹³Each is hydrogen;

R^wselected from hydrogen, halogen and C_1-4An alkyl group; and is

R^x、R^yAnd R^zEach is hydrogen;

or a salt thereof.

2. A compound of formula I

Wherein:

b is hydrogen or-L-E;

d is selected from D1, D2, D3, D4 and D5

R⁴Each independently is C_1-8An alkyl group;

R¹¹Substitution;

R⁹each is hydrogen;

R¹⁰each independently is C_1-8An alkyl group;

R¹¹each is-NR¹²R¹³；

R¹²Each and R¹³Each is hydrogen;

R^wselected from hydrogen, halogen and C_1-4An alkyl group;

R^x、R^yand R^zEach is hydrogen; and is

The substituents-A-B and-NH-D on the cyclopropyl moiety are in the trans-configuration;

or a salt thereof.

3. Pharmaceutical compositions comprising compounds of formula I

Wherein:

b is hydrogen or-L-E;

d is selected from D1, D2, D3, D4 and D5

R⁴Each independently is C₁-₈An alkyl group;

R⁷each and R⁸Each independently selected from hydrogen and C_1-8Alkyl, or R⁷And R⁸Together with the N atom to which it is attached form a saturated 3-to 7-membered heterocyclic ring optionally comprising another heteroatom selected from N, O and S, wherein one or more C atoms on the heterocyclic ring are optionally oxidized to a CO group, wherein if present, one or more S atoms on the heterocyclic ring are optionally independently oxidized to a SO group or SO₂And wherein said heterocycle is optionally substituted with one or more R¹¹Substitution;

R⁹each is hydrogen;

R¹⁰each independently is C_1-8An alkyl group;

R¹¹each is-NR¹²R¹³；

R¹²Each and R¹³Each is hydrogen;

R^wselected from hydrogenHalogen and C_1-4An alkyl group; and is

R^x、R^yAnd R^zEach is hydrogen;

or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition of claim 3, wherein the compound is a compound of formula Ia

Wherein:

b is hydrogen or-L-E;

d is selected from D1, D2, D3, D4 and D5

Wherein the cyclobutyl ring comprised in D1, the cyclopentyl ring comprised in D2, the cyclohexyl ring comprised in D3, the ring comprised in D4The heptyl ring and the cyclohexyl ring comprised in D5 are optionally substituted with one or more R⁴Substitution;

R⁴Each independently is C_1-8An alkyl group;

R¹¹Substitution;

R⁹each is hydrogen;

R¹⁰each independently is C_1-8An alkyl group;

R¹¹each is-NR¹²R¹³；

R¹²Each and R¹³Each is hydrogen;

or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein D is selected from D1, D2, D3, and D4:

7. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein D is

Wherein the cyclohexyl ring comprised in D is optionally substituted by one or more R⁴And (4) substitution.

8. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein D is

9. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein D is

Wherein the cyclobutyl rings contained in D are optionally substituted by one or more R⁴And (4) substitution.

10. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein D is

11. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein R³Is selected from-NR⁷R⁸、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸、-CONR⁷R⁸and-C_1-4alkylene-NR⁷R⁸。

12. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein R³Is selected from-NR⁷R⁸、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸-OH and-C_1-4alkylene-NR⁷R⁸。

13. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein R³Is selected from-NR⁷R⁸、-NR⁹COR¹⁰、-NR⁹SO₂R¹⁰、-NR⁹COOR¹⁰、-NR⁹CONR⁷R⁸-OH and-CONR⁷R⁸。

14. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein R³Is selected from-NR⁷R⁸-OH and-C_1-4alkylene-NR⁷R⁸。

15. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein R³Is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸。

16. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein R³is-NR⁷R⁸。

17. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein R⁷And R⁸Each independently selected from hydrogen and C_1-8An alkyl group.

18. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein R⁷And R⁸Each is hydrogen.

19. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein R⁷And R⁸Together with the N atom to which they are attached form a saturated 3-to 7-membered heterocyclic ring, optionally containing another heteroatom selected from N, O and S, wherein one or more C atoms on the heterocyclic ringOptionally oxidized to a CO group, wherein if present, one or more S atoms on the heterocycle are optionally independently oxidized to a SO group or SO₂And wherein said heterocycle is optionally substituted with one or more R¹¹And (4) substitution.

