WO2021127397A1 - Composés hétérocycliques azotés et leurs méthodes d'utilisation - Google Patents

Composés hétérocycliques azotés et leurs méthodes d'utilisation Download PDF

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WO2021127397A1
WO2021127397A1 PCT/US2020/065956 US2020065956W WO2021127397A1 WO 2021127397 A1 WO2021127397 A1 WO 2021127397A1 US 2020065956 W US2020065956 W US 2020065956W WO 2021127397 A1 WO2021127397 A1 WO 2021127397A1
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alkyl
membered
compound
aryl
halogen
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PCT/US2020/065956
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Alexander Flohr
Luca Arista
Matthew O'connor
Elizabeth Buck
Matthew C. Lucas
Iwona WRONA
Fernando Padilla
Stephane Ciblat
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Black Diamond Therapeutics, Inc.
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Publication of WO2021127397A1 publication Critical patent/WO2021127397A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • NITROGEN HETEROCYCLIC COMPOUNDS AND METHODS OF USE RELATED APPLICATION [0001] This application claims priority to, and the benefit of, U.S. Application No. 62/950,717, filed December 19, 2019, the entire content of which is incorporated herein by reference. FIELD OF DISCLOSURE [0002]
  • the present disclosure relates to new compounds as inhibitors of receptor tyrosine kinases (RTK), in particular oncogenic mutants of ErbB-receptors.
  • the disclosure also relates to methods of preparation these compounds, compositions comprising these compounds, and methods of using them in the prevention or treatment of abnormal cell growth in mammals, especially humans.
  • ErbB inhibitors are a known treatment for a number of cancers. However, not every patient is responsive satisfactorily to this treatment. Thus, there is a long-felt need in the art for new therapies that are able to address the variable responsiveness of cancer patients to known therapies.
  • the present disclosure provides compositions and methods for treating cancer in patients with these oncogenic mutations without the variable reponsivenss observed when patients having these ErbB mutants are treated using the existing standard of care.
  • Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more R Z ; each R Z independently is halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocyclooo
  • Z is of formula i wherein: R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2.
  • Y is of formula ii or iia wherein: R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3; R 5a is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C 1-3 alkoxy-aryl, unsubstituted or substituted C 1-3 alkoxy-heteroaryl or unsubstituted or substituted C 1-3 alkoxy-heterocycloalkyl; X 3 is –NH– or –NMe–.
  • Y is of formula iii or iv wherein: R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF3; R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl; X 4 is –O–, –NH–, –NMe–; L is a covalent bond or linear or branched C 1-3 alkyl; A is a C 6 aryl, a 6 membered heterocycloalkyl or a 5-6 membered heteroaryl, wherein the C 6 aryl, 6 membered heterocycloalkyl or 5-6 membered heteroaryl is unsubstituted or substituted with one or more of C 1-4 alkyl, OCH 2 F, HCF
  • Y is of formula iii, v-a, e.g., v-a-1 or v-a-2, or vi-a, e.g., vi-a-1, or vii-a, e.g., vii-a-1
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl
  • Y is of formula iii, v-a(i), v-a(ii), e.g., v-a(i)-1, v-a(ii)-1, v-a(i)-2, v-a(ii)-2, or vi-a(i), e.g., vi-a(i)-1, or vii-a(i) or vii-a(ii), e.g., vii-a(i)-1 or vii-a(ii)-1 wherein R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3; R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl; R 6 is hydrogen, C 1-4 alkyl, e
  • Y is of formula iii, v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v- a-10, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12, vi-a, vii- a-1, vii-a-2 or vii-a-3
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl;
  • X 8 ’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1.
  • Y is of formula iii, v-c-1, v-c-2, v-c-3, v-c-4, v-d-1, v-d-2, v-d-3, v- d-4, v-d-5, v-d-6, v-d-7, vi-a, vii-b-1, vii-b-2, vii-b-3 or vii-b-4
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl; and s is 0 or 1.
  • Y is of formula v-c(i)-1, v-c(ii)-1, v-c(i)-2, v-c(ii)-2, v-c(i)-3, v- c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(ii)-3, v-d(ii)-3, v-d(i)-4, v-d(ii)- 4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(ii)-7, vi-a(i), vi-a(ii), iii-(i), iii-(i), iii-(i),
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl; and s is 0 or 1.
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl;
  • X 4 is –O–, –NH–, –NMe–;
  • X 8 ’ is –O–, –S–, –NH– or –NM
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl
  • Z is selected from wherein: R 2 is hydrogen, Me or Et.
  • the present disclosure provides a composition comprising a compound as described herein or pharmaceutically acceptable salts or stereoisomers thereof.
  • the composition further comprises a pharmaceutically acceptable carrier.
  • the composition further comprises a second therapeutically active agent.
  • the second therapeutically active agent comprises a non-Type I inhibitor.
  • the non-Type I inhibitor comprises a small molecule Type II inhibitor.
  • the present disclosure provides the compound pharmaceutically acceptable salts or stereoisomers thereof or composition, as described herein for use in the treatment of cancer.
  • the present disclosure provides a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR), comprising administering the subject in need thereof a therapeutically effective amount of a compound described herein.
  • an oncogenic variant of an ErbB receptor e.g., an oncogenic variant of an EGFR
  • the present disclosure provides a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR), comprising administering the subject in need thereof a composition described herein.
  • the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a therapeutically effective amount of a compound described herein.
  • the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a composition described herein.
  • the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in the subject; and ii) administering the subject in need of the treatment a therapeutically effective amount of a compound described herein.
  • the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in the subject; and ii) administering the subject in need of the treatment a composition described herein.
  • the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject; and ii) administering the subject in need of the treatment a therapeutically effective amount of a compound described herein.
  • the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject; and ii) administering the subject in need of the treatment a composition described herein.
  • the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a therapeutically effective amount of a compound described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in the subject.
  • the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a compound described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in the subject.
  • the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a therapeutically effective amount of a compound described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in a biological sample from the subject.
  • the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a composition described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in a biological sample from the subject.
  • the present disclosure provides a compound described herein for use in the inhibition of an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR).
  • the present disclosure provides a compound described herein for use in the prevention or treatment of cancer.
  • the present disclosure provides a composition described herein for use in the inhibition of an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR).
  • an oncogenic variant of an ErbB receptor e.g., an oncogenic variant of an EGFR
  • the present disclosure provides a composition described herein for use in the prevention or treatment of cancer.
  • the present disclosure provides a compound described herein for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject.
  • the present disclosure provides a composition described herein for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject.
  • the present disclosure provides a compound described herein for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject.
  • the present disclosure provides a composition described herein for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject.
  • the present disclosure provides use of a compound described herein in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR).
  • the present disclosure provides use of a compound described herein in the manufacture of a medicament for preventing or treating cancer.
  • 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 disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control.
  • FIG. 1 is an illustration of the structure of EGFR and a group of 20 genomic mutations affecting the CR1 or CR2 regions of EGFR and which are expressed in GBM tumors.
  • Fig. 2 is a schematic depiction of an expression pattern for EGFR splicing events and mutations in the CR1 and CR2 regions for a group of 164 GBM tumors.
  • One tumor, TCGA.878, expressing four variants (EGFR-Viii, EGR-A289T, EGFR-A289V, and EGFR-A289D, is noted.
  • Fig. 3 is a graph depicting exemplary ectodomain variants of ErbB receptors that are transforming.
  • the proliferation of parental BaF3 cells cultured in the presence of IL-3 is shown as a control.
  • FIG. 4 is an illustration of the structure of EGFR and exemplary free cysteines that are formed at the extracellular dimer interface of EGFR as a result of genomic mutations and alternative splicing events in cancer.
  • Arrows note the positions of free cysteines predicted to be generated as a result of the events EGFR-A289V, EGFR-Viii, EGFR-Vii, and EGFR-Vvi. Positions are mapped onto the crystal structure of the ectodomain of EGFR (1IVO). EGF ligand is shown in green, and EGFR protomers are shown in grey and orange. [0058] Fig.
  • FIG. 5A is a series of photographs of Western blots depicting the expression of total and phosphorylated monomeric EGFR versus covalent EGFR dimers for EGFR-Viii, EGFR-Vii, EGFR-Vvi, and EGFR-A289V, detected by resolving proteins under non-reducing conditions.
  • the data demonstrate that EGFR-Viii, EGFR-Vii, EGFR-Vvi, and EGFR-A289V exist as covalently activated dimers.
  • Fig. 5B is a graph depicting the quantitation of results from Fig. 5A, and the quantitation of percentage of receptor that exists as covalent dimer for total versus phosphorylated receptor.
  • Fig. 6 is a pair of photographs of Western blots depicting the effect of EGF treatment on levels of monomeric and dimeric phosphorylated EGFR for EGFR-Vii and EGFR-Vvi. In contrast to EGFR-Viii, EGF further potentiates the formation of active covalent dimers for EGFR-Vii and EGFR-Vvi.
  • Fig.7A is a series of photographs of Western blots depicting the effect of 100nM erlotinib treatment on levels of monomeric and dimeric EGFR levels in cells expressing EGFR-Viii, EGFR- Vii, EGFR-Vvi, or EGFR-A289V.
  • Fig. 7B is a pair of photographs of Western blots depicting the effect of varying concentrations of erlotinib on monomeric and dimeric EGFR levels in cells expressing EGFR-Vii. Monomeric and dimeric EGFR levels were detected by resolving proteins under non-reducing conditions.
  • Fig. 7C is a graph quantifying the data presented in Fig. 7B. The data demonstrate that erlotinib induces a dose dependent increase in covalently dimerized receptor.
  • Fig. 8 is a series of photographs of Western blots depicting the effect of a panel of Type I and Type II inhibitors on dimeric and monomeric EGFR levels for cells expressing EGFR-Vii and EGFR-A289V. Monomeric and dimeric EGFR levels were detected by resolving proteins under non-reducing conditions. The data demonstrate that Type I, but not Type II, ErbB inhibitors enhance the formation of covalent dimers for covalently-activated EGFR variants.
  • Fig. 9 is a series of photographs of Western blots depicting the effect of 100nM erlotinib treatment on monomeric and dimeric EGFR levels for two EGFR variants.
  • Fig. 10A is a series of photographs of Western blots depicting the effect of varying concentrations of erlotinib on monomeric and dimeric levels of phosphorylated EGFR in cells expressing EGFR-Viii, EGFR-Vii, and EGFR-A289V. Monomeric and dimeric EGFR levels were detected by resolving proteins under non-reducing conditions.
  • Fig. 10B is a series of photographs of Western blots depicting the effect of varying concentrations of erlotinib treatment, followed by a 30 minute washout, on total and phosphorylated EGFR levels in cells expressing EGFR-Vii or EGFR-Vvi. Proteins were resolved under non-reducing conditions.
  • the data demonstrate that erlotinib paradoxically enhances the phosphorylation of covalent dimers for EGFR-Vii and EGFR-Vvi.
  • Fig. 10B is a series of photographs of Western blots depicting the effect of varying concentrations of erlotinib treatment, followed by a 30 minute washout, on total and phosphorylated EGFR levels in cells expressing EGFR-Vii or EGFR-Vvi. Proteins were resolved under non-reducing conditions.
  • the data demonstrate that erlotinib paradoxically enhances the phosphorylation of covalent dimers for EGFR-Vii and EGFR-Vvi.
  • FIG. 11A is a graph depicting the effect of DMSO, 37nM erlotinib, or 100nM erlotinib on the proliferation of BaF3 cells expressing EGFR-Viii. Proliferation data were collected at multiple time points over a three day period. The data demonstrate that sub-saturating concentrations of erlotinib result in paradoxical stimulation of proliferation in cells expressing splice-activated EGFR. [0069] Fig. 11B is a graph depicting the effect of varying concentrations of erlotinib on the proliferation of BaF3 cells expressing EGFR-Viii, EGFR-Vii or EGFR-A289V.
  • Fig. 12 is a series of graphs depicting the effect of 12.5nM or 1uM of WZ8040, WZ3146, or WZ4002 on the proliferation of BaF3 cells expressing EGFR-Viii. Proliferation data were collected at multiple time points over a three day period.
  • Fig.13A is an illustration of the structure of EGFR and exemplary free cysteines are formed at the extracellular dimer interface of HER2 receptors as a result of genomic mutations and alternative splicing events in cancer. Arrows point to positions of free cysteines generated by the ⁇ 16 splice event or C311R or S310F mutations.
  • Fig. 13B is a pair of graphs demonstrating that HER2 and HER4 splice variants are transforming.
  • Fig.14 is a series of photographs of Western blots depicting the expression of dimeric and monomeric levels of phosphorylated HER2 or HER4 receptors in cells expressing each variant. Monomeric and dimeric EGFR levels were detected by resolving proteins under non-reducing conditions. The data demonstrate that multiple HER2 and HER4 splicing events and mutations in the CR1 and CR2 regions result in covalently active dimers.
  • Fig.15A is a series of photographs of Western blots depicting the effect of the Type I HER2 inhibitor sapitinib or the Type I HER4 inhibitor afatinib on levels of dimerized receptors for cells expressing HER2- ⁇ 16, HER2-C311R, HER2-S310F, or HER4 ⁇ 16. Monomeric and dimeric HER2 and HER4 levels were detected by resolving proteins under non-reducing conditions. The data demonstrate that Type I inhibitors induce the formation of covalent dimers for covalently- activated HER2 and HER4 isoforms. [0075] Fig.
  • FIG. 16 is a graph depicting the effect of varying concentrations of sapitinib on the proliferation of BaF3-HER2- ⁇ 16 cells.
  • the present disclosure relates to new compounds useful as inhibitors of receptor tyrosine kinases (RTK), including oncogenic mutants of ErbB-receptors.
  • RTK receptor tyrosine kinases
  • the oncogenic mutants of ErbB-receptors are also allosteric mutants of ErbB-receptors.
  • the allosteric mutants may comprise or consist of an ErbB receptor variant having a mutation in a sequence outside of an ATP-binding site.
  • the allosteric mutants may comprise or consist of an ErbB receptor variant having a mutation in a sequence within one or more of exon 19, exon 20 or a C1-C2 extracellular dimerization interface.
  • Mutations affecting either the intracellular catalytic domain or extracellular ligand binding domain of an ErbB receptor can generate oncogenic activity (the ErbB protein family consists of 4 members including ErbB-1, also named epidermal growth factor receptor (EGFR) and Erb-2, also named HER2 in humans).
  • EGFR epidermal growth factor receptor
  • HER2 also named epidermal growth factor receptor
  • Extracellular mutants of ErbB receptors in cancer including EGFR- Viii (also EGFR-V3) and HER2-S310F, are constitutively activated in the absence of ligand, exhibit sustained signaling that is resistant to downregulation, and are both transforming and tumorigenic (Nishikawa, Ji et al. 1994, 2013, Francis, Zhang et al. 2014). Their expression is associated with metastasis and with poor long term overall survival. [0079] In glioblastoma (also glioblastoma multiforma or GBM), EGFR-Viii is expressed by 20% of tumors (Sugawa, Ekstrand et al.1990, Brennan, Verhaak et al.2013).
  • HER2-S310F is the most common mutation of HER2 expressed in human tumors, expressed by approximately 0.5% of all tumors. HER2-S310F expression is mutually exclusive with expression of HER2 amplification.
  • HER2-S310F is highly oncogenic, transforming BaF3 cells (a murine interleukin-3 (IL-3) dependent pro-B cell line) to IL-3 independence and promoting tumor growth in vivo.
  • Short insertions of within Exon 20 of EGFR and HER2 are expressed by lung adenocarcinoma tumors and other tumor groups. ErbB Exon 20 insertion mutants are expressed by 4-5% of lung adenocarcinoma tumors. Examples include HER2-YVMA, EGFR-SVD, and EGFR-NPH. These ErbB Exon 20 insertion mutants are highly oncogenic, transforming BaF3 cells to IL-3 independence and promoting tumor growth in vivo.
  • ErbB inhibitors are a known treatment for a number of cancers. However, not every patient is responsive satisfactorily to this treatment. Thus, there is a long-felt need in the art for new therapies that are able to address the variable responsiveness of cancer patients to known therapies. The present disclosure is able to overcome some of these drawbacks of the standard of care, as it existed prior to the development of the compositions and methods disclosed herein. Definitions [0083] Unless specified otherwise the following general definitions apply to all compounds of the disclosure according to the description. [0084] The term "compound of the disclosure,” as used herein, refers to compounds represented by formulae I to VII and any of the specific examples disclosed herein.
  • halogen or hal as used herein may be fluoro (F), chloro (Cl), bromo (Br), or iodo (I), e.g., fluoro (F) or chloro (Cl).
  • alkyl As used herein, “alkyl”, “C 1 , C 2 , C 3 , C 4 , C 5 or C 6 alkyl” or “C 1 -C 6 alkyl” is intended to include C 1 , C 2 , C 3 , C 4 , C 5 or C 6 straight chain (linear) saturated aliphatic hydrocarbon groups and C 3 , C 4 , C 5 or C 6 branched saturated aliphatic hydrocarbon groups.
  • C 1 -C 6 alkyl is intends to include C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkyl groups.
  • alkyl examples include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl or n-hexyl.
  • a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C 1 -C 6 for straight chain, C 3 -C 6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.
  • alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety.
  • C 1-4 alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety having 1, 2, 3 or 4 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso- butyl, tert-butyl.
  • optionally substituted alkyl refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino), acylamino (including alky
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups.
  • a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • C 2 -C 6 includes alkenyl groups containing two to six carbon atoms.
  • C3-C6 includes alkenyl groups containing three to six carbon atoms.
  • optionally substituted alkenyl refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates
  • alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups.
  • a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • C 2 -C 6 includes alkynyl groups containing two to six carbon atoms.
  • C 3 -C 6 includes alkynyl groups containing three to six carbon atoms.
  • C 2 -C 6 alkenylene linker or “C 2 -C 6 alkynylene linker” is intended to include C 2 , C 3 , C 4 , C 5 or C 6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups.
  • C 2 -C 6 alkenylene linker is intended to include C 2 , C 3 , C 4 , C 5 and C 6 alkenylene linker groups.
  • optionalally substituted alkynyl refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates
  • alkoxy or “alkoxyl” as used herein includes substituted and unsubstituted alkyl groups covalently linked to an oxygen atom.
  • alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups.
  • C 1-4 alkoxy refers to a fully saturated branched or unbranched hydrocarbon moiety having 1, 2, 3 or 4 carbon atoms, bound to an oxygen. Representative examples include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy, tert-butoxy.
  • the tern C 1-3 alkoxy-aryl refers to a C 1-3 alkoxy group which is substituted with an aryl, such as for example –O–(CH 2 ) 2 –aryl, –O–(CH 2 )–aryl, –O–(CH 2 ) 3 –aryl.
  • C 1-3 alkoxy-heteroaryl refers to a C 1-3 alkoxy group which is substituted with a heteroaryl, such as for example –O–(CH 2 ) 2 –heteroaryl, –O–(CH 2 )–heteroaryl, –O–(CH 2 ) 3 –heteroaryl.
  • C 1-3 alkoxy-heterocycloalkyl refers to a C 1-3 alkoxy group which is substituted with a heterocycloalkyl, such as for example –O–(CH 2 ) 2 –heterocycloalkyl, –O–(CH 2 )–heterocycloalkyl, –O–(CH2)3–heterocycloalkyl.
  • alkyamino as used herein includes substituted and unsubstituted alkyl groups covalently linked to a nitrogen atom.
  • C 1-4 alkylamino refers to a fully saturated branched or unbranched hydrocarbon moiety having 1, 2, 3 or 4 carbon atoms, bound to a nitrogen.
  • Representative examples include, but are not limited to, methylamino, dimethylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino, sec-butylamino, iso-butylamino, tert- butylamino.
  • the tern C 1-3 alkylamino-aryl refers to a C 1-3 alkylamino group which is substituted with an aryl, such as for example –NH–(CH 2 ) 2 –aryl, –NH–(CH 2 )–aryl, –NH–(CH 2 ) 3 –aryl, –NMe– (CH2)2–aryl, –NMe–(CH2)–aryl, –NMe–(CH2)3–aryl.
  • C1-3 alkylamino- heteroaryl refers to a C 1-3 alkylamino group which is substituted with a heteroaryl, such as for example –NH–(CH 2 ) 2 –heteroaryl, —NH–(CH 2 )–heteroaryl, –NH–(CH 2 ) 3 –heteroaryl, —NMe– (CH 2 ) 2 –heteroaryl, –NMe–(CH 2 )–heteroaryl, –NMe–(CH 2 ) 3 –heteroaryl.
  • a heteroaryl such as for example –NH–(CH 2 ) 2 –heteroaryl, –NH–(CH 2 )–heteroaryl, –NH–(CH 2 ) 3 –heteroaryl, —NMe— (CH 2 ) 2 –heteroaryl, –NMe–(CH 2 ) 3 –heteroaryl.
  • C 1-3 alkylamino-heterocycloalkyl refers to a C 1-3 alkylamino group which is substituted with a heterocycloalkyl, such as for example –NH–(CH 2 ) 2 –heterocycloalkyl, —NH–(CH 2 )– heterocycloalkyl, –NH–(CH 2 ) 3 –heterocycloalkyl, —NMe–(CH 2 ) 2 –heterocycloalkyl, –NMe– (CH2)–heterocycloalkyl, –NMe–(CH2)3–heterocycloalkyl.
  • a heterocycloalkyl such as for example –NH–(CH 2 ) 2 –heterocycloalkyl, —NH–(CH 2 )– heterocycloalkyl, –NH–(CH 2 ) 3 –heterocycloalkyl, —NMe–(CH 2 ) 2 –he
  • cycloalkyl refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8).
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, adamantly, hexahydroindacenyl. It is understood that for polycyclic (e.g., fused, bridged, or spiro rings) system, only one of the rings therein needs to be non-aromatic.
  • heterocycle or “heterocycloalkyl” as used herein refer to a saturated or partially unsaturated hydrocarbon monocyclic system having 3 to 10, e.g., 3 to 6 ring atoms selected from C, N, O, S.
  • heterocycle refers to a saturated or partially unsaturated hydrocarbon bicyclic system (e.g., fused, bridged, or spiro rings) having 3 to 10, e.g., 5 to 8 ring atoms selected from C, N, O, S.
  • Examples include, but are not limited to, epoxy, oxiranyl, thiaranyl, aziradinyl, oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4- oxathianyl 1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl, piperidinyl, morpholinyl, oxepanyl, thiepanyl, azepanyl, diazepanyl, oxazepanyl3-azabicyclo[3.1.0]hexyl, 3- azabicyclo[3.3.0]octyl,
  • aryl refers to groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure.
  • the term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. Conveniently, an aryl is phenyl. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In some embodiments, the aryl is phenyl.
  • aryl (which includes aryloxy, alkoxy-aryl, alkylamino- aryl) when used as substituent of the 6 membered aryl or 5-9 membered heteroaryl group of Y in formula I, I-1, I-2 or as part of group R 5a in formula iia is unsubstituted or substituted with one or more of a group selected from C 1-6 alkyl, C 1-6 alkoxy, halogen, CF 3 , HCF 2 , OCF 3 , OCH 2 F, hydroxy, C 1-6 alkylhydroxyl, for example C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl.
  • aryloxy means a radical of the formula aryl-O-, in which the term aryl has the significance given above.
  • heteroaryl is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. ⁇ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur.
  • the nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined).
  • heteroaryl refers to a (fully) aromatic ring system having 3, 4, 5, or 6 ring atoms, preferably 6 ring atoms, selected from C, N, O, or S, preferably C, N, or O, more preferably C, N, with the number of N atoms preferably being 0, 1, 2 or 3 and the number of O and S atoms each being 0, 1 or 2.
  • heteroaryl examples include furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl), pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, and the like.
  • Preferred examples of “heteroaryl” include pyridinyl.
  • heteroaryl which includes heteroaryloxy, alkoxy- heteroaryl, alkylamino-heteroaryl
  • the term “heteroaryl” when used as substituent of the 6 membered aryl or 5-9 membered heteroaryl group of Y in formula I, I-1, I-2 or as part of group R 5a in formula iia is unsubstituted or substituted with one or more of a group selected from C 1-6 alkyl, C 1-6 alkoxy, halogen, CF 3 , HCF 2 , OCF 3 , OCH 2 F, hydroxy, C 1-6 alkylhydroxyl, for example C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl.
  • heteroaryloxy means a radical of the formula heteroaryl-O-, in which the term heteroaryl has the significance given above.
  • the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl,
  • the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with halogen (e.g., F or Cl).
  • halogen e.g., F or Cl.
  • substituted means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound.
  • Keto substituents are not present on aromatic moieties.
  • the term “mammal” refers to any mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc. (e.g. human).
  • prevention or “preventing” refers to reducing or eliminating the onset of the symptoms or complications of a disease (e.g., cancer).
  • such prevention comprises the step of administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition containing a compound of Formula I or a pharmaceutically acceptable salt thereof) to a subject in need thereof (e.g., a mammal (e.g., a human).
  • a subject in need thereof e.g., a mammal (e.g., a human).
  • treatment or “treating” is intended to encompass therapy and cure.
  • such treatment comprises the step of administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition containing a compound of Formula I or a pharmaceutically acceptable salt thereof) to a subject in need thereof (e.g., a mammal (e.g., a human).
  • a subject in need thereof e.g., a mammal (e.g., a human).
  • the term “treating” or “treatment” refers to therapeutic treatment measures; wherein the object is to slow down (lessen) the targeted pathologic condition or disorder.
  • Those in need of treatment include those already with the disorder as well as those prone to have the disorder.
  • a subject or mammal when treating cancer according to a method of the disclosure, is successfully “treated” for cancer if, after receiving a therapeutic amount of an ErbB inhibitor according to the methods of the present disclosure, the patient shows observable and/or measurable reduction in or absence of one or more of the following: reduction in the number of cancer cells or absence of the cancer cells; reduction in the proliferation or survival of cancer cells; and/or relief to some extent, one or more of the symptoms associated with the specific infection; reduced morbidity and mortality, and improvement in quality of life issues.