20. A compound according to any one of claims 1 to 2 or a pharmaceutical composition according to any one of claims 3 to 5, wherein-NR⁷R⁸Is a group of the formula:

21. the compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein A is phenyl or naphthyl, wherein said phenyl or said naphthyl is optionally substituted with one or more R¹And (4) substitution.

22. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein A is phenyl, pyridyl, thienyl, or thiazolyl, wherein said phenyl, said pyridyl, said thienyl, or said thiazolyl is optionally substituted with one or more R¹And (4) substitution.

23. The compound of claim 22 or the pharmaceutical composition of claim 22, wherein a is phenyl, pyridyl or thiazolyl, wherein said phenyl, said pyridyl or said thiazolyl is optionally substituted with one or more R¹And (4) substitution.

24. The compound of claim 23 or the pharmaceutical composition of claim 23, wherein a is phenyl, 3-pyridyl or 5-thiazolyl, wherein said phenyl, said 3-pyridyl or said 5-thiazolyl is optionally substituted with one or more R¹And (4) substitution.

25. The compound of claim 24 or the pharmaceutical composition of claim 24, wherein a is phenyl or 3-pyridyl, wherein said phenyl or said 3-pyridyl is optionally substituted with one or more R¹And (4) substitution.

26. The compound of claim 25 or the pharmaceutical composition of claim 25, wherein a is optionally substituted with one or more R¹A substituted phenyl group.

27. The compound of claim 25 or the pharmaceutical composition of claim 25, wherein a is optionally substituted with one or more R¹Substituted 3-pyridyl.

28. The compound of claim 24 or the pharmaceutical composition of claim 24, wherein a is optionally substituted with one or more R¹A substituted 5-thiazolyl group.

29. The compound of claim 21 or the pharmaceutical composition of claim 21, wherein a is optionally substituted with one or more R¹Substituted naphthyl.

30. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein B is hydrogen.

31. A compound according to claim 30 or a pharmaceutical composition according to claim 30, wherein a is substituted with 1 or 2 groups R¹And (4) substitution.

32. The compound of claim 31 or the pharmaceutical composition of claim 31, wherein a is substituted with 1 group R¹And (4) substitution.

33. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein B is-L-E.

34. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein R¹Each independently selected from C_1-8Alkyl, hydroxy, halogen, halogeno C_1-8Alkyl, halo C_1-8Alkoxy and C_1-8An alkoxy group.

35. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein R¹Each independently selected from halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy and C_3-6A cycloalkyl group.

36. The compound of claim 30 or the pharmaceutical composition of claim 30, wherein a is not substituted by any R¹And (4) substitution.

37. The compound of claim 33 or the pharmaceutical composition of claim 33, wherein a is not substituted by any R¹And (4) substitution.

38. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein L is a bond.

39. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein L is by inclusion in the-CH₂O atom in-O-connects ring A and via a group contained in said-CH₂-CH in-O-₂-CH of the group-connecting ring E₂-O-。

40. In the application ofThe compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein L is-NH-or by inclusion in said-CH₂N atom in-NH-links ring A and via the group contained in said-CH₂-CH of-NH-₂-CH of the group-connecting ring E₂-NH-。

41. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein E is phenyl, optionally substituted with one or more R²And (4) substitution.

42. The compound of claim 41 or the pharmaceutical composition of claim 41, wherein E is phenyl.

43. The compound of claim 41 or the pharmaceutical composition of claim 41, wherein E is phenyl, which is substituted with one R²And (4) substitution.

44. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein E is pyridyl, pyrazolyl, or indazolyl, wherein said pyridyl, said pyrazolyl, or said indazolyl are optionally substituted with one or more R²And (4) substitution.

45. The compound of claim 44 or the pharmaceutical composition of claim 44, wherein E is pyridyl, pyrazolyl, or indazolyl.