  • the above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician.
  • subjects having a mutation of the disclosure may be treated for cancer by administering a therapeutically-effective amount of a composition of the disclosure, a Type II ErbB inhibitor, an EGFR-Viii selective agent/inhibitor or the NT-113 Type I inhibitor.
  • a therapeutically-effective amount refers to an amount of a composition of the disclosrue, a Type II ErbB inhibitor, an EGFR-Viii selective agent/inhibitor or the NT-113 Type I inhibitor effective to “treat” a disease or disorder (e.g. cancer) in a subject or mammal.
  • a Type II ErbB inhibitor may include a small molecule.
  • a “small molecule” is defined herein to have a molecular weight below about 1500 Daltons.
  • mutations may be detected by analyzing either nucleic acid or amino acid sequences from a subject. Nucleic acid and/or amino acid sequences may be isolated prior to sequence analysis.
  • the terms “nucleic acid” and “polynucleotide” are used interchangeably herein to refer to single- or double-stranded RNA, DNA, or mixed polymers.
  • Polynucleotides may include genomic sequences, extra-genomic and plasmid sequences, and smaller engineered gene segments that express, or may be adapted to express polypeptides.
  • An “isolated nucleic acid” is a nucleic acid that is substantially separated from other genome DNA sequences as well as proteins or complexes such as ribosomes and polymerases, which naturally accompany a native sequence. The term embraces a nucleic acid sequence that has been removed from its naturally occurring environment, and includes recombinant or cloned DNA isolates and chemically synthesized analogues or analogues biologically synthesized by heterologous systems.
  • a substantially pure nucleic acid includes isolated forms of the nucleic acid.
  • polypeptide is used in its conventional meaning, i.e., as a sequence of amino acids.
  • the polypeptides are not limited to a specific length of the product.
  • Peptides, oligopeptides, and proteins are included within the definition of polypeptide, and such terms may be used interchangeably herein unless indicated otherwise.
  • This term also does not refer to or exclude post- expression modifications of the polypeptide, for example, glycosylations, acetylations, phosphorylations and the like, as well as other modifications known in the art, both naturally occurring and non-naturally occurring.
  • a polypeptide may be an entire protein, or a subsequence thereof.
  • An “isolated polypeptide” is one that has been identified and separated and/or recovered from a component of its natural environment.
  • the isolated polypeptide will be purified (1) to greater than 95% by weight of polypeptide as determined by the Lowry method (e.g. more than 99% by weight), (2) to a degree sufficient to obtain at least 15 residues of N- terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or silver stain.
  • Isolated polypeptide includes the polypeptide in situ within recombinant cells since at least one component of the polypeptide's natural environment will not be present. In some embodiments, the isolated polypeptide will be prepared by at least one purification step.
  • a “native sequence” polynucleotide is one that has the same nucleotide sequence as a polynucleotide derived from nature.
  • a “native sequence” polypeptide is one that has the same amino acid sequence as a polypeptide (e.g. EGFR) derived from nature (e.g., from any species).
  • EGFR polypeptide.g. EGFR
  • Such native sequence polynucleotides and polypeptides can be isolated from nature or can be produced by recombinant or synthetic means.
  • a polynucleotide “variant,” as the term is used herein, is a polynucleotide that differs from a disclosed polynucleotide herein in one or more substitutions, deletions, additions and/or insertions.
  • a polypeptide “variant,” as the term is used herein, is a polypeptide that differs from a disclosed polypeptide herein in one or more substitutions, deletions, additions and/or insertions, or inversions. Such variants may be naturally occurring, non-naturally occurring, or may be synthetically generated.
  • EGFR mutations (or variants) of the disclosure may comprise one or more substitutions, deletions, additions and/or insertions, or inversions of the amino acid sequence that are alter the function of the resultant protein. Mutations may be detected, for example, by comparison or alignment of a nucleic or amino acid sequence with a wild type sequence.
  • two sequences are said to be “identical” if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence, as described below. Comparisons between two sequences are performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity.
  • Optimal alignment of sequences for comparison may be conducted using the Megalign program in the Lasergene suite of bioinformatics software (DNASTAR, Inc., Madison, WI), using default parameters. This program embodies several alignment schemes described in the following references: Dayhoff, M.O. (1978) A model of evolutionary change in proteins – Matrices for detecting distant relationships. In Dayhoff, M.O.
  • BLAST and BLAST 2.0 can be used, for example, with the parameters described herein, to determine percent sequence identity for the polynucleotides and polypeptides of the present disclosure.
  • Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information.
  • cumulative scores can be calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always ⁇ 0).
  • Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached.
  • the BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment.
  • a scoring matrix can be used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached.
  • the BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment.
  • the “percentage of sequence identity” is determined by comparing two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less (e.g. 5 to 15 percent, or 10 to 12 percent), as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences.
  • a wild type EGFR sequence of the disclosure may comprise or consist of the amino acid sequence of: [0128] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of:
  • a wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: [0130] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: [0131] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: [0132] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of:
  • Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more R Z .
  • Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more R Z ; wherein the 3- to 8-membered heterocycloalkyl is attached to X 2 via a carbon atom of the 3- to 8-membered heterocycloalkyl.
  • Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more R Z ; wherein the 3- to 8-membered heterocycloalkyl is attached to X 2 via a carbon atom of the 3- to 8-membered heterocycloalkyl, and wherein the carbon atom is substituted with R Z .
  • n z1 is an integer ranging from 0 to 6
  • n z2 is an integer ranging from 0 to 6
  • the total of n z1 and n z2 ranges from 1 to 6.
  • Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more R Z ; wherein the 3- to 8-membered heterocycloalkyl is attached to X 2 via a heteroatom (e.g., N) of the 3- to 8-membered heterocycloalkyl.
  • a heteroatom e.g., N
  • Z is 3- to 8-membered heterocycloalkyl.
  • Z is 3- to 8-membered heterocycloalkyl substituted with one or more R Z .
  • Z is 4- to 7-membered heterocycloalkyl optionally substituted with one or more R Z .
  • Z is 4- to 7-membered heterocycloalkyl.
  • Z is 4- to 7-membered heterocycloalkyl substituted with one or more R Z .
  • Z is 4-membered heterocycloalkyl optionally substituted with one or more R Z .
  • Z is 4-membered heterocycloalkyl optionally substituted with one or more halogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl, wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl is optionally substituted with one or more halogen.
  • Z is 4-membered heterocycloalkyl.
  • Z is 4-membered heterocycloalkyl substituted with one or more R Z .
  • Z is 4-membered heterocycloalkyl substituted with one or more halogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl, wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl is optionally substituted with one or more halogen.
  • Z is acetidinyl optionally substituted with one or more R Z .
  • Z is acetidinyl optionally substituted with one or more halogen, C 1 - C 6 alkyl, or C 3 -C 8 cycloalkyl, wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl is optionally substituted with one or more halogen.
  • Z is acetidinyl.
  • Z is acetidinyl substituted with one or more R Z .
  • Z is acetidinyl substituted with one or more halogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl, wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl is optionally substituted with one or more halogen.
  • Z is 5-membered heterocycloalkyl optionally substituted with one or more R Z .
  • Z is 5-membered heterocycloalkyl optionally substituted with one or more C 1 -C 6 alkyl.
  • Z is 5-membered heterocycloalkyl.
  • Z is 5-membered heterocycloalkyl substituted with one or more R Z .
  • Z is 5-membered heterocycloalkyl substituted with one or more C1- C 6 alkyl.
  • Z is pyrrolidinyl optionally substituted with one or more R Z .
  • Z is 6-membered heterocycloalkyl substituted with one or more halogen (e.g., F).
  • Z is piperidinyl optionally substituted with one or more R Z .
  • Z is piperidinyl optionally substituted with one or more halogen (e.g., F).
  • Z is piperidinyl.
  • Z is piperidinyl substituted with one or more R Z .
  • Z is piperidinyl substituted with one or more halogen (e.g., F).
  • halogen e.g., F
  • Z is piperidinyl substituted with one or more F.
  • Z is piperidinyl substituted with two or more halogen (e.g., F).
  • Z is piperidinyl substituted with two or more F.
  • Z is 2-azabicyclo[2.2.1]heptanyl optionally substituted with one or more R Z .
  • Z is 2-azabicyclo[2.2.1]heptanyl.
  • Z is 2-azabicyclo[2.2.1]heptanyl substituted with one or more R Z .
  • Z is imidazolidinyl optionally substituted with one or more R Z .
  • Z is imidazolidinyl.
  • Z is hexahydropyrimidinyl optionally substituted with one or more R Z .
  • Z is octahydropyrrolo[3,4-c]pyrrolyl or octahydropyrrolo[3,4- b]pyrrolyl optionally substituted with one or more R Z .
  • Z is octahydropyrrolo[3,4-c]pyrrolyl or octahydropyrrolo[3,4- b]pyrrolyl.
  • At least one R Z is C 1 -C 6 alkyl substituted with one or more halogen. [0241] In some embodiments, at least one R Z is C1-C6 alkyl substituted with one or more F. [0242] In some embodiments, at least one R Z is CH 2 F, CHF 2 , or CF 3 . [0243] In some embodiments, at least one R Z is C 3 -C 8 cycloalkyl optionally substituted with one or more halogen. [0244] In some embodiments, at least one R Z is C 3 -C 8 cycloalkyl. [0245] In some embodiments, at least one R Z is cyclopropyl.
  • At least one R Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more halogen.
  • X 1 and X 2 [0247] In some embodiments, X 1 is –NH–. [0248] In some embodiments, X 1 is –N(C 1 -C 6 alkyl)–. [0249] In some embodiments, X 1 is –N(CH 3 )–. [0250] In some embodiments, X 1 is –O–. [0251] In some embodiments, X 2 is –CH 2 –.
  • X 2 is —NH–, –N(C 1 -C 6 alkyl)–, –O–, or –S–. [0253] In some embodiments, X 2 is –NH–. [0254] In some embodiments, X 2 is –N(C 1 -C 6 alkyl)–. [0255] In some embodiments, X 2 is –N(CH 3 )–. [0256] In some embodiments, X 2 is –O–. [0257] In some embodiments, X 2 is –S–. [0258] In some embodiments, X 1 is –NH–; and X 2 is –CH 2 –.
  • X 1 is –NH–; and X 2 is —NH–.
  • X 1 is –NH–; and X 2 is –S–.
  • X 1 is –NH–; and X 2 is –O–.
  • X 1 is –O–; and X 2 is –CH 2 –.
  • X 1 is –O–; and X 2 is –NH–.
  • X 1 is –O–; and X 2 is –S–.
  • X 1 is –O–; and X 2 is –O–.
  • Variables Y, R Y , and R Ya [0266] In some embodiments, Y is C6 aryl optionally substituted with one or more R Y .
  • Y is C 6 aryl optionally substituted with one or more R Y ; each R Y independently: is halogen, -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, -O-(C 6 -C 10 aryl), -O-(5- to 10-membered heteroaryl), -(C 1 -C 6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C 1 -C 6 alkyl)-(3- to 10- membered cycloalkyl), -O-(C 1 -C 6 alkyl)-(3- to 10-membered heterocycloalkyl), or -O-(C 1 - C 6 alkyl)-(5- to 10-membered heteroaryl); wherein the -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, -O- (C 6 -C 10 aryl), -O
  • Y is C 6 aryl optionally substituted with one or more R Y ; each R Y independently is halogen, -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, -O-(C 6 -C 10 aryl), -O-(5- to 10-membered heteroaryl), -(C1-C6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C1-C6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C 1 -C 6 alkyl)-(3- to 10-membered heterocycloalkyl), or -O-(C 1 - C 6 alkyl)-(5- to 10-membered heteroaryl); wherein the -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, -O-(C 6 -C 10 aryl), -O-(5
  • Y is 5- to 9-membered heteroaryl is optionally substituted with one or more R Y .
  • Y is 5- to 9-membered heteroaryl optionally substituted with one or more R Y ; each R Y independently: is halogen, -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, -O-(C 6 -C 10 aryl), -O-(5- to 10-membered heteroaryl), -(C 1 -C 6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C 1 -C 6 alkyl)-(3- to 10- membered cycloalkyl), -O-(C1-C6 alkyl)-(3- to 10-membered heterocycloalkyl), or -O-(C1- C 6 alkyl)-(5- to 10-membered heteroaryl
  • Y is 5- to 9-membered heteroaryl optionally substituted with one or more R Y ; each R Y independently is halogen, -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, -O-(C 6 -C 10 aryl), -O-(5- to 10-membered heteroaryl), -(C 1 -C 6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C 1 -C 6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C 1 -C 6 alkyl)-(3- to 10-membered heterocycloalkyl), or -O-(C 1 - C 6 alkyl)-(5- to 10-membered heteroaryl); wherein the -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, -O-(C
  • At least one R Y is oxo.
  • at least one R Y is halogen, CN, -OH, or -NH 2 .
  • at least one R Y is halogen.
  • at least one R Y is F.
  • at least one R Y is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R Ya .
  • At least one R Y is 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ya .
  • At least one R Y is 3- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the - to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ya .
  • at least one R Y is 3- to 10-membered cycloalkyl optionally substituted with one or more R Ya .
  • at least one R Y is 3- to 10-membered heterocycloalkyl optionally substituted with one or more R Ya .
  • At least one R Y is C 6 -C 10 aryl optionally substituted with one or more R Ya .
  • at least one R Y is 5- to 10-membered heteroaryl is optionally substituted with one or more R Ya .
  • At least one R Y is -O-(3- to 10-membered cycloalkyl), -O-(3- to 10- membered heterocycloalkyl), -O-(C 6 -C 10 aryl), -O-(5- to 10-membered heteroaryl), -O-(C 1 -C 6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C 1 -C 6 alkyl)-(C 6 -C 10 aryl), -O-(C 1 -C 6 alkyl)-(5- to 10-membered heteroaryl), -NH-(C 1 -C 6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C 1 - C 6 alkyl)-(C 6 -C 10 aryl), or -NH-(C 1 -C 6 alkyl)-(5- to 10-membered hetero
  • At least one R Y is -O-(3- to 10-membered heterocycloalkyl), -O-(C 6 - C 10 aryl), -O-(5- to 10-membered heteroaryl), -O-(C 1 -C 6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C 1 -C 6 alkyl)-(C 6 -C 10 aryl), -O-(C 1 -C 6 alkyl)-(5- to 10-membered heteroaryl), -NH-(C1-C6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C1-C6 alkyl)-(C6-C10 aryl), or -NH-(C 1 -C 6 alkyl)-(5- to 10-membered heteroaryl), wherein the -O-(3- to 10-membered heterocycloalkyl), -O-(
  • At least one R Y is -O-(3- to 10-membered cycloalkyl) optionally substituted with one or more R Ya .
  • at least one R Y is -O-(3- to 10-membered heterocycloalkyl) optionally substituted with one or more R Ya .
  • at least one R Y is -O-(C 6 -C 10 aryl) optionally substituted with one or more R Ya .
  • at least one R Y is -O-(C 6 aryl) optionally substituted with one or more R Ya .
  • At least one R Y is -O-(5- to 10-membered heteroaryl) optionally substituted with one or more R Ya .
  • at least one R Y is -O-(pyridinyl) optionally substituted with one or more R Ya .
  • At least one R Y is -(C 1 -C 6 alkyl)-(3- to 10-membered heterocycloalkyl), -(C 1 -C 6 alkyl)-(C 6 -C 10 aryl), or -(C 1 -C 6 alkyl)-(5- to 10-membered heteroaryl), wherein the -(C 1 -C 6 alkyl)-(3- to 10-membered heterocycloalkyl), -(C 1 -C 6 alkyl)-(C 6 -C 10 aryl), or -(C 1 -C 6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R Ya .
  • At least one R Y is -(C1-C6 alkyl)-(3- to 10-membered heterocycloalkyl) optionally substituted with one or more R Ya .
  • at least one R Y is -O-(C 1 -C 6 alkyl)-(3- to 10-membered heterocycloalkyl) optionally substituted with one or more R Ya .
  • at least one R Y is -O-(C 1 -C 6 alkyl)-(C 6 -C 10 aryl) optionally substituted with one or more R Ya .
  • At least one R Y is -O-(CH 2 )-(C 6 aryl) optionally substituted with one or more R Ya .
  • at least one R Y is -O-(C1-C6 alkyl)-(5- to 10-membered heteroaryl) optionally substituted with one or more R Ya .
  • at least one R Y is -O-(CH 2 )-(pyridinyl) optionally substituted with one or more R Ya .
  • At least one R Y is -NH-(C 1 -C 6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C 1 -C 6 alkyl)-(C 6 -C 10 aryl), or -NH-(C 1 -C 6 alkyl)-(5- to 10-membered heteroaryl), wherein the -NH-(C 1 -C 6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C 1 -C 6 alkyl)-(C6-C10 aryl), or -NH-(C1-C6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R Ya .
  • At least one R Y is halogen, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, -O-(C 6 aryl), -O-(5- to 6-membered heteroaryl),-O-(CH 2 )-(6-membered heterocycloalkyl), -O-(CH 2 )-(C 6 aryl), -O-(CH 2 )-(5- to 6-membered heteroaryl); wherein the C 1 -C 6 alkyl, C 2 -C 6 alkynyl, -O-(C 6 aryl), -O-(CH 2 )-(6-membered heterocycloalkyl), -O-(CH 2 )-(C 6 aryl), -O-(CH 2 )-(5- to 6-membered heteroaryl) is optionally substituted with one or more R Ya .
  • At least one R Y is halogen, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, -O-(C 6 aryl), -O-(5- to 6-membered heteroaryl),-O-(CH2)-(6-membered heterocycloalkyl), -O-(CH2)-(C6 aryl), -O-(CH 2 )-(5- to 6-membered heteroaryl); wherein the C 1 -C 6 alkyl, C 2 -C 6 alkynyl, -O-(C 6 aryl), -O-(CH 2 )-(6-membered heterocycloalkyl), -O-(CH 2 )-(C 6 aryl), -O-(CH 2 )-(5- to 6-membered heteroaryl) is optionally substituted with one or more halogen, -OH, or C 1 -C 6 alkyl
  • At least one R Y is halogen, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or -O- (C 6 aryl); wherein the C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or -O-(C 6 aryl) is optionally substituted with one or more halogen, -OH, or C 1 -C 6 alkyl.
  • At least one R Y is halogen, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or -O- (5- to 6-membered heteroaryl); wherein the C1-C6 alkyl, C2-C6 alkynyl, or -O-(5- to 6-membered heteroaryl) is optionally substituted with one or more halogen, -OH, or C 1 -C 6 alkyl.
  • At least one R Y is halogen, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or -O- (pyridinyl); wherein the C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or -O-(pyridinyl) is optionally substituted with one or more halogen, -OH, or C 1 -C 6 alkyl.
  • At least one R Y is halogen, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or -O- (CH 2 )-(6-membered heterocycloalkyl); wherein the C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or -O-(CH 2 )-(6- membered heterocycloalkyl) is optionally substituted with one or more halogen, -OH, or C 1 -C 6 alkyl.
  • At least one R Y is halogen, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or -O- (CH 2 )-(C 6 aryl); wherein the C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or -O-(CH 2 )-(C 6 aryl) is optionally substituted with one or more halogen, -OH, or C 1 -C 6 alkyl.
  • At least one R Y is halogen, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or -O- (CH 2 )-(5- to 6-membered heteroaryl); wherein the C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or -O-(CH 2 )-(5- to 6-membered heteroaryl) is optionally substituted with one or more halogen, -OH, or C 1 -C 6 alkyl.
  • At least one R Y is halogen, -OH, C1-C6 alkyl, C2-C6 alkynyl, or -O- (CH 2 )-(pyridinyl); wherein the C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or -O-(CH 2 )-(pyridinyl) is optionally substituted with one or more halogen, -OH, or C 1 -C 6 alkyl.
  • At least one R Y together with another R Y and the intervening atoms attached thereto, form 4- to 10-membered cycloalkyl or 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered cycloalkyl or 4- to 10-membered heterocycloalkyl is optionally substituted with one or more R Ya .
  • at least one R Y together with another R Y and the intervening atoms attached thereto, form 4- to 10-membered cycloalkyl, wherein the 4- to 10-membered cycloalkyl is optionally substituted with one or more R Ya .
  • At least one R Y together with another R Y and the intervening atoms attached thereto, form 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl is optionally substituted with one or more R Ya .
  • at least one R Ya is CN.
  • at least one R Ya is -NH 2 .
  • At least one R Ya is halogen, -OH, C 1 -C 6 alkyl, or -O(C 1 -C 6 alkyl), wherein the C1-C6 alkyl or -O(C1-C6 alkyl) is optionally substituted with one or more halogen.
  • at least one R Ya is halogen.
  • at least one R Ya is F.
  • at least one R Ya is Cl.
  • at least one R Ya is –OH.
  • At least one R Ya is C 1 -C 6 alky optionally substituted with one or more halogen.
  • at least one R Ya is C 1 -C 6 alky.
  • at least one R Ya is -O(C1-C6 alkyl) optionally substituted with one or more halogen.
  • at least one R Ya is -O(C 1 -C 6 alkyl).
  • R 1 is –C ⁇ C–(CH3).
  • W CH–
  • Z is 3- to 8-membered heterocycloalkyl
  • X 1 is — NH–
  • Y is C 6 aryl one or more halogen
  • R 1 is –C ⁇ C–(C 1 -C 6 alkyl).
  • W CH–
  • X 1 is —NH–
  • Y is C 6 aryl one or more halogen
  • R 1 is –C ⁇ C–(C 1 -C 6 alkyl).
  • the compound is of Formula (I-A) or (I-B): or a pharmaceutically acceptable salt or stereoisomer thereof. [0342] In some embodiments, the compound is of Formula (I-AA), (I-AB), (I-BA), or (I-BB):
  • the compound is of Formula (I-AA1), (I-AA2), (I-AA3), (I-AA4): or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the compound is of Formula (I-AB1), (I-AB2), (I-AB3), (I-AB4):
  • the compound is of Formula (I-BA1), (I-BA2), (I-BA3), (I-BA4):
  • the compound is of Formula (I-BB1), (I-BB2), (I-BB3), (I-BB4): or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the compound is of Formula (I’): or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the compound is of Formula (I’-A) or (I’-B): or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the compound is of Formula (I’-AA), (I’-AB), (I’-BA), or (I’-BB): or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the compound is of Formula (I’-AA1), (I’-AA2), (I’-AA3), (I’- AA4): or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the compound is of Formula (I’-AB1), (I’-AB2), (I’-AB3), (I’- AB4):
  • the compound is of Formula (I’-BA1), (I’-BA2), (I’-BA3), (I’- BA4):
  • the compound is of Formula (I’-BB1), (I’-BB2), (I’-BB3), (I’-BB4): or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, heterocycloalkyl, unsubstituted or substituted C 1-3 alkoxy-aryl, unsubstituted or substituted C 1-3 alkoxy-heteroaryl, C 1-3 alkoxy-heterocycloalkyl, C 1-3 alkylamino-heterocycloalkyl, unsubstituted or substituted or substituted or substituted or substituted
  • Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C 1-3 alkoxy-aryl, unsubstituted or substituted C 1-3 alkoxy-heteroaryl, unsubstituted or substituted C 1-3 alkoxy- heterocycloalkyl, C 1-3 alkylamino-he
  • X 1 is —NH– or –NMe–, particularly –NH–.
  • W N–.
  • X 1 is —NH– or –NMe—, particularly –NH–.
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • X 1 is –NH– or –NMe–, particularly –NH–
  • X 2 is —NH–, –NMe–, –NEt– , –NPr–, –NBu–,or –O–, particularly –NH–, –NMe–, –NEt–,or –O–, particularly –NH–, –NMe–, –NEt–,or –O–.
  • X 2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or – O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • W N–
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • the compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof is represented by formula Ia or Ib wherein: Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, CHF 2 , C 3-4 heterocycloalkyl or C 3-4 cycloalkyl; X 1 is –NH–, –NMe– or –O–; X 2 is –NH–, –N(C 1-4 alkyl)–, –O– or –S–; Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membere
  • Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, heterocycloalkyl, unsubstituted or substituted C 1-3 alkoxy-aryl, unsubstituted or substituted C 1-3 alkoxy-heteroaryl, C 1-3 alkoxy-heterocycloalkyl, C 1-3 alkylamino-heterocycloalkyl, unsubstit
  • Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C 1-3 alkoxy-aryl, unsubstituted or substituted C 1-3 alkoxy-heteroaryl, unsubstituted or substituted C 1-3 alkoxy- heterocycloalkyl, unsubstituted
  • X 1 is —NH– or –NMe–, particularly –NH–.
  • R 1 is –C ⁇ C–Me.
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • X 1 is –NH– or –NMe–, particularly –NH–
  • X 2 is —NH–, –NMe– , –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH– , –NMe–, –NEt–, or –O–.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., a 4 to 6 membered saturated nitrogen heterocycle containing 1 nitrogen atom.
  • Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms, e.g. a 5 to 8 membered saturated nitrogen heterobicycle containing 1 nitrogen atom, e.g.
  • Z is of formula i wherein: R 2 is hydrogen, C1-4 alkyl –CHF2 or C3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toxxher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl or one of R a and R b and one of R c and R d form together with C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen. [0389] In some embodiments, R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl or one of R a and R b and one of R c and R d form together with C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. In some embodiments, R c and R d are each independently selected from hydrogen, methyl.
  • n 2 or 3 R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly –NH–
  • Z is of formula i and R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • X 1 is –NH– or –NMe–, particularly –NH–
  • Z is of formula i
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • R a and R b are each independently selected from hydrogen, methyl or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • m is 2 or 3
  • only one R a and one R b are not hydrogen and/or only one R a is not hydrogen.