46. The compound of claim 44 or the pharmaceutical composition of claim 44, wherein E is pyridyl, pyrazolyl, or indazolyl, wherein said pyridyl, said pyrazolyl, or said indazolyl are substituted with one R²And (4) substitution.

47. A compound according to any one of claims 1 to 2 or any one of claims 3 to 5A pharmaceutical composition of wherein R²Each independently selected from C_1-8Alkyl, hydroxy, halogen, halogeno C_1-8Alkyl, halo C_1-8Alkoxy, cyano, N-sulfonylamino and C_1-8An alkoxy group.

48. The compound of any one of claims 1-2 or the pharmaceutical composition of any one of claims 3-5, wherein R²Each independently selected from hydroxy, halogen, halo C_1-8Alkyl and N-sulfonylamino.

49. The compound of claim 48 or the pharmaceutical composition of claim 48, wherein R²Each independently selected from hydroxy, halogen and halo C_1-8An alkyl group.

50. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein R^wSelected from hydrogen, fluorine and C_1-4An alkyl group.

51. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein R^wSelected from hydrogen and fluorine.

52. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein R^w、R^x、R^yAnd R^zEach is hydrogen.

53. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein R^wSelected from halogen and C_1-4Alkyl, and R^x、R^yAnd R^zEach is hydrogen.

54. The compound of claim 53Or the pharmaceutical composition of claim 53, wherein R^wSelected from fluorine and methyl, and R^x、R^yAnd R^zEach is hydrogen.

55. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein R^wIs fluorine and R^x、R^yAnd R^zEach is hydrogen.

56. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein the substituents-a-B and-NH-D on the cyclopropyl moiety are in the trans-configuration.

57. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein D is selected from D1, D2, D3, and D4:

wherein the cyclobutyl ring comprised in D1, the cyclopentyl ring comprised in D2, the cyclohexyl ring comprised in D3 and the cycloheptyl ring comprised in D4 are optionally substituted by one or more R⁴Substitution;

R^w、R^x、R^yand R^zEach is hydrogen; and is

The substituents-A-B and-NH-D on the cyclopropyl moiety are in the trans-configuration.

58. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein D is selected from D1, D2, D3, and D4:

wherein the ring contained in D1, the ring contained in D2The pentyl ring, the cyclohexyl ring comprised in D3 and the cycloheptyl ring comprised in D4 are optionally substituted with one or more R⁴Substitution;

R³each independently selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

R^w、R^x、R^yAnd R^zEach is hydrogen; and is

59. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein D is selected from D1, D2, D3, and D4:

b is-L-E;

R^w、R^x、R^yand R^zEach is hydrogen; and is

60. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is

Wherein the cyclohexyl ring comprised in D is optionally substituted by one or more R⁴Substitution;

R³is-NR⁷R⁸；

R^w、R^x、R^yAnd R^zEach being hydrogen(ii) a And is

61. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is selected from D1, D2, D3 and D4:

R³is-NR⁷R⁸；

R^w、R^x、R^yAnd R^zEach is hydrogen; and is

62. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is

R³is-NR⁷R⁸；

R^w、R^x、R^yAnd R^zEach is hydrogen; and is

63. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is selected from D1, D2, D3 and D4:

R³is-NR⁷R⁸；

R^w、R^x、R^yAnd R^zEach is hydrogen; and is

64. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is

R³Is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

R^w、R^x、R^yAnd R^zEach is hydrogen; and is

65. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is selected from D1, D2, D3 and D4:

R³is selected from-NR⁷R⁸and-C_1-4alkylene-NR⁷R⁸；

R^w、R^x、R^yAnd R^zEach is hydrogen; and is

66. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is

The cyclohexyl ring comprised in D is optionally substituted by one or more R⁴Substitution;

R³is-NR⁷R⁸；

R⁷And R⁸Each is hydrogen; and is

R^w、R^x、R^yAnd R^zEach is hydrogen; and is

67. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is selected from D1, D2, D3 and D4:

R³is-NR⁷R⁸；

R⁷And R⁸Each is hydrogen;

R^w、R^x、R^yand R^zEach is hydrogen; and is

68. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is

R³is-NR⁷R⁸；

R⁷And R⁸Each is hydrogen;