  • X 1 is –NH– or –NMe–, particularly –NH–
  • Z is of formula i
  • R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • R c and R d are each independently selected from hydrogen, methyl or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • n is 2, only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • X 1 is –NH– or –NMe–, particularly –NH–
  • Z is of formula i and m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • Z is of formula i
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • m is 2 or 3
  • only one R a and one R b are not hydrogen and/or only one R a is not hydrogen.
  • Z is of formula i
  • R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • R c and R d are each independently selected from hydrogen, methyl or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • n is 2
  • only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • Z is of formula i and m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–
  • Z is of formula i and R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl or one of R a and R b and one of R c and R d form together with the .
  • R a and R b are each independently selected from hydrogen, methyl or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • m is 2 or 3
  • only one R a and one R b are not hydrogen and/or only one R a is not hydrogen.
  • X 2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–
  • Z is of formula i and R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl and or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • R c and R d are each independently selected from hydrogen, methyl or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • n is 2, only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • X 2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–
  • Z is of formula i and m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • the present disclosure provides the compound or the pharmaceutically acceptable salt or stereoisomer thereof of formula I-1 or I-2
  • X 1 is –NH–, –NMe– or –O–;
  • X 2 is –NH–, –N(C 1-4 alkyl)–, –O– or –S–;
  • Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C 1-3 alkoxy-aryl, unsubstituted
  • Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, heterocycloalkyl, unsubstituted or substituted C 1-3 alkoxy-aryl, unsubstituted or substituted C 1-3 alkoxy-heteroaryl, C 1-3 alkoxy-heterocycloalkyl, C 1-3 alkylamino-heterocycloalkyl, unsubstit
  • Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C 1-3 alkoxy-aryl, unsubstituted or substituted C 1-3 alkoxy-heteroaryl, unsubstituted or substituted C 1-3 alkoxy- heterocycloalkyl, unsubstituted
  • R 2 is hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH–.
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • X 1 is –NH– or –NMe–, particularly –NH–
  • X 2 is —NH–, –NMe– , –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH– , –NMe–, –NEt–, or –O–.
  • X 2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R a and R b are each independently selected from hydrogen and methyl.
  • R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly –NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • X 1 is –NH– or –NMe–, particularly –NH–
  • X 2 is —NH–, –NMe– , –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • the compounds of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof is represented by formula Ia-1 or Ia-2
  • X 1 is –NH–, –NMe– or –O–
  • X 2 is —NH–, –N(C 1-4 alkyl)–, –O– or –S–
  • Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C
  • Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, heterocycloalkyl, unsubstituted or substituted C 1-3 alkoxy-aryl, unsubstituted or substituted C 1-3 alkoxy-heteroaryl, C 1-3 alkoxy-heterocycloalkyl, C 1-3 alkylamino-heterocycloalkyl, unsub
  • Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C 1-3 alkoxy-aryl, unsubstituted or substituted C 1-3 alkoxy-heteroaryl, unsubstituted or substituted C 1-3 alkoxy- heterocycloalkyl, unsubstit
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • X 1 is –NH– or –NMe–, particularly –NH–
  • X 2 is — NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R a and R b are each independently selected from hydrogen, methyl.
  • R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly –NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • X 1 is —NH– or –NMe–, particularly –NH–
  • X 2 is — NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–,or –O–.
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • Y is of formula ii or iia wherein: R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3; R 5a is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-6 alkyl, C1-6 alkoxy, C 1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C 1-3 alkoxy-aryl, unsubstituted or substituted C 1-3 alkoxy-heteroaryl or unsubstituted or substituted C 1-3 alkoxy-heterocycloalkyl; and
  • R 5a is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C1-3 alkoxy-aryl, unsubstituted or substituted C 1-3 alkoxy-heteroaryl or unsubstituted or substituted C 1-3 alkoxy-heterocycloalkyl; the aryloxy, heteroaryloxy, C 1-3 alkoxy-aryl, C 1-3 alkoxy-heteroaryl, C 1-3 alkoxy-heterocycloalkyl is unsubstituted or substituted with one or more of C 1-4 alkyl, OCH
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5a are hydrogen, while the remaining are as defined above.
  • R 5a is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylhydroxyl.
  • R 5a is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylhydroxyl [0447]
  • R 5a is unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C 1-3 alkoxy-aryl, unsubstituted or substituted C 1-3 alkoxy-heteroaryl or unsubstituted or substituted C 1-3 alkoxy-heterocycloalkyl.
  • R 5a is unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C 1-2 alkoxy-aryl, unsubstituted or substituted C 1-2 alkoxy-heteroaryl or unsubstituted or substituted C1-2 alkoxy-heterocycloalkyl.
  • R 5a is unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C 1-3 alkoxy-aryl, unsubstituted or substituted C 1-3 alkoxy-heteroaryl or unsubstituted or substituted C 1-3 alkoxy-heterocycloalkyl.
  • R 5a is unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C 1-2 alkoxy-aryl, unsubstituted or substituted C 1-2 alkoxy-heteroaryl or unsubstituted or substituted C 1-2 alkoxy-heterocycloalkyl; the aryloxy, heteroaryloxy, C 1-2 alkoxy-aryl, C 1-2 alkoxy-heteroaryl, C 1-2 alkoxy-heterocycloalkyl is unsubstituted or substituted with one or more of C1-4 alkyl, OCH2F, HCF2, or halogen, e.g., F or Cl.
  • aryloxy, heteroaryloxy, C 1-2 alkoxy-aryl, C 1-2 alkoxy-heteroaryl, C 1-2 alkoxy-heterocycloalkyl is unsubstituted or substituted with one or
  • R 5a is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C 1-2 alkoxy-aryl, unsubstituted or substituted C 1-2 alkoxy-heteroaryl or unsubstituted or substituted C 1-2 alkoxy-heterocycloalkyl.
  • R 5a is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C1-2 alkoxy-aryl, unsubstituted or substituted C 1-2 alkoxy-heteroaryl or unsubstituted or substituted C 1-2 alkoxy-heterocycloalkyl; the aryloxy, heteroaryloxy, C 1-2 alkoxy-aryl, C 1-2 alkoxy-heteroaryl, C 1-2 alkoxy-heterocycloalkyl is unsubstituted or substituted with one or more of C 1-4 alkyl, OCH 2 F, HCF 2 , or halogen, e.g., F or Cl, CF 3
  • Y is of formula iii or iv wherein: R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3; R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl; X 4 is –O–, –NH–, –NMe–; L is a covalent bond or linear or branched C 1-3 alkyl; and A is a C 6 aryl, a 6 membered heterocycloalkyl or a 5-6 membered heteroaryl, wherein the C 6 aryl, 6 membered heterocycloalkyl or
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above for formula iii to iv.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • A is a C 6 aryl, a 6 membered heterocycloalkyl or a 5-6 membered heteroaryl, wherein the C 6 aryl, 6 membered heterocycloalkyl or 5-6 membered heteroaryl is unsubstituted or substituted with one of C 1-4 alkyl, OCH 2 F, HCF 2 , or halogen, e.g., F or Cl.
  • A is a C6 aryl, a 6 membered heterocycloalkyl or a 5-6 membered heteroaryl, wherein the C 6 aryl, 6 membered heterocycloalkyl or 5-6 membered heteroaryl is unsubstituted or substituted with one of methyl, ethyl, n-propyl, s-propyl, n-butyl, s-butyl, t-butyl, OCH 2 F, HCF 2 , or halogen, e.g., F or Cl.
  • A is a C 6 aryl, a 6 membered heterocycloalkyl or a 5-6 membered heteroaryl, wherein the C 6 aryl, 6 membered heterocycloalkyl or 5-6 membered heteroaryl is unsubstituted or substituted with one methyl, OCH 2 F, HCF 2 , or halogen, e.g., F or Cl.
  • A is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, which is unsubstituted or substituted with one or more of C 1-4 alkyl, OCH 2 F, HCF 2 , or halogen, e.g., F or Cl.
  • A is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, which is unsubstituted or substituted with one of methyl, ethyl, n-propyl, s-propyl, n-butyl, s-butyl, t-butyl, OCH 2 F, HCF 2 , or halogen, e.g., F or Cl.
  • A is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, which is unsubstituted or substituted with one methyl, OCH 2 F, HCF 2 , or halogen, e.g., F or Cl.
  • Y is of formula iii, v, vi or vii
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl;
  • X 4 is –O–, –NH–, –NMe–;
  • X 8 ’ is –O–, –S–, –NH– or –NM
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above for formula iii to vii.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 8 is –O–, –NMe– or –S–.
  • Y is of formula iii, v-a, e.g., v-a-1 or v-a-2, or vi-a, e.g., vi-a-1, or vii-a, e.g., vii-a-1
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl;
  • X 8 ’ is –O–, –S–, –NH– or –NMe–; and s is 0, 1, 2, 3.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-1.
  • X 8 is –O–, –NMe– or –S–.
  • Y is of formula iii, v-a(i), v-a(ii), e.g., v-a(i)-1, v-a(ii)-1, v-a(i)-2, v-a(ii)-2, or vi-a(i), e.g., vi-a(i)-1, or vii-a(i) or vii-a(ii), e.g., vii-a(i)-1 or vii-a(ii)-1 wherein: R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3; R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , O
  • X 8 is –O–, –NMe– or –S–.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 in formula iii are hydrogen, while the remaining are as defined above for formula iii to vii-a(ii)- 1.
  • Y is of formula iii, v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b- 10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii-a-3
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl;
  • X 8 ’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 8’ is –O–, –NMe– or –S–.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-3.
  • Y is of formula iii, v-a-3, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii- a-3.
  • s is 0 or 1 is Y is of formula v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-a-11, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12 and s is 1 for vi-a, vii-a-1, vii-a-2 or vii-a-3.
  • s is 0 or 1 is Y is of formula v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-a-11, and s is 1 for v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v- b-10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii-a-3.
  • s is 1.
  • Y is of formula iii, v-c-1, v-c-2, v-c-3, v-c-4, v-d-1, v-d-2, v-d-3, v-d-4, v-d-5, v-d-6, v-d-7, vi-a, vii-b-1, vii-b-2, vii-b-3 or vii-b-4
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl; and s is 0 or 1.
  • R 6 is hydrogen for v-d-1, v-d-2, v-d-3, v-d-4, v-d-5 and v-d-7; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for v-c-1, v-c-2, v- c-3, v-c-4, v-d-6, vii-b-1, vii-b-2, vii-b-3 and vii-b-4.
  • Y is of formula v-c(i)-1, v-c(ii)-1, v- c(i)-2, v-c(ii)-2, v-c(i)-3, v-c(ii)-3, v-c(ii)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(ii)- 3, v-d(ii)-3, v-d(i)-4, v-d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl; and s is 0 or 1.
  • s is 0 or 1 for formula v-c(i)-1, v-c(ii)-1, and 1 for v-c(i)-2, v-c(ii)- 2, v-c(i)-3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(ii)-3, v-d(ii)-3, v-d(ii)-4, v-d(ii)-4, v-d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(ii)-7, vi-a(i), vi-a(ii), vii-b(i)-
  • R 6 is hydrogen for v-d(i)-1, v-d(ii)-1, v-d(i)-3, v-d(ii)-3, v-d(i)-4, v- d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7 and v-d(ii)-7; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for v-c(i)-1, v-c(ii)-1, v-c(i)-2, v-c(ii)-2, v-c(i)- 3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-c(ii)-4,
  • Y is of formula iii, v-e-1, v-e-2, v-f-1, v-f-2, v-f-3, v-f-4, v-f-5, v-f-6a, v-f-6b, v-f-7, vi-a, vii-c-1, vii-c-2, vii-c-3 or vii-c-4
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl;
  • s is 0 or 1.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above for formula iii to vii-c-4.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 - C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • W N–.
  • X 1 is —NH– or –NMe–, particularly –NH–.
  • X 2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • X 1 is –NH– or –NMe–, particularly –NH–
  • X 2 is —NH–, –NMe– , –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH– , –NMe–, –NEt–, or –O–.
  • X 2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above for formula iii to vii.
  • X 4 is –O–.
  • L is a covalent bond, –(CH2)– or –(CH2)2–.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 8 is –O–, –NMe– or –S–.
  • the compound of formula II or III or pharmaceutically acceptable salts or stereoisomers thereof is represented by formula IIa or IIIa wherein: Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, -CHF 2 or C 3-4 cycloalkyl; X 1 is –NH–, –NMe– or –O–; X 2 is –NH–, –N(C1-4 alkyl)–, –O– or –S–; Y is a group of formula iii, v, vi or vii
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl;
  • X 4 is –O–, –NH–, –NMe–;
  • X 8 ’ is –O–, –S–, –NH– or –NM
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • Y is of formula iii, v-a, e.g., v-a-1 or v-a-2, or vi-a, e.g., vi-a-1, or vii-a, e.g., vii-a-1
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl;
  • X 8 ’ is –O–, –S–, –NH– or –NMe–; and s is 0, 1, 2, 3.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-1.
  • X 8 is –O–, –NMe– or –S–.
  • Y is of formula iii, v-a(i), v-a(ii), e.g., v-a(i)-1, v-a(ii)-1, v-a(i)-2, v-a(ii)-2, or vi-a(i), e.g., vi-a(i)-1, or vii-a(i) or vii-a(ii), e.g., vii-a(i)-1 or vii-a(ii)-1
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl;
  • X 8 ’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1.
  • X 8 is –O–, –NMe– or –S–.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 in formula iii are hydrogen, while the remaining are as defined above for formula iii to vii-a(ii)- 1.
  • Y is of formula iii, v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a- 8, v-a-9, v-a-10, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b- 12, vi-a, vii-a-1, vii-a-2 or vii-a-3
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl;
  • X 8 ’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-3.
  • X 8’ is –O–, –NMe– or –S–.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-3.
  • Y is of formula iii, v-a-3, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii- a-3.
  • s is 0 or 1 is Y is of formula v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-a-11, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12 and s is 1 for vi-a, vii-a-1, vii-a-2 or vii-a-3.
  • s is 0 or 1 is Y is of formula v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-a-11, and s is 1 for v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v- b-10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii-a-3. In some embodiments, s is 1.
  • Y is of formula iii, v-c-1, v-c-2, v-c-3, v-c-4, v-d-1, v-d- 2, v-d-3, v-d-4, v-d-5, v-d-6, v-d-7, vi-a, vii-b-1, vii-b-2, vii-b-3 or vii-b-4
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl; and s is 0 or 1.
  • R 6 is hydrogen for v-d-1, v-d-2, v-d-3, v-d-4, v-d-5 and v-d-7; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for v-c-1, v-c-2, v- c-3, v-c-4, v-d-6, vii-b-1, vii-b-2, vii-b-3 and vii-b-4.
  • Y is of formula v-c(i)-1, v-c(ii)-1, v-c(i)-2, v-c(ii)-2, v- c(i)-3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(ii)-3, v-d(ii)-3, v-d(i)- 4, v-d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(ii)-7, vi-a(
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl; and s is 0 or 1.
  • s is 0 or 1 for formula v-c(i)-1, v-c(ii)-1, and 1 for v-c(i)-2, v-c(ii)- 2, v-c(i)-3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(ii)-3, v-d(ii)-3, v-d(ii)-4, v-d(ii)-4, v-d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(ii)-7, vi-a(i), vi-a(ii), vii-b(i)-
  • R 6 is hydrogen for v-d(i)-1, v-d(ii)-1, v-d(i)-3, v-d(ii)-3, v-d(i)-4, v- d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7 and v-d(ii)-7; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for v-c(i)-1, v-c(ii)-1, v-c(i)-2, v-c(ii)-2, v-c(i)- 3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-c(ii)-4,
  • R 2 is hydrogen, C 1-4 alkyl, -CHF 2 or C 3-4 cycloalkyl
  • R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form to rejoinher an oxiranyl
  • R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle
  • m is 1, 2 or 3
  • n is 1 or 2
  • X 1 is –NH–, –NMe– or –O–
  • X 2 is —NH–, –N(C1-4 alkyl)–, –O– or –S–
  • Y is a group of formula IIb or IIIb wherein: R 2 is hydrogen, C 1-4 alkyl, -CHF 2 or C 3-4 cycloalkyl; R a , R
  • R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • Y is of formula iii, v-a, e.g., v-a-1 or v-a-2, or vi-a, e.g., vi-a-1, or vii-a, e.g., vii-a-1
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl;
  • X 8 ’ is –O–, –S–, –NH– or –NMe–; and S is 0, 1, 2, 3.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-1.
  • X 8 is –O–, –NMe– or –S–.
  • Y is of formula iii, v-a(i), v-a(ii), e.g., v-a(i)-1, v-a(ii)-1, v-a(i)-2, v- a(ii)-2, or vi-a(i), e.g., vi-a(i)-1, or vii-a(i) or vii-a(ii), e.g., vii-a(i)-1 or vii-a(ii)-1
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl;
  • X 8 ’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1.
  • X 8 is –O–, –NMe– or –S–.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 in formula iii are hydrogen, while the remaining are as defined above for formula iii to vii-a(ii)- 1.
  • Y is of formula iii, v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v- a-10, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12, vi-a, vii- a-1, vii-a-2 or vii-a-3
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl;
  • X 8 ’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-3.
  • X 8’ is –O–, –NMe– or –S–.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-3.
  • Y is of formula iii, v-a-3, v-b-1, v-b-2, v-b-3, v-b-4, v- b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii-a-3.
  • s is 0 or 1 is Y is of formula v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-a-11, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12 and s is 1 for vi-a, vii-a-1, vii-a-2 or vii-a-3.
  • s is 0 or 1 is Y is of formula v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-a-11, and s is 1 for v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v- b-10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii-a-3. In some embodiments, s is 1.
  • Y is of formula iii, v-c-1, v-c-2, v-c-3, v-c-4, v-d-1, v-d-2, v-d-3, v- d-4, v-d-5, v-d-6, v-d-7, vi-a, vii-b-1, vii-b-2, vii-b-3 or vii-b-4
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl; and s is 0 or 1.
  • R 6 is hydrogen for v-d-1, v-d-2, v-d-3, v-d-4, v-d-5 and v-d-7; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for v-c-1, v-c-2, v- c-3, v-c-4, v-d-6, vii-b-1, vii-b-2, vii-b-3 and vii-b-4.
  • Y is of formula v-c(i)-1, v-c(ii)-1, v-c(i)-2, v-c(ii)-2, v-c(i)-3, v- c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(ii)-3, v-d(ii)-3, v-d(i)-4, v-d(ii)- 4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(ii)-7, vi-a(i), vi-
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl; and s is 0 or 1.
  • s is 0 or 1 for formula v-c(i)-1, v-c(ii)-1, and 1 for v-c(i)-2, v-c(ii)- 2, v-c(i)-3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-3, v-d(ii)-3, v-d(ii)-4, v-d(ii)-4, v-d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(ii)-7, vi-a(i), vi-a(ii), vii-b(i)-1, vii-b(ii)-1, vii- b(i)-2
  • R 6 is hydrogen for v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(i)-3, v- d(ii)-3, v-d(i)-4, v-d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-7 and v-d(ii)-7; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for v-c(i)-1, v-c(ii)-1, v-c(i)-2, v-c(ii)-2, v-c(i)- 3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-c(ii)-4,
  • X 1 is –NH–, –NMe– or –O–
  • X 2 is —NH–, –N(C1-4 alkyl)–, –O– or –S–
  • R 2 is hydrogen, C 1-4 alkyl, -CHF 2 or C 3-4 cycloalkyl
  • R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form together an unsubstituted oxiranyl
  • R c , R d are each independently selected from hydrogen, C 1-4 alkyl
  • m is 1, 2 or 3
  • n is 1 or 2
  • r is 1 or 2
  • Y is a group of formula iii, v, vi or vii.
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl;
  • X 4 is –O–, –NH–, –NMe–;
  • X 8 ’ is –O–, –S–, –NH– or –NM
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl;
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, – NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • X 1 is –NH– or –NMe–, particularly – NH–
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • R 2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl.
  • R a and R b are each independently selected from hydrogen and methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen.
  • R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly – NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • X 1 is –NH– or –NMe–, particularly – NH–
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–.
  • Y is of formula iii, v-a, e.g., v-a-1 or v-a-2, or vi-a, e.g., vi-a-1, or vii-a, e.g., vii-a-1
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl;
  • X 8 ’ is –O–, –S–, –NH– or –NMe–; and s is 0, 1, 2, 3.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-1.
  • X 8 is –O–, –NMe– or –S–.
  • Y is of formula iii, v-a(i), v-a(ii), e.g., v-a(i)-1, v-a(ii)-1, v-a(i)-2, v-a(ii)-2, or vi-a(i), e.g., vi-a(i)-1, or vii-a(i) or vii-a(ii), e.g., vii-a(i)-1 or vii-a(ii)-1 wherein: R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3; R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3;
  • X 8 is –O–, –NMe– or –S–.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 in formula iii are hydrogen, while the remaining are as defined above for formula iii to vii-a(ii)- 1.
  • Y is of formula iii, v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b- 10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii-a-3
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl;
  • X 8 ’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 8’ is –O–, –NMe– or –S–.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-3.
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylhydroxyl, aryloxy, heteroaryloxy, heterocycloalkyl, C 1-2 alkoxy-aryl, C 1-2 alkoxy-heteroaryl or C 1-2 alkoxy-cycloalkyl.
  • halogen e.g., F or Cl
  • CF 3 HCF 2 , OCF 3
  • hydroxy C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylhydroxyl, aryloxy, heteroaryloxy, heterocycloalkyl, C 1-2 alkoxy-aryl, C 1-2 alkoxy-heteroaryl or C 1-2 alkoxy-cycloalkyl.
  • Y is of formula iii, v-a-3, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii- a-3.
  • s is 0 or 1 is Y is of formula v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12 and s is 1 for vi-a, vii-a-1, vii-a-2 or vii-a-3.
  • s is 0 or 1 is Y is of formula v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10 and s is 1 for v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v- b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii-a-3. In some embodiments, s is 1.
  • Y is of formula iii, v-c-1, v-c-2, v-c-3, v-c-4, v-d-1, v-d-2, v-d-3, v-d-4, v-d-5, v-d-6, v-d-7, vi-a, vii-b-1, vii-b-2, vii-b-3 or vii-b-4
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl; and s is 0 or 1.
  • R 6 is hydrogen for v-d-1, v-d-2, v-d-3, v-d-4, v-d-5 and v-d-7; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for v-c-1, v-c-2, v- c-3, v-c-4, v-d-6, vii-b-1, vii-b-2, vii-b-3 and vii-b-4.
  • Y is of formula v-c(i)-1, v-c(ii)-1, v- c(i)-2, v-c(ii)-2, v-c(i)-3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(ii)- 3, v-d(ii)-3, v-d(i)-4, v-d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(ii)
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl; and s is 0 or 1.
  • s is 0 or 1 for formula v-c(i)-1, v-c(ii)-1, and 1 for v-c(i)-2, v-c(ii)- 2, v-c(i)-3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(ii)-3, v-d(ii)-3, v-d(ii)-4, v-d(ii)-4, v-d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(ii)-7, vi-a(i), vi-a(ii), vii-b(i)-
  • R 6 is hydrogen for v-d(i)-1, v-d(ii)-1, v-d(i)-3, v-d(ii)-3, v-d(i)-4, v- d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-7 and v-d(ii)-7; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for v-d(i)-6, v-d(ii)-6, v-c(i)-1, v-c(ii)-1, v-c(i)-2, v-c(ii)-2, v-c(i)- 3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-c(ii)-4,
  • Y is of formula iii, v-e-1, v-e-2, v-f-1, v-f-2, v-f-3, v-f-4, v-f-5, v-f-6a, v-f-6b, v-f-7, vi-a, vii-c-1, vii-c-2, vii-c-3 or vii-c-4
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl; and s is 0 or 1.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above for formula iii to vii-c-4.
  • the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula IV-2, IV-3 or IV-4. [0578] In some embodiments, the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula IV-1.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl or C3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly – NH–.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or – (CH2)2–.
  • X 4 is –O– and L is a covalent bond, –(CH2)– or –(CH2)2–.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein: R 2 is hydrogen, C1-4 alkyl, -CHF2 or C3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVa-1, IVa-2, IVa-3 or IVa- 4
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, -CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly – NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or – (CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein: R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2.
  • R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl; [0609] In some embodiments of formula IVa-1, IVa-2, IVa-3 or IVa-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein: R 2 is hydrogen, Me or Et. [0610] In some embodiments, the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV- 11 or IV-12
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, -CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF3;
  • R 5 is hydrogen, halogen, e.g., F
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe– , particularly –NH–.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 4 is –O–.
  • L is a covalent bond, – (CH 2 )– or –(CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or – (CH 2 ) 2 –.
  • X 8 is –O–, –NMe– or – S–.
  • Z is of formula i wherein: R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0626] In some embodiments R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV-11 or IV-12 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein: R 2 is hydrogen, Me or Et.
  • R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV-11 or IV-12 is represented by formula IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVa-10, IVa-11 or IVa-12
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C– Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 8 is –O–, – NMe– or –S–.
  • Z is of formula i wherein: R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0638] In some embodiments R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • formula IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVa-10, IVa-11 or IVa-12 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein: R 2 is hydrogen, Me or Et.
  • R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • X 1 is —NH– or – NMe–, particularly –NH.
  • W N-.
  • R 1 is –C ⁇ C–Me.
  • X 1 is —NH– or – NMe–, particularly –NH–
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen.
  • R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or – NMe–, particularly –NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • X 4 is —O–.
  • L is a covalent bond, –(CH2)– or –(CH2)2–.
  • X 4 is –O– and L is a covalent bond, –(CH2)– or –(CH 2 ) 2 –.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVb-5 to IVb-12, IVc-5 to IVc-12
  • X 1 is –NH–, –NMe– or –O–;
  • X 4 is —O–, –NH–, –NMe–;
  • X 8 ’ is –O–, –S–, –NH– or –NMe—;
  • L is a covalent bond or linear or branched C 1-3 alkyl
  • R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g.,
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly – NH.