R^w、R^x、R^yand R^zEach is hydrogen; and is

69. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is selected from D1, D2, D3 and D4:

R³is-NR⁷R⁸；

R⁷And R⁸Each is hydrogen;

R^w、R^x、R^yand R^zEach is hydrogen; and is

70. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is

R³is-NR⁷R⁸；

A is phenyl, pyridyl or thiazolyl, wherein said phenyl, said pyridyl or said thiazolyl is optionally substituted with one or moreR¹Substitution;

R^w、R^x、R^yand R^zEach is hydrogen; and is

71. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is selected from D1, D2, D3 and D4:

R³is-NR⁷R⁸；

A is phenyl, pyridyl or thiazolyl, wherein said phenyl, said pyridyl or said thiazolyl is optionally substituted with one or more R¹Substitution;

R^w、R^x、R^yand R^zEach is hydrogen; and is

72. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is

R³is-NR⁷R⁸；

R^w、R^x、R^yand R^zEach is hydrogen; and is

73. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is selected from D1, D2, D3 and D4:

R³is-NR⁷R⁸；

R^w、R^x、R^yand R^zEach is hydrogen; and is

74. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is

R³is-NR⁷R⁸；

A is optionally substituted by one or more R¹Substituted phenyl;

R^w、R^x、R^yand R^zEach is hydrogen; and is

75. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is selected from D1, D2, D3 and D4:

R³is-NR⁷R⁸；

A is optionally substituted by one or more R¹Substituted phenyl;

R^w、R^x、R^yand R^zEach is hydrogen; and is

76. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is

R³is-NR⁷R⁸；

A is optionally substituted by one or more R¹Substituted phenyl;

R^w、R^x、R^yand R^zEach is hydrogen; and is

77. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is selected from D1, D2, D3 and D4:

R³is-NR⁷R⁸；

A is optionally substituted by one or more R¹Substituted phenyl;

R^w、R^x、R^yand R^zEach is hydrogen; and is

78. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is

R³is-NR⁷R⁸；

A is optionally substituted by one or more R¹Substituted phenyl;

b is hydrogen;

R^w、R^x、R^yand R^zEach is hydrogen; and is

79. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is selected from D1, D2, D3 and D4:

wherein the cyclobutyl ring comprised in D1, the cyclopentyl ring comprised in D2, the cyclohexyl ring comprised in D3 and the cycloheptyl ring comprised in D4 are optionallyBy one or more R⁴Substitution;

R³is-NR⁷R⁸；

A is optionally substituted by one or more R¹Substituted phenyl;

b is hydrogen;

R^w、R^x、R^yand R^zEach is hydrogen; and is

80. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is

R³is-NR⁷R⁸；

A is optionally substituted by one or more R¹Substituted phenyl;

b is hydrogen;

R^w、R^x、R^yand R^zEach is hydrogen; and is

81. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is selected from D1, D2, D3 and D4:

R³is-NR⁷R⁸；

A is optionally substituted by one or more R¹Substituted phenyl;

b is hydrogen;

R^w、R^x、R^yand R^zEach is hydrogen;and is

82. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is

R³is-NR⁷R⁸；

R⁷And R⁸Each is hydrogen;

a is optionally substituted by one or more R¹Substituted phenyl;

b is hydrogen;

R^w、R^x、R^yand R^zEach is hydrogen; and is

83. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is selected from D1, D2, D3 and D4:

R³is-NR⁷R⁸；

R⁷And R⁸Each is hydrogen;

a is optionally substituted by one or more R¹Substituted phenyl;

b is hydrogen;

R^w、R^x、R^yand R^zEach is hydrogen; and is

84. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is

R³is-NR⁷R⁸；

R⁷And R⁸Each is hydrogen;

a is optionally substituted by one or more R¹Substituted phenyl;

b is hydrogen;

R^w、R^x、R^yand R^zEach is hydrogen; and is

85. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is selected from D1, D2, D3 and D4:

R³is-NR⁷R⁸；

R⁷And R⁸Each is hydrogen;

a is optionally substituted by one or more R¹Substituted phenyl;

b is hydrogen;