  • W N–.
  • R 1 is –C ⁇ C–Me.
  • X 1 is —NH– or –NMe—, particularly – NH–
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • R 2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl.
  • R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen. [0667] In some embodiments of a compound of formula IVb-5 to IVb-12, IVc-5 to IVc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl.
  • n 2 or 3 R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly – NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or – (CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IVb-1, IVb-2, IVb-3, IVb-4, IVc-1, IVc-2, IVc-3 or IVc-4, X 4 is —O–, such that the compound is represented by formula IVd-1, IVd-2, IVd-3, IVd-4, IVe-1, IVe-2, IVe-3 or IVe- 4
  • X 1 is —NH–, –NMe– or –O–
  • X 8 ’ is –O–, –S–, –NH– or –NMe—;
  • L is a covalent bond or linear or branched C1-3 alkyl
  • R 2 is hydrogen, C 1-4
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or – NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen.
  • R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or – NMe–, particularly –NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 1 is —NH–, –NMe– or –O–;
  • X 4 is —O–, –NH–, –NMe–;
  • X 8 ’ is –O–, –S–, –NH– or –NMe–;
  • L is a covalent bond or linear or branched C 1-3 alkyl
  • R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen,
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or – NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • X 1 is —NH– or – NMe–, particularly –NH–
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen.
  • R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly – NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • X 4 is –O–.
  • L is a covalent bond, –(CH2)– or –(CH2)2–.
  • X 4 is –O– and L is a covalent bond, –(CH2)– or –(CH 2 ) 2 –.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IVb-5 to IVb12, IVc-5 to IVc12, X 4 is –O—, such that the compound is represented by formula IVd-5 to IVd-12, IVe-5 to IVe-12
  • X 1 is –NH–, –NMe– or –O–;
  • X 8 ’ is –O–, –S–, –NH– or –NMe–;
  • L is a covalent bond or linear or branched C 1-3 alkyl
  • R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly – NH.
  • W N–.
  • R 1 is –C ⁇ C–Me.
  • R 2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen.
  • R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly – NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • L is a covalent bond, –(CH 2 )– or – (CH2)2–.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly – NH.
  • R 1 is –C ⁇ C–Me.
  • X 1 is —NH– or –NMe—, particularly – NH–
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • R 2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl.
  • R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen. [0718] In some embodiments of a compound of formula IVf-5 to IVf-12, IVg-5, IVg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl.
  • n 2 or 3 R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly – NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • X 4 is –O–.
  • L is a covalent bond, –(CH2)– or – (CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVh-1, IVh-2, IVh-3, e.g., IVh-3a or IVh-3b, or IVh-4
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 ,
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe– , particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0732] In some embodiments R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • formula IVh-1, IVh-2, IVh-3, e.g., IVh-3a or IVh-3b, or IVh-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe– , particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0742] In some embodiments R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • formula IVi-1, IVi-2, IVi-3, e.g., IVi-3a or IVi-3b, or IVi-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVh-5, IVh-6, IVh-7, IVh- 8, IVh-9, IVh-10 preferably IVh-11, IVh-12, IVh-13 or IVh-14 IVh-15, or IVh-16
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 ,
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0752] In some embodiments R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0761] In some embodiments R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalky or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe– , particularly –NH.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0770] In some embodiments R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • formula IVj-1, IVj-2, IVj-3, e.g., IVj-3a or IVj-3b, or IVj-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe– , particularly –NH.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • Z is of formula i wherein R 2 is hydrogen, C1-4 alkyl, CHF2 or C3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0779] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • formula IVk-1, IVk-2, IVk-3, e.g., IVk-3a or IVk-3b, or IVk-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • X 8 is –O–, –NMe– or –S.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVj-5, IVj-6, IVj-7, IVj-8, IVj-9, IVj-10, e.g., IVj-11, IVj-12, IVj-13, IVj-14 or IVj-5, or IVj-16
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 8 is —O–, –NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0788] In some embodiments R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • formula IVj-5, IVj-6, IVj-7, IVj-8, IVj-9, IVj-10 e.g., IVj-11, IVj-12, IVj-13, IVj-14 or IVj-5, or IVj-16 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 - C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0796] In some embodiments R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 8 is –O–, –NMe– or –S–.
  • Z in D1 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form to rejoinher an oxiranyl; R c , R d are each independently selected from hydrogen, C1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0807] In some embodiments R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl. [0808] In some embodiment
  • R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVm-1 to IVm-25
  • D2 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 8 is –O–, –NMe– or –S.
  • Z in D2 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Z is selected from wherein R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVn-1 – IVn-17 wherein D 1 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • R 6 is hydrogen for IVn-5, IVn-7, IVn-8, IVn-9, IVn-11; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for IVn-1, IVn-2, IVn-3, IVn-4, IVn-6, IVn-10,IVn-14, IVn-15, IVn-16, IVn-17.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • Z in D1 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Z is selected from
  • D 2 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • R 6 is hydrogen for IVo-5 IVo-7, IVo-8, IVo-9, IVo-11; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for IVo-1, IVo-2, IVo-3, IVo-4, IVo-6, IVo-10, IVo-14, IVo-15, IVo-16, IVo-17.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 8 is –O–, –NMe– or –S–.
  • Z in D2 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form to rejoinher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Z is selected from wherein R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVn-18 – IVn-51 wherein D 1 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • R 6 is hydrogen for IVn-25 to IVn27, IVn30 to IVn-35, IVn-38, IVn- 39; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for IVn-28, IVn-29, IVn-36, IVn-37, IVn-18 to IVn-25, IVn-44 to IVn-51.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • Z in D1 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • D 2 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • R 6 is hydrogen for IVo-25 to IVo27, IVo30 to IVo-35, IVo38, IVo- 39; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for IVo-18 to Ivo-25, IVo28, IVo29, IVo-36, IVo-37, IVo-44 to IVo-51.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 8 is –O–, –NMe– or –S.
  • Z in D2 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • R 2 is hydrogen, Me or Et.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • Z in D1 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • formula IVp-1 – IVp-15 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVq-1 – IVq-15
  • D2 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 8 is –O–, –NMe– or –S.
  • Z in D2 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C1-4 alkyl; or one of R a and R b and one of R c and R d form together with the CC-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • formula IVq-1 – IVq-15 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVp-16 – IVp-45
  • D1 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 ,
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • Z in D1 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • formula IVp-16 – IVp-45 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVq-16 – IVq-45
  • D2 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 8 is –O–, –NMe– or –S–.
  • Z in D2 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form to rejoinher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • R 2 is hydrogen, Me or Et.
  • the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula V-1, V-2, V-3 or V-4
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH–.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0910] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl. [0911] In some embodiments of formula V-1, V-2, V-3 or V-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Va-1, Va-2, Va-3 or Va-4 wherein Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly – NH.
  • R 1 is —C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or – (CH2)2–.
  • X 4 is –O– and L is a covalent bond, –(CH2)– or –(CH2)2–.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0923] In some embodiments, R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • Z is selected from wherein R 2 is hydrogen, Me or Et.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl; X 1 is –NH–,
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • W N–.
  • X 1 is —NH– or –NMe—, particularly –NH–.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0938] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • formula V-5, V-6, V-7, V-8, V-9, V-10, V-11 or V-12 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-5, V-6, V-7, V-8, V-9, V-10, V-11 or V-12 is represented by formula Va-5, Va-6, Va-7, Va-8, Va-9, Va-10, Va-11 or Va-12
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or – NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 4 is —O– and L is a covalent bond, –(CH 2 )– or – (CH 2 ) 2 –.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0950] In some embodiments R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • W N–.
  • R 1 is –C ⁇ C–Me.
  • X 1 is —NH– or –NMe–, particularly –NH–
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen.
  • R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly –NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • X 4 is –O–.
  • L is a covalent bond, – (CH 2 )– or –(CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or – (CH2)2–.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly – NH.
  • W N–.
  • R 1 is –C ⁇ C–Me.
  • X 1 is –NH– or –NMe–, particularly – NH–
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • R 2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl.
  • R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen. [0977] In some embodiments of a compound of formula Vb-5 to Vb-12, Vc-5 to Vc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl.
  • n 2 or 3 R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly – NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or – (CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • W N–.
  • R 1 is –C ⁇ C–Me.
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen.
  • R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly –NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • L is a covalent bond, — (CH 2 )– or –(CH 2 ) 2 –.
  • X 1 is —NH–, –NMe– or –O–;
  • X 4 is —O–, –NH–, –NMe–;
  • X 8 ’ is –O–, –S–, –NH– or –NMe–;
  • L is a covalent bond or linear or branched C 1-3 alkyl
  • R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen,
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • X 1 is –NH– or –NMe–, particularly –NH–
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen.
  • R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly – NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • X 4 is –O–.
  • L is a covalent bond, – (CH 2 )– or –(CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or – (CH2)2–.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vb-5 to Vb12, Vc-5 to Vc12, X 4 is –O–, such that the compound is represented by formula Vd-5 to Vd-12, Ve-5 to Ve-12
  • X 1 is –NH–, –NMe– or –O–;
  • X 8 ’ is –O–, –S–, –NH– or –NMe–;
  • L is a covalent bond or linear or branched C 1-3 alkyl
  • R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly – NH.
  • W N–.
  • R 1 is –C ⁇ C–Me.
  • R 2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen.
  • R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly – NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • L is a covalent bond, –(CH 2 )– or – (CH 2 ) 2 –.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly – NH.
  • R 1 is –C ⁇ C–Me.
  • X 1 is —NH– or –NMe—, particularly – NH–
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • R 2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl.
  • R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen. [1029] In some embodiments of a compound of formula Vf-5 to Vf-12, Vg-5, Vg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl.
  • n 2 or 3 R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly – NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or – (CH2)2–.
  • X 4 is –O– and L is a covalent bond, –(CH2)– or –(CH2)2–.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1043] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1053] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Vi-1, Vi-2, Vi-3, e.g., Vi-3a or Vi-3b, or Vi-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vh-5, Vh-6, Vh-7, Vh-8, Vh- 9, Vh-10 preferably Vh-11, Vh-12, Vh-13 or Vh-14 Vh-15, or Vh-16
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 ,
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 - C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1063] In some embodiments, R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • Vh-5, Vh-6, Vh-7, Vh-8, Vh-9 e.g., Vh-10, Vh-11, Vh- 12 or Vh-13 Vh-14, or Vh-15 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1072] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Vi-5, Vi-6, Vi-7, Vi-8, Vi-9, Vi-10, e.g., Vi-11 Vi-12, Vi-13, Vi-14 or Vi-15, or Vi-16 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • X 8 is –O–, –NMe– or –S–.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl or C3-4 cycloalkyl [1077] In some embodiments of a compound of formula Vj-1, Vj-2, Vj-3, e.g., Vj-3a or Vj-3b, or Vj-4 or pharmaceutically acceptable salts or stereoisomers thereof, X 1 is —NH– or –NMe–, particularly –
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1082] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Vj-1, Vj-2, Vj-3, e.g., Vj-3a or Vj-3b, or Vj-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl [1086] In some embodiments of a compound of formula Vk-1, Vk-2, Vk-3, e.g., Vk-3a or Vk- 3b, or Vk-4 or pharmaceutically acceptable salts or stereoisomers thereof, X 1 is —NH– or –NMe–
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1091] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Vk-1, Vk-2, Vk-3, e.g., Vk-3a or Vk-3b, or Vk-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • X 8 is –O–, –NMe– or –S.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vj-5, Vj-6, Vj-7, Vj-8, Vj-9, Vj-10, e.g., Vj-11, Vj-12, Vj-13, Vj-14 or Vj-5, or Vj-16
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl [1096] In some embodiments of a compound of formula Vj-5, Vj-6, Vj-7, Vj-8, Vj-9, Vj-10, e.g., Vj-11, Vj-12, Vj
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1100] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Vj-5, Vj-6, Vj-7, Vj-8, Vj-9, Vj-10 e.g., Vj-11, Vj-12, Vj-13, Vj-14 or Vj-5, or Vj-16 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1108] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Vk-5, Vk-6, Vk-7, Vk-8, Vk-9, Vk-10 e.g., Vk-11, Vk- 12, Vk-13, Vk-14 or Vk-5, or Vk-16 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vl-1 to Vl-25
  • D1 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 ,
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 8 is –O–, –NMe– or –S–.
  • Z in D1 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form to rejoinher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • n 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Z is selected from
  • R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vm-1 to Vm-25
  • D2 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 8 is –O–, –NMe– or –S.
  • Z in D2 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vn-1 – Vn-17 wherein D 1 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • R 6 is hydrogen for Vn-5, Vn-7, Vn-8, Vn-9, Vn-11; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for Vn-1, Vn-2, Vn-3, Vn-4, Vn-6, Vn-10,Vn-14, Vn-15, Vn-16, Vn-17.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • Z in D1 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vo-1 – Vo-17 wherein D 2 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., e
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • R 6 is hydrogen for Vo-5, Vo-7, Vo-8, Vo-9, Vo-11; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for Vo-1, Vo-2, Vo-3, Vo-4, Vo-6, Vo-10, Vo-14, Vo-15, Vo-16, Vo-17.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 8 is –O–, –NMe– or –S–.
  • Z in D2 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form to rejoinher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Z is selected from wherein R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vn-18 – Vn-51 wherein D 1 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1- 4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • R 6 is hydrogen for Vn-25 to Vn-27, Vn-30 to Vn-35, Vn-38, Vn- 39; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for Vn-18 to Vn-25, Vn-28, Vn-29, Vn-36, Vn-37, Vn-44 to Vn-51.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • Z in D1 is of formula i wherein R 2 is hydrogen, C1-4 alkyl, CHF2 or C3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • D 2 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • R 6 is hydrogen for Vo-25 to Vo-27, Vo-30 to Vo-35, Vo-38, Vo- 39; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for Vo-18 to Vo-25, Vo-28, Vo-29, Vo-36, Vo-37 Vo-44 to Vo-51.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 8 is –O–, –NMe– or –S.
  • Z in D2 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vp-1 – Vp-15 wherein D1 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • Z in D1 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • formula Vp-1 – Vp-15 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vq-1 – Vq-15
  • D2 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 8 is –O–, –NMe– or –S.
  • Z in D2 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • formula Vq-1 – Vq-15 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vp-16 – Vp-45
  • D1 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 ,
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • Z in D1 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • formula Vp-16 – Vp-45 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vq-16 – Vq-45
  • D 2 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 8 is –O–, –NMe– or –S–.
  • Z in D2 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form to rejoinher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Z is selected from wherein R 2 is hydrogen, Me or Et.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly – NH–.
  • X 1 is —NH– or –NMe—, particularly – NH–.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or – (CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1225] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • formula VI-1, VI-2, VI-3 or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIa-1, VIa-2, VIa-3 or VIa- 4
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl or C3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly – NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or – (CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • formula VIa-1, VIa-2, VIa-3 or VIa-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI- 11 or VI-12
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF3;
  • R 5 is hydrogen, halogen, e.g., F or Cl
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe– , particularly –NH–.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 4 is –O–.
  • L is a covalent bond, – (CH 2 )– or –(CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or – (CH 2 ) 2 –.
  • X 8 is –O–, –NMe– or – S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1256] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI-11 or VI-12 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI-11 or VI-12 is represented by formula VIa-5, VIa-6, VIa-7, VIa-8, VIa-9, VIa-10, VIa-11 or VIa-12
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C– Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 8 is –O–, – NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1268] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • formula VIa-5, VIa-6, VIa-7, VIa-8, VIa-9, VIa-10, VIa-11 or VIa-12 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or – NMe–, particularly –NH.
  • W N–.
  • R 1 is –C ⁇ C–Me.
  • X 1 is —NH– or – NMe–, particularly –NH–
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen.
  • R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or – NMe–, particularly –NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIb-5 to VIb-12, VIc-5 to VIc-12
  • X 1 is –NH–, –NMe– or –O–;
  • X 4 is —O–, –NH–, –NMe–;
  • X 8 ’ is –O–, –S–, –NH– or –NMe—;
  • L is a covalent bond or linear or branched C 1-3 alkyl
  • R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g.,
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly – NH.
  • R 1 is –C ⁇ C–Me.
  • X 1 is –NH– or –NMe–, particularly – NH–
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • R 2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl.
  • R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen. [1295] In some embodiments of a compound of formula VIb-5 to VIb-12, VIc-5 to VIc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl.
  • n 2 or 3 R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly – NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or – (CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or – NMe–, particularly –NH.
  • W N–.
  • R 1 is –C ⁇ C–Me.
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen.
  • R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or – NMe–, particularly –NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 1 is —NH–, –NMe– or –O–;
  • X 4 is —O–, –NH–, –NMe–;
  • X 8 ’ is –O–, –S–, –NH– or –NMe–;
  • L is a covalent bond or linear or branched C 1-3 alkyl
  • R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen,
  • R 2 is hydrogen, C 1- 4 alkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or – NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • X 1 is –NH– or – NMe–, particularly –NH–
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen.
  • R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly – NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or –(CH 2 ) 2 –.
  • X 4 is –O– and L is a covalent bond, –(CH 2 )– or – (CH2)2–.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VIb-5 to Vb12, VIc-5 to Vc12, X 4 is –O–, such that the compound is represented by formula VId-5 to VId-12, VIe-5 to VIe-12
  • X 1 is –NH–, –NMe– or –O–;
  • X 8 ’ is –O–, –S–, –NH– or –NMe–;
  • L is a covalent bond or linear or branched C 1-3 alkyl
  • R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly – NH.
  • W N–.
  • R 1 is –C ⁇ C–Me.
  • R 2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen.
  • R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly – NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • L is a covalent bond, –(CH 2 )– or – (CH 2 ) 2 –.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly – NH.
  • R 1 is –C ⁇ C–Me.
  • X 1 is —NH– or –NMe—, particularly – NH–
  • X 2 is —NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
  • R 2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl.
  • R a and R b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R a and one R b are not hydrogen and/or only one R a is not hydrogen. [1347] In some embodiments of a compound of formula VIf-5 to VIf-12, VIg-5, VIg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R c and R d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R c and R d are each independently selected from hydrogen, methyl.
  • n 2 or 3 R c and one R c are not hydrogen and/or only one R c is not hydrogen.
  • m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed.
  • X 1 is –NH– or –NMe–, particularly – NH–
  • R 2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl.
  • X 4 is –O–.
  • L is a covalent bond, –(CH 2 )– or – (CH2)2–.
  • X 4 is –O– and L is a covalent bond, –(CH2)– or –(CH2)2–.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula Vh-1, Vh-2, Vh-3, e.g., Vh- 3a or Vh-3b, or Vh-4
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1361] In some embodiments, R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1371] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • formula VI-1, VI-2, VI-3, e.g., VI-3a or VI-3b, or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula Vh-5, Vh-6, Vh-7, Vh-8, Vh-9, Vh-10 preferably Vh-11, Vh-12, Vh-13 or Vh-14 Vh-15, or Vh-16
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 ,
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl.
  • R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form to togetherher an oxiranyl;
  • R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle;
  • m is 1, 2 or 3;
  • n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Vh-5, Vh-6, Vh-7, Vh-8, Vh-9 e.g., Vh-10, Vh-11, Vh- 12 or Vh-13 Vh-14, or Vh-15 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1390] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl or C3-4 cycloalkyl.
  • X 1 is —NH– or –NMe– , particularly –NH.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1400] In some embodiments, R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • formula VIj-1, VIj-2, VIj-3, e.g., VIj-3a or VIj-3b, or VIj-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl;
  • R 6 is hydrogen, C 1-4 alky
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe– , particularly –NH.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • Z is of formula i wherein R 2 is hydrogen, C1-4 alkyl. CHF2 or C3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1409] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • formula VIk-1, VIk-2, VIk-3, e.g., VIk-3a or VIk-3b, or VIk-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • X 8 is –O–, –NMe– or –S.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIj-5, VIj-6, VIj-7, VIj-8, VIj-9, VIj-10, e.g., VIj-11, VIj-12, VIj-13, VIj-14 or VIj-5, or VIj-16
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1418] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • VIj-5, VIj-6, VIj-7, VIj-8, VIj-9, VIj-10 e.g., VIj-11, VIj-12, VIj-13, VIj-14 or VIj-5, or VIj-16 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • R 6 is
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 - C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 8 is –O–, –NMe– or –S–.
  • Z is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form tofinishher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1426] In some embodiments, R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • VIk-5, VIk-6, VIk-7, VIk-8, VIk-9, VIk-10 e.g., VIk- 11, VIk-12, VIk-13, VIk-14 or VIk-5, or VIk-16 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIl-1 to VIl-25
  • D1 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 ,
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 8 is –O–, –NMe– or –S–.
  • Z in D1 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form to rejoinher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • n 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Z is selected from
  • R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIm-1 to VIm-25
  • D2 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • At least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 8 is –O–, –NMe– or –S.
  • Z in D2 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIn-1 – VIn-17 wherein D 1 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • R 6 is hydrogen for VIn-5, VIn-7, VIn-8, VIn-9, VIn-11; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for VIn-1, VIn-2, VIn-3, VIn-4, VIn-6, VIn-10,VIn-14, VIn-15, VIn-16, VIn-17.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • Z in D1 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIo-1 – VIo-17 wherein D 2 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g.,
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • R 6 is hydrogen for VIo-5, VIo-7, VIo-8, VIo-9, VIo-11; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for VIo-1, VIo-2, VIo-3, VIo-4, VIo-6, VIo-10, VIo-14, VIo-15, VIo-16, VIo-17.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • X 8 is –O–, –NMe– or –S–.
  • Z in D2 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form to rejoinher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • Z is selected from wherein R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIn-18 – VIn-51 wherein D 1 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • R 6 is hydrogen for VIn-25 to VIn-27, VIn-30 to VIn-35, VIn-38, VIn-39; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for VIn- 18 to VIn-25, VIn-28, VIn-29, VIn-36, VIn-37, VIn-44 to VIn-51.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • Z in D1 is of formula i wherein R 2 is hydrogen, C1-4 alkyl, CHF2 or C3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • R 2 is hydrogen, C 1-4 alkyl or C 3-4 cycloalkyl.
  • D 2 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • R 6 is hydrogen for VIo-25 to VIo-27, VIo-30 to VIo-35, VIo-38, VIo-39; and R 6 is hydrogen, C 1-4 alkyl, e.g., methyl, HCF 2 , OCH 2 F or halogen, e.g., F, Cl, for VIo- 18 to VIo-25, VIo-28, VIo-29, VIo-36, VIo-37, VIo-44 to VIo-51.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • X 8 is –O–, –NMe– or –S.
  • Z in D2 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • m is 1, 2 or 3; n is 1 or 2.
  • formula VIo-18 – VIo-51 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3- 4 heterocycloalkyl or C 3-4 cycloalkyl.
  • X 1 is —NH– or –NMe–, particularly –NH.
  • R 1 is –C ⁇ C–Me.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
  • at least one, at least two, e.g., two, substituents of R 3 , R 4 , R 3 ’, R 4 ’, R 5 are hydrogen, while the remaining are as defined above.
  • Z in D1 is of formula i wherein R 2 is hydrogen, C 1-4 alkyl, CHF 2 or C 3-4 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-4 alkyl or form toadmiher an oxiranyl; R c , R d are each independently selected from hydrogen, C 1-4 alkyl; or one of R a and R b and one of R c and R d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle.
  • m is 1, 2 or 3; n is 1 or 2.
  • R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • R 2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl.
  • formula VIp-1 – VIp-15 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from wherein R 2 is hydrogen, Me or Et.
  • the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIq-1 – VIq-15
  • D2 is Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3-4 heterocycloalkyl, CHF 2 or C 3-4 cycloalkyl;
  • X 1 is –NH–, –NMe– or –O–;
  • R 3 , R 4 , R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF 3 and OCF 3;
  • R 5 is hydrogen, halogen, e.g., F or Cl, CF 3 , HCF 2 , OCF 3 , hydroxy, C 1-4 alkoxy or C 1-4 alkylhydroxyl;
  • Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R 1 -C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 3- 4 heterocycloalkyl or C3-4 cycloalkyl.
  • X 1 is –NH– or –NMe–, particularly –NH.
  • Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.

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Abstract

La présente invention concerne des composés de formule (I) : et des sels pharmaceutiquement acceptables et des stéréoisomères de ceux-ci. La présente invention concerne également des procédés de préparation des composés, des compositions comprenant les composés et des méthodes d'utilisation des composés en tant qu'inhibiteurs de récepteurs tyrosines kinases, en particulier des mutants oncogènes de récepteurs ErbB, par exemple dans le traitement du cancer.
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WO2022269531A1 (fr) * 2021-06-26 2022-12-29 Array Biopharma Inc. Inhibiteurs de mutation her2
WO2023175185A1 (fr) 2022-03-17 2023-09-21 Forx Therapeutics Ag Dérivés de 2,4-dioxo-1,4-dihydroquinazoline utilisés en tant qu'inhibiteurs de parg pour le traitement du cancer
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US11834453B2 (en) 2020-06-30 2023-12-05 Array Biopharma Inc. Substituted pyrimido[5,4-d]pyrimidines as HER2 inhibitors
WO2022269531A1 (fr) * 2021-06-26 2022-12-29 Array Biopharma Inc. Inhibiteurs de mutation her2
CN114213315A (zh) * 2021-12-31 2022-03-22 上海陶术生物科技有限公司 含氮杂环类化合物及其中间体的合成方法
WO2023175185A1 (fr) 2022-03-17 2023-09-21 Forx Therapeutics Ag Dérivés de 2,4-dioxo-1,4-dihydroquinazoline utilisés en tant qu'inhibiteurs de parg pour le traitement du cancer

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