R^w、R^x、R^yand R^zEach is hydrogen; and is

86. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is

R³is-NR⁷R⁸；

R⁷And R⁸Each is hydrogen;

a is phenyl;

b is hydrogen;

R^w、R^x、R^yand R^zEach is hydrogen; and is

87. The compound of any one of claims 1-2 or the pharmaceutical composition of claim 3 or 5, wherein:

d is selected from D1, D2, D3 and D4:

R³is-NR⁷R⁸；

R⁷And R⁸Each is hydrogen;

a is phenyl;

b is hydrogen;

R^w、R^x、R^yand R^zEach is hydrogen; and is

88. A compound, wherein the compound is selected from:

n1- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1S, 2R) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1S, 2R) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1R, 2S) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1R, 2S) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (thiazol-5-yl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

N1-methyl-N4- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine;

n1- ((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) cyclobutane-1, 3-diamine;

n1- ((trans) -2-phenylcyclopropyl) -2, 3-dihydro-1H-indene-1, 3-diamine;

n1- ((trans) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

n1- ((1S, 2S) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

n1- ((1R, 2R) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

1-methyl-N4- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

4- (aminomethyl) -N- ((trans) -2-phenylcyclopropyl) cyclohexylamine;

n1- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 3-diamine;

n1- ((cis) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(4- (((trans) -2-phenylcyclopropyl) amino) cyclohexyl) carbamic tert-butyl ester;

1-ethyl-3- (4- (((trans) -2-phenylcyclopropyl) amino) cyclohexyl) urea;

4-morpholino-N- ((trans) -2-phenylcyclopropyl) cyclohexylamine;

n1- ((trans) -2- (4-bromophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- (2- (o-tolyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- (2- (4- (trifluoromethyl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- (2- (4-methoxyphenyl) cyclopropyl) cyclohexane-1, 4-diamine;

4- (2- ((4-aminocyclohexyl) amino) cyclopropyl) phenol;

n1- (2- (2-fluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- (2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- (2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- (2-methyl-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1S, 2R) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1S, 2R) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclo-propyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1R, 2S) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclo-propyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1R, 2S) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclo-propyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4-cyclopropylphenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((cis) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (o-tolyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4-methoxyphenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (2-fluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2-methyl-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1S, 2R) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1R, 2S) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1R, 2S) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1S, 2R) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1S, 2R) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine;

(trans) -N1- ((1R, 2S) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine;

(cis) -N1- ((1R, 2S) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine;

(trans) -N1- ((1S, 2R) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine;

(cis) -N1- ((1S, 2R) -2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1R, 2S) -2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1R, 2S) -2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1S, 2R) -2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1S, 2R) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1R, 2S) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1R, 2S) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1S, 2R) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1S, 2R) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1R, 2S) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1R, 2S) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1S, 2R) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n- (4 '- ((1R, 2S) -2- (((cis) -4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) piperazine-1-sulfonamide;

n- (4 '- ((1S, 2R) -2- (((trans) -4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) piperazine-1-sulfonamide;

n- (4 '- ((1S, 2R) -2- (((cis) -4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) piperazine-1-sulfonamide;

n- (4 '- ((1R, 2S) -2- (((trans) -4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) piperazine-1-sulfonamide;

(cis) -N1- ((1S, 2R) -2- (4- ((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1R, 2S) -2- (4- ((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1R, 2S) -2- (4- ((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1S, 2R) -2- (4- ((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

and pharmaceutically acceptable salts thereof.

89. A pharmaceutical composition comprising a compound selected from the group consisting of

N1- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1S, 2R) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1S, 2R) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1R, 2S) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(trans) -N1- ((1R, 2S) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (thiazol-5-yl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

N1-methyl-N4- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine;

n1- ((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) cyclobutane-1, 3-diamine;

n1- ((trans) -2-phenylcyclopropyl) -2, 3-dihydro-1H-indene-1, 3-diamine;

n1- ((trans) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

n1- ((1S, 2S) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

n1- ((1R, 2R) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

1-methyl-N4- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

4- (aminomethyl) -N- ((trans) -2-phenylcyclopropyl) cyclohexylamine;

n1- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 3-diamine;

n1- ((cis) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

1-ethyl-3- (4- (((trans) -2-phenylcyclopropyl) amino) cyclohexyl) urea;

4-morpholino-N- ((trans) -2-phenylcyclopropyl) cyclohexylamine;

n1- ((trans) -2- (4-bromophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- (2- (o-tolyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- (2- (4- (trifluoromethyl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- (2- (4-methoxyphenyl) cyclopropyl) cyclohexane-1, 4-diamine;

4- (2- ((4-aminocyclohexyl) amino) cyclopropyl) phenol;

n1- (2- (2-fluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- (2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- (2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- (2-methyl-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4-cyclopropylphenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((cis) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (o-tolyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (4-methoxyphenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (2-fluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2- (3, 4-difluorophenyl) cyclopropyl) cyclohexane-1, 4-diamine;

n1- ((trans) -2-methyl-2-phenylcyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1S, 2R) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1R, 2S) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine;

(cis) -N1- ((1S, 2R) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine;

(trans) -N1- ((1R, 2S) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine;

(cis) -N1- ((1R, 2S) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine;

(trans) -N1- ((1S, 2R) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine;

and a pharmaceutically acceptable salt thereof,

and a pharmaceutically acceptable carrier.

90. The compound of claim 1 or the pharmaceutical composition of claim 3, wherein the compound is N1- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine or a salt thereof.

91. The compound of claim 1 or the pharmaceutical composition of claim 3, wherein the compound is (cis) -N1- ((1S, 2R) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine or a salt thereof.

92. The compound of claim 1 or the pharmaceutical composition of claim 3, wherein the compound is (trans) -N1- ((1S, 2R) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine or a salt thereof.

93. The compound of claim 1 or the pharmaceutical composition of claim 3, wherein the compound is (cis) -N1- ((1R, 2S) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine or a salt thereof.

94. The compound of claim 1 or the pharmaceutical composition of claim 3, wherein the compound is (trans) -N1- ((1R, 2S) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine or a salt thereof.

95. The compound of claim 1 or the pharmaceutical composition of claim 3, wherein the compound is N1- ((trans) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclopropyl) cyclohexane-1, 4-diamine or a salt thereof.

96. The compound of claim 1 or the pharmaceutical composition of claim 3, wherein the compound is (cis) -N1- ((1R, 2S) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclo-propyl) cyclohexane-1, 4-diamine, or a salt thereof.

97. The compound of claim 1 or the pharmaceutical composition of claim 3, wherein the compound is (trans) -N1- ((1R, 2S) -2- (3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -4-yl) cyclo-propyl) cyclohexane-1, 4-diamine, or a salt thereof.

98. The compound of claim 1 or the pharmaceutical composition of claim 3, wherein the compound is 4- (aminomethyl) -N- ((trans) -2-phenylcyclopropyl) cyclohexylamine or a salt thereof.

99. The compound of claim 1 or the pharmaceutical composition of claim 3, wherein the compound is N1- ((trans) -2-phenylcyclopropyl) cyclobutane-1, 3-diamine or a salt thereof.

100. The compound of claim 1 or the pharmaceutical composition of claim 3, wherein the compound is N1- ((trans) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1, 4-diamine or a salt thereof.

101. The compound of claim 1 or the pharmaceutical composition of claim 3, wherein the compound is N1-methyl-N4- ((trans) -2-phenylcyclopropyl) cyclohexane-1, 4-diamine or a salt thereof.

102. The compound of claim 1 or the pharmaceutical composition of claim 3, wherein the compound is N1- ((trans) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1, 4-diamine or a salt thereof.

103. The compound of claim 1 or the pharmaceutical composition of claim 3, wherein the compound is N- (4 '- ((trans) -2- ((4-aminocyclohexyl) amino) cyclopropyl) - [1, 1' -biphenyl ] -3-yl) piperazine-1-sulfonamide or a salt thereof.

104. The compound of claim 1 or the pharmaceutical composition of claim 3, wherein the compound is N1- ((trans) -2- (4- ((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1, 4-diamine or a salt thereof.

105. Use of a compound of any one of claims 1-2, 88, or 90-104, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a cancer associated with LSD 1.

106. The use of claim 105, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, skin cancer, leukemia, lymphoma, and myeloma.

107. The use of claim 105, wherein the cancer is leukemia, lymphoma or myeloma.

108. The use of claim 105, wherein the cancer is leukemia.

109. The use according to any one of claims 106-108, wherein the leukemia is selected from the group consisting of Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL), and hairy cell leukemia.

110. Use of a compound of any one of claims 1-2, 88, or 90-104, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a neurological disease.

111. The use of claim 110, wherein the neurological disease is selected from depression, alzheimer's disease, huntington's disease, parkinson's disease, amyotrophic lateral sclerosis, dementia with lewy bodies, or frontotemporal dementia.

112. Use of a compound of any one of claims 1-2, 88, or 90-104, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a viral infection.

113. The use of claim 112, wherein the viral infection is a herpes virus infection.

114. The use of claim 113, wherein said herpes viral infection is caused by and/or associated with a herpes virus selected from the group consisting of HSV-1, HSV-2, and epstein barr virus.

115. The use of claim 112, wherein the viral infection is caused by and/or associated with HIV.

116. The use of claim 112, wherein the viral infection is caused by and/or associated with a hepadnavirus.

117. The use of claim 116, wherein said hepadnavirus is hepatitis b virus.

118. The use of claim 112, wherein the viral infection is caused by and/or associated with a flavivirus.

119. The use of claim 118, wherein said flavivirus is selected from the group consisting of Hepatitis C Virus (HCV), yellow fever virus, west nile virus, dengue fever virus, and japanese encephalitis virus.

120. Use of a compound of any one of claims 1-2, 88, or 90-104, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing viral reactivation after a latency period.

121. The use of claim 120, wherein the reactivated virus is a herpes virus.

122. The use of claim 121, wherein the herpes virus is selected from the group consisting of HSV-1, HSV-2, and epstein barr virus.

123. The use of claim 120, wherein the reactivated virus is HIV.

124. Use of a compound of formula I for the preparation of a medicament for the treatment or prevention of LSD 1-related cancer

Wherein:

b is hydrogen or-L-E;

d is selected from D1, D2, D3, D4 and D5

R⁴Each independently is C_1-8An alkyl group;

R¹¹Substitution;

R⁹each is hydrogen;

R¹⁰each independently is C_1-8An alkyl group;

R¹¹each is-NR¹²R¹³；

R¹²Each and R¹³Each is hydrogen;

R^wselected from hydrogen, halogen and C_1-4An alkyl group; and is

R^x、R^yAnd R^zEach is hydrogen;

or a pharmaceutically acceptable salt thereof.

125. The use of claim 124, wherein the compound is of formula Ia

Wherein:

b is hydrogen or-L-E;

d is selected from D1, D2, D3, D4 and D5

R²each independently selected from C_1-8Alkyl, 3-8 membered monocyclic heterocyclic group, hydroxy, halogen, halogeno C_1-8Alkyl, aryl, heteroaryl, and heteroaryl,Halogen substituted C_1-8Alkoxy, cyano, N-sulfonylamino and C_1-8An alkoxy group;

R⁴Each independently is C_1-8An alkyl group;

R¹¹Substitution;

R⁹each is hydrogen;

R¹⁰each independently is C_1-8An alkyl group;

R¹¹each is-NR¹²R¹³；

R¹²Each and R¹³Each is hydrogen;

or a pharmaceutically acceptable salt thereof.

126. Use of a compound of any one of claims 1-2, 88, or 90-104, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a disease associated with LSD 1.

127. A process for the preparation of a compound of formula I or a salt thereof as defined in claim 1, which process comprises reacting a compound of formula II

A, B, R therein^w、R^x、R^yAnd R^zHaving the meaning as defined for compounds of the formula I in claim 1, with compounds of the formula III in the presence of reducing agents,

wherein D has the meaning as defined for the compounds of the formula I in claim 1, and wherein the radical R on the ring D³Optionally protected by a protecting group, and optionally protected by a protecting group,

any protecting groups that may be present are then removed.

128. The method of claim 127, wherein the reducing agent is a borohydride.